JPH0567142B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to novel pyridylaminophenol derivatives and salts thereof having pharmacological effects, and methods for producing the same. PRIOR ART The pyridylaminophenol derivative of the present invention is
This is a new compound that has not been published in any literature. Problems to be Solved by the Invention An object of the present invention is to provide a pyridine aminophenol derivative having valuable pharmacological effects as described below. Means for Solving the Problems The present invention is based on the general formula

[In the formula, R ¹ and R ² each represent a lower alkyl group, R ³ represents a hydrogen atom or a lower alkyl group, R ⁴ represents a hydrogen atom or a lower alkyl group, R ⁵ represents a lower alkoxycarbonyl group, lower alkoxycarbonyl, lower alkyl group, amino group, lower alkylamino group, piperidino group, morpholino group, lower alkylcarbonylamino group, lower alkoxy group, phenyl lower alkoxy group, lower alkylthio group, phenylthio group, halogen atom, lower alkyl group, carboxyl group or carboxy lower R 6 represents an alkyl group, and R ⁶ represents a hydrogen atom, a lower alkyl group, or a formyl group. However, when R ³ and R ⁴ are both hydrogen atoms, or when one of them is a hydrogen atom and the other is a lower alkyl group, R ⁵ must not be a lower alkyl group and R ⁶ must not be a hydrogen atom. ]

The present invention relates to a pyridylaminophenol derivative represented by the above formula, a pharmacologically acceptable salt thereof, and a method for producing the same. Examples of the lower alkyl group in the above general formula (1) include linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. Examples of lower alkoxy groups include methoxy,
Ethoxy, propoxy, isopropoxy, sec-
Examples include straight-chain or branched-chain alkoxy groups such as butoxy, tert-butoxy, pentyloxy, and hexyloxy groups. Examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-methyl-1-ethoxycarbonyl, butoxycarbonyl, 2-methyl-1
-propoxycarbonyl, 1,1-dimethyl-1
Examples include ethoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups. Examples of the lower alkoxycarbonyl lower alkyl group include methoxycarbonylmethyl, 2-
(methoxycarbonyl)ethyl, 1-(methoxycarbonyl)ethyl, ethoxycarbonylmethyl,
Examples include 2-(ethoxycarbonyl)ethyl, 1-(ethoxycarbonyl)ethyl, 3-(methoxycarbonyl)propyl, and 1-(methoxycarbonyl)propyl groups. Examples of lower alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, and hexylamino groups. Examples of lower alkylcarbonylamino groups include methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, 1-methyl-1-ethylcarbonylamino, butylcarbonylamino, 2-methyl-1-propylcarbonylamino, 1,1-dimethyl Examples include -1-ethylcarbonylamino, pentylcarbonylamino, and hexylcarbonylamino groups. Examples of phenyl lower alkoxy groups include benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 2-phenyl-2,2-dimethylethoxy, 5-phenylpentyloxy, 6-phenylhexyl. Examples include oxy groups. Examples of lower alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, and hexylthio groups. Examples of the halogen atom include fluorine, chlorine, bromine, and iodine atoms. Examples of carboxy lower alkyl groups include carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 2-carboxy-1-methylethyl, 4-carboxybutyl, 2-carboxy1,1-dimethylethyl, 5-carboxypentyl, Examples include 6-carboxyhexyl group. The pyridylaminophenol derivatives of the present invention represented by the above general formula (1) and their salts have inhibitory and regulatory effects on the biosynthesis of prostaglandins and leukotrienes, and lipid-lowering effects on animals, especially mammals. It exhibits anti-inflammatory, anti-rheumatic, anti-nephritis, anti-asthmatic, anti-allergic, antipyretic, analgesic, platelet aggregation inhibition, arteriosclerosis improvement, and antihyperlipidemic effects. Therefore, the compounds of the present invention can be used as anti-inflammatory agents, anti-rheumatic agents, renal disease therapeutic agents, anti-asthmatic agents, anti-allergy agents, antipyretics, analgesics, antithrombotic agents, myocardial infarction therapeutic agents, antihyperlipidemic agents, etc. It is useful as a medicine. The compound represented by the general formula (1) of the present invention can be produced, for example, by the methods shown in the following reaction schemes -1 to -4. <Reaction scheme-1>

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[In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as above. R ⁵ ' is lower alkoxycarbonyl group, lower alkoxycarbonyl lower alkyl group, amino group, lower alkylamino group, piperidino group, morpholino group, lower alkylcarbonylamino group, lower alkoxy group, phenyl lower alkoxy group, lower alkylthio group, phenylthio group, halogen atom, or lower alkyl group. However, when R ³ and R ⁴ are both hydrogen atoms, or when one of them is a hydrogen atom and the other is a lower alkyl group, R ⁵ ' must not be a lower alkyl group. ]

According to the method shown in Reaction Scheme-1 above, a condensation reaction between a benzoquinone derivative of general formula (2) and an aminopyridine derivative of general formula (3), followed by a reduction operation, results in a reaction of general formula (1a). The compound of the present invention can be obtained. The benzoquinone derivative (2) and aminopyridine derivative (3), which are the raw materials here, are known compounds or can be obtained by known methods. For example, aminopyridine derivatives (3) are available from The Chemistry of Heterocyclic Compounds [E.
Klingsberg, ed., The Chemistry of
Heterocyclic Compounds, Volume 14 (Part 3), 1962
John Wiley & Sons and R.A. Abramovitch
ed., same volume, Volume 14 (Supplement Part 3), 1974
It can be manufactured according to the method described in 2011, published by the same company. The condensation reaction shown in the above reaction scheme-1 is carried out with benzoquinone derivative (2) in the presence of a halide Lewis acid such as aluminum chloride, ferric chloride, titanium tetrachloride, tin chloride, zinc chloride, etc. The aminopyridine derivative (3), which also serves as a deoxidizing agent, is mixed in an inert organic solvent such as 1,2-dichloroethane, chloroform, toluene, benzene, etc. at room temperature to approx.
carried out by reacting at a temperature of 120°C,
Compound (4) is obtained by this reaction. In the above reaction, an inert organic base such as pyridine or triethylamine can also be used as a deoxidizing agent. The ratio of benzoquinone derivative (2) and aminopyridine derivative (3) to be used is not particularly limited, but usually about 1 to 10 times the molar amount of compound (3) to compound (2),
It is preferable to use about 1 to 3 times the molar amount. The above reaction using titanium tetrachloride is described in the Journal of Organic Chemistry [J.Org.Chem., Vol. 32, p. 3246 (1967)].
It can be carried out according to the method of Weingarten et al. described in . In addition, the above condensation reaction can be carried out by using a Lewis acid other than the above-mentioned halide Lewis acids, such as boron trifluoride/ethyl ether, in a solvent such as tetrahydrofuran or dioxane, to form a benzoquinone derivative (2).
and the aminopyridine derivative (3) at room temperature to about 100°C.
It can also be carried out by reacting at a temperature of
Compound (4) can also be produced by this method. This reaction was carried out by the method of Figueras et al. [J.Org.
Chem., vol. 36, p. 3497 (1971)]. Furthermore, the above compound (4) is a benzoquinone derivative (2)
It can also be produced by heating and reacting aminopyridine derivative (3) to about 100 to 200°C.
This method is described in detail by Reiker and Kessler in Tetrahedron (1967). Compound (4) obtained as described above is It can be isolated from the system and subjected to the subsequent reduction reaction, but it may also be subjected to the subsequent reaction without isolation.The reduction reaction can be carried out by a conventional method, for example, using sodium hydrosulfite, zinc and acetic acid. This can be carried out by
is obtained. The above reduction reaction can also be carried out using hydrogen gas in the presence of a catalyst such as palladium on carbon or platinum. <Reaction scheme-2>

[ka]

[In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as above. R ⁵ ″ is a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a piperidino group, a morpholino group, a lower alkylcarbonylamino group, a lower alkoxy group, a phenyl lower alkoxy group, a lower alkylthio group, a phenylthio group, a halogen atom, or a lower alkyl group In addition, R ⁶ ' represents a lower alkyl group.]

The alkylation reaction shown in the above reaction scheme-2 is:
Organic Reaction (MLMoore,
Organic Reaction, p. 5, p. 301 (1957)]. That is, compound (1b) can be obtained by reacting compound (1a') with an aliphatic aldehyde having 1 to 6 carbon atoms and formic acid at a temperature of about 50 to 100°C. <Reaction scheme-3>

[ka]

[In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ ″ are the same as above.]

The formylation reaction shown in the above reaction scheme-3 is
This reaction is carried out by reacting compound (1a') with formic acid at a temperature of about 50 to 100°C, and through this formylation reaction, compound (1b') can be obtained. <Reaction scheme-4>

[ka]

[In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as above. R ⁸ represents a lower alkoxycarbonyl group or a lower alkoxycarbonyl lower alkyl group, and R ⁵ represents a carboxyl group or a carboxy lower alkyl group. ]

The hydrolysis reaction shown in reaction scheme-4 above is carried out by the method of Eliel et al. [Organic Syntheses,
Vol., p. 169 (1963)]. That is, compound (1c) is obtained by reacting a suitable acid such as hydrochloric acid or hydrobromic acid with compound (1a'') without a solvent or in a suitable solvent such as acetic acid at a temperature of room temperature to about 120°C. The ratio of acid to compound (1a″) is not particularly limited, but it usually ranges from a catalytic amount to approx.
It is preferable to use a 10-fold molar amount. The compound (1) of the present invention obtained by the method shown in each of the above reaction schemes can be easily isolated and purified by commonly used separation means such as solvent extraction, recrystallization, column chromatography, etc. can. Furthermore, the compound (1) of the present invention can be converted into a pharmaceutically acceptable salt by subjecting it to an addition reaction with a suitable acidic compound according to a conventional method. Examples of acidic compounds that can form the above salts include hydrochloric acid,
Examples include inorganic acids such as sulfuric acid, phosphoric acid, and hydrobromic acid, and organic acids such as maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and benzenesulfonic acid. Further, among the compounds of the present invention, those having a free carboxyl group can be easily converted into alkali metal salts such as sodium salts and potassium salts, and pharmaceutically acceptable salts such as calcium salts and magnesium salts according to conventional methods. . The acid addition salts and metal salts thus obtained also have the same pharmacological activity as the free form of the compound of the present invention, and the present invention also encompasses such salts. Examples Hereinafter, production examples of raw material compounds for producing the compounds of the present invention will be listed as reference examples, and then production examples of the compounds of the present invention will be listed as examples. Reference example 1 2,6-di-tert-butyl-4-[(5-methoxycarbonyl-3-pyridyl)imino]-2,
Production of 5-cyclohexadien-1-one [Method] 7.4 ml of pyridine was dissolved in 300 ml of dichloroethane, 2.5 ml of titanium tetrachloride was added thereto, and the mixture was heated under reflux for 15 minutes. Then 10 g of 2,6-di-tert-butyl-1,4-benzoquinone and 3-amino-5
-Add 7.0g of methoxycarbonylpyridine,
The mixture was heated to reflux for an hour. The reaction mixture was cooled to room temperature, filtered through Celite, and insoluble materials were washed with dichloro. The crude product obtained by concentrating the liquid was purified by silica gel column chromatography (ether:hexane=1:9) to obtain 10.5 g of the target compound as a pale yellow substance. [Method] Dissolve 0.81 ml of pyridine in 30 ml of dichloroethane, add 0.44 g of aluminum chloride powder,
The mixture was heated to reflux for 15 minutes. Then 2,6-di-tert-
1.10 g of butyl-1,4-benzoquinone and 0.76 g of 3-amino-5-methoxycarbonylpyridine were added, and the mixture was heated under reflux for 15 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and insoluble materials were washed with dichloromethane. The crude product obtained by concentrating the liquid was purified by silica gel column chromatography (ether:hexane = 1:9),
1.25 g of the target compound was obtained. [Method] 2.20 g of 2,6-di-tert-butyl-1,4-benzoquinone and 1.52 g of 3-amino-5-methoxycarbonylpyridine were mixed at 150°C with stirring.
heated for an hour. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (ether:hexane=1:9) to obtain 1.41 g of the target compound.
I got it. Physical properties of the obtained compound (melting point and ¹ H-NMR
values) are shown in Table 1. Reference Examples 2 to 23 Each compound shown in Table 1 was produced in the same manner as the method, method, or method of Reference Example 1.

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[Table] Example 1 Production of 2,6-di-tert-butyl-4-[(5-methoxycarbonyl-3-pyridyl)amino]phenol 2,6-di-tert-butyl-4-[(5- Methoxycarbonyl-3-pyridyl)imino]-2,5
- 6.0 g of cyclohexadien-1-one (produced in Reference Example 1) was added to 100 ml of tetrahydrofuran.
A solution of 60 g of sodium hydrosulfite in 500 ml of water was added at room temperature, stirred at room temperature for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was recrystallized from ethyl acetate-n-hexane (2:1) to obtain the target compound 5.6.
g was obtained as colorless crystals. Physical properties of the obtained compound (melting point and ¹ H-NMR
values) are shown in Table 2. Examples 2 to 23 In the same manner as in Example 1, corresponding compounds of the present invention were produced from the compounds obtained in Reference Examples 2 to 23, respectively. The physical properties of these compounds are shown in Table 2 below. Example 24 2,6-di-tert-butyl-4-[(N-(6-
Preparation of methoxy-3-pyridyl)-N-methyl]amino]phenol 2,6-di-tert-butyl-4-[(6-methoxy-3-pyridyl)amino]phenol (Example
12), a mixture of 1.0 g of 37% formaldehyde aqueous solution and 3.0 g of formic acid at 90-100 g.
Heated at ℃ for 3.5 hours. The reaction mixture was cooled to room temperature, poured into 5% aqueous sodium bicarbonate solution, and extracted with dichloromethane. 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,
Further recrystallization from hexane yielded 0.3g of the target compound.
was obtained as colorless crystals. Physical properties of the obtained compound (melting point and ¹ H-NMR
values) are shown in Table 2. Example 25 Preparation of 2,6-di-tert-butyl-4-[[N-formyl-N-(6-methoxy-3-pyridyl)]amino]phenol 2,6-di-tert-butyl-4- [(6-methoxy-3-pyridyl)amino]phenol (Example
12) was dissolved in 40 ml of formic acid,
This was heated at 90-100°C for 1 hour. The reaction mixture was cooled to room temperature, poured into water, and extracted with dichloromethane. The organic layer was washed with 5% aqueous sodium bicarbonate and then with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography (dichloromethane/ethyl acetate =
3:1) and further recrystallized from ethyl acetate-ether (1:20) to obtain 3.7 g of the target compound as colorless crystals. Physical properties of the obtained compound (melting point and ¹ H-NMR
values) are shown in Table 2. Example 26 Production of 2,6-di-tert-butyl-4-[(5-carboxy-2-pyridyl)amino]phenol hydrochloride 2,6-di-tert-butyl-4-[(5-methoxy A mixture of 1.0 g of carbonyl-2-pyridyl)amino]phenol (prepared in Example 2), 3 ml of 36% hydrochloric acid and 6 ml of acetic acid was heated at 50 DEG C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was recrystallized from ethyl acetate to obtain the target compound.
0.69 g was obtained as pale yellow crystals. Physical properties of the obtained compound (melting point and ¹ H-NMR
values) are shown in Table 2. Example 27 In the same manner as in Example 26, the corresponding compound of the present invention was produced from the compound obtained in Example 3. The physical properties of the obtained compound are shown in Table 2 below.

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[Table] Pharmacological test 5-Lipoxygenase inhibitory effect Cell preparation and measurement of 5-lipoxygenase activity were performed by the method of Bokoch et al. [J.Biol.
Chem., 256, 4156 (1981)] and Ochi et al. [J. Biol. Chem., 258, 5754 (1983)]. That is, guinea pigs were intraperitoneally administered with 2% casein, 14 to 16 hours later, they were bled to death, and the peritoneal cavity was washed to collect wet cells. 1mM _CaCl2 and 5.5mM
2.5 mL of the above cells in phosphate buffer containing glucose
The cells were suspended at a concentration of ×10 ⁷ cells/ml. After incubating this cell suspension at 30°C for 2 minutes,
A 10 μM test compound solution was added and the mixture was further incubated for 2 minutes. Then 10 μM ionophore A23187 was added followed by 10 μM ¹⁴ C-arachidonic acid. After incubation for 3 minutes, the reaction was stopped by adding 0.2M citric acid and the product was extracted with ethyl acetate. The extract was spotted on a thin plate, and after development, arachidonic acid, 5-HETE and other parts were scraped off, and ¹⁴ C was counted using a scintillator.
The 5-lipoxygenase inhibitory activity of the test compound is
It was expressed as the inhibition rate relative to the control 5-HETE production rate. The results are shown in the table below.

[Table] From the above table, it can be seen that the compound of the present invention exhibits excellent 5-lipoxygenase inhibitory activity and is an effective compound as an antiallergic agent for the prevention and treatment of allergic diseases such as bronchial asthma and allergic rhinitis. . Suppressive effect on carrageenan-induced paw edema SD male rats (170-190g, fasted) 1 group 5
C.A. Winter (CA
Winter) et al. [Proc.Soc.Exp.Biol.Med.,
111, 544 (1962)]. That is, 100 mg/Kg of the test compound suspended in a 5% aqueous gum albia solution was orally administered, and 1 hour later, 1
% carrageenan solution was injected subcutaneously into the right footpad.
The paw volume after 3 hours was measured, the increase rate (edema rate) with respect to the volume before carrageenin treatment was determined, and this was compared with the increase rate of the control group to determine the inhibition rate (%). The results are shown in the table below.

[Table] From the above table, it can be seen that the compound of the present invention exhibits excellent edema-suppressing activity and is an effective compound as an anti-inflammatory agent for the prevention and treatment of various inflammatory diseases such as arthritis and rheumatism.

Claims (1)

[Claims] 1 General formula [Formula] [In the formula, R ¹ and R ² each represent a lower alkyl group, R ³ represents a hydrogen atom or a lower alkyl group, R ⁴ represents a hydrogen atom or a lower alkyl group, R ⁵ is a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, an amino group, a lower alkylamino group, a piperidino group, a morpholino group, a lower alkylcarbonylamino group, a lower alkoxy group, a phenyl lower alkoxy group, a lower alkylthio group, a phenylthio group, a halogen atom, a lower alkyl group, a carboxyl group or a carboxy lower alkyl group, and R ⁶
represents a hydrogen atom, a lower alkyl group or a formyl group. However, when R ³ and R ⁴ are both hydrogen atoms, or when one of them is a hydrogen atom and the other is a lower alkyl group, R ⁵ must not be a lower alkyl group and R ⁶ must not be a hydrogen atom. ] A pyridylaminophenol derivative represented by these and a pharmacologically acceptable salt thereof. 2 General Formula [Formula] [In the formula, R ¹ and R ² each represent a lower alkyl group. ] Compounds represented by the general formula [Formula] [In the formula, R ³ is a hydrogen atom or a lower alkyl group, R ⁴
is a hydrogen atom or a lower alkyl group, R ⁵ ' is a lower alkoxycarbonyl group, lower alkoxycarbonyl lower alkyl group, amino group, lower alkylamino group, piperidino group, morpholino group, lower alkylcarbonylamino group, lower alkoxy group, phenyl Indicates a lower alkoxy group, a lower alkylthio group, a phenylthio group, a halogen atom, or a lower alkyl group. However, when R ³ and R ⁴ are both hydrogen atoms, or when one of them is a hydrogen atom and the other is a lower alkyl group, R ⁵ ' must not be a lower alkyl group. [In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ ′ are as defined above] same. ] A compound represented by the formula is obtained, and then the compound is reduced to form a compound represented by the general formula: [In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ ' are the same as above. ] A compound represented by is obtained, and R ⁵ ' of the compound (1a) is a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a piperidino group, a morpholino group, a lower alkylcarbonylamino group, a lower alkoxy group, a phenyl lower alkoxy group. group, lower alkylthio group,
In the case of a phenylthio group, a halogen atom, or a lower alkyl group, the compound has the general formula R ⁷ CHO [R ⁷ represents a hydrogen atom or a lower alkyl group. ] By reacting the compound represented by with formic acid or by reacting with formic acid, a compound of the general formula [Formula R ¹ , R ² , R ³ and R ⁴ are the same as above]. R ⁵ ″ is a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a piperidino group, a morpholino group, a lower alkylcarbonylamino group, a lower alkoxy group, a phenyl lower alkoxy group, a lower alkylthio group, a phenylthio group, a halogen atom, or a lower alkyl group and R ⁶ represents a lower alkyl group or a formyl group.] In addition, when R ⁵ ' of the above compound (1a) is a lower alkoxycarbonyl group or a lower alkoxycarbonyl lower alkyl group, The compound is hydrolyzed to produce a compound represented by the general formula: [In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as above. R ⁵ represents a carboxyl group or a carboxy lower alkyl group] A method for producing a pyridylaminophenol derivative and a pharmacologically acceptable salt thereof, characterized in that it obtains a compound represented by the general formula [Formula] [wherein R ¹ and R ² each represent a lower alkyl group] and the general formula [Formula] [In the formula, R ³ is a hydrogen atom or a lower alkyl group, R ⁴
is a hydrogen atom or a lower alkyl group, and R ⁵ ' is a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, an amino group, a lower alkylamino group, a piperidino group, a morpholino group, a lower alkylcarbonylamino group, a lower alkoxy group,
Indicates a phenyl lower alkoxy group, a lower alkylthio group, a phenylthio group, a halogen atom, or a lower alkyl group. However, when R ³ and R ⁴ are both hydrogen atoms, or when one of them is a hydrogen atom and the other is a lower alkyl group, R ⁵ must not be a lower alkyl group. ] A condensation reaction is carried out at 100 to 200°C with a compound represented by the formula [Formula] [wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ ' are the same as above. ] A compound represented by the formula is obtained, and then the compound is reduced to form a compound represented by the general formula: [In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ ' are the same as above. ] A compound represented by is obtained, and R ⁵ ' of the compound (1a) is a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a piperidino group, a morpholino group, a lower alkylcarbonylamino group, a lower alkoxy group, a phenyl lower alkoxy group. group, lower alkylthio group,
In the case of a phenylthio group, a halogen atom, or a lower alkyl group, the compound has the general formula R ⁷ CHO [R ₇ represents a hydrogen atom or a lower alkyl group. ] By reacting the compound represented by with formic acid or by reacting with formic acid, a compound of the general formula [Formula R ¹ , R ² , R ³ and R ⁴ are the same as above]. R ⁵ ″ is a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a piperidino group, a morpholino group, a lower alkylcarbonylamino group, a lower alkoxy group, a phenyl lower alkoxy group, a lower alkylthio group, a phenylthio group, a halogen atom, or a lower alkyl group , and R ⁶ represents a lower alkyl group or a formyl group.] In addition, when R ⁵ ' of the above compound (1a) is a lower alkoxycarbonyl group or a lower alkoxycarbonyl lower alkyl group, The compound is hydrolyzed to produce a compound represented by the general formula: [In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as above. R ⁵ represents a carboxyl group or a carboxy lower alkyl group] 1. A method for producing a pyridylaminophenol derivative and a pharmacologically acceptable salt thereof.