JPS6324498B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a novel 3,5-tertiary
Butylstyrene derivatives or their salt-formable salts, and anti-inflammatory and analgesic products containing the same as active ingredients.
This invention relates to an antipyretic agent and a platelet aggregation inhibitor. More specifically, the present invention relates to general formula (1) [In the formula, R ¹ is R ³ COO (R ³ is hydrogen or C ₁ to _{C 6}
acyloxy group represented by R ⁴ O (R ⁴ represents an alkyl group of C ₁ to _{C 4} ), a hydroxyl group, or hydrogen, and R ² is

【formula】

[Formula] (R ⁵ represents hydrogen or a C ₁ to C ₃ alkyl group, X ¹ represents CH ₂ or oxygen)
or

[Formula] (X ² represents oxygen or sulfur)] A novel 3,5-di-tertiary-butylstyrene derivative or a salt-formable salt thereof, and an anti-inflammatory product containing the same as an active ingredient. , analgesics, antipyretics, and platelet aggregation inhibitors. The present inventors extensively tested the pharmacological effects of 3,5-di-tertiary-butylstyrene derivatives and found that the compound represented by general formula (1) and its salts have excellent anti-inflammatory, analgesic, antipyretic, and platelet aggregation inhibition properties. It was discovered that the present invention has an effect, and the present invention was achieved. Hereinafter, the present invention will be explained in detail. 1 Compound The novel compound according to the present invention is represented by the following general formula (1). [In the formula, R ¹ is R ³ COO (R ³ is hydrogen or C ₁ to _{C 6}
acyloxy group represented by R ⁴ O (R ⁴ represents an alkyl group of C ₁ to _{C 4} ), a hydroxyl group, or hydrogen, and R ² is

【formula】

[Formula] (R ⁵ represents hydrogen or a C ₁ to C ₃ alkyl group, X ¹ represents CH ₂ or oxygen)
or

[Formula] (X ² represents oxygen or sulfur). ] Among the compounds according to the present invention, a compound in which R ¹ is a hydroxyl group can form a salt with a base. Any item is eligible. 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. When using these salts as anti-inflammatory, analgesic, antipyretic agents or platelet aggregation inhibitors, physiologically acceptable salts should be selected. Representative examples of the compounds according to the present invention are shown in Table 1.

【table】

[Table] 2. Manufacture of compounds Examples of methods for synthesizing the compound represented by general formula (1) of the present invention include the following. For example, (1) GAHowie et al.'s method [Journal of
Medicinal Chemistry 17 , 840 (1974)]
According to the general formula (2) [Here, R ¹ is R ³ COO (R ³ is hydrogen or C ₁
- acyloxy group represented by C ₆ alkyl group), alkoxy group represented by R ⁴ O (R ⁴ represents a C ₁ to _{C 4} alkyl group), hydroxyl group or hydrogen] 3, 5-Di-tertiary butylbenzaldehyde and general formula

[Formula] (Ar is an aryl group, R ⁵ is hydrogen or C ₁ - _{C 3}
α-(triarylphosphoranylidene)-γ-butyrolactones represented by (representing an alkyl group) or the general formula

[Formula] (Ar is an aryl group, R ⁵ is hydrogen or C ₁ ~
α- represented by C ₃ alkyl group)
It can be synthesized by reacting (triarylphosphoranylidene) with cyclopentanones. This method uses the so-called Witzteich reaction, but as the ylide to be reacted with the benzaldehydes, in addition to the above-mentioned compounds, ylides derived from trialkylphosphine and dorifhenylalumine can also be used. (2) According to the method of H. Zimmer et al. [Journal of Organ Chemistry 24 , 28 (1959)], general formula (2) [Here, R ¹ is R ³ COO (R ³ is hydrogen or C ₁
- acyloxy group represented by C ₆ alkyl group), alkoxy group represented by R ⁴ O (R ⁴ represents a C ₁ to _{C 4} alkyl group), hydroxyl group or hydrogen] 3, 5-Di-tertiary butylbenzaldehyde and general formula

[Formula] (R ⁵ is hydrogen or a C ₁ to C ₃ alkyl group,
X ¹ represents CH ₂ or oxygen), or a compound represented by the general formula

It is synthesized by condensing a compound represented by the formula (X ² represents oxygen or sulfur) with a base or acid as a catalyst. Bases that can be used as catalysts include alkali metal alcoholates such as sodium methylate and sodium ethylate; alkali metal hydrides 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 diisopropylamide; and alkali metal salts of organic acids such as sodium acetate and potassium acetate. Furthermore, examples of acids that can be used as catalysts include boron trifluoride, titanium tetrachloride, p-toluenesulfonic acid, and benzenesulfonic acid. (3) According to the method of S. Tsuboi et al. [Chemistry Letters, 1325 (1978)], general formula (2) [Here, R ¹ is R ³ COO (R ³ is hydrogen or C ₁
- acyloxy group represented by C ₆ alkyl group), alkoxy group represented by R ⁴ O (R ⁴ represents a C ₁ to _{C 4} alkyl group), hydroxyl group or hydrogen] 3, 5-Di-tertiary butylbenzaldehyde and general formula

[Formula] (R ⁵ is hydrogen or a C ₁ to C ₃ alkyl group,
It is synthesized by reacting a compound represented by (X ¹ represents CH ₂ or oxygen) with a basic catalyst such as potassium carbonate. (4) General formula (2) [Here, R ¹ is R ³ COO (R ³ is hydrogen or C ₁
- acyloxy group represented by C ₆ alkyl group), alkoxy group represented by R ⁴ O (R ⁴ represents a C ₁ to _{C 4} alkyl group), hydroxyl group or hydrogen] 3, It can be synthesized by reacting 5-di-tertiary-butylbenzaldehydes with the compounds shown below.

【formula】

【formula】

【formula】

【formula】

[Formula] (R ⁵ is hydrogen or a C ₁ to C ₃ alkyl group,
^{( 5} ) General _formula ^{( 3 )} [Here, R ¹ is R ³ COO (R ³ is hydrogen or C ₁
~ _C6 alkyl group)), an alkoxy group represented by ^R4O ( ^R4 represents a _C1 to _C4 alkyl group), a hydroxyl group or hydrogen] 1, 3-Di-tertiary butylbenzenes and general formula

【formula】

[Formula] (R ⁵ is hydrogen or a C ₁ to C ₃ alkyl group,
Friedel-Crafts reaction with a compound represented by (X ¹ is CH ₂ or oxygen, X ² is oxygen or sulfur, and Hal is a halogen atom) using a Lewis acid such as aluminum chloride or tin chloride as a catalyst. It can be synthesized by General formula (1) In the compound represented by R ¹ is an acyloxy group represented by R ³ COO (R ³ is hydrogen or a C ₁ to C ₆ alkyl group), and R ² is an acyloxy group represented by

【formula】

[Formula] (R ₅ represents hydrogen or a C ₁ to C ₃ alkyl group, X ¹ represents CH ₂ or oxygen),
or

The compound represented by the formula (X ² represents oxygen or sulfur) can also be synthesized as follows. That is, the above
Among the compounds synthesized according to methods (1) to (5), general formula (4) [Here R ² is

【formula】

[Formula] (R ₅ represents hydrogen or a C ₁ to C ₃ alkyl group, X ¹ represents CH ₂ or oxygen),
or

[Formula] (X ² represents oxygen or sulfur)] and (R ¹⁰ CO) ₂ O (R ¹⁰ is C ₁ -
C ₆ alkyl group)) and an acid such as sulfuric acid, p-toluenesulfonic acid, etc.
Alternatively, by reacting in the presence of a base such as pyridine or lutidine, or by reacting with the compound represented by the general formula (4) and R ³ COX ³ (R ³ is hydrogen or C ₁
~ _C6 alkyl group, ^X3 represents a halogen atom)
It can be synthesized by reacting an acid halide represented by the following in the presence of an inorganic base such as an alkali metal hydroxide such as sodium hydroxide, or an organic base such as pyridine or triethylamine. The method described above synthesizes the target compound by an esterification reaction of a phenolic hydroxyl group, and the method for obtaining the target compound does not need to be limited to the above method. Other reagents can be used as well. Furthermore, general formula (1) In the compound represented by R ¹ is R ⁴ O (R ⁴ is C ₁ ~
is an alkoxy group represented by (representing a C ₄ alkyl group), and R ² is

【formula】

[Formula] (R ₅ represents hydrogen or a C ₁ to C ₃ alkyl group, X ¹ represents CH ₂ or oxygen),
or

The compound represented by the formula (X ² represents oxygen or sulfur) can also be synthesized as follows. That is, the above
General formula (4) synthesized according to methods (1) to (5) [Here, R ² is

【formula】

[Formula] (R ₅ represents hydrogen or a C ₁ to C ₃ alkyl group, X ¹ represents CH ₂ or oxygen),
or

Reaction of a compound represented by [Formula] (X ² represents oxygen or sulfur) with a diazoalkane represented by R ¹¹ CHN ₂ (R ¹¹ represents hydrogen or a C ₁ to C ₃ alkyl group) Let or R ⁴ X ⁴
(R ⁴ is a C ₁ to C ₄ alkyl group, X ⁴ is a halogen atom) and an inorganic base such as sodium hydride, potassium hydride, sodium amide, potassium amide, etc. ―
It can be synthesized by reaction in the presence of an organic base such as diazabicyclo[5,4,0]undec-7-ene. The method described above synthesizes the target compound by the etherification reaction of the phenolic hydroxyl group, and the method for obtaining the target compound does not need to be limited to the above method. Other reagents can be used as well. Next, as an example of a specific method for producing the compound of the present invention, α-(3,5-di-tertiary butyl-
The method for producing 4-hydroxybenzylidene)-γ-butyrolactone (compound) will be described. 3,5-di-tert-butyl-4-hydroxybenzaldehyde and α-(triphenylphosphoranylidene)-γ-butyrolactone were dissolved in dimethyl sulfoxide (DMSO) and heated on a hot water bath for 80 minutes.
React for 20 hours with stirring at °C. After the reaction was completed, chloroform was added to the cooled reaction solution, washed with water to remove DMSO, and the chloroform layer was separated. After removing chloroform under reduced pressure, crystallization was performed from ethanol to obtain colorless rod-shaped crystals. The substance obtained here 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 ) Furthermore, the structure of this compound (compound) This was confirmed by absorption spectrum (Figure 1), infrared absorption spectrum (Figure 2), and nuclear magnetic resonance spectrum (Figure 3). 3. Anti-inflammatory, analgesic, antipyretic and platelet aggregation inhibitor The anti-inflammatory, analgesic, antipyretic and platelet aggregation inhibitor according to the present invention contains the novel compound represented by the above general formula (1) or a salt of its salt-formable salt as an active ingredient. That is. The pharmacological action and toxicity of these compounds are as shown in the following test examples. The anti-inflammatory effect of carrageenan to suppress footpad edema was determined by the method of CA Winter et al.
Of Society for Experimental Biology and Medicine, 111 ,
544 (1962)], the inhibitory effect on granulation proliferation was determined by the method of Yukio Hara et al. [Japanese Pharmacological Journal, 73 , 557 (1977)], and the inhibitory effect on adjuvant arthritis was determined by the method of DTWalz et al. [The Journal of Pharmacology and Experimental Therapeutics, 178 , 223
(1971)]. The antipyretic effect was determined by the method of Yoshikazu Yanagi et al. [Japanese Pharmacological Journal,
74, 735 (1978)], and the analgesic effect was determined by the method of R. Koster et al. [Federation Procedures, 18 , 412
(1959)], the platelet aggregation effect of arachidonic acid is
JB Smith et al.'s method [The Journal of Clinical Investigation, 53 , 1468
(1978)]. From the results shown in Tables 2 to 8, it is clear that the compounds according to the present invention have excellent pharmacological action and high safety. The compound numbers of the present invention in Tables 2 to 8 correspond to the compound numbers shown in Table 1. Anti-inflammatory effect (1) Carrageenin footpad edema suppressive effect Male Wistar rats (body weight 150-180 g) were used, with 6 rats per group. 1.0ml/100g of the test compound suspended in 2.5% gum arabic aqueous solution
It was administered orally in proportion to body weight. One hour later, 0.1 ml of 1% carrageenan was subcutaneously injected into the footpad of one hind leg to induce inflammation. The swelling volume of the hind paw was measured 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] (2) Granulation growth inhibitory effect Male Wistar rats (body weight 150-180 g) were used, with 6 rats per group. Under anesthesia, after removing hair from the back, an approximately 1 cm incision was made in the skin along the midline, and one sterilized antibiotic assay paper disk (29
±1 mg) was inserted under the skin of both shoulder flaps, and the incisions were sutured. A test compound suspended in a 2.5% gum arabic aqueous solution was orally administered at a rate of 1 ml/100 g body weight for 7 days from the day the paper disk was inserted. Seven days after paper disk insertion, the animals were sacrificed and the granulation tissue containing the paper disk was excised. After drying the excised granulation tissue at 60°C for 24 hours,
It was weighed and the paper disk weight was subtracted to determine the dry weight of granulation, and the inhibition rate was determined using the following formula. Inhibition rate (%) = (1 - average dry weight of granulation of test compound administration group/average dry weight of granulation of control group) x 100 The results are shown in Table 3. It can be seen that the compounds according to the present invention have a strong granulation growth inhibiting effect.

[Table] (3) Suppressive effect on arthritis of Ajiyuband Using SD male rats (body weight 190-230g),
There were 8 animals in each group. As an adjuvant, liquid paraffin for injection is used with Mycobacterium
butyricum) suspended at a ratio of 10 mg/ml, and 0.05 ml of the suspension was injected into the footpad of one hind leg. 21 times consecutively once a day from the day of adjuvant treatment
A test compound suspended in a 2.5% gum arabic aqueous solution was orally administered at a rate of 0.5 ml/100 g body weight for days. After the adjuvant treatment, the swelling volume of both hind limbs was measured on the 14th and 21st day, 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 4. It has been found that the compounds of the present invention have strong adjuvant arthritis suppressive effects.

[Table] Analgesic effect Using male DDY mice (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 0.1 ml of 0.6 acetic acid/
Immediately after intraperitoneal injection at a rate of 10 g body weight, the number of stretching events occurring over 20 minutes 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) x 10
0 The results are shown in Table 5. It turns out that the compounds according to the invention have a strong analgesic effect.

【table】

[Table] Antipyretic action 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, and only rats whose body temperature rose to 38.6°C or higher were selected for use in the experiment. Immediately after body temperature measurement, test compound
1. Suspended in 2.5% gum arabic aqueous solution
It was administered orally at a rate of ml/100g body weight. After administration,
Rectal temperature was measured at 1, 3 and 5 hours, and the inhibition rate was calculated using the following formula. Suppression rate (%) = (1-average increased body temperature of test compound administration group/average increased body temperature of control group) x 100 The results are shown in Table 6. It turns out that the compounds according to the invention have a strong antipyretic action.

[Table] Platelet aggregation inhibitory effect 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)
Collect and centrifuge at 1000 rpm for 10 minutes.
The supernatant was used as a 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 platelet aggregometer.
After incubation at 37°C for 1 minute, 0.05 ml of arachidonic acid solution, which is a platelet aggregation-inducing agent, was added. Changes in permeability due to platelet aggregation were tracked, and the ability of the test compound to inhibit platelet aggregation was measured. Measurements were carried out at various concentrations 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 7. It has been found that the compounds according to the present invention have a strong platelet aggregation inhibiting effect.

[Table] Acute toxicity Using ICR female mice (body weight 20-25 g),
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. For two weeks after administration, general symptoms were observed, 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 8. It can be seen that all the compounds of the present invention have low toxicity.

Table: Preparation and Dosage The compounds of the invention are effective for oral, rectal or parenteral administration and may be in the form of tablets, capsules, granules, injections, syrups, suppositories or ointments. It can be used. Carriers for formulations containing the compounds according to the invention include organic or inorganic solids or liquids suitable for oral, enteral or other parenteral administration.
Usually an inert pharmaceutical carrier material is used. Specific examples include crystalline cellulose, gelatin, lactose, starch, magnesium stearate, polyalkylene glycol, and others. The proportion of the compound of the invention to the carrier in the formulation can vary between 0.2 and 100%. In addition, preparations containing the compound of the present invention as an anti-inflammatory, analgesic, antipyretic, or platelet aggregation inhibitor component may contain other anti-inflammatory, analgesic, antipyretic, platelet aggregation inhibitors, or other pharmaceuticals that are compatible with the compound of the present invention. . In this case, it goes without saying that the compound of the present invention does not need to be the main ingredient in the preparation. Compounds of the invention are generally administered at dosages that achieve the desired effect without side effects.
Although the specific value should be determined by a doctor's judgment, it will generally be administered at about 10 mg to 10 g, preferably about 20 mg to 5 g, per day for adults. The compound of the present invention has a dosage of 1 mg as an active compound.
It can be administered as a pharmaceutical preparation in unit doses of ~5g, preferably 3mg to 1g. Next, the present invention will be specifically explained with reference to production examples of the compounds of the present invention, but these Examples are not intended to limit the present invention. Example 1 Synthesis of compound 0.43 g of 3.5-di-tert-butylbenzaldehyde and 0.63 g of α-triphenylphosphoranylidene-γ-butyrolactone were dissolved in 10 ml of dimethyl sulfoxide (DMSO) and stirred at 80°C for 2 hours. Made it react. After the reaction was completed, 100 ml of chloroform was added to the cooled reaction solution, which was washed five times with the same amount of water to remove the solvent DMSO. After separating the chloroform layer, it was concentrated to dryness under reduced pressure to remove chloroform. Add ethanol to the residue to perform crystallization, and then recrystallize from the same solvent.
0.39 g of the target compound I was obtained (yield 68%). Example 2 Synthesis of compound 18 g of 3,5-di-tertiary-butyl-4-hydroxybenzaldehyde and 27 g of α-triphenylphosphoranylidene-γ-butyrolactone were dissolved in 150 ml of dimethyl sulfoxide (DMSO) and heated on a hot water bath for 80 g. The reaction was allowed to proceed for 20 hours while stirring at °C. 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,
It was concentrated to dryness under reduced pressure to remove chloroform.
Add ethanol to the residue to perform crystallization, and then recrystallize from the same solvent to obtain the desired compound, 18
g (yield 77%). Example 3 Synthesis of compound 2.0 g of the compound was suspended in 3.0 g of acetic anhydride, 1 drop of concentrated sulfuric acid was added to this suspension, mixed well, and stirred at 80°C for 30 minutes.
Allowed time to react. After the reaction was completed, the reaction solution was poured into 10 g of crushed ice. The product initially separates as an oil, but gradually solidifies. After the product was sufficiently solidified, it was separated and washed with water. The product obtained separately was crystallized from ethanol and further recrystallized from ethanol to obtain 1.8 g of the compound (yield 79%). Example 4 Synthesis of compound 3.0 g of the compound was suspended in 10 ml of propionic anhydride, 1 drop of concentrated sulfuric acid was added to this suspension, and the mixture was thoroughly mixed.
The reaction was carried out at 80°C for 3 hours. Thereafter, 1.47 g of the target compound was obtained by the same operation as in Example 3 (yield: 41%). Example 5 Synthesis of compound 3.0 g of the compound was suspended in 10 ml of valeric anhydride, 1 drop of concentrated sulfuric acid was added to this suspension, mixed well, and reacted at 80° C. for 3 hours. Following the same procedure as in Example 3, 1.88g of the target compound was obtained (yield: 49
%). Example 6 Synthesis of compound 3 g of the compound was dissolved in 50 ml of tetrahydrofuran, and then sodium hydride (oil-based, content 60
%), 5 ml of methyl iodide was added, and the mixture was heated under reflux for 2 hours. After cooling, the reaction mixture was poured into 100 ml of water, acidified with dilute sulfuric acid, and extracted twice with 100 ml of chloroform. The extract was washed twice with water, dried over anhydrous sodium sulfate, and then chloroform was distilled off under reduced pressure. N-hexane was added to the obtained red syrup to crystallize the target compound. 2.4 g of colorless crystals were obtained (yield 76%). Example 7 Synthesis of compound 3 g of the compound was dissolved in 50 ml of tetrahydrofuran, and then sodium hydride (oil-based, content 60
%), 6.4 ml of ethyl iodide was added, and the mixture was heated under reflux for 3 hours. Thereafter, 0.76 g of the target compound was obtained by the same operation as in Example 6 (yield 23%). Example 8 Synthesis of compound 3.3 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 5 g of α-triphenylphosphoranylidene-γ-valerolactone were dissolved in 25 ml of DMSO and stirred at 80°C on a water bath. The reaction was allowed to proceed for 24 hours. After the reaction was completed, 150 ml of chloroform was added to the cooled reaction solution, which was washed five times with the same amount of water to remove the solvent DMSO. After separating the chloroform layer, it was concentrated to dryness under reduced pressure to remove chloroform. Ethanol was added to the residue and crystallization was performed to obtain 1.5 g of the target compound (yield: 34
%). Example 9 Synthesis of compound 6 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 9 g of α-triphenylphosphoranylidenecyclopentanone were
It was dissolved in 60 ml of DMSO and reacted for 24 hours with stirring at 80°C on a water bath. After the reaction was completed, 300 ml of chloroform was added to the cooled reaction solution, which was washed five times with the same amount of water to remove the solvent DMSO. After separating the chloroform layer, it was concentrated to dryness under reduced pressure to remove chloroform. Add ethanol to the residue to perform crystallization, and then recrystallize twice from the same solvent.
3.1g of the compound was obtained (yield 40%). Example 10 Synthesis of Compound X Add 3.5-
11.7 g of di-tert-butyl-4-hydroxybenzaldehyde and 5 g of hydantoin were added, and after further heating to 70°C, 9.2 ml of ethanolamine was added. The mixture was further heated to 90°C and reacted for 5 hours with stirring. After the reaction is complete, add 40% water to the reaction solution.
ml was added to form a precipitate and this precipitate was separated. Next, in order to remove the ethanolamine attached to the precipitate, the precipitate obtained by filtration was again soaked in 100% water.
ml, adjusted to pH 4.0 with 1N hydrochloric acid, and separated again. After thoroughly washing the separated precipitate with water, it was crystallized from acetone and recrystallized twice from the same solvent to obtain 1.5 g of Compound X (yield 9.5%). Example 11 Synthesis of Compound XI Add 3,5-ditertiary
Butyl-4-hydroxybenzaldehyde 11.7g
and 6.9 g of thiohydantoin were added, and after heating to 80°C, 9.2 ml of ethanolamine was added. The mixture was further heated to 90°C and reacted for 6 hours with stirring. After the reaction was completed, 40 ml of water was added to the reaction solution to form a precipitate, which was separated. Next, in order to remove the ethanolamine attached to the precipitate, the precipitate obtained from the filtration was resuspended in 100 ml of water.
After adjusting the pH to 4.0 with 1N hydrochloric acid, the mixture was separated again. This separated precipitate was dissolved in 100 ml of chloroform and thoroughly washed with 1N hydrochloric acid to form a precipitate in the chloroform, which was separated. The separated precipitate was crystallized from methanol and further recrystallized from acetone to obtain 0.9 g of Compound XI (yield 5.4%).

[Brief explanation of drawings]

Figure 1 shows the ultraviolet absorption spectrum of the compound of the present invention (compound), Figure 2 shows the infrared absorption spectrum of the same,
Figure 3 shows the nuclear magnetic resonance spectrum.

Claims (1)

[Scope of Claims] 1. A 3,5-di-tert-butylstyrene derivative represented by the following general formula and its salt-formable salt. [In the formula, R ¹ is R ³ COO (R ³ is hydrogen or C ₁ to _{C 6}
R 2 is an acyloxy group represented by R ⁴ O (R ⁴ represents an alkyl group of C ₁ to _{C 4} ), a hydroxyl group, or hydrogen, and R ² is [Formula] [Formula ] (R ⁵ represents hydrogen or a C ₁ to C ₃ alkyl group, X ¹ represents CH ₂ or oxygen)
or [Formula] (X ² represents oxygen or sulfur). ] 2 An acyloxy group in which R ¹ is represented by R ³ COO (R ³ represents hydrogen or a C ₁ to C ₆ alkyl group),
an alkoxy group, hydroxyl group or hydrogen represented by R ⁴ O (R ⁴ represents a C ₁ to C ₄ alkyl group),
R ² is [Formula] [Formula] (R ⁵ represents hydrogen or a C ₁ to C ₃ alkyl group, and X ¹ represents CH ₂ or oxygen)
3,5-di according to claim 1, which is
Tertiary butylstyrene derivatives and their salt-formable salts. 3 R ¹ is an acyloxy group represented by R ³ COO (R ³ represents hydrogen or a C ₁ to C ₆ alkyl group),
an alkoxy group, hydroxyl group or hydrogen represented by R ⁴ O (R ⁴ represents a C ₁ to C ₄ alkyl group),
The 3,5-di-tert-butylstyrene derivative and its salt-formable salts according to claim 1, wherein R ₂ is [Formula]. 4 R ¹ is an acyloxy group represented by R ³ COO (R ³ represents hydrogen or a C ₁ to C ₆ alkyl group),
an alkoxy group, hydroxyl group or hydrogen represented by R ⁴ O (R ⁴ represents a C ₁ to C ₄ alkyl group),
The 3,5-di-tert-butylstyrene derivative and its salt-formable salts according to claim 1, wherein R ² is [Formula]. 5 R ¹ is an acyloxy group represented by R ³ COO (R ³ represents hydrogen or a C ₁ to C ₆ alkyl group),
an alkoxy group, hydroxyl group or hydrogen represented by R ⁴ O (R ⁴ represents a C ₁ to C ₄ alkyl group),
The 3,5-di-tert-butylstyrene derivative and salt thereof according to claim 1, wherein R ² is [Formula] [Formula] (R ⁵ represents a C ₁ -C ₃ alkyl group) Salt of what is possible. 6 3, as set forth in claim ¹ , wherein R 1 is a hydroxyl group and R ² is [Formula] (X ² represents oxygen or sulfur);
5-Ditertiary butylstyrene derivatives and salts thereof. 7 formula 3 of claim 1 expressed as
5-di-tertiary butylstyrene derivative. 8 formula 3 of claim 1 expressed as
5-Ditertiary butylstyrene derivatives and salts thereof. 9 formula 3 of claim 1 expressed as
5-di-tertiary butylstyrene derivative. 10 formula 3 of claim 1 expressed as
5-di-tertiary butylstyrene derivative. 11 formula 3 of claim 1 expressed as
5-di-tertiary butylstyrene derivative. 12 formula 3 of claim 1 expressed as
5-di-tertiary butylstyrene derivative. 13 formula 3 of claim 1 expressed as
5-di-tertiary butylstyrene derivative. 14 formula 3 of claim 1 expressed as
5-di-tertiary butylstyrene derivatives and salts thereof. 15 formula 3 of claim 1 expressed as
5-Ditertiary butylstyrene derivatives and salts thereof. 16 formula 3 of claim 1 expressed as
5-Ditertiary butylstyrene derivatives and salts thereof. 17 formula 3 of claim 1 expressed as
5-Ditertiary butylstyrene derivatives and salts thereof. 18 An anti-inflammatory, analgesic, and antipyretic agent containing a 3,5-di-tertiary-butylstyrene derivative represented by the following general formula or a physiologically acceptable salt thereof as an active ingredient. [In the formula, R ¹ is R ³ COO (R ³ is hydrogen or C ₁ to _{C 6}
R 2 is an acyloxy group represented by R ⁴ O (R ⁴ represents an alkyl group of C ₁ to _{C 4} ), a hydroxyl group, or hydrogen, and R ² is [Formula] [Formula ] (R ⁵ represents hydrogen or a C ₁ to C ₃ alkyl group, X ¹ represents CH ₂ or oxygen)
or [Formula] (X ² represents oxygen or sulfur). [19] A platelet aggregation inhibitor containing a 3,5-di-tert-butylstyrene derivative represented by the following general formula or a physiologically acceptable salt thereof as an active ingredient. [In the formula, R ¹ is R ³ COO (R ³ is hydrogen or C ₁ to _{C 6}
R 2 is an acyloxy group represented by R ⁴ O (R ⁴ represents an alkyl group of C ₁ to _{C 4} ), a hydroxyl group, or hydrogen, and R ² is [Formula] [Formula ] (R ⁵ represents hydrogen or a C ₁ to C ₃ alkyl group, X ¹ represents CH ₂ or oxygen)
or [Formula] (X ² represents oxygen or sulfur). ]