JP2527652B2 - P-aminophenol derivative, its production method and use - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a p-aminophenol derivative having a pharmacological action, a synthetic intermediate thereof, a salt thereof, a compound thereof and the like, and pharmacological use thereof.

2. Description of the Related Art The p-aminophenol derivative, its synthetic intermediate and salts thereof according to the present invention are all novel compounds which have not been published in the literature.

JP-A-1-25756, JP-A-60-258173,
JP-A-62-123180, JP-A-62-87580, and JP-A-63-115860 disclose various p-amino compounds as compounds which are somewhat related to the p-aminophenol derivative of the present invention. Although a phenol derivative is described, there is no description about the compound relating to the present invention in each publication.

The present invention provides a novel p-aminophenol derivative having a valuable pharmacological action, particularly an anti-inflammatory action, as described below.
It is an object of the present invention to provide a synthetic intermediate, a salt thereof, a method for producing the same, and a pharmacological use thereof.

DISCLOSURE OF THE INVENTION According to the present invention, p- represented by the following general formula (1)
Provided are an aminophenol derivative and a salt thereof, a compound represented by the following general formula (1 ′) which is a synthetic intermediate thereof, and a salt thereof.

[In the formula, R ¹ and R ² are each independently a hydrogen atom or C ₁ to
Indicates a C ₆ acyl group. Ar represents a pyrazine ring group, a pyrazine N-oxide ring group, a thiazole ring group, a benzene ring group, a pyridine ring group, a pyridazine ring group, a pyrimidine ring group or a triazine ring group. R ³ is a hydrogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆
Alkoxycarbonyl -C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, a halogen atom or a carboxy -C ₁ -C ₆ alkyl group. A is a C ₁ -C ₆ alkylene group and B is C ₁
Shows a -C ₆ alkyl groups, respectively. ] [In the formula, R ¹ represents a hydrogen atom or a C ₁ -C ₆ acyl group. Ar is a pyrazine ring group, a pyrazine N-oxide ring group, a thiazole ring group, a benzene ring group, a pyridine ring group, a pyridazine ring group,
A pyrimidine ring group or a triazine ring group is shown. R ³ is hydrogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxycarbonyl-
C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, a halogen atom or a carboxy -C ₁ -C ₆ alkyl group. A is C ₁
To C ₆ alkylene group, and B represents a C _{1 to} C ₆ alkyl group, respectively. In the present specification, the pyrazine N-oxide ring group defined by Ar includes pyrazine 1-oxide-2-yl and pyrazine 1-oxide 3-yl groups, and the thiazole ring group includes 2-thiazolyl and 4-thiazolyl. , 5-thiazolyl group, 2-pyridyl, 3-pyridyl, 4-pyridyl group as the pyridine ring group, 3-pyridazinyl, 4-pyridazinyl group as the pyridazine ring group, 2-pyrimidinyl as the pyrimidine ring group, 4-pyrimidinyl and 5-pyrimidinyl groups, and triazine ring groups as 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,
1,2,4-triazin-6-yl, 1,3,5-triazin-2
Examples include -yl, 1,2,3-triazin-4-yl and 1,2,3-triazin-5-yl groups.

The C ₁ -C ₆ acyl group has, for example, 1 carbon atom such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, trimethylacetyl and hexanoyl groups.
The straight-chain or branched-chain acyl group of ~ 6 can be illustrated.

Examples of the C _{1 to} C ₆ alkyl group include methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, tert-
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as butyl, pentyl and hexyl groups.

Examples of the C _{1 to} C ₆ alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-
Examples thereof include linear or branched alkoxy groups having 1 to 6 carbon atoms such as butoxy, tert-butoxy, pentyloxy and hexyloxy groups.

Examples of the C _{1 to} C ₆ alkoxycarbonyl-C _{1 to} C ₆ alkyl group include ethoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl,
1-methyl-1-methoxycarbonylethyl, 4-methoxycarbonylbutyl, 5-methoxycarbonylpentyl, 6-methoxycarbonylhexyl, 1-ethoxycarbonylethyl, butoxycarbonylmethyl, 2-tert
Examples thereof include linear or branched alkoxycarbonylalkyl groups having 1 to 6 carbon atoms such as butoxycarbonylethyl, pentyloxycarbonylmethyl and hexyloxycarbonylmethyl groups.

Examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms.

Examples of the carboxy-C ₁ -C ₆ alkyl group include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-carboxy-1-methylethyl, 3-carboxypropyl, 4-carboxybutyl and 2-carboxy-1. , 1-dimethylethyl, 5-carboxypentyl,
Examples thereof include linear or branched carboxyalkyl groups having 1 to 6 carbon atoms such as 6-carboxyhexyl group.

As the C _{1 to} C ₆ alkylene group, for example, methylene, ethylene, trimethylene, 1-methylmethylene, tetramethylene, 2-methyltrimethylene, pentamethylene, hexamethylene, 1,1-dimethylethylene group, and the like having 1 to 1 carbon atoms.
The linear or branched alkylene group of 6 can be exemplified.

Among the compounds of the present invention represented by the above general formula (1), preferred compounds can be represented by the following general formula (1A).

[In the formula, R ¹ , R ² , A and B are the same as defined above. Ar 'represents a pyrazine ring group or a thiazole ring group. R ³ 'represents a hydrogen atom. The following compounds may be mentioned as specific examples of the preferred compound of the present invention belonging to the general formula (1A).

2- (1,1-Dimethylethyl) -6- (1,1-dimethyl-2-hydroxyethyl) -4-pyrazinylaminophenol 2- (1,1-dimethylethyl) -6- (1,1 -Dimethyl-2-hydroxyethyl) -4- [N- (2-thiazolyl) amino] phenol 2- (2-acetoxy-1,1-dimethylethyl) -6
-(1,1-Dimethylethyl) -4- [N- (2-thiazolyl) amino] phenol 2- (2-acetoxy-1,1-dimethylethyl) -6
-(1,1-Dimethylethyl) -4- [N-acetyl-N
-(2-thiazolyl) amino] phenol The compound of the present invention represented by the general formula (1) and a salt thereof can be applied to animals, particularly mammals, for example, anti-inflammatory, anti-rheumatic, anti-asthmatic, anti-allergic, antipyretic. , Pain,
Inhibits platelet aggregation, improves arteriosclerosis, exhibits anti-hyperlipidemic and other pharmacological effects, and is therefore an anti-inflammatory agent, anti-rheumatic agent, anti-asthma agent,
It is useful as a drug such as an antiallergic agent, antipyretic agent, analgesic agent, antithrombotic agent, therapeutic agent for arteriosclerosis, and antihyperlipidemic agent.

Further, 4-imino-2 represented by the above general formula (1 ′),
The 5-cyclohexadiene-1-one derivative and its salt are useful as an intermediate for the production of the derivative of the present invention represented by the general formula (1).

The p-aminophenol derivative of the present invention can be produced by various methods. A specific example is shown in the following reaction process formula.

[In the formula, Ar, A and B are the same as above. R ^3a is a hydrogen atom, C ₁
-C ₆ alkyl group, C ₁ -C ₆ alkoxycarbonyl -C ₁ -C ₆
Alkyl group, a C ₁ -C ₆ alkoxy group or a halogen atom. According to the method represented by the above Reaction Scheme-1, the compound of the present invention (1) is obtained by the condensation reaction of the benzoquinone derivative (2) and the aromatic amine derivative (3) and the subsequent reduction reaction.
a) can be manufactured.

In the above, the benzoquinone derivative (2) and the aromatic amine derivative (3) which are the raw material compounds are known compounds, and some of them are commercially available.

The condensation reaction is carried out in the presence of a benzoquinone derivative (2) in the presence of a halide Lewis acid such as titanium tetrachloride, aluminum chloride, ferric chloride, stannic chloride or zinc chloride.
It can be carried out by reacting the aromatic amine derivative (3) also serving as a deoxidizing agent in an inert organic solvent at a temperature of room temperature to about 120 ° C. Examples of the inert organic solvent used here include 1,2-dichloroethane, chloroform,
Examples thereof include benzene and toluene. An inert organic base such as pyridine or triethylamine may be added and used as a deoxidizing agent in the above reaction system. The ratio of the benzoquinone derivative (2) and the aromatic amine derivative (3) to be used is not particularly limited, but the latter is usually used in an amount of about 1 to 10 times, preferably about 2 to 4 times the molar amount of the former. Is desirable. The above reaction using titanium tetrachloride is described in, for example, Journal of Organic Chemistry [J.Org.
em., 32 , 3246 (1967)].
It can be carried out according to the method of arten) et al. The compound (4) obtained as described above can be isolated from the reaction system and subjected to the subsequent reduction reaction, or may be subjected to the subsequent reaction without isolation.

The subsequent reduction reaction of the compound (4) can be carried out by using hydrogen gas in the presence of a catalyst such as palladium-carbon or platinum, and thus the desired compound (1a) of the present invention can be obtained. The reduction reaction can also be carried out by a method using, for example, sodium hydrosulfite, N, N-diethylhydroxylamine, zinc and acetic acid and the like.

[Wherein Ar, A, B and R ^3a are the same as above. R ^1a and R ^2a are the same or different and each represents a C _{1 to} C ₆ acyl group. According to the reaction step formula-2, the compound (5) is obtained by the O-acylation reaction of the compound (4) and the subsequent reduction reaction.
Thus, the compound (1b) of the present invention can be produced. In addition, the N-acylation reaction of compound (1b) or N, O-of compound (1a)
The compound (1c) of the present invention can be produced by the diacylation reaction.

The O-acylation reaction of the compound (4) shown in the above formula-2 is
To the starting compound (4), a suitable chain C ₁ -C ₆ alkanoic acid anhydride such as acetic anhydride or propionic anhydride is added without solvent or in a suitable solvent such as pyridine, lutidine, collidine or acetic acid, It can be carried out by operating at a temperature of room temperature to about 120 ° C. The ratio of the acid anhydride used to the compound (4) is not particularly limited, but it is usually desirable to select it in the range of about 1 to 10 times the molar amount.

The compound (5) obtained as described above may be isolated from the reaction system or may be subjected to the subsequent reduction reaction without isolation. The reduction reaction can be carried out under the same conditions as in the reduction reaction represented by the above formula-1.

In addition, the N-acylation reaction of the compound (1b) and the N, O-diacylation reaction of the compound (1a) represented by the above formula-2 is 2 to 20%.
This can be carried out under the same conditions as the O-acylation reaction of the above compound (4) using a double molar amount of the chain C ₁ -C ₆ alkanoic acid anhydride, thus obtaining the compound (1c) of the present invention.

Wherein Ar, A, B and R ² are the same as above. R ^3b represents a C ₁ -C ₆ alkyl group, and E represents a C ₁ -C ₆ alkylene group. ] The hydrolysis reaction shown in the above-mentioned reaction process formula-3 is, for example, methanol, ethanol, tetrahydrofuran (THF),
In a mixed solvent of a suitable inert organic solvent such as dioxane and water, add about 2 to 20 times molar amount of sodium hydroxide, potassium hydroxide or the like to the compound (1d), and further, if necessary. Add a reducing agent such as sodium hydrosulfite to the compound (1d) in a molar amount of about 1 to 20 times, and add 0 ° C.
~ It can be carried out by treating under a temperature condition of a boiling point temperature of the solvent, preferably 0 ° C to around room temperature. The desired compound (1e) of the present invention can be obtained by the hydrolysis reaction.

The compound of the present invention obtained by the reaction shown in each of the above reaction schemes can be easily isolated and purified by a conventional separation means.
Examples of the separating means include solvent extraction method, recrystallization method, column chromatography and the like.

The compound of the present invention can be easily converted into a pharmaceutically acceptable acid addition salt by addition-reacting a suitable acidic compound according to a conventional method, and the acid addition salt has the same pharmacology as the free form of the compound of the present invention. Have activity. The present invention includes such acid addition salts. Examples of the acidic compound capable of forming the acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and benzenesulfone. Examples thereof include organic acids such as acids. Further, among the compounds of the present invention, there are those which can be converted into a pharmaceutically acceptable salt by reacting a basic compound according to a conventional method. This salt includes alkali metal salts such as lithium salt, sodium salt, potassium salt and the like, alkaline earth metal salts such as calcium salt, magnesium salt and other metal salts such as copper salt, and the like. Salts also have similar pharmacological activity and are included within the scope of this invention.

The compound of the present invention is usually used in the form of a general pharmaceutical preparation (pharmaceutical composition) containing an effective amount thereof. The preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets,
Examples include pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), ointments and the like. When forming into a tablet form, as a carrier, for example, lactose, sucrose, sodium chloride, glucose, urea,
Excipients such as starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, cerac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc. Binder, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, white sugar, stearin ,
Cocoa butter, disintegration inhibitor such as hydrogenated oil, quaternary ammonium base, absorption promoter such as sodium lauryl sulfate, humectant such as glycerin and demp, starch, lactose,
Adsorbents such as kaolin, bentonite and colloidal silicic acid, refined talc, stearates, boric acid powder, lubricants such as polyethylene glycol and the like can be used. Further, the tablet may be a tablet coated with a usual coating, if necessary, for example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet or a multilayer tablet. In the case of molding in the form of pills, as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, binders such as ethanol, laminaran. , Disintegrating agents such as agar and the like can be used. For molding into a suppository, examples of the carrier include polyethylene glycol, cocoa butter,
Higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like can be used. Capsules are usually prepared by mixing the compound of the present invention with the various carriers exemplified above and filling hard gelatin capsules, soft capsules and the like according to a conventional method. When prepared as an injection, a liquid preparation,
Emulsions and suspensions are preferably sterile and isotonic with blood, and when molded into these forms, diluents such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxy are used as diluents. Isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, glucose, glycerin or the like for adjusting the isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent, etc. are added. You may. Furthermore, colorants, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals may be contained in the above various pharmaceutical preparations, if necessary. When forming into a paste, cream or gel, white petrolatum, paraffin, glycerin, a cellulose derivative, polyethylene glycol, silicone, bentonite, etc. can be used as a diluent.

The amount of the compound of the present invention to be contained in the pharmaceutical preparation of the present invention is not particularly limited and is appropriately selected from a wide range, but it is usually 1 to 70% by weight in the pharmaceutical preparation.

The administration method of the above-mentioned pharmaceutical preparation is not particularly limited and is determined according to various preparation forms, age of the patient, sex and other conditions, degree of disease and the like. For example, tablets, pills, solutions, suspensions,
Emulsions, granules and capsules are administered orally. The injection is intravenously administered alone or in admixture with glucose, amino acids, and other usual fluid replacements, and further intramuscularly alone if necessary.
It is administered subcutaneously or intraperitoneally. Suppositories are administered rectally.

The dose of the above-mentioned pharmaceutical preparation is appropriately selected according to the usage, age of the patient, sex and other conditions, degree of disease, etc., but the amount of the compound of the present invention as an active ingredient is usually 1 kg of body weight per day.
The amount is preferably about 0.5 to 500 mg, and the preparation can be administered in 2 to 4 divided doses per day.

Examples Hereinafter, in order to explain the present invention in more detail, Production Examples of the starting compounds for producing the compounds of the present invention will be described as Reference Examples, and then Production Examples of the compounds of the present invention will be described as Examples.

Reference Example 1 2- (1,1-Dimethylethyl) -6- (1,1-dimethyl-
Preparation of 2-hydroxyethyl) -1,4-benzoquinone Step 1 2- (1,1-Dimethylethyl) -4-methoxyphenol 400 g, 40% glyoxal solution 360 g and 36% hydrochloric acid 20
was dissolved in 1600 ml of acetic acid and heated at 120 ° C. for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure, left to stand overnight, and the resulting solid was washed with diethyl ether and treated with 7- (1,1-
105 g of (dimethylethyl) -5-methoxy-2 (3H) -benzofuranone was obtained as a pale red solid.

Water was added to the above liquid and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried over magnesium sulfate, and concentrated. The crude product thus obtained was crystallized from diethyl ether-hexane (1: 1), and further 90 g of 7- (1,1-dimethylethyl) -5-methoxy-2 (3H) -benzofuranone was obtained as a light red color. Obtained as crystals.

Melting point: 117-118 ° C ¹ H-NMR (CDCl ₃ ): δ 1.37 (s, 9H), 3.69 (s, 2H) 3.79 (s, 3H) 6.68 (d, J = 2.6Hz, 1H) 6.79 (d , J = 2.6Hz, 1H) Step 2 60.7 g of 60% sodium hydride is suspended in 400 ml of N, N-dimethylformamide (DMF), and this is suspended at 50 ° C or below for 7-
(1,1-Dimethylethyl) -5-methoxy-2 (3H)-
A solution of 160 g of benzofuranone in 1000 ml of DMF was added dropwise and stirred for 30 minutes. Subsequently, a solution of 230 g of iodomethane in 100 ml of DMF was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) and washed with cold hexane to give 3,3.
104 g of -dimethyl-7- (1,1-dimethylethyl) -5-methoxy-2 (3H) -benzofuranone were obtained as a pale yellow solid.

Melting point: 63.5-64.5 ° C ¹ H-NMR (CDl ₃ ): δ 1.39 (s, 9H), 1.49 (s, 6H) 3.81 (s, 3H) 6.59 (d, J = 2,6Hz, 1H) 6.77 ( d, J = 2.6Hz, 1H) Step 3 18g of lithium aluminum hydride was added to diethyl ether 5
The suspension was stirred at room temperature, and 400 ml of a diethyl ether solution of 104 g of 3,3-dimethyl-7- (1,1-dimethylethyl) -5-methoxy-2 (3H) -benzofuranone was added thereto for 1 hour. Was added, and the mixture was further stirred at room temperature for 1 hour. Ethyl acetate 60m while cooling the reaction mixture in an ice bath
l, 100 ml of water and 900 ml of 10% hydrochloric acid were sequentially added, and the mixture was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The obtained crude product was crystallized from hexane to obtain 100 g of 2- (1,1-dimethylethyl) -6- (1,1-dimethyl-2-hydroxyethyl) -4-methoxyphenol as colorless crystals. .

Melting point: 102.5 to 103.5 ¹ H-NMR (CDCl ₃ ): δ 1.42 (s, 9H), 1.44 (s, 6H) 2.56 (t, J = 4.3Hz, 1H) 3.77 (s, 3H) 3.80 (d, J = 4.3Hz, 2H) 6.71 (d, J = 3.0Hz, 1H) 6.81 (d, J = 3.0Hz, 1H) 8.74 (s, 1H) Step 4 2- (1,1-Dimethylethyl) -6- (1,1-Dimethyl-2-hydroxyethyl) -4-methoxyphenol 55
g in a mixture of 275 ml of acetonitrile and 165 ml of water, and cooled with an ice bath,
297 g of 440 ml of a 50% aqueous solution of acetonitrile were added over 10 minutes. The reaction mixture was stirred for 30 minutes and then poured into water,
It was extracted with ethyl acetate. Wash the organic layer with saturated saline,
After drying over magnesium sulfate, the mixture was concentrated. The obtained crude product was crystallized from hexane to obtain 49 g of the target compound as yellow crystals.

Melting point: 92-94 ° C ¹ H-NMR (CDCl ₃ ): δ 1.26 (s, 6H), 1.28 (s, 9H) 1.81 (t, J = 5.6Hz, 1H) 3.80 (d, J = 5.6Hz, 2H) 6.53 (d, J = 2,6Hz, 1H) 6.58 (d, J = 2,6Hz, 1H) Example 1 2- (1,1-dimethylethyl) -6- (1,1-dimethyl-
Production of 2-hydroxyethyl) -4-pyrazinylaminophenol [Compound 1] Step 1 13.4 g of pyridine was dissolved in 800 ml of dichloroethane, 8.1 g of titanium tetrachloride was added thereto, and the mixture was heated under reflux for 15 minutes. Then, 2- (1,1-dimethylethyl) -6- (1,1-dimethyl-2-hydroxyethyl) -1,4-benzoquinone (10.0 g) and aminopyrazine (12.1 g) were added, and the mixture was heated with stirring at 85 ° C. for 15 minutes. . The reaction mixture was cooled to room temperature, passed through Celite, the insoluble matter was washed with chloroform, the liquid was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform: ethyl acetate = 6: 1 → 3: 1),
2- (1,1-dimethylethyl) -6- (1,1-dimethyl-
2-hydroxyethyl) -4-pyrazinyl imino-2,5
8.3 g of cyclohexadiene-1-one [compound 1a] was obtained as a pale red solid.

Also, 2- (1,1-dimethylethyl) -6- (1,1-dimethyl-2-hydroxyethyl) -1,4-benzoquinone
3.7 g was recovered.

Structure and physical properties of the obtained compound (melting point and ¹ H-NMR
The values are shown in Table 1.

Step 2 Compound 1a (2.5 g) was dissolved in ethyl acetate (450 ml), 10% palladium-carbon (0.30 g) was added as a catalyst to the solution, and the atmosphere in the container was replaced with hydrogen gas, followed by stirring at room temperature. After consuming 180 ml of hydrogen, the catalyst was removed by passing through Celite, washed with ethyl acetate, the liquid was concentrated under reduced pressure, and the obtained crude product was washed with diethyl ether to obtain 2.3 g of the target compound as a colorless solid. It was Table 2 shows the structure and physical properties of the obtained compound.

Examples 2 to 11 Compound 2 to Compound 11 Production of 2- (1,1-dimethylethyl) -6- (1,1-dimethyl-2-hydroxyethyl) -1 in the same manner as in Step 1 of Example 1. , 4-benzoquinone and 3-aminopyrazine 1
-Oxide, 2-aminothiazole, 2-amino-4-
Methylthiazole, ethyl 2-amino-4-thiazoleacetate, aniline, 4-fluoroaniline, 3-aminopyridine, 3-amino-6-methoxypyridazine, 2-aminopyrimidine and 3-amino-1,2,4-triazine From each compound selected from
2a to compound 11a] were each produced. Table 1 shows the structure and physical properties of the obtained compound.

In addition, from each of the compounds obtained above, the compound of the present invention [Compound 2 to Compound 11] is prepared in the same manner as in Step 2 of Example 1.
Was manufactured. Table 2 shows their structures and physical properties.

Example 12 2- (2-acetoxy-1,1-dimethylethyl) -6-
Production of (1,1-dimethylethyl) -4-pyrazinylaminophenol [Compound 12] Step 1 Compound 1a (produced in Step 1 of Example 1) 2.2 g,
A mixture of 1.7 ml of acetic anhydride and 50 ml of pyridine was stirred at room temperature for 8 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (diethyl ether: hexane = 1: 3 → 1: 2) to give 2- (2-acetoxy-1,1).
1-Dimethylethyl) -6- (1,1-dimethylethyl)-
4-pyrazinyl imino-2,5-cyclohexadiene-1
1.6 g of -one [compound 12a] was obtained as a red oil.
Table 1 shows the structure and physical properties of the obtained compound.

Step 2 In the same manner as in Step 2 of Example 1, compound 12a was hydrogenated in the presence of palladium-carbon to obtain the desired compound of the present invention. Table 2 shows the structure and physical properties of the compound.

Example 13 2- (2-acetoxy-1,1-dimethylethyl) -6-
Production of (1,1-dimethylethyl) -4- (2-thiazolylamino) phenol [Compound 13] Step 1 In the same manner as in Step 1 of Example 12, compound 3a (Example 3).
The target compound [compound 13a] was prepared from the compound prepared in step 1 of 1.) and acetic anhydride. Table 1 shows the structure and physical properties of the obtained compound.

Step 2 1.3 g of compound 13a was dissolved in 50 ml of THF, and a solution of 6.5 g of sodium hydrosulfite in 150 ml of water was added to the solution. The mixture was stirred at room temperature for 10 minutes, extracted with ethyl acetate, and the organic layer was washed with saturated saline. The extract was dried over magnesium acetate and concentrated. The obtained crude product was washed with diethyl ether-hexane to give 1.0 g of the desired compound as a colorless solid. Table 2 shows the structure and physical properties of the obtained compound.

Example 14 2- (2-acetoxy-1,1-dimethylethyl) -6-
(1,1-dimethylethyl) -4- [N-acetyl-N-
Preparation of (2-thiazolyl) amino] phenol [Compound 14] A mixture of 0.50 g of Compound 13 (prepared in Example 13) and 6 ml of acetic anhydride was heated at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature and concentrated, and the obtained crude product was subjected to silica gel column chromatography (diethyl ether: hexane = 1: 1).
Purification in 2) gave 0.50 g of the desired compound as a colorless solid. Table 2 shows the structure and physical properties of the target compound.

Example 15 Preparation of 2- [3- (1,1-dimethylethyl) -5- (1,1-dimethyl-2-hydroxyethyl) -4-hydroxyphenylamino] -4-thiazoleacetic acid [Compound 15] Compound 3.2 g of 5 (produced in Example 5) in 40 ml of THF
And 80 ml of ethanol, and a solution of 5 g of sodium hydrosulfite in 50 ml of water and then 30 ml of a 2N aqueous sodium hydroxide solution were added at room temperature, followed by stirring for 1 hour. The reaction mixture was ice-cooled, 1N hydrochloric acid (50 ml) was added, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated at about 0 ° C. The obtained crude product was crystallized from methylene chloride, and further washed with diethyl ether to give 0.80 g of the desired compound as colorless crystals. Table 2 shows the structure and physical properties of the obtained compound.

Hereinafter, examples of pharmacological tests using the compound of the present invention will be shown.

<Pharmacological Test Example 1> The anti-inflammatory effect of the compound of the present invention was measured by the air pouch method according to the method described in the literature [Proc.Soc.Exp.Biol.Med., 82 , 328-333 (1953)] as follows. It was measured.

That is, Wistar male rats (average weight)
200g, 1 group 7 animals), under occlusion of pentobarbital anesthesia, put an oval (2 x 5cm) hollow cardboard on the back of the hair, pick up the skin from the center, and inject 10ml of air subcutaneously. And created an air sac. After that, 1 ml of 2% croton oil as a stimulant was injected into the sac, the cardboard was removed so as to make sufficient contact with the inner wall of the sac, and the rat was gently rotated.

From the day after the preparation of the pouch, a 5% gum arabic suspension of the test compound was intracapsally administered (25 mg / kg / day) once a day for 6 days. This is called "experimental group".

On the 8th day, exsanguination was carried out, the amount of exudate (ml) in the sac was measured, and the control group (the group to which no test compound was administered) used the same measurement result as a standard to suppress inflammation in the experimental group. The rate was calculated by the following formula.

The results are shown in Table 3 below.

As is clear from Table 3 above, the compound of the present invention exhibits a significant anti-inflammatory effect, and it is understood that it is an excellent anti-inflammatory agent.

 Hereinafter, examples of pharmaceutical formulations using the compound of the present invention will be described.

Formulation Example 1 Compound 1 (the compound of the present invention obtained in Example 1) 250 g Crystalline cellulose (Japanese Pharmacopoeia) 30 g Corn starch (Japanese Pharmacopoeia) 17 g Talc (Japanese Pharmacopoeia) 2 g Magnesium stearate (Japanese Pharmacopoeia) Product) 1g Total amount 300g That is, according to the above formulation, each component is finely pulverized and thoroughly mixed to form a uniform mixture, which is then filled into a gelatin capsule for oral administration having a desired size to obtain the target capsule. The agent (1000 pieces) was manufactured.

Formulation Example 2 Compound 3 (the compound of the present invention obtained in Example 3) 100 g Crystalline cellulose (trade name “Avicel pH 101, manufactured by Asahi Kasei Corporation) 40 g Corn starch 30 g Magnesium stearate 2 g Total amount 172 g Hydroxypropyl methylcellulose (trademark) Name "TC-5", manufactured by Shin-Etsu Chemical Co., Ltd. 8.0g Polyethylene glycol 6000 2.4g Pigment 0.6g Titanium dioxide 4.0g Water 85.0g Total amount 100g Compound 3, crystalline cellulose, corn starch and magnesium stearate After mixed polishing, sugar coating R8mm
Tablet with the key. The obtained tablets were coated with a film coating agent consisting of hydroxypropylmethyl cellulose (“TC-5”), polyethylene glycol 6000, a dye, titanium dioxide and water to produce a film coated tablet having the above composition.

Formulation 3 Compound 14 (the compound of the present invention obtained in Example 14) 2g Purified lanolin 5g White beeswax 5g White petrolatum 88g Total amount 100g White beeswax is heated to form a liquid,
14. Purified lanolin and white petrolatum were added, and the mixture was heated until it became liquid and then stirred until it began to solidify to prepare an ointment of the above composition.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location A61K 31/44 ABE A61K 31/44 ABE 31/495 ACD 31/495 ACD 31/50 ABF 31/50 ABF 31/505 AAG 31/505 AAG C07C 251/22 9451-4H C07C 251/22 C07D 213/74 C07D 213/74 237/22 237/22 239/42 239/42 241/20 241/20 253/06 253 / 06 277/42 277/42

Claims (10)

(57) [Claims] 1. A general formula [In the formula, R ¹ and R ² are each independently a hydrogen atom or C _{1 to} C ₆
Indicates an acyl group. Ar represents a pyrazine ring group, a pyrazine N-oxide ring group, a thiazole ring group, a benzene ring group, a pyridine ring group, a pyridazine ring group, a pyrimidine ring group or a triazine ring group. R ³ is a hydrogen atom, a C _{1 to} C ₆ alkyl group, a C _{1 to} C ₆ alkoxycarbonyl-C _{1 to} C ₆ alkyl group, a C _{1 to} C ₆ alkoxy group, a halogen atom or a carboxy-C _{1 to} C ₆ alkyl group. Indicates. A is a C ₁ -C ₆ alkylene group and B is C ₁ -C ₆
Each is an alkyl group. ] The p-aminophenol derivative and its salt represented by these. 2. General formula [In the formula, R ¹ represents a hydrogen atom or a C ₁ -C ₆ acyl group. Ar represents a pyrazine ring group, a pyrazine N-oxide ring group, a thiazole ring group, a benzene ring group, a pyridine ring group, a pyridazine ring group, a pyrimidine ring group or a triazine ring group. R ³ is hydrogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxycarbonyl-
C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, a halogen atom or a carboxy -C ₁ -C ₆ alkyl group. A is C ₁
To C ₆ alkylene group, and B represents a C _{1 to} C ₆ alkyl group, respectively. ] 4-imino-2,5-cyclohexadiene-represented by
1-one derivatives and salts thereof. 3. General formula [In the formula, R ¹ , R ² , A and B are the same as defined above. Ar 'represents a pyrazine ring group or a thiazole ring group. R ³ represents a hydrogen atom. ] The compound of Claim 1 represented by these. 4. 2- (1,1-Dimethylethyl) -6- (1,1
-Dimethyl-2-hydroxyethyl) -4-pyrazinylaminophenol, 2- (1,1-dimethylethyl) -6
-(1,1-Dimethyl-2-hydroxyethyl) -4-
[N- (2-thiazolyl) amino] phenol, 2-
(2-acetoxy-1,1-dimethylethyl) -6- (1,1
-Dimethylethyl) -4- [N- (2-thiazolyl) amino] phenol, 2- (2-acetoxy-1,1-dimethylethyl) -6- (1,1-dimethylethyl) -4-
A compound according to claim 3 selected from the group consisting of [N-acetyl-N- (2-thiazolyl) amino] phenol and salts thereof. 5. A general formula IN FORMULA, A AND B IS THE SAME AS THE ABOVE-MENTIONED. The compound of the general formula H ₂ N-Ar-R ^3a [wherein Ar represented by are as defined above. R ^3a represents a hydrogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxycarbonyl -C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a halogen atom. ] The compound of the general formula [In the formula, A, B, Ar and R ^3a are the same as above. ] The general formula characterized by reducing the compound represented by [In the formula, A, B, Ar and R ^3a are the same as above. ] The manufacturing method of the p-aminophenol derivative represented by these. 6. A general formula [In the formula, A, B, Ar and R ^3a are the same as above. ] O-acylation reaction of the compound represented by [In the formula, A, B, Ar and R ^3a are the same as above. R ^1a represents a C ₁ -C ₆ acyl group. ] The compound represented by the general formula characterized by causing a reduction reaction [In the formula, A, B, Ar, R ^1a and R ^3a are the same as defined above. ] The manufacturing method of the p-aminophenol derivative represented by these. 7. General formula [Formulas A, B, Ar and R ^3a are the same as above. ] The compound represented by the formula, N, O-diacylation reaction characterized by the general formula [In the formula, A, B, Ar, R ^1a and R ^3a are the same as defined above. R ^2a is R ^1a
The same or different C _{1 to} C ₆ acyl groups are shown. ] The manufacturing method of the p-aminophenol derivative represented by these. 8. The general formula [In the formula, A, B, Ar, R ^1a and R ^3a are the same as defined above. ] The general formula characterized by carrying out N-acylation reaction of the compound represented by [In the formula, A, B, Ar, R ^1a , R ^2a and R ^3a are the same as defined above. ] The manufacturing method of the p-aminophenol derivative represented by these. 9. General formula [In the formula, A, B, Ar and R ² are the same as defined above. R ^3b represents a C ₁ -C ₆ alkyl group, and E represents a C ₁ -C ₆ alkylene group. ] The general formula characterized by hydrolyzing the compound represented by [In the formula, A, B, E, Ar and R ² are the same as defined above. ] The manufacturing method of the p-aminophenol derivative represented by these. 10. General formula [In the formula, A, B, Ar, R ¹ , R ² and R ³ are the same as defined above. ] The anti-inflammatory agent containing the effective amount of at least 1 sort (s) chosen from the p-aminophenol derivative represented by these, and its salt.