JPH0667911B2 - p-aminophenol derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a p-aminophenol derivative having a pharmacological action and a salt thereof.

2. Description of the Related Art The compounds according to the present invention are novel compounds that have not been published in the literature.

Problems to be Solved by the Invention An object of the present invention is to provide a compound useful as a medicine as described below.

Means for Solving the Problems According to the present invention, a p-aminophenol derivative represented by the following general formula (1) and a salt thereof are provided.

[In the formula, R ¹ and R ² are the same or different and each represents a lower alkyl group. R ³ represents a hydrogen atom or a lower alkyl group.
R ⁴ represents a hydrogen atom, a lower acyl group or a carboxy lower acyl group. R ⁵ represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkylsulfonyl group, a lower acyl group, a benzoyl group, a carboxy lower alkyl group or a hydroxy lower alkyl group. A is a pyrazine ring group which may have a lower alkyl group or a lower alkoxy group,
The pyridazine ring group which may have a lower alkyl group or a lower alkoxy group or the pyrimidine ring group which may have a lower alkyl group or a lower alkoxy group is shown. However, the case where R ⁴ and R ⁵ are simultaneously hydrogen atoms is excluded. In the present specification, examples of the lower alkyl group include linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl groups.

Examples of the lower acyl group include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, trimethylacetyl, and hexanoyl groups.

Examples of the carboxy lower acyl group include carboxyacetyl, 3-carboxypropionyl, 2-carboxypropionyl, 4-carboxybutyryl, 3-carboxybutyryl, 2-carboxybutyryl, 5-carboxyvaleryl, 4-carboxyvaleryl. , 3-carboxyvaleryl, 2-carboxyvaleryl, 6-carboxyhexanoyl, 5-carboxyhexanoyl, 4-carboxyhexanol, 3-carboxyhexanoyl, 2-carboxyhexanoyl, 2-carboxy-2-methyl Examples include propionyl and 4-carboxy-3-methylbutyryl groups.

Examples of the phenyl lower alkyl group include benzyl, phenethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 3-phenylbutyl and 4-phenylbutyl.
Phenylbutyl, 2-methyl-3-phenylpropyl,
Examples include 5-phenylpentyl and 6-phenylhexyl groups.

Examples of the lower alkoxycarbonyl lower alkyl group include methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 1-methoxycarbonyl-1-methylethyl, 4-methoxycarbonylbutyl, 5-methoxycarbonylpentyl and 6-.
Examples thereof include methoxycarbonylhexyl, ethoxycarbonylmethyl, 1-methylethoxycarbonylmethyl, butoxycarbonylmethyl, 2- (1,1-dimethylethoxycarbonyl) ethyl, pentyloxycarbonylmethyl, and hexyloxycarbonylmethyl groups.

Examples of the lower alkylsulfonyl group include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl and hexylsulfonyl groups.

Examples of the carboxy lower alkyl group include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-methyl-1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl and 1,1-dimethyl-2-carboxyethyl. , 5-carboxypentyl, 6
Examples thereof include a carboxyhexyl group.

Examples of the hydroxy lower alkyl group include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-methyl-1-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and 1,1-dimethyl-2-hydroxyethyl. , 5-hydroxypentyl, 6
Examples thereof include a hydroxyhexyl group.

Examples of the pyrazine ring group which may have a lower alkyl group include 2-pyrazinyl, 3-methyl-2-pyrazinyl, 5-methyl-2-pyrazinyl, 6-methyl-2-pyrazinyl, 5-ethyl-2-pyrazinyl. , 6-propyl-2-pyrazinyl, 5-tert-butyl-2-pyrazinyl, 6-hexyl-2-pyrazinyl group and the like.

Examples of the pyrazine ring group which may have a lower alkoxy group include 2-pyrazinyl, 3-methoxy-2-pyrazinyl, 5-methoxy-2-pyrazinyl, 6-methoxy-2-pyrazinyl, 5-ethoxy-2-pyrazinyl. , 6
-Propoxy-2-pyrazinyl, 5-tert-butoxy-
Examples thereof include 2-pyrazinyl and 6-hexyloxy-2-pyrazinyl groups.

Examples of the pyridazine ring group which may have a lower alkyl group include 3-pyridazinyl, 4-pyridazinyl, 4
-Methyl-3-pyridazinyl, 5-methyl-3-pyridazinyl, 6-methyl-3-pyridazinyl, 5-methyl-
4-pyridazinyl, 3-methyl-5-pyridazinyl, 4
Examples include -methyl-5-pyridazinyl, 6-ethyl-3-pyridazinyl, 5-propyl-3-pyridazinyl and 6-hexyl-3-pyridazinyl groups.

Examples of the pyridazine ring group which may have a lower alkoxy group include 3-pyridazinyl, 4-pyridazinyl,
4-methoxy-3-pyridazinyl, 5-methoxy-3-
Pyridazinyl, 6-methoxy-3-pyridazinyl, 5-
Examples include methoxy-4-pyridazinyl, 3-methoxy-5-pyridazinyl, 4-methoxy-5-pyridazinyl, 6-ethoxy-3-pyridazinyl, 5-propoxy-3-pyridazinyl, 6-hexyloxy-3-pyridazinyl group. it can.

Examples of the pyrimidine ring group which may have a lower alkyl group include 2-pyrimidinyl, 4-pyrimidinyl, 5
-Pyrimidinyl, 4-methyl-2-pyrimidinyl, 5-
Methyl-2-pyrimidinyl, 2-methyl-4-pyrimidinyl, 5-methyl-4-pyrimidinyl, 6-methyl-4
-Pyrimidinyl, 2-methyl-5-pyrimidinyl, 4-
Examples include methyl-5-pyrimidinyl, 4-ethyl-2-pyrimidinyl, 4-propyl-2-pyrimidinyl and 4-hexyl-2-pyrimidinyl groups.

Examples of the pyrimidine ring group which may have a lower alkoxy group include 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 4-methoxy-2-pyrimidinyl,
5-methoxy-2-pyrimidinyl, 2-methoxy-4-
Pyrimidinyl, 5-methoxy-4-pyrimidinyl, 6-
Examples include methoxy-4-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 4-methoxy-5-pyrimidinyl, 4-ethoxy-2-pyrimidinyl, 4-propoxy-2-pyrimidinyl, 4-hexyloxy-2-pyrimidinyl group and the like. it can.

Examples of the lower alkylene group include linear or branched alkylene groups such as methylene, ethylene, trimethylene, 1-methylmethylene, tetramethylene, 2-methyltrimethylene, pentamethylene and hexamethylene groups.

The compounds of the present invention represented by the above general formula (1) and salts thereof can be applied to animals, especially mammals, for example, anti-inflammatory, anti-rheumatic, anti-asthmatic, anti-allergic, antipyretic, analgesic,
Inhibits platelet aggregation, improves arteriosclerosis, exhibits antihyperlipidemic and other pharmacological effects, and accordingly anti-inflammatory agents, anti-rheumatic agents, anti-asthmatic agents,
It is useful as a drug such as an antiallergic agent, antipyretic agent, analgesic agent, antithrombotic agent, therapeutic agent for arteriosclerosis, and antihyperlipidemic agent.

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.

<Reaction process formula-1> [In the Formula, R < ¹ >, R < ² >, R < ³ > and A are the same as the above.

R ^4a represents a lower acyl group or a carboxy lower acyl group, and R ^5a represents a hydrogen atom or a lower acyl group. In the N-acylation reaction shown in the above reaction process formula-1, the compound (2) as a raw material is added to the compound (2) without solvent or in a suitable solvent such as pyridine, lutidine, collidine, acetic acid, etc., acetic anhydride, propionic anhydride Suitable chain lower alkanoic acid anhydride such as acid or suitable cyclic lower alkanoic acid anhydride such as succinic anhydride, glutaric anhydride, 3-methylglutanic anhydride,
It can be carried out by operating at a temperature of about 50 to 200 ° C. The ratio of the acid anhydride used to the compound (2) is not particularly limited, but it is usually desirable to select it in the range of about 1 to 30 times the molar amount.

Further, in the raw material compound (2), when the R ¹ group and the R ² group are sterically small and the reactivity of the phenolic hydroxyl group is high,
In the N-acylation reaction using the above chain lower alkanoic acid anhydride, the N, O-acylation reaction of the starting compound can be carried out by employing the same conditions by using the anhydride in an amount of 2 to 30 times. It can be carried out.

<Reaction process formula-2> [In formula, R < ¹ >, R < ² >, R < ³ > and A are the same as the above.

R ^4b represents a lower acyl group, and R ^5b represents a lower alkyl group, a phenyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkylsulfonyl group, a lower acyl group or a benzoyl group. According to Reaction Scheme-2, compound (1c) can be produced by the O-alkylation reaction, O-sulfonylation reaction, O-acylation reaction or O-benzoylation reaction of compound (1b).

Details of each reaction are shown below.

The O-alkylation reaction can be carried out using an appropriate alkylating agent in the presence of a base in an inert solvent. Here, as the inert solvent, for example, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, tetrahydrofuran (THF) and the like can be advantageously used. Examples of the base include sodium hydride, sodium amide, sodium methoxide, potassium tert-butoxide and the like. Examples of the alkylating agent include halogenated lower alkanes such as iodomethane, bromoethane, 1-bromopropane, 1-bromobutane, 1-bromopentane, and 1-bromohexane, α-bromotoluene, and (2-
Halogenated lower alkylbenzene such as bromoethyl) benzene, (5-bromopentyl) benzene, (1-bromohexyl) benzene or ethyl bromoacetate, ethyl 3-bromopropionate, ethyl 5-bromovalerate, 2-
Examples thereof include halogenated lower alkanoic acid esters such as ethyl bromohexanoate. The amount of the alkylating agent used can be appropriately determined, but it is usually appropriate to select from the range of about 1 to 5 times the molar amount of the compound (1b). The reaction generally proceeds well under a temperature range of about -20 to 100 ° C for 1 to 20 hours.

The O-sulfonylation reaction, O-acylation reaction and O-benzoylation reaction are the same as the above-mentioned O-alkylation reaction, in the same inert solvent and in the presence of the same base, respectively, a sulfonylating agent, It can be carried out using an acylating agent and a benzoylating agent. Here, examples of the sulfonylating agent include methanesulfonyl chloride, ethanesulfonyl chloride, and 1 chloride.
Examples thereof include halogenated lower alkanesulfonyl such as butanesulfonyl and 1-hexanesulfonyl chloride. Examples of the acylating agent include acetyl chloride, acetyl bromide,
Examples thereof include lower acyl halides such as propionyl chloride, n-butyryl chloride, isobutyryl chloride, n-valeryl chloride, isovaleryl chloride, trimethylacetyl chloride and hexanoyl chloride. Moreover, benzoyl chloride can be illustrated as a typical benzoylating agent.

<Reaction process formula-3> [In the formula, R ¹ , R ² , R ³ , R ^4b , R ^5b and A are the same as defined above. The de-N-acylation reaction of the compound (1c) represented by the reaction formula-3 can be carried out as follows depending on the kind of R ^5b group. That is, when the R ^5b group is a lower alkyl group, a phenyl lower alkyl group, a lower alkylsulfonyl group, a lower acyl group or a benzoyl group, the above compound (1c)
The de-N-acylation reaction of is usually about 5 to 5 in an alcohol solvent such as methanol, ethanol, tert-butanol and the like.
Using a 100-fold molar amount of hydrazine hydrate, about 0.5-
The reaction can be carried out by heating from room temperature to the boiling point of the solvent for about 20 hours, and by this reaction, the compound (1d)
Can be obtained. Further, when the R ^5b group is a lower alkyl group, a phenyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group or a lower alkylsulfonyl group, the de-N-acylation reaction of the compound (1c) is usually methanol, ethanol, Isopropanol, tert-amyl alcohol, etc. in a lower alcohol solvent that does not adversely affect the reaction, using a suitable acid such as hydrochloric acid or hydrobromic acid, can be carried out by heating from room temperature to the boiling temperature of the solvent, Thus, the desired compound (1d) can be obtained.

<Reaction process formula-4> IN FORMULA, R < ¹ >, R < ² >, R < ³ >, R < ⁴ > AND A ARE THE SAME AS THE ABOVE-MENTIONED. R
^5c represents a lower alkyl group, and E represents a lower alkylene group. The hydrolysis reaction shown in the above reaction process formula-4 is about 1 to 30 times the amount of compound (1e) in a mixed solvent of water with a suitable inert organic solvent such as methanol, ethanol, THF and dioxane. It can be carried out by allowing a molar amount of sodium hydroxide, potassium hydroxide and the like to act under a temperature condition of 0 ° C to the boiling point of the solvent, preferably 0 ° C to around room temperature.

<Reaction process formula-5> [Wherein R ¹ , R ² , R ³ , A and E are the same as defined above. R ^5d
Represents a hydrogen atom or a lower alkyl group. The compound (1h) can be produced from the compound (1g) by the reduction reaction shown in the above reaction process formula-5.

The reduction reaction of the compound (1 g) is carried out under a temperature condition of about 0 to 50 ° C., preferably about 0 ° C. to about room temperature in an inert organic solvent such as diethyl ether or THF. It can be carried out using a suitable reducing agent such as lithium aluminum hydride, aluminum hydride, diborane or the like in an amount of about 1 to 10 times the molar amount of 1 g), and thus the target compound (1h) can be obtained.

The compound of the present invention obtained by the reactions shown in 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.

Further, the compound of the present invention can be easily converted into a pharmaceutically acceptable acid addition salt by subjecting the compound of the present invention to an appropriate acidic compound by an addition reaction according to a conventional method, and the acid addition salt is a free form of the compound of the present invention. It has the same pharmacological activity as, and the present invention also includes such an acid addition salt. Examples of the acidic compound capable of forming the acid addition salt include hydrochloric acid, sulfuric acid, phosphoric acid,
Examples thereof include inorganic acids such as hydrobromic acid and organic acids such as maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and benzenesulfonic acid. Furthermore, some of the compounds of the present invention can be converted into pharmaceutically acceptable salts 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.

EXAMPLES Hereinafter, in order to explain the present invention in more detail, production examples of starting compounds for producing the compounds of the present invention will be given as reference examples, and then production examples of the compounds of the present invention will be given as Examples.

Reference Example 1 2,6-di-tert-butyl-4-pyrazinylaminophenol (Compound 1b) Step 1 2,6-di-tert-butyl-1,4-benzoquinone 47
g and 20 g of aminopyrazine were added to 300 ml of THF and heated to dissolve. 35ml of pyridine in advance
To a 200 ml solution of dichloroethane in 12 ml, a yellow suspension prepared by adding 12 ml of titanium tetrachloride dropwise under stirring with ice cooling was added, and
Heated to reflux for hours. Further, to the reaction mixture, 70m of pyridine
1, a mixed suspension of 24 ml of titanium tetrachloride and 200 ml of dichloroethane was added, and the mixture was heated under reflux for 2 hours and then 17 m of pyridine.
1, a mixed suspension of 6 ml of titanium tetrachloride and 100 ml of dichloroethane was added, and heating under reflux for 30 minutes was repeated. Then the reaction mixture was cooled to room temperature and passed through Celite. The crude product obtained by washing the insoluble matter with ethyl acetate and concentrating the solution was subjected to silica gel column chromatography (diethyl ether: hexane = 1: 10 → 1: 1).
And washed with cold hexane.

Thus, 58 g of 2,6-di-tert-butyl-4-pyrazinylimino-2,5-cyclohexadien-1-one (Compound 1a) was obtained as a yellow solid.

Melting point: 115.5-116.5 ° C. ¹ H-NMR (CDCl ₃ ): δ 1.21 (s, 9H), 1.33 (s, 9H) 6.87 (d, J = 2.5 Hz, 1H) ) 7.04 (d, J = 2.5 Hz, 1H) 8.33 to 8.51 (m, 3H) Step 2 2,6-di-tert-butyl-4-pyrazinylimino-
60 g of 2,5-cyclohexadiene-1-one in THF
It was dissolved in 450 ml, and a suspension of 10% palladium-carbon (1.5 g) in DMF (10 ml) was added as a solvent to the container. After consuming 4.5 liters of hydrogen, the catalyst was removed by passing through Celite to remove THF150.
After washing with ml, the solution was concentrated under reduced pressure. The obtained crude product was recrystallized from 550 ml of ethyl acetate using 5.5 g of activated carbon powder to obtain 41 g of the objective compound as colorless crystals.

Melting point: 175.5 to 176 ° C. ¹ H-NMR (CDCl ₃ ): δ 1.45 (s, 18H), 5.15 (s, 1H) 6.53 (broads, 1H) 7.14 (s, 2H ) 7.88 (d, J = 3HZ, 1H) 8.03 (dd, J = 3Hz, 1Hz, 1H) 8.09 (d, J = 1Hz, 1H) In the same manner as in Step 1 of Reference Example 1 above. , 2,6-di-tert
-Butyl-1,4-benzoquinone or 2,3,6-trimethyl-1,4-benzoquinone, and aminopyrazine, 3-aminopyridazine, 3-amino-6-methylpyridazine, 3-amino-6-methoxy The following compounds (2a to 7a) were obtained from one kind selected from pyridazine and 2-aminopyrimidine.

Next, each compound was subjected to the same reduction reaction as in Step 2 of Reference Example 1 to obtain each compound (2b to 7b) shown in Reference Examples 2 to 7 below.

Reference Example 2 2,6-di-tert-butyl-4- (3-pyridazinylimino) -2,5-cyclohexadiene-1-one (Compound 2a) Melting point: 169.5-170.5 ° C ¹ 1 H-NMR (CDCl ₃ ): δ 1.20 (s, 9H), 1.34 (s, 9H) 6.82 (d, J = 2.6 Hz, 1H) 7.04 (d, J = 2. 6 Hz, 1 H) 7.27 (dd, J = 8.6 Hz, 1.5 Hz, 1 H) 7.56 (dd, J = 8.6 Hz, 4.6 Hz, 1 H) 9.02 (dd, J = 4. 6 Hz, 1.5 Hz, 1 H) 2,6-di-tert-butyl-4- (3-pyridazinylamino) phenol (Compound 2b) Melting point: 194.5-195.5 ° C. ¹ H-NMR (CDCl _{3): δ 1.44 (s,} 18H) 6.91 (dd, J = 9.1Hz, 1.3Hz, 1H) 7.10 (s, 2H) 7.16 ( d, J = 9.1 Hz, 4.4 Hz, 1H) 8.57 (dd, J = 4.4 Hz, 1.3 Hz, 1H) Reference Example 3 2,6-di-tert-butyl-4- (6- Methyl-3-pyridazinylimino) -2,5-cyclohexadiene-1
-One (compound 3a) Melting point: 157.5 to 159.5 ° C ¹ H-NMR (CDCl ₃ ): δ 1.21 (s, 9H), 1.33 (s, 9H) 2.74 (s, 3H). ) 6.92 (d, J = 2.6 Hz, 1H) 7.03 (d, J = 2.6 Hz, 1H) 7.18 (d, J = 8.8 Hz, 1H) 7.41 (d, J = 8.8 Hz, 1H) 2,6-di-tert-butyl-4- (6-methyl-3-pyridazinylamino) phenol (Compound 3b) Melting point: 233-235 ° C ¹ H-NMR (CDCl ₃ ): Δ 1.44 (s, 18H), 2.55 (s, 3H) 6.86 (d, J = 9.0Hz, 1H) 7.06 (d, J = 9.0Hz, 1H) 7. 08 (s, 2H) Reference Example 4 2,6-di-tert-butyl-4- (6-methoxy-3-)
Pyridazinylimino) -2,5-cyclohexadiene-
1-one (compound 4a) Melting point: 137.5-138 ° C ¹ H-NMR (CDCl ₃ ): δ 1.23 (s, 9H), 1.33 (s, 9H) 4.16 (s, 3H). 7.01 (d, J = 2.6 Hz, 1 H) 7.06 (d, J = 2.6 Hz, 1 H) 7.06 (d, J = 9.2 Hz, 1 H) 7.26 (d, J = 9.2 Hz, 1H) 2,6-di-tert-butyl-4- (6-methoxy-3-
Pyridazinylamino) phenol 11/2 fumarate (Compound 4b) Melting point: 188.5-189 ° C (decomposition) ¹ H-NMR [(CD ₃ ) ₂ SO]: δ 1.40 (s, 18H) ) 3.91 (s, 3H) 6.63 (s, 3H, fumaric acid) 6.94 (d, J = 10Hz, 1H) 7.09 (d, J = 10Hz, 1H) 7.46 (s , 2H) 8.61 (broad s, 1H) Reference Example 5 2,6-di-tert-butyl-4- (2-pyrimidinylimino) -2.5-cyclohexadien-1-one (Compound 5a) Melting point: 148 to 150 ° C. ¹ H-NMR (CDCl ₃ ): δ 1.19 (s, 9H), 1.32 (s, 9H) 6.63 (d, J = 2.7 Hz, 1H) 7.08 (d , J = 2.7 Hz, 1H) 7.12 (t, J = 5.1 Hz, 1H) 8.75 (d, J = 5.1 Hz, 1H) , 6-di -tert- butyl-4- (2-pyrimidinyl amino) phenol (Compound 5b) ^{mp: 144.5~145 ℃ 1 H-NMR (} CDCl 3): δ 1.45 (s, 18H), 5 .01 (s, 1H) 6.58 (t, J = 5Hz, 1H) 7.32 (s, 2H) 8.30 (d, J = 5Hz, 1H) Reference Example 6 2,3,6-trimethyl- 4-pyrazinyl imino-2,
5-Cyclohexadiene-1-one (Compound 6a) Melting point: 82.5-83.5 ° C ¹ H-NMR (CDCl ₃ ): δ 1.96 (d, J = 1.5 Hz, 3H) 2.10 ( d-like, J = 0.9 Hz, 3 H) 2.28 (d-like, J = 0.9 Hz, 3 H) 6.70 (q, J = 1.5 Hz, 1 H) 8.33 (d, J = 1. 3Hz, 1H) 8.38 (d, J = 2.6Hz, 1H) 8.45 (dd, J = 2.6Hz, 1.3Hz, 1H) 2,3,6-trimethyl-4-pyrazinylamino Phenol (compound 6b) Melting point: 221-223 ° C. ¹ H-NMR [(CD ₃ ) ₂ SO]: δ 2.01 (s, 3H), 2.13 (s, 6H) 6.83 (s, 1H). 7.72 (d, J = 2.6 Hz, 1H) 7.84 to 7.95 (m, 2H) 8.02 (s, 1H), 8.42 (s, 1H) Reference example 2,3,6-trimethyl-4- (2-pyrimidinyl imino) -2,5-cyclohexadiene-1-one (Compound 7a) ^{mp: 114~115 ℃ 1 H-NMR (} CDCl 3): δ 1.93 (D, J = 1.3 Hz, 3H) 2.08 (d-like, J = 1.0 Hz, 3H) 2.29 (d-like, J = 1.0 Hz, 3H) 6.52 (q, J = 1 .3 Hz, 1 H) 7.10 (t, J = 5.0 Hz, 1 H) 8.72 (d, J = 5.0 Hz, 2 H) 2,3,6-trimethyl-4- (2-pyrimidinylamino) phenol (Compound 7b) Melting point: 254-255 ° C. ¹ H-NMR [(CD ₃ ) ₂ SO]: δ 1.97 (s, 3H), 2.10 (s, 3H) 2.11 (s, 3H) 6 .60 (t, J = 4.8 Hz, 1H) 6.77 (s, 1H), 7.95 (s, 1H) 8.24 (d, = 4.8Hz, 2H) 8.54 (s, 1H) Example 1 2,6-di -tert- butyl-4-(N-acetyl -N-
Preparation of pyrazinylamino) phenol (Compound 1) 2,6-di-tert-butyl-4-pyrazinylaminophenol (produced in Reference Example 1) 10.0 g of a mixture of acetic anhydride and 80 ml of 1 Heated for 5 hours. The reaction mixture was cooled to room temperature and concentrated to remove the resulting solid, which was washed with diethyl ether. The obtained crude product was recrystallized from ethyl acetate-hexane to obtain 11.0 g of the objective compound as a colorless solid.

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

Examples 2 to 5 Production of Compound 2 to Compound 5 In the same manner as in Example 1, each of the compounds produced in Reference Examples 2 to 5 (free base of 2b, 3b, 5b or 4b) and acetic anhydride were used to give Invention compounds were prepared.

Table 1 shows the structure and physical properties of the obtained compounds.

Example 6 Preparation of 4- [N- (3,5-di-tert-butyl-4-hydroxyphenyl) -N-pyrazinylamino] -4-oxobutanoic acid (Compound 6) 2,6-Di-tert-butyl- A mixture of 5.0 g of 4-pyrazinylaminophenol (produced in Reference Example 1) and 5.7 g of succinic anhydride was heated at 85 to 91 ° C for 21 hours. The crude product obtained by cooling the reaction mixture to room temperature was subjected to silica gel column chromatography (chloroform →
Purification with chloroform: methanol = 20: 1) gave 3.0 g of the desired compound as a colorless solid.

Table 1 shows the structure and physical properties of the obtained compound.

Example 7 Production of Compound 7 Compound 1b produced in Reference Example 1 in the same manner as in Example 6
The compound of the present invention was produced from and glutaric anhydride.

Its structure and physical properties are shown in Table 1.

Example 8 Acetic acid 2,3,6-trimethyl-4- (N-acetyl-N)
Preparation of -pyrazinylamino) fanyl) compound 8) 1.0 g of 2,3,6-trimethyl-4-pyrazinylaminophenol (obtained in Reference Example 6) and 12 ml of acetic anhydride.
And were heated at 100 ° C. for 38.5 hours. The reaction mixture was cooled to room temperature, concentrated and the resulting solid was collected and washed with diisopropyl ether to obtain 1.1 g of the target compound as a colorless solid.

Table 1 shows the structure and physical properties of the obtained compound.

Example 9 A compound of the present invention was produced in the same manner as in Example 8 from the compound 7b obtained in Reference Example 7 and acetic anhydride.

Table 1 shows the structure and physical properties of the compound.

Example 10 2,6-Di-tert-butyl-4- (N-acetyl-N-
Preparation of Pyrazinylamino) anisole (Compound 10) 0.30 g of 60% sodium hydride was suspended in 10 ml of DMF, and 2,6-di-tert-butyl-4- was added thereto at room temperature.
A solution of (4-acetyl-N-pyrazinylamino) phenol (produced in Example 1) (2.0 g) in DMF (20 ml) was added dropwise, and the mixture was stirred for 10 minutes. Then, a solution of 1.0 g of iodomethane in 5 ml of DMF was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into water and 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 (diethyl ether: dichloromethane = 1: 2) and further recrystallized from diethyl ether-hexane to obtain 1.2 g of the objective compound as colorless crystals.

Table 1 shows the structure and physical properties of the obtained compound.

Examples 11 to 18 Production of compounds 11 to 18 In the same manner as in Example 10, each compound (1 to 5) produced in Examples 1 to 5 and iodomethane, 1-bromopropane,
The compound of the present invention was produced from any of 1-bromobutane, α-bromotoluene and ethyl bromoacetate.

Table 1 shows their structures and physical properties.

Example 19 Methanesulfonic acid 2,6-di-tert-butyl-4- (N
-Acetyl-N-pyrazinylamino) phenyl (Compound 19) 0.30 g of 60% sodium hydride was suspended in 20 ml of DMF and 2,6-di-tert-butyl-4- was added thereto at room temperature.
2.0 g of (N-acetyl-N-pyrazinylamino) phenol (produced in Example 1) was added little by little. Subsequently, 0.74 g of methanesulfonyl chloride was added dropwise,
Stir for 20 minutes at room temperature. The reaction mixture was poured into water and extracted with diethyl ether. 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 (diethyl ether: hexane = 1: 1 → 2: 3) to obtain 1.95 g of the target compound as a colorless solid.

Table 1 shows the structure and physical properties of the obtained compound.

Example 20 Acetate 2,6-di-tert-butyl-4- (N-acetyl-
Preparation of N-pyrazinylamino) phenyl (Compound 20) 0.30 g of 60% sodium hydride was suspended in 20 ml of DMF, and 2,6-di-tert-butyl-4- was added thereto at room temperature.
2.0 g of (N-acetyl-N-pyrazinylamino) phenol (produced in Example 1) was added little by little. Then, 0.51 g of acetyl chloride was added dropwise, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with diethyl ether. 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 (diethyl ether: hexane = 1: 1) and further recrystallized from diethyl ether-hexane to give 1.0 g of the target compound.
Was obtained as colorless crystals.

Table 1 shows the structure and physical properties of the obtained compound.

Examples 21 and 22 Production of Compound 21 and Compound 22 In the same manner as in Example 20, the compounds of the present invention were produced from the respective compounds (4 and 5) obtained in Examples 4 and 5 and acetyl chloride.

Table 1 shows the structure and physical properties of the obtained compound.

Example 23 Preparation of 2,6-di-tert-butyl-4- (N-acetyl-N-pyrazinylamino) phenyl benzoate (Compound 23) 0.55 g of 60% sodium hydride was suspended in 30 ml of DMF. 2,6-di-tert-butyl-4-at room temperature
3.0 g of (N-acetyl-N-pyrazinylamino) phenol (produced in Example 1) was added in small portions. Subsequently, 1.5 g of benzoyl chloride was added at room temperature to 70
Heated at ℃ for 18 hours. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was 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 (diethyl ether: hexane = 1: 1) and recrystallized from diethyl ether-hexane to obtain 1.5 g of the target compound as colorless crystals.

Table 1 shows the structure and physical properties of the obtained compound.

Example 24 Preparation of 2,6-di-tert-butyl-4-pyrazinylaminoanisole (Compound 24) 2,6-di-tert-butyl-4- (N-acetyl-N-)
1.15 g of pyrazinylamino) anisole (produced in Example 10), 15 ml of 36% hydrochloric acid and ethanol 3
0 ml of the mixture was heated to reflux for 20 minutes. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium hydrogen carbonate, and 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 (diethyl ether: hexane = 1: 1), the obtained oily substance was dissolved in diethyl ether, and 2.4 ml of 4N hydrogen chloride solution in ethyl acetate was added thereto. The precipitated solid was collected to obtain 1.0 g of the target compound as a red solid.

Table 1 shows the structure and physical properties of the obtained compound.

Examples 25 to 33 Production of Compounds 25 to 33 In the same manner as in Example 24, the compounds of the present invention were obtained from the respective compounds (11 to 19) produced in Examples 11 to 19 and 36% hydrochloric acid.

Table 1 shows their structures and physical properties.

Example 34 Preparation of 2,6-di-tert-butyl-4-pyrazinylaminophenyl acetate (Compound 34) 2,6-Di-tert-butyl-4- (N-acetyl-acetate)
A mixture of 26 g of N-pyrazinylamino) phenyl (prepared in Example 20), 150 ml of 90% hydrazine hydrate and 150 ml of ethanol was heated at 75 ° C. for 2 hours.
The reaction mixture was cooled to room temperature, poured into water and 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 (diethyl ether: hexane = 1: 1) and recrystallized from diethyl ether-hexane to obtain 21 g of the target compound as colorless crystals.

Table 1 shows the structure and physical properties of the obtained compound.

Examples 35 to 37 Production of Compounds 35 to 37 In the same manner as in Example 34, the objective compound of the present invention was obtained from the compounds (21 to 23) produced in Examples 21 to 23 and 90% hydrazine hydrate. .

Table 1 shows the structure and physical properties of the obtained compound.

Example 38 Preparation of 2,6-di-tert-butyl-4-pyrazinylaminophenoxyacetic acid (Compound 38) Ethyl 2,6-di-tert-butyl-4-pyrazinylaminofinoxyacetic acid (Example 32) 1.8
g was dissolved in 18 ml of methanol, a solution of 0.56 g of sodium hydroxide in 10 ml of water was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was washed with diethyl ether to obtain 1.1 g of the objective compound as a colorless solid.

Table 1 shows the structure and physical properties of the obtained compound.

Example 39 Preparation of 2- (2,6-di-tert-butyl-4-pyrazinylaminophenoxy) ethanol (Compound 39) 3.95 g lithium aluminum hydride are suspended in 100 ml diethyl ether, 0-5 To this was added ethyl 2,6-di-tert-butyl-4-pyrazinylaminophenoxyacetate (prepared in Example 32) while stirring at <RTIgt;
5.33 g of diethyl ether solution (100 ml) was added, and the mixture was further stirred at room temperature for 1 hour. Water was added while cooling with an ice bath, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was produced by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain 3.20 g of the objective compound as a colorless solid.

Table 1 shows the structure and physical properties of the obtained compound.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location // A61K 31/495 ABE 7431-4C 31/50 ABG 7431-4C 31/505 AAG 7431-4C AAH 7431-4C ABF 7431-4C ABX 7431-4C ACB 7431-4C ACD 7431-4C ADN 7431-4C

Claims (1)

[Claims] 1. A general formula [In the formula, R ¹ and R ² are the same or different and each represents a lower alkyl group. R ³ represents a hydrogen atom or a lower alkyl group.
R ⁴ represents a hydrogen atom, a lower acyl group or a carboxy lower acyl group. R ⁵ represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkylsulfonyl group, a lower acyl group, a benzoyl group, a carboxy lower alkyl group or a hydroxy lower alkyl group. A is a pyrazine ring group which may have a lower alkyl group or a lower alkoxy group,
The pyridazine ring group which may have a lower alkyl group or a lower alkoxy group or the pyrimidine ring group which may have a lower alkyl group or a lower alkoxy group is shown. However, the case where R ⁴ and R ⁵ are simultaneously hydrogen atoms is excluded. ] The p-aminophenol derivative and its salt represented by these.