JPH0576462B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to novel di-lower alkylphenol derivatives and salts thereof. Prior Art The di-lower alkylphenol 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 The present invention aims to provide a compound useful as a pharmaceutical, as described later. Means for Solving the Problems According to the present invention, a compound represented by the following general formula (1) is provided.

[Formula R ¹ is a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a halogeno-substituted lower alkyl group, a lower alkyl carbonyl group , a phenyl group having 1 to 3 of the same or different substituents selected from a lower alkylthio group and a phenylthio group, a hydroxyl group or a carboxyl group together with the above substituents, or a hydroxyl group and a carboxyl group. R ² and R ³ are each the same or different and represent a lower alkyl group. ] In this specification, the term lower alkyl group is
It refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include methyl, ethyl, propyl, isopropyl, butyl,
Examples include isobutyl, sec-butyl, t-butyl, pentyl, and hexyl groups. As mentioned above, the term "lower alkoxy group" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, sec-butoxy, t-
Examples include -butoxy, pentyloxy, hexyloxy groups, and the like. Halogen atoms include fluorine, chlorine, bromine and iodine atoms. As mentioned above, the term hydroxy lower alkyl group refers to a linear or branched hydroxyalkyl group having 1 to 6 carbon atoms, examples of which include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl. , 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-
Hydroxy-1-methylethyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl, 5-hydroxy pentyl, 1-hydroxyhexyl, 2
Examples include -hydroxyhexyl, 6-hydroxyhexyl, and the like. Examples of lower alkoxycarbonyl lower alkyl groups include methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl, pentyloxycarbonylmethyl, hexyloxycarbonylmethyl, 1-methoxycarbonylethyl. , 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 2-methoxycarbonylbutyl, 4-
Methoxycarbonylbutyl, 3-methoxycarbonylpentyl, 5-methoxycarbonylpentyl, 4-methoxycarbonylhexyl, 6-methoxycarbonylhexyl, 4-ethoxycarbonylbutyl, 3-(1-butoxy)carbonylpropyl, 6-(1-propoxy) ) Carbonylhexyl group, etc. can be exemplified. Examples of the term carboxy lower alkyl group include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 2-carboxybutyl, 4-carboxybutyl, 3-carboxypentyl, 5-carboxypentyl, 3-carboxyhexyl, 5-carboxyhexyl, 6-
Examples include carboxyhexyl group. Specific examples of the term halogeno-substituted lower alkyl group include, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, iodomethyl, diiodomethyl, triiodomethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl,
1,2-dichloroethyl, 2,2-dichloroethyl, 2-chloro-2-fluoroethyl, 2-bromoethyl, 2,2-dibromoethyl, 2,2,2
-trifluoroethyl, 1,3-difluoropropyl, 3,3,3-trifluoropropyl, 3,
3-dichloropropyl, 2,4-dibromobutyl, 4,4,4-tribromobutyl, 4,4-difluorobutyl, 3,5-dichloropentyl,
5,5-difluoropentyl, 5,5,5-trifluoropentyl, 6,6-dibromohexyl,
Examples include 6,6,6-trifluorohexyl group. Specific examples of the term lower alkylcarbonyl include acetyl, ethylcarbonyl, 1-
propylcarbonyl, 2-propylcarbonyl,
1-butylcarbonyl, 2-butylcarbonyl,
Examples include t-butylcarbonyl, 1-pentylcarbonyl, 2-pentylcarbonyl, 3-pentylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyl, and 3-hexylcarbonyl groups. Specific examples of the term lower alkylthio group include:
For example, methylthio, ethylthio, 1-propylthio, 2-propylthio, 1-butylthio, 2-butylthio, t-butylthio, 1-pentylthio,
Examples include 2-pentylthio, 3-pentylthio, 1-hexylthio, 2-hexylthio, and 3-hexylthio groups. Further, as specific examples of the phenyl group having 1 to 3 of the above groups as substituents, the following groups can be exemplified. 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
2-bromophenyl, 3-bromophenyl, 4-
Bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl,
2,4,6-trifluorophenyl, 2,4,6
-Trichlorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4
-trifluoromethylphenyl, 3,5-di(trifluoromethyl)phenyl, 2-carboxymethylphenyl, 3-carboxymethylphenyl,
4-Carboxymethylphenyl, 2,4-dicarboxymethylphenyl, 2-ethoxycarbonylmethylphenyl, 3-ethoxycarbonylmethylphenyl, 4-ethoxycarbonylmethylphenyl, 2,4-diethoxycarbonylmethylphenyl enyl, 2,4,6-triethoxycarbonylmethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,4,6-trimethoxy Phenyl, 3,4,5-trimethoxyphenyl, 2-
Ethoxyphenyl, 4-ethoxyphenyl, 2,
4-diethoxyphenyl, 2,4,6-triethoxyphenyl, 2-carboxymethylphenyl,
3-carboxymethylphenyl, 4-carboxymethylphenyl, 2,4-dicarboxymethylphenyl, 2,4,6-tricarboxymethylphenyl, 2-acetylphenyl, 3-acetylphenyl, 4- Acetyl phenyl, 2,4-diacetylphenyl, 2-(1-carboxyethyl)phenyl, 3-(1-carboxyethyl)phenyl,
4-(1-carboxyethyl)phenyl, 2,4
-di(1-carboxyethyl)phenyl, 2-
(2-carboxyethyl)phenyl, 3-(2-carboxyethyl)phenyl, 4-(2-carboxyethyl)phenyl, 2,4-di-(2-carboxyethyl)phenyl, 2-methylthiophenyl, 3- Methylthiophenyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2,
4,6-trimethylthiophenyl, 3,4,5-
Trimethylthiophenyl, 2-phenylthiophenyl, 3-phenylthiophenyl, 4-phenylthiophenyl, 2-(1-pentylthio)phenyl, 3-(1-pentylthio)phenyl, 4-( 1
-pentylthio)phenyl, 2,4-di-(1-
pentylthio)phenyl, 2-methylphenyl,
3-methylphenyl, 4-methylphenyl, 2,
4-dimethylphenyl, 2,4,6-trimethylphenyl, 2-(1-butyl)phenyl, 3-(1
-butyl)phenyl, 4-(1-butyl)phenyl, 2,4-di(1-butyl)phenyl, 2,
4,6-tri-(1-butyl)phenyl, 3-chloro-2-hydroxyphenyl, 4-chloro-2
-Hydroxyphenyl, 5-chloro-2-hydroxyphenyl, 6-chloro-2-hydroxyphenyl, 4-chloro-3-hydroxyphenyl, 5
-chloro-3-hydroxyphenyl, 2-(3-
Carboxypropyl)phenyl, 3-(3-carboxypropyl)phenyl, 4-(3-carboxypropyl)phenyl, 2,4-di(3-carboxypropyl)phenyl, 2-hydroxy-4-
Carboxymethylphenyl, 2-hydroxy-5
-carboxymethylphenyl, 2-hydroxy-
6-carboxymethylphenyl, 3-hydroxy-5-carboxymethylphenyl, 2-chloro-
6-carboxyphenyl, 4-chloro-6-carboxyphenyl, 2-chloro-4-carboxyphenyl, 3-chloro-5-carboxyphenyl,
2-cyanophenyl, 3-cyanophenyl, 4-
cyanophenyl, 3,5-dicyanophenyl,
2,4,6-tricyanophenyl, 4-methyl-
2-carboxyphenyl, 6-methyl-2-carboxyphenyl, 2-methyl-4-carboxyphenyl, 3-methyl-5-carboxyphenyl,
4-hydroxy-3-carboxyphenyl, 4-
Hydroxy-2-carboxyphenyl, 6-hydroxy-2-carboxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2,6-di(hydroxymethyl)phenyl, 2,4,6-tri(hydroxymethyl)phenyl, 2-(2-hydroxyethyl)phenyl, 3-(2-hydroxyethyl)phenyl, 4-(2-hydroxyethyl)phenyl, 3,5-di(2 -hydroxyethyl)phenyl, 2-(1-hydroxyethyl)phenyl, 3-(1-hydroxyethyl)phenyl,
4-(1-hydroxyethyl)phenyl, 2,4
-di(1-hydroxyethyl)phenyl, 2,
4,6-tri(1-hydroxyethyl)phenyl, 2-(3-hydroxypropyl)phenyl,
3-(3-hydroxypropyl)phenyl, 4-
(3-hydroxypropyl)phenyl, 3,5-
Di(3-hydroxypropyl)phenyl, 2,4
-di(3-hydroxypropyl)phenyl, 2-
(4-hydroxybutyl)phenyl, 3-(4-hydroxybutyl)phenyl, 4-(4-hydroxybutyl)phenyl, 2,4-di(4-hydroxybutyl)phenyl, 2-(1-hydroxyisopropyl)phenyl , 3-(1-hydroxyisopropyl)phenyl, 4-(1-hydroxyisopropyl)phenyl, 2,6-di(1-hydroxyisopropyl)phenyl, 2-chloro-6-hydroxymethylphenyl, 3-chloro-6 -Hydroxymethylphenyl, 4-chloro-6-hydroxymethylphenyl, 2-chloro-4-hydroxymethylphenyl, 2-chloro-5-hydroxymethylphenyl, 2-hydroxy-4-(2-hydroxyethyl ) phenyl, 2-hydroxy-5
-(2-hydroxyethyl)phenyl, 2-hydroxy-6-(2-hydroxyethyl)phenyl,
3-hydroxy-5-(2-hydroxyethyl)
Phenyl, 6-methyl-2-(hydroxymethyl)
Phenyl, 5-methyl-2-(hydroxymethyl)
Phenyl, 4-methyl-2-(hydroxymethyl)
Phenyl, 2-methyl-4-(hydroxymethyl)
phenyl group etc. The compound represented by the above general formula (1) of the present invention and its salt have an effect of blocking or regulating prostaglandin biosynthesis and a hypolipidemic effect, and have anti-inflammatory and anti-inflammatory effects on animals, especially mammals. Shows rheumatism, antiallergy, analgesia, diuresis, platelet aggregation inhibition, blood pressure lowering, and antihyperlipidemic effects. Therefore, this is
It is useful as a medicine such as an anti-inflammatory agent, an anti-rheumatic agent, an anti-allergic agent, an analgesic, a diuretic, an antithrombotic agent, an antihypertensive agent, and an antihyperlipidemic agent. The compounds of the present invention can be produced, for example, by the methods shown in the following reaction schemes. <Reaction process formula 1>

[In the formula, R ¹ , R ² and R ³ are the same as above. ] According to reaction scheme-1, benzoquinone derivative
The compound (1) of the present invention can be obtained by a condensation reaction between (2) and the aniline derivative (3) and a subsequent reduction operation. The above condensation reaction can be carried out using known methods, such as the method described in Tetrahedron, Vol. 23, p. 3723 (1967) by A. Reiker et al., or the method described by J. Figueras et al.
It can be carried out according to the method described in J.Org.Chem., 36 , 3497 (1971). More specifically, the above condensation reaction uses acetic acid, BF ₃ · Et ₂ O, etc. as a catalyst,
Compound (3) is used in an amount of 1 to 5 times the molar amount of compound (2), and the compound is used without a solvent or, for example, in tetrahydrofuran (THF), ether, dioxane, chloroform,
1,2-dichloroethane, benzene, toluene,
It is carried out in a suitable solvent such as xylene at a temperature range of about 30-200°C. Compound (4) obtained above can be subjected to the subsequent reduction reaction without being isolated from the reaction system, but may of course be isolated. The reduction reaction can be carried out according to a conventional method, for example, by transferring the above reaction product into water and adding an aqueous solution of hydrosulfite (Na ₂ S ₂ O ₄ ) in an amount of 2 to 50 times the molar amount. The above reduction reaction can be carried out depending on the type of substituent of the R ₁ group of compound (4), for example, using zinc powder in acetic acid, ethyl acetate,
It can also be carried out by a method of catalytic hydrogenation using palladium-carbon or PtO ₂ as a catalyst in a solvent such as alcohol, THF, or water. Furthermore, in the compound (1) of the present invention, R ¹ is a phenyl group having a hydroxy lower alkyl group, and R ¹ is a phenyl group having a carboxy lower alkyl group or a phenyl group having a lower alkoxycarbonyl lower alkyl group, which is obtained according to the above method. Compound (1), which is a group, is reduced with about 1 to 7 times the molar amount of LiAlH ₄ in a suitable solvent such as ether or THF, or a compound in which R ¹ is a phenyl group having a lower alkylcarbonyl group. It can also be obtained by reducing (1) with about 1.5 to 5 times the molar amount of NaBH ₄ in a suitable solvent such as a mixed solvent of methanol, ethanol, isopropanol and the like with THF, dioxane, etc. be able to. The compound (1) of the present invention obtained by each of the above reactions is:
Conventional separation means such as solvent extraction, recrystallization,
Easily isolated by column chromatography, etc.
Can be purified. Furthermore, the compound (1) of the present invention can be converted into a pharmaceutically acceptable acid addition salt by subjecting it to an addition reaction with a suitable acidic compound, and the present invention also includes such acid addition salts. Examples of acidic compounds that can form the above acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid; Examples include organic acids. Furthermore, among the compounds of the present invention, those having a free carboxyl group may be treated with alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and other copper salts. and these also have the same pharmacological activity as the free form of the compound of the present invention,
are included within the scope of the present invention. Examples Examples will be given below to explain the present invention in more detail. Example 1 4-(4-fluorophenylamino)-2,6-
Production of di-t-butylphenol 2.2 g of 2,6-di-t-butyl-1,4-benzoquinone and 3.3 g of p-fluoroaniline,
It was dissolved in 60 ml of THF, and 0.3 ml of BF ₃ ·Et ₂ O was added thereto and refluxed for 6 hours. After cooling, add 50 ml of water, then add a solution of 20 g of Na ₂ S ₂ O ₄ in 150 ml of water at room temperature.
Stirring was continued for about 15 minutes until the red color of the reaction mixture disappeared. It was then transferred to water, extracted with ethyl ether, the organic layer was washed with saturated brine, and _MgSO4
The crude product obtained by drying and concentrating was subjected to column chromatography (Et ₂ O: hexane = 1:10).
Purification was performed to obtain 2 g of the target compound. The physical properties of the obtained compound are shown in Table 1 as No. 1. Examples 2 to 21 Compound Nos. shown in Table 1 were prepared in the same manner as in Example 1.
2 to 10 were produced. In addition, free bases of Compounds Nos. 11 to 21 were prepared in the same manner, and 4N hydrochloric acid/ethyl acetate was added to each of the free bases to obtain each of the target compounds in the form of hydrochloride. Table 1 shows the physical properties of each compound obtained. Reference example 1 4-(3-carboxyphenylamino)-2,6
-Production of di-t-butylphenol 6.6 g of 2,6-di-t-butyl-1,4-benzoquinone, 4.2 g of m-aminobenzoic acid, and 6 drops of acetic acid were heated and stirred for 2 hours, and then allowed to cool. Then, add about 50 ml of water to the reaction mixture, then add 200 ml of THF, and then add a solution of 50 g of Na ₂ S ₂ O ₄ in 300 ml of water at room temperature, stir for about 15 minutes until the red color turns brown, and then transfer to water. The organic layer was treated in the same manner as in Example 1 and purified by column chromatography (CH ₂ Cl ₂ :THF=5:1) to obtain 6.7 g of the target compound. Melting point: 257-258.5℃ (decomposition) 1H-NMR [DMSO- _d6 ]: 7.98 (1H, bs), 7.57 (1H, bs), 7.00-7.30
(3H, s), 6.92 (2H, s), 6.65 (1H, bs), 1.38
(18H, s) Examples 22 to 25 Compounds No. 22 to 25 are shown in Table 1 in the same manner as Reference Example 1.
Compounds designated as 25 were obtained. Furthermore, a free base of Compound No. 25 was prepared in the same manner, and 4N hydrochloric acid/ethyl acetate was added thereto to obtain the target compound in the form of a hydrochloride. Example 26 4-(3-hydroxymethylphenylamino)-
Production of 2,6-di-t-butylphenol hydrochloride Dissolve 1.8 g of 4-(3-carboxyphenylamino)-2,6-di-t-butylphenol obtained in Reference Example 1 in 30 ml of THF. and the solution,
It was added dropwise to a suspension of 1.7 g of LiAlH ₄ in 150 ml of ethyl ether under stirring at room temperature, and then the reaction mixture was
Refluxed for 3.5 hours. After cooling, water-containing ethyl ether,
Excess LiAlH ₄ is then carefully decomposed using water, the organic layer is separated, dried over MgSO ₄ and concentrated to give a crude product, which is again diluted with ethyl ether 100
ml, and 6 ml of 4N hydrochloric acid/ethyl acetate solution was added thereto, and the precipitated crystals were collected, washed with ethyl ether, and air-dried to obtain 1.5 g of the target compound. The physical properties of this compound are shown in Table 1 as Compound No. 26. Examples 27-35 Compounds No. 27-35 shown in Table 1 were obtained by the same operation as in Example 26. Example 36 Production of 4-(3-α-methylhydroxymethylphenylamino)-2,6-di-t-butylphenol hydrochloride 4-(3-acetylphenylamino) obtained in Example 9 -1 g of 2,6-di-t-butylphenol (compound No. 9) was added to 17 ml of ethanol and
Dissolved in 3 ml of THF and added NaBH ₄ to this under ice-cooling stirring.
200 mg were added slowly and the reaction mixture was stirred for 1 hour. The reaction mixture was transferred to water and extracted with ethyl ether until the yellow-red color of the organic layer faded.
The organic layer was washed with 10% Na ₂ S ₂ O ₄ aqueous solution, then washed with saturated saline, dried over MgSO ₄ and concentrated to about 100 ml, then 6 ml of 4N hydrochloric acid/ethyl acetate solution was added.
The precipitated crystals were collected, washed with ethyl ether, and air-dried to obtain 1 g of the target compound. The physical properties of this compound are shown in Table 1 below as Compound No. 36.

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Claims (1)

[Scope of Claims] 1 General Formula [Formula] [In the formula, R ¹ is a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, or a halogeno group. It has 1 to 3 of the same or different substituents selected from a substituted lower alkyl group, a lower alkylcarbonyl group, a lower alkylthio group and a phenylthio group, or it has a hydroxyl group or a carboxyl group together with the above substituents, or it has a hydroxyl group and a carboxyl group. represents a phenyl group having R ² and R ³ are both tert−
Indicates a butyl group. ] A di-lower alkylphenol derivative represented by these and its salt.