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Syntheses Antiinflammatory and Analgesic Activities of Arylbiurets.

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355
Arylbimts
Syntheses, Antiinflammatory, and Analgesic Activities of Arylbiurets
Makoto Kajitani’, Tomio Yamazaki, Shozo Yarnada, Motoaki Tanaka,
Chemical Synthesis Research Laboratory,Taiho Pharmaceutical Company, Ltd., 200-22 Toyohara Motohara, Kamikawa-cho. Kodama-gun,
Saitama 367-02, Japan
Kazuo Ogawa, Takaji Honna, Hidekazu Miyake,
Tokushima Research Institute, Taiho PharmaceuticalCompany, Ltd., 224-2 Ebisuno, Kawauchi-cho,Tokushima 771-0 1, Japan
Takahiro Yabuuchi,
Research Institute for Production Development, 15-Morimoto-cho, Shimogamo,Sakyo-ku, Kyoto 606, Japan
Hajime Fujimura
Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto 607, Japan
Received May 16,1989
A number of arylbiurets were prepared and evaluated as antiinflammatory
and analgesic agents by using the carrageenan paw edema and acetic acid
stretching tests. Among them,the antiinflammatory activity of 1.3-dimethyl5-phenylbiuret (7). l-ethy1-3-methyl-5-phenylbiuret (11). and 1,1,3-trimethyl-5-phnylbiuret (13) were found to be more potent than phenylbuwne.
analgesic activity of 7 and of 5-(4-ch]o~p~ny])-l,1,3-trimethy]pheny]biuret (16)is higher than that of aminopyrine.
Synthese, antiinflammatorische und analgetkche Wirkungen von Arylbiuret-Derivaten
A number of nonsteroidal antiinflammatory drugs have been developed
and actually used in clinic”. Among them, acidic antiinflammatory drugs
in which the acetic acid or enolic acid moiety is involved, axe generally excellent against inflammatory diseases. However, these drugs cause undesirable harmful side effect such as gastric mucosal damage in some ca~es’’~).
Therefore, the development of more safe new drugs has been desired.
reaction of ureas with is~cyanates’~.’~),
is general for the
preparation of biurets and involves three procedures: the absence of any catalyst (method A-1), the presence of NaH
(method A-2) and SnCb (method A-3)”). Especially
method A-3 is most widely and effectively utilized. We
could also prepare several compounds 3 by these procedures from mono, di, or trialkylureas 1 and arylisocyanates
2 in comparatively low yields. Method B16-18),which consists of the reaction of ureas with phosgene followed by
conversion to amides, was successfully used for the one-pot
preparation of a variety of biurets 3. In the reaction of 1alkyl-3-arylureas with phosgene, the introduction of the
chlorocarbonyl group preferentially occured on N-1 similarly as it is described by Brantky’8). The resulting compound
5 was converted to 3 without isolation and purification. All
the compounds prepared are summarized in Table 1 and 2.
*
In an attempt to find novel antiinflammatory agents, we
have found 1-phenylcarbamoyl-2-imidazolidinone(PCI)
derivatives to possess antiinflammatory and analgesic activities, though those activities were weak4’.
Next, we examined antiinflammatory and analgesic activities of 1.3-dimethyl-5-phenylbiuret(7) which corresponds
to the cleavaged of the C-C bond in the imidazoldinone ring
of PCI (Chart 1).
No other study has hitherto been reported on antiinflamrnatory and analgesic activities of arylbiurets. We now report upon preparation and biological activities of a series of
arylbiurets.
Einige -lbimt-kriv*
wurden synthetisch dargestellt und im Carrageenin-induzierten Rattenpfoten-Odem und Essigdure-induziern Writhing1,3-DimethY1-5Test beweat Die entziindun@kmmnde wukung
phenylbiuret (7).l-Ethyl-3-methyl-5-phenylbiuret
(11) und 1,1,3-Trimethyl5-phenylbiuret (13) war sti4rker als die von Phenylbutazon.. 7 und 544Chlorphenyl>l,l,3-trimethylphenylbiuret (16) zeigten stirkere analgetische
Wukung als Aminopyrin.
Pharmacological Results
Chemistry
Various methods for the syntheses of biurets have been reThe arylbiurets 3 were prepared by two different
methods, A and B, shown in Chart 2. Method A, the
Arch. Pharm. (Weinheim) 323,355-359(1990)
The antiinflammatory and analgesic activities of the
arylbiurets prepared were measured by the carrageenan-induced paw’ederna and the acetic acid stretching tests, respectively. The results are shown in Table 3.
OVCH VerlagsgesellschaftmbH. D-6940 Weinheim, 1990
0365-6233/90/0606-0355$ M.50/0
356
Kajitani and coworkers
PI
K ' - X H - C N-C-NH-
Tab. 1: I-Substituted, and 1,3-Disubstituted-5-Arvlbiurets
It
II
0
0
Calcd
Found
MpOC
Crystn'
Solvent
Yield%
Synthetic
Method
H
C 56.0
H 5.74
N 21.8
55.9
5.59
21.8
121-122
C
13
A- 1
H
c 57.9
58.1
6.39
20.2
93-95
D
94
B
50.0
4.96
17.3
169-171
E
48
A- 1
49.7
5.09
17.2
143-145
E
43
A- 1
55.7
6.63
17.5
110-1 I 1
E
53
B
59.8
7.00
18.7
8 1-82
D
54
B
H 6.83
N 19.0
C 61.3
H 7.28
N 17.9
61.2
7.52
17.5
74-76
D
54
B
Comp.
R'
R2
X
6
CH3
H
1
CH3
CH3
Formula
H 6.32
N 20.3
8
CH3
CH3
2-CI
c 49.7
H 5.00
N 17.4
9
CH3
CH3
4-CI
c 49.7
H 5.00
N 17.4
10
CH3
CH3
4-OCH3
c 55.7
H 6.37
N 17.7
11
12
CzH5
n-C3H7
CH3
CH3
H
H
c 59.7
C=Ethanol-water;D=Ether-petroleum ether; E=Ethanol.
The antiinflammatory activity (inhibition 66%, 100 mg/kg
PO) of 7 was more potent than that (inhibition 55%, 100
m a g PO) of phenylbutazone, and the analgesic activity
(ED5p12 m a g PO) of 16 was more potent than that
( E D 5 ~ 3 5m a g PO)of aminopyrine.
As to the antiinflammatory activity, it should be noted that
compounds 6, 10, 11, and 12, in which no substituents exist
in the benzene ring, were found to exhibit the activity approximately or more potent as that of phenylbutazone.
Though the structure-activity correlation is not apparent, the
antiinflammatory effect of arylbiurets having no substituent
in the benzene ring were generally stronger than that of
arylbiurets possessing substituents, and in arylbiuret 6 not
substituted by alkyl groups at N-3 the effect decreased. The
influence of the length of alkyl group on the nitrogen for the
effect was not confirmed in 1,3-disubstituted-5-arylbiurets
7,11, and 12, but C2H5 (20) and n-C3H7 (21) in 1,1,3-trisubstituted-5-arylbiurets decreased the effect remarkably.
As to the analgesic activity, introduction of halogen,
methoxy, and methyl groups at 4-position in the benzene
ring of the arylbiurets induced significant increased activity.
Especially, compounds 16 and 19 were found to exhibit an
activity approximately or more potent than that of aminopyrine.
We are thankful to Professor Dr. M.Furuknwa, Faculty of Pharmaceutical Sciences, Kumamoto University, for his suggestion during the preparation of this paper. We also thank Dr. M.Yaswnoto,the director of Chemical
Synthesis Research Laboratory, for many useful discussions during the
preparation of this paper, and the Analytical Laboratory of Tokushima Research Institute for NMR spectra. mass spectra and elemental analyses.
Experimental Part
Melting point: Yanagimoto micro melting point apparatus, uncorrected.Elemental analyses: Yanagimoto CHN CORDER MT-3.- Ultraviolet spectra: Hitachi 124.- 'H-NMR spectra: Hitachi 22 (90 MHz); TMS as internal
standard.- Mass spectra: JEOL JMS OI-SG.
1 -Methyl-S-phenylbiuret(6); (Method A-1).
To a stirred solution of 3.7 g (0.05 mol) of methylurea in 50 mL of dry
dioxane were slowly added 5.9 g (0.05 mol) of phenylisocyanate.The mixture was stirred at room temp. for 15 h, and then concentrated to dryness
under reduced pressure. The residue was recrystallized from ethanol and
water to obtain 1.3 g (13%) of 6. Mp. 121-122°C.- UV (cyclohexane):
h a x 240 (&:19600).- 'H-NMR (MezSO-4): 6 (ppm) = 9.82 (broad, IH),
8.91 (broad, lH),6.90-7.55(m,5H),3.28(~,
lH),2.67(d,J=5.4Hz,3H).
8 and 9 were synthesized by the same method.
1 ,I ,3-Trimethyl-5-(4-chlorophenyl)biuret
(16); (Method A-2).
To a stirred suspension of 2.9 g (0.06 mol) of NaH (50% in oil) in 200
mL of dry tetrahydrofuran were added 6.1 g (0.06 mol) of 1.1,3-uimethylurea below 10°C. The mixture was stirred at m m temp. for 15 h and then
cooled below 0°C. A solution of 9.2 g (0.06 mol) of p-chlorophenylisocyanate in 50 mL of dry tetrahydrofuran was added drop-wise with stirring.
Stirring was continued at about 0°C for 3 h, then the solution was concentrated under reduced pressure, and ice-water was added to the residue. The
resulting mixture was made acidic with a suitable amount of HCI and
Arch. Pharm. (Weinheim) 323,355-359 (1990)
357
Arylbiurets
Tab. 2: 1.1.3-Trisubstituted-5-Arvlbiure~s
Comp.
13
R
X
8 8
Formula
H
14
2-Cl
15
3-C1
lirc
4-C1
17
4-Br
18
2-OCH3
19
4-OCH3
20
4-CH3
21
H
22
H
Calcd.
Found
MpT
Crystn'
Solvent
Yield,%
Synthetic
Method
c 59.7
59.8
6.92
18.8
51.6
5.59
16.2
51.5
89-90
E
88
B
90-91
E
31
A-2
87-89
C
29
A-2
94-95
E
26
A-2
105-106
E
37
B
112-114
F
52
B
88-89
G
80
B
115-117
G
53
B
89-91
D
22
B
63-64
D
40
A-3
H 6.83
N 19.0
C 51.7
H 5.52
N 16.4
C 51.7
H 5.52
N 16.4
C 51.7
H 5.52
N 16.4
c 44.0
H 4.70
N 14.0
c 57.4
H 6.82
N 16.7
c 57.4
H 6.82
N 16.7
C 61.3
H 7.28
N 16.7
C 61.3
H 7.28
N 17.9
C 62.6
H 7.68
N 16.9
5.51
16.2
51.6
5.56
16.6
43.6
4.73
13.9
57.6
6.86
16.6
57.5
6.83
16.5
61.4
7.15
16.5
61.3
7.44
17.6
62.8
7.65
16.9
C=Ethanol; =Ether-petroleum ether, E=Ethanol; F=Ethanol-ether; G=Ethanol-petroleumether.
extracted with chloroform. The chloroform layer was separated and dried
over anhydrous Na2SO4 The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain 4.0 g (26%)
of 16. Mp. 94-95°C.- UV (cyclohexane): h a x 250 (~:22700).-'H-NMR
(CDC13): 6 (pprn) = 9.70 (broad, lH), 7.20-7.45 (m, 4H), 3.12 (s, 3H), 2.93
(s, 6H).
14 and 15 were synthesized by the same method.
13-Dimethyl-1 -propyl-5-phenylbiuret (22);(Method A-3).
To a stirred mixture of 13.0 g (0.1 mol) of 1,3-dimethyl-l-piopylureaand
12.0 g (0.1 mol) of phenylisocyanate in 300 mL of anhydrous dichloromethane were added dropwise 26.0 g (0.1 mol) of anhydrous SnC14 upon
cooling with ice. Stirring was then continued at room temp. for 15 h, and
the resulting precipitates were separated by filmtion. The suspended mixture of the precipitates in 60 mL of 20% HC1 and 120 mL of chloroform
was stirred until the mixture became transparent. Then the chloroform layer
was separated, washed with water, and dried over anhydrous Na2SO4 The
solvent was distilled off under reduced pressure to dryness,and the residue
was recrystallized from ligroin to obtain 10 g (40%) of 22. Mp. 6364°C.UV (cyclohexane): lcmax 244 (~:19200).- 'H-Nh4R (CDC13): 6 (ppm) =
9.4-9.7 (broad, IH), 6.9-7.5 (m, 5H). 3.22 (t. J = 7.1 Hz, 2H), 3.10 (s, 3H),
2.89 (s, 3H). 1.35-1.85 (m, 2H), 0.90 (t. J = 7.3 Hz. 3H).
Arch. P h r m . (Weinheim) 323,355-359
I .I 3-Trimethyl-5-(4-methoxyphenyl)biuret(19);
(Method 8).
A solution of phosgene (30% W/V) in 46 mL (0.14 mol) of CC14 was
added to a stirred solution of 25.2 g (0.14 mol) of 1-(4-methoxyphenyl)-3methylurea in 150 mL of anhydrous tetrahydrofuran at room temp. After
stirring for 15 h at room temp., the mixture was warmed to 6O0C, and N2
was passed through the mixture until the evolution of HCI subsided. Upon
cooling with stirring below OOC, anhydrous dimethylamine was bubbled
into the mixture until it was made basic to litmus. Water was added into the
mixture to dissolved the separated precipitates. The org. solvent was
removed under reduced pressure, and the residue was collected by filtration
and purified by recrystallization from ethanol and petroleum ether to obtain
28 g (80%) of 19. Mp. 88-89°C.- UV (cyclohexane): h a x 250.5
(~:17500).-'H-NMR (CM=13):6 (ppm) = 8.94 (broad, IH), 6.75-7.40 (m,
4H), 3.66(s, 3H),2.98 (s, 3H), 2.83 (s, 6H).
7, 10, 11, 12, 13, 17, 18, 20, and 21 were synthesized by the same
method.
Antiinflammatory activity
According to the method of acute carrageenan-induced inflammatory
test'), the Wistar strain of 6 male rats (weight 130-189 g) were used as the
test animals. After the rats were fasted for 18 h, the test compound was administered orally, 1 h after the administration, 0.1 mL of 1% carrageenan
358
Kajitani and coworkers
solution was injected subcutaneously to the right hindopaw of the rat, and
the volume of the hindopaw was measured 3 h after the carrageenan injection. The swelling was calculated from the observed volume as compared
with the pre-treatment paw volume, and the inhibitory percent was calculated by comparing the swelling with that in the control group
.when it was
recognized statistical significance (Srudenr'st-test).
Tab. 3: Pharmacological data
Comp.
Anti-edema
Inhibition (%)
100 mg/kg. PO.
PCI
6
Analgesic")
ED^,,*)
104(81- 134)
Phenylbutazone
25
28
66
53C'
43
40
63
67
59
38
nam
47
na
na
39
na
34
na
55
618
418
318"
718
718
418"
518
618
318
518
718
718
318
618
518
418
618')
318
Aminopyrine
73
818
I
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
")
Analgesic
35(16- 77)
Analgesic acriviry
According to Kosfer et
the ddy strain of 8 male mice (weight 1620 g) were used as the test animals. After the mice were fasted for 18 h, the
test compound was administered orally, and then 30 min after the administration, 0.1 mWlO g of 0.7% acetic acid solution was injected intraperitoneally. The number of stretching symptom by each mouse was counted
during a period of 10 to 20 min after the acetic acid injection. It was judged
that the test compound possessed analgesic effect when the number of
stretching of each mouse was under the half of that of the control group.
The test compounds revealing analgesic effects by administration orally
(100 mg/kg) were tested at lower dose. The EDSOvalues and 95% confidence limits were calculated by using the method of Probif.
40(21- 76)
43(24- 78)
70(44- I 12)
75(43-132)
12( 4- 36)
60(48- 76)
39(21- 73)
50(26- 95)
References
35( 16-68)
1
2
3
4
The number of mice recognized analgesic effecvthe number of mice
used for testing.
95% confidence limits.
200 mg/kg, PO.
d, No activity.
b,
c,
e,
60 mg/kg,
Chart
PO.
1
rilN - 5 - N H -
H Ny
5
6
7
8
9
10
07) 0
CH3
I
HxC-NH-C-N-C-NH-
II
II
0
Chart
Method
0
11
12
13
14
15
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2
A
2
-
1
-
3
-
of
A-l
:
in
the
absence
A-2
:
in
the
presence
A-3
:
in
the
presence of S n C 1 ,
any
catalyst
of N a H
B
Method
R3-NH-C-NH-
ax
+
COC1,
-
R3
C1C-N-C-NH-
3
0
-4
5
-
Arch. Pharm. (Weinheim) 323.355-359 (1990)
Arylbiurets
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