CA1182835A - Phenylguanidine acetylsalicylate compounds, process for production thereof, and pharmaceutical composition thereof - Google Patents
Phenylguanidine acetylsalicylate compounds, process for production thereof, and pharmaceutical composition thereofInfo
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- CA1182835A CA1182835A CA000376591A CA376591A CA1182835A CA 1182835 A CA1182835 A CA 1182835A CA 000376591 A CA000376591 A CA 000376591A CA 376591 A CA376591 A CA 376591A CA 1182835 A CA1182835 A CA 1182835A
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Abstract
Abstract of the Disclosure A compound of the formula
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) 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,
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) 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
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
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 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 13~
resonance spectroscopyO
~able 1 ,OCO.CH3 ~ , 2 -COOH~H2N-C-NH ~ -R3 NH ~ R
_ __ ~ __ . ~/1 R2 X3 R4 mel tin70point ~ ~ ~ ~ . ~
2 CH3 H H H 12705 - 128~5 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 9 H Cl H EI 122 - 123 12 OCH3 H H Cl 144.5 - 145 14 H H COCEI3 H 1~5 ~ 126 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 ~ 110 ~5 1~ 85 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 (%) ~ ) . _._ ~
2 ~801 3 2~oO
11 25~2 12 8~9 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~
3~ii ~able 4 __ Compound IC O ~/ml) ~ J
___ ____ _ 6 5'7 7 2.5 9 5~2 0 > 20 12 10~,8 13 12.2 14 8.8 ~' 20 h P~ Aspi.rin ~ 12l6 Il~ ,,,._. _ Final concentration at 50% inhibition of platelet aggregationO
~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 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 13~
resonance spectroscopyO
~able 1 ,OCO.CH3 ~ , 2 -COOH~H2N-C-NH ~ -R3 NH ~ R
_ __ ~ __ . ~/1 R2 X3 R4 mel tin70point ~ ~ ~ ~ . ~
2 CH3 H H H 12705 - 128~5 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 9 H Cl H EI 122 - 123 12 OCH3 H H Cl 144.5 - 145 14 H H COCEI3 H 1~5 ~ 126 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 ~ 110 ~5 1~ 85 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 (%) ~ ) . _._ ~
2 ~801 3 2~oO
11 25~2 12 8~9 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~
3~ii ~able 4 __ Compound IC O ~/ml) ~ J
___ ____ _ 6 5'7 7 2.5 9 5~2 0 > 20 12 10~,8 13 12.2 14 8.8 ~' 20 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
___ _____ 2 30L~
~i 307 40~3
~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
___ _____ 2 30L~
~i 307 40~3
6 1~9
7 401
8 407
9 500 12 L~ol 14 Llo6 16 ~1o5 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 ~00 ~ 800 11 ~00 1~ 600 1~ 600 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 ~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.
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 ~00 ~ 800 11 ~00 1~ 600 1~ 600 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 ~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.
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a compound of the formula (I) (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) (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.
3. A compound of the formula 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.
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000376591A CA1182835A (en) | 1981-04-30 | 1981-04-30 | Phenylguanidine acetylsalicylate compounds, process for production thereof, and pharmaceutical composition thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000376591A CA1182835A (en) | 1981-04-30 | 1981-04-30 | Phenylguanidine acetylsalicylate compounds, process for production thereof, and pharmaceutical composition thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1182835A true CA1182835A (en) | 1985-02-19 |
Family
ID=4119862
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000376591A Expired CA1182835A (en) | 1981-04-30 | 1981-04-30 | Phenylguanidine acetylsalicylate compounds, process for production thereof, and pharmaceutical composition thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1182835A (en) |
-
1981
- 1981-04-30 CA CA000376591A patent/CA1182835A/en not_active Expired
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