JPS6360015B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a novel 3,5-di-tertiarybutyl-4-hydroxystyrene derivative and a salt thereof. More specifically, the present invention relates to general formula (1) [Here, R ¹ is a carboxyl group or -COOR ³
(R ³ represents a lower alkyl group), R ² represents a lower hydroxyalkyl group] A novel 3,5-di-tert-butyl-4-hydroxystyrene derivative and its salt It is. (Means and Effects for Solving the Problems) As a result of extensive testing of the pharmacological action of 3,5-di-tertiarybutyl-4-hydroxystyrene derivatives, the present inventors found that The present invention has been achieved based on the discovery that the compound and its salt have excellent anti-inflammatory, analgesic, antipyretic, and platelet aggregation inhibiting effects. The present invention will be specifically explained below. 1 Compound The novel compound according to the present invention is represented by the following general formula (1). Here, R ¹ is a carboxyl group or -
Ester represented by COOR ³ (R ³ represents a lower alkyl group), R ² represents a lower hydroxyalkyl group. The compound according to the present invention can form a salt with a base, and the salt of the compound according to the present invention includes any salt that can be formed from the compound according to the present invention and a base. Specifically, for example, (1) metal salts, especially salts with alkali metals, alkaline earth metals, and aluminum, (2) ammonium salts, and (3) amine salts, especially methylamine, ethylamine, dimethylamine, diethylamine, triethylamine. , pyrrolidine, piperidine, morpholine, hexamethyleneimine, aniline, pyridine, etc. These salts are anti-inflammatory,
When used as an analgesic, antipyretic, or platelet aggregation inhibitor, a physiologically acceptable agent should be selected. Representative examples of compounds according to the invention are listed in Table 1.

[Table] 2 Manufacture of Compounds Among the compounds represented by the general formula (1) of the present invention, the compounds in which R ¹ is a carboxyl group and R ² is a lower hydroxyalkyl group are those of the general formula (2) synthesized by the method described below. ) It can be synthesized by hydrolyzing a compound represented by (R ⁴ represents hydrogen or a lower alkyl group) using an appropriate acid or base. Acids that can be used in this hydrolysis reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, organic acids such as p-toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, and trichloroacetic acid, and cation exchange resins. can be mentioned. Similarly, bases that can be used for hydrolysis include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; and pyrrolidine. , amines such as morpholine; and organic bases such as anion exchange resins. Particularly preferred bases used in this reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. There are the following methods for synthesizing the compound represented by general formula (2). For example, (1) according to the method of GAHowie et al. {Journal of Medicinal Chemistry, 17 , 840 (1974)}, 3.
5-Di-tertiarybutyl-4-hydroxybenzaldehyde and general formula

α-(Triarylphosphoranylidene)-γ represented by [Formula] (Ar is an aryl group, R ⁴ is hydrogen or a lower alkyl group)
- Can be synthesized by reacting with butyrolactones. This method uses the so-called Witteitz reaction, and the ylide to be reacted with the benzaldehyde includes, in addition to the above-mentioned compounds, trialkylphosphine,
Ylides derived from triphenylarsine can be used as well. (2) According to the method of H. Zimmer et al. {Journal of Organ Chemistry, 24 , 28 (1959)}, 3,5-
Di-tertiarybutyl-4-hydroxybenzaldehyde and general formula

It is synthesized by condensing a compound represented by the formula (R ₄ represents hydrogen or a lower alkyl group) using a base or an acid as a catalyst. Bases that can be used as catalysts include alkali metal alcoholates such as sodium methylate and sodium ethylate; alkali metal hydrogen compounds such as sodium hydride and potassium hydride; amines such as piperidine, morpholine, and ethanolamine; potassium hydroxide. , alkali metal hydroxides such as sodium hydroxide; alkali metal amides such as lithium-di-isopropylamide; and alkali metal salts of organic acids such as sodium acetate. Acids that can be used as catalysts include boron trifluoride, titanium tetrachloride, p
- Examples include toluenesulfonic acid. (3)S.
Tsuboi et al.'s method {Chemistry Letters,
1325 (1978)}, the general formula

A compound represented by the formula (R ⁴ represents hydrogen or a lower alkyl group) and a 3,5-
It is synthesized by reacting di-tertiarybutyl-4-hydroxybenzaldehyde with a base catalyst such as potassium carbonate. (4)3,5-
It can be synthesized by reacting di-tertiarybutyl-4-hydroxybenzaldehyde with the compounds shown below. (R ⁴ is hydrogen or lower alkyl group, R ⁵ , R ⁶ ,
R ⁷ and R ⁸ represent an alkyl group). (5)2,6-G-
Tertiary butylphenol and general formula (R ⁴ represents hydrogen or a lower alkyl group) using a Lewis acid such as aluminum chloride or stannic chloride as a catalyst.
It can be synthesized by a Crafts reaction. Furthermore, among the compounds represented by general formula (1),
R ¹ is −COOR ³ (R ³ represents a lower alkyl group)
The ester represented by R ² is a lower hydroxyalkyl group, and the compound represented by the general formula (3) is produced by the above-mentioned hydrolysis reaction. The compound represented by (R ² represents a lower hydroxyalkyl group) can be synthesized by subjecting it to the following esterification reaction. Examples of esterification reactions include esterification with diazoalkanes such as diazomethane; esterification with alcohols such as methanol and ethanol using boron trifluoride, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, etc. as catalysts; dimethyl sulfate, diethyl Examples include esterification with dialkyl sulfuric acid such as sulfuric acid; esterification with alkyl halides such as methyl iodide and ethyl iodide, and various known reactions for esterifying a carboxyl group can be used. In addition, the compound represented by the above general formula (2) can be prepared by catalyzing R ³ OH (R ³ represents a lower alkyl group) with an appropriate base or acid.
It can be synthesized by subjecting it to a transesterification reaction with an alcohol represented by: Bases that can be used here include alkali metal carbonates such as potassium carbonate and sodium carbonate; alkali metal alcoholates such as sodium methylate and sodium ethylate; acids that can be used similarly include sulfuric acid. , p-toluenesulfonic acid, etc., and there is no need to be particularly limited as long as it causes a transesterification reaction. Moreover, the compound of the present invention can be synthesized by the method described below. (1) 3,5-di-tertiarybutyl-4-hydroxybenzaldehyde and

[Formula] {Ar is an aryl group, R ¹ is an ester represented by -COOR ³ (R ³ is a lower alkyl group), R ²
represents a lower hydroxyalkyl group} according to the method of O. Isler et al. It is synthesized by hydrolyzing an ester using an acid or base. This method also uses the so-called Witteitz reaction, and in addition to the above-mentioned compounds, ylides derived from trialkylphosphine, trialkylphosphite, and triphenylarsine are also reacted with the benzaldehyde. I can do it. In addition, as acids or bases that can be used for hydrolysis, the above-mentioned general formula
Examples include those that can be used for hydrolysis of the compound represented by (2). Specific examples include acids such as sulfuric acid, p-toluenesulfonic acid, and trifluoroacetic acid; and bases such as sodium hydroxide, potassium hydroxide, barium hydroxide, and pyrrolidine. (2) 3,5-di-tertiarybutyl-4-hydroxybenzaldehyde and R ²
A lower hydroxyalkylmalonic acid represented by -CH(COOH) ₂ (R ² represents a lower hydroxyalkyl group) is mixed with piperidine in a pyridine solvent.
It can be synthesized by reacting with pyrrolidine or the like as a catalyst. 3 Anti-inflammatory, analgesic, antipyretic and platelet aggregation inhibitor The anti-inflammatory, analgesic, antipyretic and platelet aggregation inhibitor of the compound of the present invention contains the novel compound represented by the above general formula (1) or a salt thereof as an active ingredient. be. The pharmacological action and toxicity of these compounds are as shown in the test examples below.
The anti-inflammatory effect was determined according to the method described in "Inflammatory Animal Experiment Methods" (1975, Igaku Shoin), edited by Kimio Yasuhira et al., and the antipyretic effect was determined according to the method of Yoshikazu Yanagi et al. (Japanese Pharmacological Journal, 74 , 735 (1978)). }, the platelet aggregation inhibitory effect of arachidonic acid was tested according to the method of JB Smith et al. {The Journal of Clinical Investigation, 53, 1468 (1978)}. From the results shown in Tables 2 to 6, it is clear that the compounds according to the present invention have excellent pharmacological action and high safety. In addition, Tables 7 to 8
The compound numbers of the present invention therein correspond to the compound numbers shown in Table 1. Anti-inflammatory effect (1) Carrageenin footpad edema suppressing effect Male Wistar rat (weight 150-180g)
The number of animals per group was 6. 2.5% test compound
1.0ml/gum arabic suspension in aqueous solution
It was administered orally at a rate of 100g body weight. 1 hour later
0.1 ml of 1% carrageenan was subcutaneously injected into the footpad of one hind leg to cause inflammation. The swelling volume of the hind paw was measured at 3 and 5 hours after the onset of inflammation, and the inhibition rate was calculated using the following formula. Inhibition rate (%) = (1-average swelling volume of test compound administration group/average swelling volume of control group) x 100 The results are shown in Table 2. It can be seen that the compounds according to the present invention have a strong carrageenan edema inhibitory effect.

[Table] Analgesic effect Using ddY male mice (body weight 20-25 g),
The group consisted of 10 animals. A test compound suspended in a 2.5% gum arabic aqueous solution was orally administered at a rate of 0.1 ml/10 g body weight. After 1 hour, add 0.1ml/0.6% acetic acid.
Immediately after intraperitoneal injection at a rate of 10 g body weight, the number of stretching events occurring over a 20 minute period was measured. The suppression rate was calculated from the following formula by comparing with the number of stretches of the control group. Suppression rate (%) = (1 - average number of stretching times in test compound administration group/average number of stretching times in control group)
×100 The results are shown in Table 3. It can be seen that the compounds according to the invention have a strong analgesic effect.

【table】

[Table] Antipyretic effect Male Wistar rats (body weight 150-180 g) were used, with 5 rats per group. Dry yeast was suspended in physiological saline to make a 20% suspension and injected subcutaneously into the back at a rate of 1 ml/100 g body weight. After 18 hours, rectal temperature was measured using a thermistor thermometer.
Rats whose body temperature rose to 38.6°C or higher were selected for use in the experiment. Immediately after measuring the body temperature, a suspension of the test compound in a 2.5% aqueous gum arabic solution was orally administered at a rate of 1 ml/100 g body weight. Post-dose 1, 3 and 5
Rectal temperature was measured at time and compared with the rectal temperature of the control group. The results are shown in Table 4. It turns out that the compounds according to the invention have a strong antipyretic action.

[Table] Platelet aggregation inhibitory effect The platelet aggregation inhibitory effect was tested by the method shown below. (1) Preparation of platelet-rich plasma (PRP solution) Blood from the carotid artery of a Japanese white male rabbit (9 volumes of blood: 1 volume of 3.8% sodium citrate solution)
was collected and centrifuged at 1000 rpm for 10 minutes, and the supernatant was used as the PRP solution. (2) Preparation of arachidonic acid solution Sodium arachidonic acid was dissolved in physiological saline to prepare a 2 mg/ml solution of arachidonic acid. (3) Measurement Put 0.9ml of PRP solution and 0.01ml of methanol solution of the test compound into the cuvette of the platelet aggregometer.
After incubation at 37°C for 1 minute, 0.05 ml of arachidonic acid, a platelet aggregation-inducing agent, was added. Track changes in permeability associated with platelet aggregation,
The ability of the test compound to inhibit platelet aggregation was measured. Measurements were performed while varying the concentration of the test compound, and the minimum concentration of the test compound required to completely inhibit platelet aggregation was determined. The results are shown in Table 5. It can be seen that the compounds according to the invention have a strong anti-platelet aggregation effect.

[Table] Acute toxicity Using ICR male mice (body weight 20-25g),
There were 6 animals in the group. A test compound suspended in a 2.5% gum arabic aqueous solution was orally administered at a rate of 0.1 ml/10 g body weight. After administration, general symptoms were observed for two weeks, the number of deaths/number of test cases was determined, and the 50% lethal dose LD ₅₀ (mg/Kg) was estimated. The results are shown in Table 6. It can be seen that all the compounds of the present invention have low toxicity.

[Table] (Examples) Next, the present invention will be specifically explained with reference to Examples of the compounds of the present invention, but these Examples are not intended to limit the present invention. Example 1 α-(3,5-di-tertiarybutyl-4-
Synthesis of 3,5-di-tert-butyl-4-hydroxybutylbenzaldehyde 18g and α-triphenylphosphoranylidene-γ-butyrolactone 27g
was dissolved in 150 ml of dimethyl sulfoxide (DMSO) and reacted for 20 hours with stirring at 80°C on a hot water bath. After the reaction is complete, add chloroform to the cooled reaction solution.
Add 800ml, wash 5 times with the same amount of water, and remove the solvent.
DMSO was removed. After separating the chloroform layer,
The mixture was concentrated to dryness under reduced pressure to remove chloroform. Crystallization was performed by adding ethanol to the residue, and recrystallization was performed from the same solvent to obtain 18 g of the compound (yield 77.4
%). Synthesis of compound 15 g of the compound obtained above was added to 100 ml of 0.01N sodium hydroxide aqueous solution, and heated on an oil bath in a nitrogen stream for 90~
The hydrolysis reaction was carried out at 100°C for 1 hour while stirring. After the reaction was completed, 10% sulfuric acid was added little by little to the cooled reaction solution to make it acidic and to form a precipitate. The precipitate was separated and washed well with water. The precipitate was dissolved in benzene and crystallized to obtain 1.0 g of the target compound (yield 62.5%). The compound is a colorless rod-shaped crystal that is insoluble in water, slightly soluble in methanol and ethanol, and easily soluble in tetrahydrofuran, chloroform, acetone, and DMSO, and its properties are as follows. Melting point: 153-155℃ Molecular weight: 302.42 Elemental analysis value: C H O Experimental value 75.68% 8.51% 15.81% Theoretical value 75.46% 8.67% 15.87% (C ₁₉ H ₂₆ O ₃ ) The structure of the compound can be seen from the infrared absorption spectrum ( (Fig. 3) and nuclear magnetic resonance spectrum (Fig. 4). The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound are shown in FIGS. 1 and 2. Example 2 Synthesis of compound 900 mg of the compound obtained in Example 1 {3,5-di-tertiarybutyl-4-hydroxy-α-(β-hydroxyethyl)cinnamic acid} was dissolved in 50 ml of ether, and diazomethane was added to the solution. 9 ml of an ether solution (0.5 mmole/ml) was added thereto and left overnight to react. The reaction solution was filtered to remove a small amount of precipitate formed. The obtained liquid was dried under reduced pressure to obtain 890 mg of the target compound (yield:
94.8%). Infrared absorption spectrum (KBr tablet method) max (cm ^-1 ): 3620, 3460, 2970, 1710, 1630,
1605, 1440 isonuclear magnetic resonance spectrum (solvent _CDCl3 ) δ (ppm):
1.43 (s, 18H), 2.13~2.33 (br, 1H), 2.87 (t, 2H), 3.80 (s, 3H), 3.90 (t, 2H), 5.40 (s, 1H), 7.28 (s, 2H) , 7.72 (s, 1H) s: singlet, t: triplet, br: broad absorption

[Brief explanation of the drawing]

Figure 1 is an infrared absorption spectrum diagram of the compound () of the present invention, Figure 2 is a nuclear magnetic resonance spectrum diagram of the same compound, Figures 3 and 4 are infrared absorption spectrum diagrams and nuclear magnetic resonance spectrum diagrams of the compound (), respectively. It is a spectrum diagram.

Claims (1)

[Scope of Claims] 1. A 3,5-di-tert-butyl-4-hydroxystyrene derivative represented by the following general formula and a salt thereof. [Here, R ¹ is a carboxyl group or -COOR ³
(R ³ represents a lower alkyl group), R ² represents a lower hydroxyalkyl group] 2 Formula 3 and 5 of claim 1 expressed as
-Di-tertiarybutyl-4-hydroxystyrene derivatives and salts thereof. 3 formulas 3 and 5 of claim 1 expressed as
-Di-tertiarybutyl-4-hydroxystyrene derivatives and salts thereof.