JPH0567141B2 - - 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. Prior Art The compound according to the present invention is a novel compound that has not been described in any literature. Problems to be Solved by the Invention The purpose of the present invention is to provide a novel compound having valuable pharmacological effects as described below. Means for Solving the Problems According to the present invention, a compound represented by the following general formula (1) and a salt thereof are provided.

[In the formula, R ¹ represents a lower alkyl group. ^R2 and ^R3 each represent a hydrogen atom or a lower alkyl group, or both represent a -( _CH2 ) _4- group or a -CH=CH-CH=CH- group. However, the case where R ¹ and R ² are both tert-butyl groups and R ³ is a hydrogen atom is excluded. ]

In this specification, the lower alkyl group is
Examples include straight-chain or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups. The compound of the present invention represented by the above general formula (1) and its salt exhibit pharmacological effects such as anti-inflammatory, anti-rheumatic, anti-asthmatic, anti-allergic, antipyretic and analgesic effects on animals, especially mammals, Therefore, it is useful as a pharmaceutical agent such as an anti-inflammatory agent, an anti-rheumatic agent, an anti-asthma agent, an anti-allergy agent, an antipyretic agent, and an analgesic agent. The pyridylaminophenol derivative of the present invention is
For example, it can be produced by the method shown in the following reaction scheme. <Reaction scheme-1>

[ka]

[ka]

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

According to the method shown in Reaction Scheme-1 above, the compound of the present invention is produced by a condensation reaction between a quinone derivative (2) and an aminopyrine derivative (3) and a subsequent reduction reaction.
(1) can be manufactured. Quinone derivative (2) which is the raw material compound in the above
Among them, alkylbenzoquinones are known or are described, for example, in Chemical Pharmaceutical Bulletin [Chem.Pharm.Bull., 34 , 121 (1986)].
[J.Org.Chem., 48 , 2932]
(1983)]. Alkylnaphthoquinones are also known or described, for example, in the Journal of American Chemical Society [J.Am.Chem.Soc., 70 ,
3165 (1948)] according to the method of Fieser. The other raw material compound, an aminopyridine derivative, is a known compound. The condensation reaction shown in the above reaction scheme-1 can be performed using, for example, aluminum chloride, ferric chloride, titanium tetrachloride,
In the presence of a halide Lewis acid such as stannic chloride or zinc chloride, the quinone derivative (2) and the aminopyridine derivative (3) which also serves as a deoxidizing agent are mixed with an inert organic solvent,
For example, 1,2-dichloroethane, chloroform,
In a solvent such as toluene or benzene, from room temperature to about 120
It is carried out by reacting at a temperature of °C. The above reaction system also includes a deoxidizing agent such as pyridine,
Inert organic bases such as triethylamine can also be used in addition. The ratio of the quinone derivative (2) and the aminopyridine derivative (3) to be used is not particularly limited, but is usually about 1 to 10 times the molar amount of the latter to the former.
Preferably, about 1 to 3 molar amounts are used.
Incidentally, reactions using titanium tetrachloride are described, for example, in the Journal of Organic Chemistry [J.
Org.Chem., 32 , 3246 (1967)] according to the method of Weingarten et al. In addition, the above reaction may be performed using a Lewis acid other than the above, such as boron trifluoride/ethyl ether.
It can also be carried out by reacting both starting compounds in a suitable solvent such as tetrahydrofuran or dioxane at a temperature of room temperature to about 100°C. This reaction is
The method of Figueras et al. (J.Org.
Chem., 36 , 3497 (1971)].
Compound (4) can thus be obtained. Compound (4) obtained as described above can be isolated from the reaction system and subjected to the subsequent reaction, or may be subjected to the subsequent reaction without being isolated. The subsequent reduction reaction of compound (4) above can be carried out by a conventional method, for example, a method using sodium hydrosulfite, zinc and acetic acid, and thus the compound (1) of the present invention can be 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. The compound (1) of the present invention obtained by the reaction shown in the above reaction scheme can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, recrystallization, column chromatography, and the like. Furthermore, the compound of the present invention thus obtained can be easily converted into a pharmaceutically acceptable acid addition salt by subjecting it to an addition reaction with a suitable acidic compound according to a conventional method. It has the same pharmacological activity as the compound of the present invention, and the present invention also includes such acid addition salts. Examples of acidic compounds that form the above acid addition salts include hydrochloric acid, sulfuric acid,
Inorganic acids such as phosphoric acid and hydrobromic acid and maleic acid,
Examples include organic acids such as fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and benzenesulfonic acid. 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-tert-butyl-6-isopropyl-1,4
- Manufacture of benzoquinone 160g of sodium dichromate dihydrate, 97
% sulfuric acid and 230 ml of water.
tert-butyl-6-isopropylphenol 45.0
5 to 350 ml of ethyl ether solution under stirring.
The addition took 2.5 hours at 10°C. The reaction mixture was poured into water and extracted with ethyl ether. The organic layer was washed with saturated aqueous sodium bicarbonate and then with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (ethyl ether:hexane=1:10) to obtain 12.7 g of the target compound as a pale yellow oil. ¹ H-NMR (CDCl ₃ ): δ 1.12 (d, J = 6.8 Hz, 6H) 1.29 (s, 9H), 3.09 (d septet, J = 6.8 Hz, 1.1 Hz, 1H) 6.45 (dd, J = 2.6 Hz, 1.1Hz, 1H), 6.53 (d, J = 2.6Hz, 1H) Reference example 2 Production process 1 of 2-tert-butyl-5,6,7,8-tetrahydro-1,4-naphthoquinone 2-tert -Butyl-1,4-benzoquinone 120
Suspend g in 370 ml of acetic acid and add butadiene under ice cooling.
52 g was blown into the flask, the flask was stoppered, and the mixture was left at room temperature for 48 hours. Thereafter, 9 g of sodium acetate was added to the reaction mixture, heated under reflux for 30 minutes, and concentrated. The residue was dissolved in dichloromethane, washed with water, and then dried over magnesium sulfate. The crude product obtained by concentration was washed with hexane, and 2-tert-butyl-5,8-
75 g of dihydro-1,4-naphthohydroquinone was obtained as a pale red solid. Melting point 122-124℃ ¹ H-NMR (CDCl ₃ ): δ 1.39 (s, 9H), 3.23 (d, J = 1.5Hz, 4H),
4.35 (broad, 2H), 5.90 (broad s, 2H), 6.64 (s, 1H) Step 2 2-tert-butyl-5,8-dihydro-1,4
- 50 g of naphthohydroquinone was suspended in 300 ml of ethyl acetate, 300 mg of platinum dioxide was added, and hydrogen gas was passed into the flask and the mixture was stirred at room temperature. hydrogen gas
After 5.1 was consumed, the reaction mixture was passed through Celite and the liquid was concentrated. The obtained crude product was washed with hexane, 2-tert-butyl-5,
39 g of 6,7,8-tetrahydro-1,4-naphthohydroquinone was obtained as a pale red solid. Melting point 134-135℃ ¹ H-NMR (CDCl ₃ ): δ 1.38 (s, 9H), 1.70-1.90 (m, 4H), 2.50-
2.70 (m, 4H), 4.40 (broad s, 2H), 6.63 (s, 1H) Step 3 22 g of 2-tert-butyl-5,6,7,8-tetrahydro-1,4-naphthohydroquinone was dissolved in acetic acid.
Suspend in 100ml of nitric acid 10% while stirring at room temperature.
g was added slowly. The reaction mixture was stirred for 20 minutes, poured into water, and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to obtain 21 g of the target compound as a pale yellow solid. Melting point 50-52℃ ^1H -NMR ( _CDCl3 ): δ 1.27 (s, 9H), 1.60-1.80 (m, 4H), 2.30-
2.50 (m, 4H), 6.51 (s, 1H) 6.51 (s, 1H) Example 1 2-tert-butyl-6-isopropyl-4-
(3-pyridylamino)phenol [Compound 1]
Manufacturing process 1 1.62 ml of pyridine was dissolved in 60 ml of dichloroethane, 0.55 ml of titanium tetrachloride was added thereto, and the mixture was heated under reflux for 15 minutes. Then 2.06 g of 2-tert-butyl-6-isopropyl-1,4-benzoquinone and 3-
20ml dichloroethane solution of 0.94g aminopyridine
was added and heated under reflux for 2 hours. After the reaction mixture was cooled to room temperature, it was 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 (ethyl ether:hexane = 1:4) to obtain 2-tert-butyl-6-isopropyl-4.
1.09 g of -(3-pyridylimino)-2,5-cyclohexadien-1-one [Compound 1a] was obtained as a pale red solid. Physical properties of the obtained compound (melting point and ¹ H-NMR
values) are shown in Table 1. Step 2 2-tert-butyl-6-isopropyl-4-
(3-pyridylimino)-2,5-cyclohexadien-1-one (1.00 g) in tetrahydrofuran (13 ml)
A solution of 10.6 g of sodium hydrosulfite in 40 ml of water was added thereto at room temperature, stirred 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 purified by silica gel column chromatography (chloroform), and then washed with hexane to obtain the target compound [Compound 1].
Obtained 0.98 g as a colorless solid. Physical properties of the obtained compound (melting point and ¹ H-NMR
values) are shown in Table 2. Examples 2 to 11 Production of Compounds 2 to 11 In the same manner as in Step 1 of Example 1, 2,6-dimethyl-1,4-benzoquinone, 2,6-diisopropyl-1,4-benzoquinone, 2-tert -butyl-6-methyl-1,4-benzoquinone, 2-
tert-butyl-6-isopropyl-1,4-benzoquinone, 2,5-di-tert-butyl-1,4-
Benzoquinone, 2,3,6-trimethyl-1,4
-benzoquinone, 2-methyl-5,6,7,8-
Tetrahydro-1,4-naphthoquinone, 2-tert
-butyl-5,6,7,8-tetrahydro-1,
Each of 4-naphthoquinone and 2-methyl-1,4-naphthoquinone was reacted with 2-, 3- or 4-aminopyridine to produce each of the target compounds (Compounds 2a to 11a). Table 1 shows the physical properties of each compound obtained. In addition, from each compound obtained above, Example 1
In the same manner as Step 2, the compound of the present invention (Compound 2
~ Compound 11) was produced. The physical properties of these compounds 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. .

Claims (1)

[Claims] 1 General formula [Formula] [In the formula, R ¹ represents a lower alkyl group. R ² and R ³ each represent a hydrogen atom or a lower alkyl group, or both represent a -(CH ₂ ) ₄ - group or -CH=CH-CH=CH-
Indicates the group. However, the case where R ¹ and R ² are both tert-butyl groups and R ³ is a hydrogen atom is excluded. ] A pyridylaminophenol derivative represented by these and its salt.