COMPOSES D'ACETYLSALICYLATE DE PHENYLGUANIDINE, PROCEDE DE PRODUCTION ET COMPOSES PHARMACEUTIQUES LES CONTENANT

PHENYLGUANIDINE ACETYLSALICYLATE COMPOUNDS, PROCESS FOR PRODUCTION THEREOF, AND PHARMACEUTICAL COMPOSITION THEREOF

Abrégé anglais

Abstract of the Disclosure
A compound of the formula
<IMG>
wherein R1 is a member selected from the group consisting of a hydrogen
atom, lower alkyl groups and lower alkoxy groups, R2 is a member selected
from the group consisting of a hydrogen atom, halogen atoms, lower alkyl
groups, a hydroxyl group and a trifluoromethyl group, R3 is a member
selected from the group consisting of a hydrogen atom, halogen atoms,
lower alkyl groups, lower alkoxy groups, an acetyl group, a carbamoyl
group and lower alkyl carboxylate groups, and R3 represents a hydrogen
atom or a halogen atom. The phenylguanidine acetylsalicylate compounds
are prepared by reacting a corresponding guanidine compound with acetyl-
salicylic acid and are useful as antipyretic-analgesic agents, anti-
inflammatory agents, platelet aggregation inhibitors and prostaglandin
formation inhibitors.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a compound of the formula (I)
<IMG> (I)
wherein R1 is a member selected from the group consisting of
a hydrogen atom. lower alkyl groups and lower alkoxy groups,
R2 is a member selected from the group consisting of a hydrogen
atom, halogen atoms, lower alkyl groups, a hydroxy group and a
trifluoromethyl group, R3 is a member selected from the group
consisting of a hydrogen atom, halogen atoms, lower alkyl
groups, lower alkoxy groups, an acetyl group, a carbamoyl
group and lower alkyl carboxylate groups, and R4 represents a
hydrogen or halogen atom,
which process comprises reacting a guanidine compound of the formula (II)
<IMG> (II)
wherein R1, R2, R3 and R4 are as defined above, with acetyl-
salicylic acid.
2. A process of claim 1, wherein the starting guanidine compound
of formula (II), before the reaction with acetylsalicylic acid, is freed
from the salt of a hydrohalic acid, sulfuric acid or carbonic acid.
17

3. A compound of the formula
<IMG>
wherein R1 is a member selected from the group consisting of a hydrogen
atom, lower alkyl groups and lower alkoxy groups, R2 is a member selected
from the group consisting of a hydrogen atom, halogen atoms, lower alkyl
groups, a hydroxyl group and a trifluoromethyl group, R3 is a member
selected from the group consisting of a hydrogen atom, halogen atoms,
lower alkyl groups, lower alkoxy groups, an acetyl group, a carbamoyl
group and lower alkyl carboxylate groups, and R4 represents a hydrogen
atom or a halogen atom, whenever prepared or produced by the process of
claim 1 or 2, or by an obvious chemical equivalent thereof.
4. The process of claim 1 or 2 wherein in the guanidine salt of
formula (II) R1 is a member selected from the group consisting of a
hydrogen atom, a methyl group and/or a methoxy group, R2 is a member
selected from the group consisting of a hydrogen atom, a chlorine atom,
a methyl group, a hydroxyl group and a trifluoromethyl group, R3 is a
member selected from the group consisting of a hydrogen atom, a chlorine
atom, a methyl group, C1-C2 alkoxy groups, an acetyl group, a carbamoyl
group and an ethoxycarbonyl group, and R4 represents a hydrogen atom or
a chlorine atom.
5. The process of claim 1 or 2, wherein in the guanidine salt of
formula (II) R1 is a hydrogen atom or a methyl group, R2 is a hydrogen
atom or a methyl group, R3 is a hydrogen atom, a methyl group or an
alkoxy group having 1 or 2 carbon atoms, and R2 is a hydrogen atom.
18

6. A process of claim 1, wherein the guanidine salt of formula (II)
a salt of a guanidine compound selected from the group consisting of
2-methylphenylguanidine, 3-methylphenylguanidine, 4-methylphenylguanidine,
3,4-dimethylphenylguanidine, 4-methoxyphenylguanidine, and 4-ethoxyphenyl-
guanidine.
7. A compound selected from the group consisting of 2-methylphenyl-
guanidine acetylsalicylate, 3-methylphenylguanidine acetylsalicylate,
4-methylphenylguanidine acetylsalicylate, 3,4-dimethylphenylguanidine
acetylsalicylate, 4-methoxyphenylguanidine acetylsalicylate, and 4-ethoxy-
phenylguanidine acectylsalicylate, whenever prepared or produced by the
process of claim 6 or by an obvious chemical equivalent thereof.
8. A process of claim 2, wherein the guanidine compound, before
the reaction with acetylsalicylic acid, is freed from its hydrochloride.
19

Description

13~ii
This invention relates to novel phenylguanidine acetylsallcylate
compounds and tc a process for production thereof, useful as an active
ingredient of a pharmaceutical composition~
Salicylic acid and acetylsalicylic acid have already been used
as antipyretic, analgesic and anti-inflammatory agents. But they have low
water solubility and may induce side-effects such as gastrointestinal
troubles at large doses. The water solubility of acetylsalicylic acid
may be increased by converting it to an alkali metal salt, but the alkali
metal salt has the defect that it is easily deacetylated to the alkali
metal salicylate.
The present inventors made investigations in order to provide
a compound which is free from such a trouble or defect, and succeeded in
synthesizing many novel salts of acetylsalicylic acid and guanidines.
Examination of these salts has finally led to the discovery that phenyl-
guanidine acetylsalicylate compounds of the following formula
OCOCH3 Rl R2
'H2N-~-NH ~ -R3 (I)
NH R4
wherein Rl is a member selected from the group consisting of
a hydrogen atom, lower alkyl groups and lower alkoxy groups,
R2 is a member selected from the group cons.isting of a hydrogen
atom, halogen atoms, lowcr alkyl groups, a l~ydroxyl group and a
trifluoromethyl group, R3 is a mem~er selected from the group
consisting of a hydrogen atom, halogcn atoms, lower alkyl
groups, lower alkoxy groups, an acetyl group, a carbamoyl
group and lower alkyl carboxylate groups, and R~ represents a
hydrogen atom or a halogen atom,
- 2 -

- \
have a higher solubility in water than acetylsalicylic acid, and possess
high pharmacological activities which make them useful as antipyretic-
analgesic agents, anti-inflammatory agents, platelet aggregation in-
hibitors and prostaglandin formation inhibitors. It has also been found
that these compo~mds of formula (I) can be formulated into injectable
solutions applicable both intravenously and intramuscularly, and in oral
administration, too, they cause much less gastrointes~inal troubles than
acetyl.salicylic acid because their hydrogen ion concentration is close
to neutrality.
According to one aspect of the invention, there is provided
a phenylguanidine acetylsalicylate compound of formula (I) when prepared
by a process mentioned hereinafter.
Another aspect of the invention provides a process for producing
a phenylguanidine acetylsalicylate compound of formula (I~, which process
comprises:
reacting a guanidine compound of the following formula
l ~ 2
H2N-C-N~ R3 (Ir)
Ntl
R~
wherei.n Rl, R2, R3 and R~ are as deflned hereinabove, wl.th
acetylsalicylic acid. Preferably, the guanidine compound of formula (:tI),
before the reaction with acetylsalicylic acid, is freed from its hydrohalic
acid, sulfurlc acid or carbonic acid, salt which can be obtained by a method
known per se, for example the method described in Charles E. Braun, J. Am.
Chem. Soc., vol. 55, p. 1281 (1933). The conversion into the free base
form may be conducted beforehand or the conversion may be performed in
situ.

~21~3~
The reaction o:E the guanidine compound of formula (II) with
acetylsali~ylic acid can be carried out easily by contacting the compound
of formula (II) as a free base with acetylsalicylic acid in a solvent such
as anhydrous ethanol, chloroform or acetone, as illustrated in Examples to be
given hereinbelow. The reaction proceeds easily at room temperature, and
no cooling or heating is required in particular. The product can be further
purified by recrystallization from acetone, a mix~ure of acetone and ligroin,
etc., as shown in the Examples.
Preferred compounds of formula (I) which can be obtained in the
aforesaid manner include compounds of formula (I) in which ~1 is a member
selec~ed from the group consisting of a hydrogen atom, a methyl group and
a methoxy group, especially preferably a hydrogen atom or a methyl group;
R2 is a member selected from the group consisting of a hydrogen atom, a
chlorine atom, a methyl group, a hydroxyl group and a trifluoromethyl
group, especially preferably a hydrogen atom or a methyl group; R3 is a
member selected from the group consisting of a hydrogen atom, a chlorine
atom, a methyl group Cl-C2 alkoxy groups, an acetyl group, a carbamoyl
group and an ethoxycarbonyl group, especially preferably a hydrogen atom, a
methyl group

3~;
or a Cl-C2 alko~y group; and RL~ iS a hydrogen atom or a chlorine
atom, especiall~r pre~erably a hydrogen atomO
Examples of especially preferred compounds of ~ormula
~I) are 2-methylphenylguanidine acetylsalicylate, 3~methy1-
phenylguanidine acetylsalicylate, 4~methylphe~ylguanidineacetylsalicylate, 354-dimethylphenylguanidine acetylsalicylate9
4 methoxyphenylguanidine acetylsalicylate~ and 4 ethoxyphenyl-
guanidine acetylsalicylateO
~he compounds of formula (I) are useful as antipyretic-
analgesic agents~ anti-inflammatory agents, platelet aggre~atio~
i~hibitor~, and prostaglandin formation inhibitorsO Accordingly,
the present invention can provide a pharmaceutical composition
comprising an antipyretically and analgesically effective
amou~t of a compou~d of formula (I) and a pharmaceutically
acceptable carrier or diluent; a pharmaceuti~al composition
comprising an anti-inflamatorily e~fective amount of a compound
of ~ormula (I) and a pharmaceutically acceptable carrier or
diluent; a pharmaceutical composition comprisi~g an amou~t,
effective for inhibition of platelet aggregation, o~ a compound
of ~ormula (I) and a pharmaceutically acceptable carrier or
diluent; and a pharmaceutical composition comprising an amount,
e~fective for inhibition of prostaglandin formation, of a com-
pound of ~ormula (I) and a pharmaceutically acceptable carrier
or diluentO
~he pharmaceutically acceptable carrier or diluent
used in preparing such pharmaceutical compositions is known,
and may include known carriers or diluents used in preparing
various known pharmaceutical preparations such as powders,
granules, tablets~ capsules and injectable preparationsO For

~2~
example, they include solid carriers or diluents such as lactose,
glucose, starch, magne~um carbona-te and capsules, and liquid
car~iers or diluents such as distilled deionized water, Rin~er's
solution, infusions and an isotonic sodium chloride solutionO
The effect.ive amount o~ the compou~d of formula (I)
in the above pharmaceutical compositio~s is from about 0.5 to
about 6~/o by weight. ~he dose of the pharmaceutical compositions
of this invention, as can be derived from the results of tests
shown in the ~xamples, is, for example, about 5 to about 30 mg
of the active ingredient/kg for antipyretic and analgesic
purposes, about 5 -to about 30 mg of the active ingredient/kg
Xor anti-inflammatory purposes, about 3 to a~out 10 mg of the
active i~gredient/kg for inhibiting platelet aggregation, and
about 2 to about 5 mg of the active ingredient/kg for i~hibit-
ing prostaglandin formation, when the pharmaceutical compositionsare in the form of ~)owders, granules, tablets and capsulesO
When the compositions are in the ~orm of an injectable prepara-
tion, the dose is, ~or example, about 005 to about 3 mg~kg ~or
antipyretic and analgesic purposes, about 005 to about 3 mg~kg
~or anti-inflc~mmatory purposes, about 003 to about 1 mgfkg for
inhibiting platelet aggregation, and about 0.2 to about 0.5
mg~kg for inhibiting prostaglandin formation~
As the Examples show, the active ingredien-ts in
accordance with this invention are low in toxicity.
The following ~xamples illustrate the present in-
vention more specifically.
2-Methylphenylguanidine acetylsalicylate:-
307g of 2-meth~lphenylguanidine hydrochloride was

3~
dissolved in 150 ml of anhydrous ethanol, and 004~g of metallic
sodium was added to the solutionO The mixture was stirrad a-t
room temperature until the metallic sodium dissolved completely.
The resulting precipi~ate was removed by filtration, and the
excess of ethanol was distilled offO The residue was extracted
with benzene to give 2.8g of free guanidineO It was then dis-
solved in 100 ml of chloroform and 302g of acetylsalicylic acid
was added~ The mixture was stirred at room temperature for
3 hours~ After the reaction, chloroform was distilled off,
and the residue was recrystallized from acetone.
Melting point: 12705 to 12805C
Amount yielded: 20 5g (420~/o)
~.~
4-Methoxyphenylguanidine acetylsalicylate:
400g of 4-methoxyphenylguanidine hydrochloride was
treated with metallic sodium in anhydrous ethanolO The result-
ing precipitate was removed by filtration, and the excess of
e-thanol was distilled offO The residue was extracted with
benzeneO Benzene was distilled off, and the residue was dis-
sol~ed in 150 ml of chloroform, and 3.2g of ace~ylsal:icylic
acid was addedO ~he mixture wcas stirred at room temperature
for 3 hours. After the reaction, chloroform was distilled
off, and the residue was recrystallized from a mixture of
acetone and ligroin.
Melting poin-t: 134 to 135C
Amount yielded: 40 2g (6~o 3%)
4-Carbamoylphenylguanidine acetylsalicylate:-
505g of 4-carbamoylphe~ylguanidine hydrochloride was
-- 7 --

283~ii
dissolved in water, aad an equivalent weight of sodium hydroxide
was added, whereupon crystals precipitatedO The crystals were
collected by filtration, dried, and then suspended in 250 ml
of acetoneO r~he suspension was stirred at room temperature,
and 402g of acetylsalicylic acid was addedO ~he crystals
.immediately dissolved~ and then white crystals precipitatedO
Stirring was continued for 3 hoursG After the reac-5ion, the
crystals were collected by filtrationg well washed with acetone
and -then with ether, and driedO
Melting point: 165 to 166C
Amount yielded: 7O7g (93O4%)
3-~ydroxy-L~carboethoxyphenylguanidine
acetylsalicylate:-
408g of 3-hydroxy-4-carboethoxyphenylguanidine was
suspended in 200 ml of chloroform, and 309g of acetylsalicylic
acid was addedO ~he mixture was stirred at room temperature
for 3 houxsO After the reactlon, the reaction mixture was
cooled, and the resulting crystals were collected by filtrationO
~he crystals were then recrystallized from a mixtllre of acetone
and ligroinO
Melting point: 122 to 124C
Amount yielded: 509g (67D8%)
Some examples of the novel compounds of formula (I)
?5 are tabulated below together with their physical constantsO
~hese examples are merely illustrative and do not in any way
limit the scope of the inventionO ~he structures of the novel
co~pounds of formula (I) ar~ determined by elemental analysis9
infrared absorption spectroscopy, and proton nuclear magnetic
-- 8 --

13~
resonance spectroscopyO
~able 1
,OCO.CH3 ~ , 2
-COOH~H2N-C-NH ~ -R3
NH ~ R
_ __ ~ __
. ~/1 R2 X3 R4 mel tin70point
~ ~ ~ ~ . ~
1 H H H H 13505 - 13605
2 CH3 H H H 12705 - 128~5
3 H CH3 H H 116 - 118
4 H H CH3 H 12505 - 126~5
H CH3 CH3 H 143 - 144.5
6 H Cl CH3 H 116 - 11705
7 CH3 H Cl H 122 _ 123
8 H H C1 H 122 - 123
9 H Cl H EI 122 - 123
OCH3 H H H 111 - 113
11 H H OCH3 H 134 - 135
12 OCH3 H H Cl 144.5 - 145
13 H H C2H5 II 127 - 128
14 H H COCEI3 H 1~5 ~ 126
H CF3 H H 138 - 139
16 H H CO~H2 H 165 _ 166
17 H ~ ~ ~ 5~ H l~Z - 12C
The pharmacological activities, toxicities and side~
effects of the compounds of formula (I) were tested as follows:
1~ Anti-inflammatory activity
Male guinea pigs having a body weight of about 350g
g .

were used~ ~he back hair of each guinea pig was removed, and
ultraviolet light was irradiated onto the backO Each of the
compounds shown in ~able 1 was admi~istered orally one hour
before the irradiation, or intraperitoneally 30 minutes before
the irradiation, a~d the degrees of infla~mation were compared
using ~p~ and mefenamic acid as controlsO The results are
shown in Table 2O
Table 2
__~
Compound
1 140
2 65
~ 110
4 90
~5
6 35
7 40
8 25
9 180
11 95
12 95
1~ 85
14 85
100
16 200
17
Aspirin~ 90
acld ...
~ 'r~æ~k - 10

3~i
20 Antipyretic-analgesic activity
(1) Antipyretic activity
Male rats having a body weigh-t of 200 to 250g were
used~ Rises in body temperature (the temperat~re of the rectum)
were induced by subcutaneous injection of 5% pepto~e (005 mV 100
g body weight), and the antipyretic activity of each of the
compounds was compared with those of ~R and mefenamic acid
as a controlO ~he results are shown in Table 30
. ~ ~ r * ~ ~
Compound I~hibiting ratio (%) ~ )
. _._ ~
1 7401
2 ~801
3 2~oO
4 8309
3001
6 201
7 9009
8 3001
9 8801
3202
11 25~2
12 8~9
13 6209
14 5100
100
16 7200
17
Aspirin~ ~ 81 D O
Mefenamic acid 75 0

35;
(*): Inhibiti~g ratio agairlst the contr~l in oral
administration at a dose of 200 mg/kg (rat)O
(2) Analgesic activity ~
r~he analgesic activity was tested by the acetic acid
writhing methodO Male mice having a body weight of 18 to 20g
were usedO Each of the compounds show~ in r~able 1 was
administered orally, intravenously and lntraperitoneally, and
then 0~2 ml of a 0O~/0 aqueous solution of acetic acid was
admi~istered intraperito~eally 60 minutes (in oral administra~
tion), 10 minutes (in intravenous administration~, and 15 minutes
(in intrapexitoneal administration) after the administration
of the test compoundsO r~he number of writhings which were
observed from 5 minutes after the administration of aeetic acid
~Sp,r,'v~ ~
L~ to 25 minutes was counted, and compared against as~ and
mefenamic acid as a controlO In comparison with the controls,
a marked a~algesic activi-ty was noted in compound NOa 5, but
the other compounds did not show a significant differerlce
from the controls~
3~ Inhibition of platelet aggregation
r~his was measured by t~e method of Born et al.
Specifically, using colla~en as an aggregation inducer, each
of the compounds shown in r~able 1 was tested to measure the
inhibition of platelet aggregation in rabbit's platelet-rich
plasma (PRP~. Aspirin and mefenamic acid were used as controlsO
r~he results are shown in r~able 4O
~)~~ ~na r~
-- 12 --

3~ii
~able 4
__
Compound IC O ~/ml) ~ J
___ ____ _
1 600
2 1005
3 700
4 405
200
6 5'7
7 2.5
8 902
9 5~2
0 > 20
11 906
12 10~,8
13 12.2
14 8.8
~' 20
16 120 5
17
h P~ Aspi.rin ~ 12l6
Il~ ,,,._. _
Final concentration at 50% inhibition
of platelet aggregationO
5 ~. Inhibition of prostaglandin synthesis
Each of the compounds shown in ~able 1 was tested
to measure the inhibition of prostaglandin synthesis in a
washed platelet suspension by measuring the malondialdehyde
formation following the addition o~ arachi~onic acid in vitroO
~r~ ~a~k - 13 -

Aspirin and mefenamic acid were used as controlsO ~he results
are shown in Table 50
Compound IC~o (llg/ml~ ~ J
___ _____
1 403
2 30L~
~i 307
4 204
40~3
6 1~9
7 401
8 407
9 500
0 401
3-3
12 L~ol
13 400
14 Llo6
502
16 ~1o5
17
BAspirin ~ 20 4
Mefenamic acid lo 4
(*): Final concentration at 50% inhibition of
malondialdehyde formation~
Acute toxicity and influences on the stomach
and intestines
(1) Acute toxicity
~ r~ k lL,~_

~he LD50 (50~0 lethal doses) in l~ice of er-lch of -the
~ Sk~, n ~
compounds shown in ~able 1 and ~e~ and mefenamic acid were
measured, and are shown in ~able 60
~a~le 6
__
~ __~
Compound LD 0 (mg/kg) oral
` __
1 4~0
2 400
3 400
4 600
~00
6 400
7 1600
8 1100
~ 800
800
11 ~00
12 1200
1~ 600
1~ 600
800
16 1600
17 1100
Aspirin* ~ 95
n,~ 3~i~ hOO
(2) Influences on the s-tomach and intestines
~he influences of each of the compounds shown in
Table 1 on the stomach and intestines were determined against
*~ ~G~cma-~k
-- 15 --

~2~313~ii
aspirin and mefenamic acid as controls 6 and 14 hours respectively
after oral administrationO It was found that the compounds
tested cause little gastrointestinal troubles 7 or even where
they caused gastrointestinal troubles, the degree of such
troubles was less than those induced by ~ ~ and mefenamic
acidO No trouble to the liver and kindneys was noted.
- 16 -