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Non-Steroidal Anti-inflammatory AgentsNovel Pyrazolyl- 12-Oxazolyl- and 13-Diazinyl Derivatives of 43H-Quinazolinones.

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27
F'yrazolyl-, Oxazolyl-, and Diazinyl Derivatives
Non-Steroidal Anti-inflammatory Agents:
Novel Pyrazolyl-, 1,2-Oxazolyl-, and 1,3-Diazinyl Derivatives of 4(3H)Quinazolinones
M.A. Khalil', R. Soliman, A.M. Farghaly, and A.A. Bekhit
Pharmaceutical Chemistry Department, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt
Received November 24, 1992; revised form received January 11, 1993
Nichtsteroidale entziindungshemmende Wirkstoffe:
Synthese neuer Pyrazolyl-, 1,2-Oxazolyl- und 1,3-Diazinyl-Derlvate
von 4(3H)-Chinazolinonen
Vier neue Serien von 4(3H)-Chinazolinonen wurden hergestellt durch
Four novel series of 4(3H)quinazolinone derivatives have been prepared
by cyclization of the key intermediates 3-aryl-2-(3-aryl-3-oxopmpenyl)-4- Cyclisierung von 3-Aryl-2-(3-aryl-3-oxopropenyl)-4(3H)-chinazolinonen
(3H)-quinazolinones with different reagents: 3-aryl-I-iminocarbamoyl- mit verschiedenen Reagentien: 3 - 4 1 - 1 -iminocarbamoyl-lH-pyrazolyl-51H-pyrazol-5-yl)-4(3H)-quinazolinones,3-aryl-2-(3-aryI-l-thiocarba- yl)-4(3H)chinazolinone, 3-Aryl-2-(3-aryl-l-thiocarbamoyl-1H-pyrazol-5moy1-1H-pyrazol-5-y1)-4(3H)-quinazolinones,
3-aryl-2-(3-aryl-4,5-dihy- yl)-4(3H)-chinazolinone. 3-Aryl-2-(3-aryl-4.5-dihydro-1.2-oxazol-5-y1)1,2,5,6-tetrahydro-1.3dro-1.2-0xazol-5-yl)-4( 3H)-quinazolinones, and 3-aryl-2-(4-aryl-2-thioxo- 4(3H)-chinazolinone und 3-Aryl-2-(4-aryl-2-thioxodiazin-6-yl)-4(3H)-chinazolinone. Die entziindungshemmende AktivitPt
1,2,5.6-tetrahydro-l,3-diazin-6-y1)-4(3H)-quinazolinones.The antieiniger repdsentativer Verbindungen wurde studiert, sie zeigten h l i c h e
inflammatory activity of representatives of these compounds is comparaoder hohere Aktivittit als Proquazone.
ble to or higher than that of proquazone.
As a continuation of our work in the field of non-steroidal antiinflammatory agents'-3).the present investigation deals with compounds having in
their molecules both 4(3H)-quinazolinone and pyrazole, 1.2-ox-k
Or
1,3-diazinenuclei joined to each other. As these nuclei exhibit anti-inflammatory activityc9). such combination might enhance their anti-inflammatory activities.
The designed compounds were prepared as outlined in the
Scheme, The key intermediates 3-aryl-2-(3-aryl-3-oxopropenyl)-4(3H)-quinazolinones2) 2a-f have been prepared by
condensation of ~ ~ a r y ~ ~ 2 ~ m e ~ y ~ ~ ~ 3 ~ ) - q u ~ n1)a z o ~ ~ n o n
la-c with arylglyoxal in acetic anhydride.
I
;1
3 a-f
4 a-f
X = NH
X = 5
w
2a-f
Sa-1
Scheme
Arch. Pharm. (Weinheim) 327,27-30 (1994)
Q VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1994
0365-6233/94/0lOl-o027$5.00 + .25/0
Khalil, Soliman, and Bekhit
28
Cyclization of 2a-f by heating with aminoguanidine or
thiosemicarbazide in acetic acid afforded the corresponding
pyrazole derivatives 3a-f or 4a-f, respectively. When 2a-f
reacted with hydroxylamine hydrochloride in the presence
of sodium acetate, the corresponding 1,%-oxazole derivatives 5a-f arose. When 2a-f were treated with thiourea in
EtOH/H2S04the 1,3-diazinyl derivatives 6a-f were formed.
Table 1: 3-Aryl-2-(3-aryl-1-iminocarbamoyl-1H-pyrazol-5-y1)-4(3H)quinazolinones 3a-f
RZ
Yield
9%
M.P.
R1
3b
CH,
H
81
174-6
k
Br
H
85
167-9 C,H,,BrN,O
(485.3)
M
H
CH,
76
215-7
COmpd.
No.
OC
Anti-inflammatory Activity
The local anti-inflammatory activity of 3a, 3b, 3c, 4a, 4b,
4c, Sa, Sb, 6a, 6b, was evaluated employing the cotton-pellet granuloma bioassay in rats'*). The results (Table 5 )
depict that all the tested compounds significantly inhibit the
granuloma formation at a dose of 0.01 mole/cotton pellet.
The inhibition by 3a, 3b, 3c, 4a, 4b, and 5b is higher than
that of the reference standard proquazone*) (1-isopropyl-7methyl-4-phenyl-2( 1H)-quinazolinone) at the same dose,
while the inhibition by 5a is comparable to that of proquazone. So it can be concluded that combination of quinazolinone and pyrazol (3a, 3b, 3c, 4a, 4b, 4c) or 1,2-oxazole
moieties (Sa, 5b) in one frame produces compounds with
anti-inflammatory activity comparable to or higher than that
of proquazone, while compounds having the 1,3-diazine
moiety joined to the 4(3H)-quinazolinone ring (6a, 6b)
exhibit lower activity.
Molecular
Formula
C25H@,O
(420.5)
C25H&5O
(420.5)
3f
Br
CH3
83
195-6
~Hl$rNaO
(499.3)
Analyses: Values of C,H,N within 0.3% of the theoretical value.
Table 2: 3-Aryl-2-(3-aryl-1-thiocarbamoyl-lH-pyrazol-5-yl)-4(3H)-quinazolinones 4a-f
Experimental Part
No.
R1
R'
Yield
46
M.P.
OC
Molecular
Formula
Melting points: uncorrected.- IR spectra (KBr): Beckman 4210 spectrophotometer.- 'H-NMR: EM-360 L spectrometer in CDC13,TMS as internal
standard, chemical shifts as 6 (ppm).- Analytical data: Analytical Unit,
Faculty of Science, Cairo University. Egypt.
48
H
H
72
181-3
C24H17NpS
(423.5)
3-ArjI-2-(3-aryl-I -iniinocarbanioyl-lH-pyrazol-S-yl)-4(3H)-quina:oli-
4c
4d
H
CH3
76
221-3
CzsH1dr(~OS
(437.5)
4e
CH,
CH3
78
206%
C26HzlNsOS
(451.5)
4f
Br
CH,
85
209-11
COmpd.
nones 3a-f
The solution of 2a-f (1 mmole) in EtOH-glacial acetic acid (1: 1, 20 ml)
and aminoguanidine (0.1 g. 1.3 mmole) was heated under reflux for 6 h,
cooled and then poured into cold water (50 ml). The product was filtered,
washed with water and recrystallized from aqueous ethanol (Table 1).- 1R:
3420-3400 (NH?), 3280-3250 (NH), 1685-1680 (C=O), 1650-1640 cm-l
(C=N).- 'H-NMR of 3b: 6 (ppm) = 2.5 (s, 3H. CH3); 7.0-7.9 (m, 16H,
NH2. NH, phenyl-H, pyrazole-4-H, quinazolinone-6,7.8-H); 8.0 (dd, J, =
8, J2 = I .5 Hz, IH, quin.-5-H.)
C,H,,BrN,OS
(516.41
Analyses: Values of C,H,N,S within 0.3% of the theoretical value.
3-Ary1-2-(3-arvl-I -thiocarbamoyl-1H-pyraaol-S-y1)-4(3H)-quina~olinones
4a-f
2a-f (1 mmole) and thiosemicarbazide (0.I 1 g, 1.2 mmole) in glacial
acetic acid (20 ml) were heated under reflux for 8 h. After cooling the mixture was poured into cold water (50 ml). The precipitate was washed with
water and crystallized from aqueous EtOH (Table 2).- IR: 3270-3250
(NH,), 1685.1680 (C=O), 1650-1635 (C=N), 1250-1230 cm-l (C=S).- 'HNMR of 4a: 6 (ppm) = 2.3 (br. s, 2H. NH2, D-exch.). 7.0-7.8 (m, 14H, 2
phenyl-Hi. pyrazole-4-H, quin.-6,7.8-H), 8.1 (dd, J, = 8.4, J2 = 1.7 Hz, 1H
quin.-5-H).
*)
BiarisonR, Wander
3-AryI-2-(3-aryI-4,5-dihydro-l.2-oxa:ol-5-yl)-4(3H)-quinazolinones
5a-f
The mixture of 2a-f (1 mmole), glacial acetic acid (20 ml), H2NOH.HC1
(0.06 g, 1 mmole). and anhydrous sodium acetate (0.1 g, 1.2 mmole), was
heated under reflux for 5 h, cooled and poured into cold water (50 ml). The
precipitate was washed with water, dried, and crystallized from CHC13EtOH (Table 3).- IR: 1685-1680 (C=O), 1650-1630 cm'l (C=N).- 'H-NMR
of Sb: 6 (ppm) = 2.3 (m, 5H, CH, and ox.-4-H), 3.5 (dd, J I = 10.5, J Z = 7
Hz, IH, ox.-5-H), 7.0-7.8 (m, 12 H, 2 phenyl-H, quin.-6,7,8-H), 8.1 (dd, J l
= 8.4, J2 = 1.7 Hz, lH, quin.-5-H.)
Arch. Pharm. (Weinheim) 327,27-30(1994)
29
Pyrazolyl-, Oxazolyl-. and Diazinyl Derivatives
Table 3: 3-Aryl-2-( 3-aryl-4.5-dihydro-1,2-0xazol-5-yl)-4(3H)-quinazolinones 5a-f
Molecular
R'
R3
Yield
%
M.P.
NO.
OC
Formula
5.
H
H
72
113-5
Compd.
C,yH,,N3O,
(367.4)
5b
CH3
H
75
107-8
CaH19N302
(38 1.4)
k
Br
H
81
118-20
CZ3H,,BrN3O2
(446.3)
Sd
5c
st
H
CH3
82
CH3
CH3
86
Br
CH,
78
C24H1br(302
(381.4)
120-1
C2SH2$J302
(3955)
1424
Anli-inflammatory Activiry
Adult male Sprague-Dawley rats (120-140 g) were maintained on standard laboratory conditions with water ad libitum and kept under controlled
condition for one week prior to use and divided into groups (6 rats each).
Cotton pellets (35 k 1 mg) from dental rolls were impregnated each with
0.2 ml (containing 0.01 mmole) of a solution of the test compound in chloroform. The solvent was evaporated at room temp. Each cotton pellet was
subsequently injected with 0.2 ml of an aqueous solution of 1 mg penicillin G and 1.3 mg dihydrostreptomycin/ml. Two pellets were implanted
subcutaneously, one in each axilla of the rat under mild general anaesthesia. One group of animals received the reference proquazone and the antibiotics at the same dose level. Pellets containing only the antibiotics were
similarly implanted in the control rats. Seven days later, the animals were
sacrificed and the cotton pellets, with their adhering granulomas, were
removed. dried for 48 h at 60°C and weighed. The increment in dry weight
was taken as a measure of granuloma formation. The mean dry weight of
granuloma (k S.E.) was calculated for each group and the percentage
reduction in dry weight of granuloma from control value was also calculated (Table 5).
C,H,,BrN,O
(460.3)
Table 5: Effect of tested compounds on granuloma formationa
Analyses: Values of C.H.N within 0.3% of the theoretical value.
Test
complds
Dose
Dry weight of
mg/cotton
garnuloma (mg)
The mixture of 2a-f (1 mmole) in absol. ethanol (30 ml), conc. HpS04
(0.5 ml) and thiourea (0.076 g. 1 mmol) was heated under reflux for 6 h.
cooled, and poured into water (50 ml). The separated product was washed
with water and crystallized from aqueous ethanol (Table 4).- IR: 34003390 (NH), 1680-1675 (C=O), 1250-1240 cm-' (C=S).- 'H-NMR of 6b: 6
(ppm) = 2.3 (m,2H. diazine-5-H), 3.3 (s, 3H, CH3), 4.3 (m, IH, diazine-6H), 7.0-7.9 (m,13H, NH, 2 phehyl-H, quin.-6.7,8-H), 8.1 (dd, J , = 8.6, 32
= 1.6 Hz, IH, quin.-5-H).
proquawoe
Table 4: 3-Aryl-2-(4-aryl-2-thioxo-I ,2.5,6-tetrahydro- I ,3-diazin-6-yl)4(3H)-quinazolinones 6a-f
R'
R2
Yield
%
M.P.
OC
Molecular
No.
6a
H
H
68
201-3
Cz4HleN,OS
Coapd.
Formula
(4 10.4)
CH3
H
82
2624
6c
Br
H
85
2444
H
CH3
80
2244
CH3
CH3
86
215-7
CzsHz$(rOS
CxHaN4OS
(438.5)
6f
Br
CH3
82
249-51
C,,H,$rN40S
Analyses: Values of C,H,N,S within 0.3% of the theoretical value.
Arch. Pharm. (Weinheim) 327,27-30 (1994)
2.8
39.75 f 1.64
45.62
3a
4.1
35.16 f 1.60
5 1.95
4.2
31.38 f 1.51
57.08
3c
4.8
36.87 f 2.65
49.56
4a
4.2
32.63 f 1.89
55.37
4b
4.4
36.75 f 3.19
49.72
4c
5 .o
48.88 f 2.52
33.15
5a
3.7
39.13 f 3.80
46.47
Sb
3.8
32.63 f 3.06
5537
6a
4.1
50.25 f 3.76
31.26
4.2
53.00 f 3.64
27.49
6b
~
a.
~~
Means f S.E. of 6 animals.
All data are significantly different from control (P> 0.001).
CUH1,BrN4OS
(424.5)
6e
73.10 f 2.13
C,Hd40S
(424.3
(489.3)
6d
0
3b
b.
6b
inhibition
'k
pellet
3-A,yl-2-(4-aryl-2-lhhio.ro-l.25,6-tetrahydro-l,3-diazin-6-y1)-4(3H)-q~rinaiolinones 6a-f
Control
Granuloma
References
A.M. Farghaly, I. Chaaban, M.A. Khalil, A.A. Bekhit, Arch. Pharm.
(Weinhcim) 1990,323,833-836.
A.M. Farghaly, I. Chaaban, M.A. Khalil, A.A. Bekhit, Arch. Pharm.
(Weinheim) 1990,323, 31 1-315.
A.M. Farghaly, I. Chaaban, M.A. Khalil, A.A. Bekhit,Alex.J. Pharm.
Sci. 1990,4,52-56; Chem. Abstr. 1991.114, 122242g.
I.P. Singh, A.K. Saxena, J.N. Sinha, K.P. Bhargava, K. Shanker.
Indian J. Chem. Section B 1984,23,592-594.
R. Agarwal, C. Aganval, C. Singh, V. Misra. J. Chem. SOC.Pak. 1984,
6,89-94; Chern. Abstr. 1985,102,45870~.
30
6) P. Miiller, H.G. Dammann, B. Simon. Arzneim.-Forsch., 1986, 36,
1399-1400.
7) F. Bandavalli, 0. Bruno,A. Ranise, P. Schenone, R. Russo, A. Lo*da, V. De Novellis, C. Lo Sasso, E. Marmo, II Furmuco 1988, 43,
1019- 1034.
8) R. Ceraulo, S. Plescia, G. Diadone, M.L. Bajardi, J . Hererocycl.
Chem. 1984.21, 1209-1213.
9) S. Plescia. G. Diadone, D. Raffa, M.L. Bajardi, A. Caruso. V. Catuli,
M.A. Roxas, II Furmuco 1992,47,465-475.
Khalil, Soliman, and Bekhit
10) H. Stephen, B. Staskun,J. Chem. Soc. 1956,980-985.
11) H.W. Grimmel, A. Guenther, J.F. Morgan, J . Am. Chem. Soc. 1946,
68,542-543.
12) R. Meier, W. Schuler, P. Desaulles, Experientiu 1950,6,469.
[Ph12 I ]
Arch. Pharm. (Weinheim) 327,27-30 (1994)
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quinazolinone, oxazolyl, 43h, pyrazolyl, non, inflammatory, anti, steroidal, agentsnovel, derivatives, diazinyl
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