JPH09249628A - Phenol derivatives - Google Patents

Abstract

PROBLEM TO BE SOLVED: To suppress the progression of arteriosclerosis by suppressing the formation of foam cells of macrophages by an excellent antioxidant action and ACAT inhibitory action, and to provide an excellent antioxidant action. It is intended to provide a novel phenol derivative and a salt thereof which suppress cell injury and arrhythmia during myocardial infarction-reperfusion. The present invention provides a compound represented by the general formula (1): (In the formula, R ⁰ represents a hydrogen atom or the like, ^one of R ¹ and R ³ represents a hydrogen atom, and the other forms a naphthalene ring or an oxygen-containing bicyclic heterocycle together with R ² and a benzene ring. , W represents an oxygen atom, a sulfur atom, etc., R ⁴ represents a substituted or unsubstituted amino group or a substituted or unsubstituted alkyl group, and OR ⁵ represents an optionally protected hydroxyl group.) And a pharmaceutically acceptable salt thereof.

Description

Detailed Description of the Invention

[0001]

[0001] The present invention relates to a novel phenol derivative.

[0002]

2. Description of the Related Art Due to recent changes in the standard of living and westernization of eating habits, changes to eating habits containing a large amount of high calories and high cholesterol and an increase in the proportion of elderly people in the total population Diseases of ischemic heart disease such as arteriosclerosis and myocardial infarction due to the amount of deposited cholesterol in the inside have increased and become a social problem.

[0003] Drugs that reduce the amount of cholesterol in the blood have been developed so far, but those that suppress the absorption of cholesterol in the gastrointestinal tract and the deposition of cholesterol on the blood vessel wall, or atherosclerotic lesions No drug has yet been found to regress itself.

[0004] By the way, accumulation of monocyte / macrophage-derived foam cells in the subendothelium has been recognized as an initial lesion at the onset of arteriosclerosis. Accumulation of lipids in foam cells
1) Low density lipoprotein (LDL) in blood is chemically modified under vascular endothelial cells and is taken up by monocytes / macrophages via scavenger receptors. 2) It is taken up by oxidative alteration. Cholesterol esters in LDL are hydrolyzed in lysosomes, the free cholesterol produced is transferred to the cytoplasm, 3) where it is re-esterified by acyl coenzyme A cholesterol acyltransferase (ACAT) and accumulates as lipid droplets, Form foam cells, which are atherosclerotic lesions. Therefore, by inhibiting the action of ACAT, it is possible to suppress the incorporation of cholesterol into the living body and further suppress the production of cholesterol ester.

[0005] Compounds having such ACAT inhibitory activity are described in, for example, JP-A-2-188568 and JP-A-2-92950, but the compounds shown therein have an ACAT inhibitory action. No particular effect has been shown on the oxidative alteration of LDL, which causes macrophage foaming, which is important for the formation of atherosclerotic lesions.

[0006] Foam cells that play an important role in the formation of atherosclerotic lesions are oxidatively altered LD cells.
As a result of L being taken up by macrophages, the macrophages are foamed. The fact that LDL subjected to such oxidative alteration causes foaming of macrophages and plays an important role in the formation of atherosclerotic lesions is described by Diane W. et al. Reported by Morel et al. (ARTERIOS CLEROSIS, Vol. 35
7-364, 1984). Furthermore, the prevention of oxidative deterioration of LDL causes regression of atherosclerotic plaque, which is reported by TORUKITA et al. (Proc Nat
l. Acad. Sci. USA, 84 vol., 5928-5
931, 1987). Therefore,
In addition to the above-described ACAT inhibitory action, suppressing the oxidative alteration of LDL can prevent the formation and expansion of atherosclerotic lesions,
And its regression is extremely important.

[0007] On the other hand, although the mechanism by which the lipid peroxidation reaction leads to cell membrane damage and, consequently, cell death has not been completely elucidated, enhanced production of active oxygen plays an important role in such a cell damage process. Is understood as a common understanding. Furthermore, it is known that active oxygen causes not only lipid peroxidation but also denaturation of enzymes and proteins and damage of nucleic acids, which cause various organ damages. In the heart, for example, in the early stage of a myocardial infarction attack caused by occlusion of coronary arteries, a serious condition such as cardiogenic shock or lethal arrhythmia may occur, so the initial treatment should be reperfusion to restart blood flow at the infarcted site. Therapy (thrombolysis, percutaneous coronary angioplasty (PTCA), coronary artery bypass surgery (CAB)
G) etc. are enforced. However, recently, a pathological condition called ischemia / reperfusion injury, in which myocardial tissue damage is exacerbated by resumption of blood flow, has attracted attention. The involvement of active oxygen has been reported as one of the pathogenic mechanisms. Oxygen radicals generated during reperfusion induce reperfusion arrhythmia, which results in cell damage associated with ATP production disorder and cell membrane destruction associated with increased enzyme protein activity. It has been a problem to cause myocardial damage.

[0008]

The present invention is effective in suppressing arteriosclerosis, myocardial infarction, cell injury during ischemia / reperfusion and arrhythmia, etc. by eliminating active oxygen and having an antioxidant effect. The present invention provides a novel phenol derivative. The present invention also provides a method for producing such a novel phenol derivative.

[0009]

[Means for Solving the Problems] In order to solve the above-mentioned problems, the inventors of the present invention have, as a result of diligent research, found that by suppressing foam cell formation of macrophages with an excellent antioxidant action and ACAT inhibitory action, The present invention has been completed by finding a novel phenol derivative that suppresses the progress of hardening and suppresses cell damage and arrhythmia during myocardial infarction and ischemia / reperfusion due to its excellent active oxygen scavenging action and antioxidant action.

That is, the present invention provides a compound represented by the general formula (1):

[0011]

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(In the formula, R ⁰ represents a hydrogen atom, an alkyl group or an alkyloxy group, ^one of R ¹ and R ³ represents a hydrogen atom, and the other represents a naphthalene ring or a ring containing R ² and a benzene ring. Forming an oxygen bicyclic heterocycle, W represents an oxygen atom, a sulfur atom or NR ⁷ , R ⁷ is a hydrogen atom,
It represents an alkyl group, an aryl group, a hydroxyl group or an alkyloxy group, R ⁴ represents a substituted or unsubstituted amino group or a substituted or unsubstituted alkyl group, and OR ⁵ represents an optionally protected hydroxyl group. ) And a pharmacologically acceptable salt thereof.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (1) of the above phenol derivative of the present invention, the alkyl group represented by R ⁰ includes an alkyl group having 1 to 20 carbon atoms, such as a methyl group, an ethyl group, A linear or branched alkyl group such as an isopropyl group, a hexyl group, an octyl group, and a hexadecyl group is preferable, and the alkyloxy group has 1 to 20 carbon atoms.
And a lower alkyloxy group such as a methyloxy group, an octyloxy group, and a tetradecyloxy group are preferable, and a methyloxy group is particularly preferable. As R ⁰ , a hydrogen atom is particularly preferable.

The substituent represented by R ¹ , R ² and R ³ is, for example, when R ¹ is a hydrogen atom and R ³ is R ^2.
And a benzene ring forming a naphthalene ring, R ³ is a hydrogen atom, and R ¹ forms a dihydrobenzofuran ring or a 1,3-benzo [d] dioxole ring together with R ² and a benzene ring. Some of them are listed.

When W is represented by NR ⁷ , the alkyl group in R ⁷ is a lower alkyl group such as a methyl group or an ethyl group, the aryl group is a phenyl group, and the alkyloxy group is a methyloxy group or an ethyloxy group. And the like, lower alkyloxy groups and the like can be mentioned. As W, an oxygen atom and a sulfur atom are preferable, and an oxygen atom is particularly preferable.

When R ⁴ is a substituted amino group, the substituent is a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group,
Examples thereof include a substituted or unsubstituted heterocyclic group, and when R ⁴ is a substituted alkyl group, examples of the substituent include a substituted or unsubstituted alkyl group and a substituted or unsubstituted cycloalkyl group.

Preferred examples of the substituted or unsubstituted alkyl group include pyridyl group-substituted lower alkyl group (eg, pyridylmethyl group), aryl group-substituted lower alkyl group (eg, phenylmethyl group, phenylethyl group), Lower alkyloxycarbonyl lower alkyl group (eg, ethoxycarbonylpropyl group) and the like. Preferred examples of the substituted or unsubstituted cycloalkyl group include unsubstituted cycloalkyl group (eg, cyclohexyl group) and the like. As a preferred example of the substituted or unsubstituted aryl group, an unsubstituted aryl group (for example,
A phenyl group, a naphthyl group), a phenyl group which may be mono- or di-substituted with a lower alkyl group (for example, 2,
6-diisopropylphenyl group), a naphthyl group which may be substituted with a hydroxyl group (for example, a 2-hydroxynaphthyl group), and the like. Preferred examples of the substituted or unsubstituted heterocyclic group include hydroxyl-substituted 2,3 -Dihydrobenzofuranyl group (for example, 5-hydroxy- (2,3-dihydrobenzofuran) -6-yl group), lower alkylenedioxyphenoxy group (for example, 4,5-methylenedioxyphenol-2-yl group) ) And the like.

As the optionally protected hydroxyl-protecting group represented by OR ⁵ , a conventional protecting group which can be a hydroxyl-protecting group can be used, and examples thereof include an acyl group, a lower alkyloxy lower alkyl group and a lower alkyl group. Examples thereof include an oxycarbonyl group, a lower alkylcarbonyloxy lower alkyl group and an aralkyl group.

When the optionally protected hydroxyl group is protected with an acyl group, examples of the acyl group include an aliphatic acyl group and an aromatic acyl group. A carbonyl group or a lower cycloalkylcarbonyl group is preferred.

The acyl group may have a substituent, and examples thereof include alanine, valine, glycine, aspartic acid, glutamic acid, lysine, and other α-amino acids having a hydroxyl group removed. The amino group of the α-amino acid excluding the hydroxyl group may be protected, and examples thereof include those that can be a protective group for the amino group. Examples include lower alkylcarbonyl groups such as acetyl group and propionyl group, and lower groups. Examples thereof include an acyl group such as a phenyl lower alkyloxycarbonyl group such as an alkyloxycarbonyl group or a benzyloxycarbonyl group.

Preferred examples of the optionally protected hydroxyl group represented by OR ⁵ include a hydroxyl group and a lower alkylcarbonyloxy lower alkyloxy group (eg, tert.
-Butylcarbonyloxymethyloxy group), acyloxy group (for example, acetyloxy group, ethoxycarbonyloxy group, benzoyloxy group, glycinyloxy group, alanyloxy group, valyloxy group, aspartyloxy group, glutamyloxy group, lysyloxy group), lower Examples thereof include an alkyloxy lower alkyl group (eg, methoxymethyl group), and a hydroxyl group is particularly preferable.

Among the object compounds (1) of the present invention, particularly preferable compounds are 2- [3- (3-pyridylmethyl) ureido] -4,5-methylenedioxyphenol, 2-
[3- (2,6-diisopropylpyrphenyl) ureido]
-4,5-Methylenedioxyphenol, 1- [3-
(3-Ethoxycarbonylpropyl) -3-phenylureido] -2-naphthol, 1- [3- (3-pyridylmethyl) ureido] -2-naphthol, 6- [3- (5
-Hydroxy-2,3-dihydrobenzofuran-6-yl) ureido] -5-hydroxy-2,3-dihydrobenzofuran, 2- [3- (4,5-methylenedioxyphenol-2-yl) ureido]- 4,5-methylenedioxyphenol, 2- [3- (3-ethoxycarbonylpropyl) -3- (1-naphthyl) ureido] -4,
5-methylenedioxyphenol, 1- (3-phenylureido) -2-naphthol, 1- [3- (2-hydroxynaphthalen-1-yl) ureido] -2-naphthol, 2- (3-phenylthioureido) ) -4,5-Methylenedioxyphenol, 2- (3-cyclohexyl-)
3-Phenylmethylureido) -4,5-methylenedioxyphenol and 2- (2-cyclohexyl-3-phenylpropionylamino) -4,5-methylenedioxyphenol.

Although the objective compound (1) of the present invention may have an optically active substance based on an asymmetric carbon, the present invention includes any of these optical isomers and a mixture thereof.

The object compound (1) of the present invention can be used in medicinal use in a free form or in the form of a pharmaceutically acceptable salt. Such pharmaceutically acceptable salts include, for example, inorganic acid salts such as hydrochloride, sulfate and hydrobromide, and organic acid salts such as acetate, fumarate, oxalate and methanesulfonate. Is raised. When the compound has a substituent such as a carboxyl group, it can be used as a basic salt (eg, an alkali metal salt such as a sodium salt or a potassium salt or an alkaline earth metal salt such as a calcium salt).

The object compound (1) of the present invention or a salt thereof can be administered orally or parenterally, and, for example, tablets, granules, capsules, powders, injections, inhalants can be prepared by a conventional method. It can be used as an appropriate pharmaceutical preparation such as an agent.

The dose of the objective compound (1) of the present invention or a pharmaceutically acceptable salt thereof will vary depending on the administration method, age, weight and condition of the patient, but usually the daily dose is oral. The dose is preferably about 5 to 50 mg / kg for administration, and about 0.1 to 10 mg / kg for parenteral administration.

The compound represented by the general formula (1) of the present invention can be produced by various methods, for example, the methods shown below.

[Method A] W is an oxygen atom or a sulfur atom, R ⁴
The object compound (1) of the present invention in which is a substituted or unsubstituted amino group can be represented by the general formula (a):

[0029]

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(In the formula, OR ⁵¹ represents an optionally protected hydroxyl group, and other symbols have the same meanings as described above.)
By reacting an aniline derivative represented by or a salt thereof with phosgene, triphosgene or thiophosgene, and then reacting with the general formula (b)

[0031]

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(Wherein R ⁴¹ represents a substituted or unsubstituted amino group) and OR ⁵¹ is a protected hydroxyl group, it is optionally reacted with the amine derivative or salt thereof. It can be prepared by removing the protecting group.

[Method B] The object product (1) of the present invention in which R ⁴ is a mono-substituted amino group is the aniline derivative (a) or a salt thereof and the general formula (c).

[0034]

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(In the formula, R ⁴² represents a hydrogen atom or a substituent of an amino group, and other symbols have the same meanings as described above), and OR ⁵¹ is a protected hydroxyl group. In some cases, it can be produced by removing the protective group for the hydroxyl group, if desired.

[Method C] The object compound (1) of the present invention in which W is an oxygen atom and R ⁴ is a substituted or unsubstituted amino group is
(I) Aniline derivative (a) or a salt thereof and a general formula (d)

[0037]

[Chemical 6]

(Wherein the symbols have the same meaning as described above) or by reacting with a carbamate derivative represented by (ii) the general formula (e)

[0039]

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(In the formula, symbols have the same meanings as described above.) The phenylcarbamic acid ester derivative is reacted with the amine derivative (b) or a salt thereof, and OR ⁵¹
When is a protected hydroxyl group, it can be produced by removing the protective group of the hydroxyl group, if desired.

[Method D] W is an oxygen atom or a sulfur atom, R ⁴
The object compound (1) of the present invention, in which is a substituted or unsubstituted alkyl group, is the aniline derivative (a) or a salt thereof and the general formula (f).

[0042]

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(In the formula, R ⁴⁴ represents a substituted or unsubstituted alkyl group, W ¹ represents an oxygen atom or a sulfur atom.), And a (thio) carboxylic acid or a reactive derivative thereof is reacted to form OR. ^{When 51} is a protected hydroxyl group, it can be produced by removing the protective group of the hydroxyl group, if desired.

[Method E]: Target product (1) in which W is NR ^7.
Is a compound (1) in which W is a sulfur atom and a compound represented by the general formula (g) R ⁷ —NH ₂ (g) (wherein R ⁷ has the same meaning as described above), and OR ⁵¹ When is a protected hydroxyl group, it can be produced by removing the protective group of the hydroxyl group, if desired.

As the salt of the aniline derivative (a) or the amine derivative (b), for example, a salt with an inorganic acid such as a hydrochloride or a sulfate and a salt with an organic acid such as tosylic acid can be used.

Hereinafter, the above [Method A], [Method B], [C]
Method], [D Method] and [E Method] will be described in detail.

[Method A]: The reaction of the aniline derivative (a) or a salt thereof with phosgene, triphosgene or thiophosgene, and the subsequent reaction of the amine derivative (b) or a salt thereof, in the presence of a base, in a suitable solvent. Alternatively, it can be carried out without a solvent.

As the base, triethylamine, pyridine, dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] -7-undecene, diisopropylethylamine, etc., and as the solvent, dichloromethane,
Solvents such as chloroform, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, dimethyl ether, dioxane, ethylene glycol, dimethylformamide, dimethyl sulfoxide, toluene and benzene can be preferably used.

This reaction is carried out at -30 to 100 ° C., especially 0 to
Proceeds favorably at 50 ° C.

In this reaction, 1 mol of the aniline derivative (a) or a salt thereof is added to the amine derivative (b) or a salt thereof.
It is carried out using a 2-3 molar amount, preferably a 0.5-1.5 molar amount.

[Method B]: The reaction between the aniline derivative (a) or a salt thereof and the isocyanate derivative (c) is carried out by using dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, dimethyl ether, dioxane, ethylene glycol, dimethyl. It can be carried out in a suitable solvent such as formamide, dimethylacetamide, dimethylsulfoxide, toluene, benzene, hexamethylphosphoramide, sulfolane, 1,3-dimethyl-2-imidazolidinone or without solvent.

This reaction is carried out at -30 to 100 ° C., especially 0
It proceeds favorably at ５０50 ° C.

In this reaction, 1 mol of the aniline derivative (a) or 1 mol of its salt was used to prepare 0.2 parts of the isocyanate derivative (c).
~ 3 molar amounts, preferably 0.5-1.5 molar amounts.

[Method C]: (i) The reaction between the aniline derivative (a) or a salt thereof and the carbamic acid ester derivative (d) is carried out by using benzene, cyclohexane, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, ether, It can be carried out in a suitable solvent such as tetrahydrofuran.

The present reaction suitably proceeds at 50 to 150 ° C, especially 50 to 100 ° C.

In this reaction, 1 mol of the aniline derivative (a) or a salt thereof is used for the carbamate derivative (d).
It is carried out using 0.2-2.0 molar amounts.

(Ii) The reaction of the phenylcarbamic acid ester derivative (e) with the amine derivative (b) or a salt thereof can be carried out in a suitable solvent. As the solvent, for example, benzene, toluene, xylene, dichloromethane, tetrahydrofuran, chloroform and the like can be appropriately used.

The present reaction suitably proceeds at 50 to 150 ° C, especially 50 to 100 ° C.

This reaction is carried out using 0.2 to 2.0 mol of the amine derivative (b) or a salt thereof with respect to 1 mol of the phenylcarbamic acid ester derivative (e).

[Method D]: The reaction of the aniline derivative (a) or a salt thereof with the reactive derivative of the (thio) carboxylic acid (f) can be carried out in the presence of a base in a suitable solvent.

Examples of the reactive derivative of carboxylic acid include acid halides, acid anhydrides, activated acid amides and activated esters.

Examples of the reactive derivative of thiocarboxylic acid include thioacid halides, thioacid anhydrides, activated thioacid amides and activated thioesters.

As the base, an organic amine such as pyridine and tri-lower alkylamine is used, and as the solvent, dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, dimethyl ether,
Dioxane, ethylene glycol, dimethylformamide, dimethylsulfoxide, toluene, benzene and the like can be preferably used.

On the other hand, the reaction of the aniline derivative (a) or its salt with the free (thio) carboxylic acid (f) can be carried out in the presence of a dehydrating agent in a suitable solvent.

As the dehydrating agent, dicyclohexylcarbodiimide and the like, and as the solvent, dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether,
Tetrahydrofuran, dimethyl ether, dioxane,
Ethylene glycol, dimethylformamide, dimethyl sulfoxide, toluene, benzene and the like can be preferably used.

These reactions suitably proceed at -30 to 100 ° C, especially 0 to 50 ° C.

This reaction is carried out using 0.2 to 3 mol of (thio) carboxylic acid or thiocarboxylic acid (f) or its reactive derivative, relative to 1 mol of aniline derivative (a) or its salt.

[Method E]: The reaction of the compound (1) in which W is a sulfur atom and the compound (g) can be carried out in the presence of a copper catalyst in a suitable solvent.

As the copper catalyst, copper sulfate or the like can be preferably used. On the other hand, the solvent is not particularly limited as long as it is an inert solvent for the reaction, and for example, dioxane, ethylene glycol, dimethyl ether, dimethylacetamide, dimethylformamide, hexamethylphosphoramide, benzene, tetrahydrofuran, dioxane, toluene, acetic acid. Ethyl, lower alcohol, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, 1,3-dimethyl-2-imidazolidinone, acetic acid,
Diethyl ether, dimethoxyethane, dimethylsulfoxide, carbon disulfide, acetone, water or a mixed solvent thereof can be appropriately used.

This reaction is carried out at 0 to 150 ° C., especially 50 to 50 ° C.
Suitably proceeds at 100 ° C.

This reaction is based on 1 mol of the compound (1),
It is carried out using 0.2 to 3 molar amount of compound (g).

[Method A], [Method B], [Method C], [Method D]
And in [Method E], when OR ⁵¹ is a protected hydroxyl group, the protecting group for the hydroxyl group may be removed by a known method, if desired. The removal of the protective group can be carried out by an ordinary method such as hydrolysis, acid treatment, reduction and the like according to a conventional method depending on the kind of the protective group.

The starting compound (a) of the present invention includes a novel compound, for example, the compound represented by the general formula (h)

[0074]

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(Where the symbols have the same meaning as described above), the compound can be produced by azotization or azidation and then reducing.

In the present invention, the alkyl group and the alkyl group moiety have 1 to 20 carbon atoms, especially 1 to 1 carbon atoms.
0, especially 1 to 6 alkyl groups and alkyl group moieties. The lower alkyl group and the lower alkyl group moiety include those having 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. Examples of the cycloalkyl group include those having 3 to 10 carbon atoms, especially those having 5 to 8 carbon atoms. As a halogen atom,
Examples include chlorine, bromine, fluorine or iodine. Examples of the aryl group include a phenyl group and a naphthyl group.

[0077]

EXAMPLES Specific synthetic methods of the compounds of the present invention are shown below as examples.

Example 1 (1) 1.85 g of (2-amino-4,5-methylenedioxyphenoxy) methoxymethane and 1.27 g of phenylthioisocyanate were added to tetrahydrofuran (THF).
After stirring in 50 ml of solvent at room temperature for 4 hours, water is added and the mixture is extracted with ethyl acetate. After washing and drying the extract, the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: ethyl acetate = 10: 1) and recrystallized from a mixed solution of ethyl acetate-isopropyl ether.
1.83 g (yield: 59%, melting point: 137-139 ° C.) of (2- (3-phenylthioureido) -4,5-methylenedioxyphenoxy) methoxymethane are obtained.

(2) 1.77 g of (2- (3-phenylthioureido) -4,5-methylenedioxyphenoxy) methoxymethane was dissolved in a mixed solution of 20 ml of methanol and 20 ml of methylene chloride, and 2 ml of concentrated hydrochloric acid was added, Stir at room temperature for 7 hours. The solvent is distilled off under reduced pressure, the residue is extracted with ethyl acetate, washed and dried, and the solvent is distilled off under reduced pressure. Diethyl ether was added to the obtained residue, and collected by filtration.
2- (3-phenylthioureido) -4 described in Table 1 below.
1.15 g of 5-methylenedioxyphenol (yield: 7
5%, property: powder, IR: 3494, 3312, 159
6,1552, 1500 cm ^-1 ) is obtained.

Example 2 The corresponding raw material compound and phenylisocyanate were used in Example 1
Is treated in the same manner as above to obtain the compounds shown in Table 1 below.

[0081]

[Table 1]

Example 3 (1) A solution of 1.847M phosgene-dichloromethane solution (1.65 ml) in 100 ml of dichloromethane-
After cooling to 78 ° C., a mixed solution of (2-amino- (4,5-methylenedioxyphenoxy) methoxymethane 3.01 g, triethylamine 6.4 ml and dichloromethane 20 ml was added dropwise, and then the temperature was raised to 0 ° C. and the solvent was added. Dichloromethane (60 ml) is added to the residue to form a solution, and a solution of 3-aminomethylpyridine (1.65 g), triethylamine (3.2 ml) and dichloromethane (40 ml) is added dropwise at room temperature, and the mixture is further stirred for 1 hour. After drying, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel (solvent; chloroform: ethanol = 10: 1).
Purify. Further, it was recrystallized from ethyl acetate to produce {2- [3
3.00 g (yield: 59%, melting point: 134-135 ° C.) of-(3-pyridylmethyl) ureido] -4,5-methylenedioxyphenoxy} methoxymethane are obtained.

(2) 3.00 g of this product and 25 m of methanol
3 ml of concentrated hydrochloric acid is added to the mixed solution with 1, and the mixture is stirred at room temperature for 5 hours. Precipitated crystals were collected by filtration, recrystallized from methanol, and 1.11 g of 2- [3- (3-pyridylmethyl) ureido] -4,5-methylenedioxyphenol shown in Table 2 below.
(Yield: 38%, melting point: 167-170 ° C.) is obtained.

Examples 4 to 11 The corresponding starting compounds and phosgene or triphosgene are treated in the same manner as in Example 3 to obtain the compounds shown in Table 2 below.

[0085]

[Table 2]

[0086]

[Table 3]

Example 12 (1) A mixture of 2.478 g of 2-cyclohexyl-3-phenylpropionic acid, 1.6 ml of thionyl chloride and 25 ml of chloroform is heated under reflux for 2 hours. Evaporate under reduced pressure, add chloroform to the residue and evaporate again under reduced pressure. A solution of the residue in 10 ml of chloroform was added to (2-amino-4,
5-methylenedioxyphenoxy) methoxymethane 2.
Chloroform 25m of 103g and pyridine 0.95g
1 solution under ice-cooling, and stirred at room temperature for 30 minutes. The reaction solution was washed with water and dried, the solvent was distilled off, isopropyl ether was added to the crystalline residue, and the crystals were collected by filtration and recrystallized from ethyl acetate to give {2- (2-cyclohexyl-3-phenylpropionylamino) -4. , 5-methylenedioxyphenoxy} methoxymethane 2.191 g (yield: 50
%, Melting point: 146-148 ° C.).

(2) 2.13 g of this product, 1.5 m of concentrated hydrochloric acid
1, a mixture of 30 ml of methanol and 30 ml of dichloromethane is stirred at room temperature for 2 hours and further at 40 ° C. for 2 hours.
The reaction solution was evaporated to dryness under reduced pressure, and the crystalline residue was recrystallized from methanol to give 1.344 g of 2- (2-cyclohexyl-3-phenylpropionylamino) -4,5-methylenedioxyphenol shown in Table 3 below. Ratio: 71%, melting point: 17
1-174 ° C).

[0089]

[Table 4]

Reference Example 1 To 25.0 g of 1-amino-2-naphthol hydrochloride was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate.
After drying, the solvent is distilled off. To a solution of the residue in 200 ml of dimethylformamide (DMF), 4.95 g of 62% sodium hydride is added at 0 ° C, and the mixture is stirred at room temperature for 1 hour. A mixed solution of 9.7 ml of methoxymethyl chloride and 50 ml of DMF was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 1.5 hours. DMF
Is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with ethyl acetate.
The extract was washed and dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 3: 1) to give (1-aminonaphthalene-2-
15.5 g (yieloxy) methoxymethane (yield: 60
%, Properties: brown oil).

NMR (CDCl ₃ ): 3.54 (3H,
s), 4.23 (2H, s), 5.26 (2H, s),
7.23-7.46 (4H, m), 7.72-7.79
(2H, m) Reference Example 2 (1) 3.54 g of aniline, 9.3 ml of hydrochloric acid and 2 parts of water
Dissolve in 8.5 ml and under ice cooling, sodium nitrite 2.8
A solution of 8 g of water in 10 ml is added dropwise. This mixture was cooled with ice, and 5.00 g of sesamol (3,4-methylenedioxyphenol) and 5N aqueous sodium hydroxide solution 37.8.
Add dropwise to the mixed solution of ml and stir at the same temperature for 30 minutes. Concentrated hydrochloric acid was added dropwise to adjust the pH to 3, and the precipitated crystals were collected by filtration, washed, dried, and recrystallized from ethanol to give 2-phenylazo-4,5-methylenedioxyphenol 8.3.
7 g (yield: 95%, melting point: 118-120 ° C.) are obtained.

(2) A mixed solution of 7.00 g of this product and 70 ml of dimethylformamide (DMF) was cooled with ice to 62%.
1.23 g of sodium hydride are added. After stirring at room temperature for 20 minutes, the mixture was ice-cooled again and methoxymethyl chloride 2.4 was added.
Add 1 ml dropwise. After stirring at room temperature for 1 hour, DMF was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed and dried, the solvent was evaporated, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate =).
4: 1) and then recrystallized from hexane to give (2-phenylazo-4,5-methylenedioxyphenoxy) methoxymethane (6.90 g, yield: 83%, melting point: 81-83).
° C).

(3) 6.50 g of ethanol 100 of this product
10% Palladium-Carbon (Pd-C) 2 in ml solution
g, and catalytically reduced at room temperature and atmospheric pressure for 2 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 2 :).
1) 3.14 g of purified (2-amino-4,5-methylenedioxyphenoxy) methoxymethane (yield: 70
%, Melting point: 44-46 ° C.).

Reference Example 3 (1) Lithium aluminum hydride (LiAlH ₄ )
To a suspension of 3.8 g and tetrahydrofuran (THF) 100 ml, a mixed solution of (2,5-dimethoxyphenyl) acetic acid 19.8 g and THF 100 ml was added dropwise under ice cooling. After stirring at room temperature for 45 minutes, under ice cooling, 3.8 ml of water, 1
5.7 ml of 0% sodium hydroxide aqueous solution and 10 ml of water are sequentially added dropwise. Insoluble matter is filtered off and the filtrate is concentrated to
(2-Hydroxyethyl) -1,4-dimethoxybenzene 15.7 g (Yield: 85%, Property: Oil, IR: 3
351, 2941, 1590 cm ^-1 ) are obtained.

(2) 11 ml of phosphorus tribromide (PBr ₃ ) was added dropwise to 14.06 g of this product under ice cooling, and the temperature was raised to room temperature. After stirring for 2 hours, the reaction solution is poured into ice water and extracted with diethyl ether. The extract was washed and dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 5: 1) to give 2-
(2-Bromoethyl) -1,4-dimethoxybenzene 6.35 g (Yield: 34%, Property: Oil, IR: 29
51, 2834, 1501, 1225 cm ^-1 ).

(3) To 6.35 g of this product, boron tribromide (B
Br ₃ ) 1.66 ml was slowly added dropwise to 70 ° C.
Heat for 10 minutes. After cooling, 8.2 g of sodium carbonate
Of 150 ml of water is slowly added. After heating to 70 ° C., ice-cooling, acidification with 10% hydrochloric acid and extraction with diethyl ether. After drying the extract, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform: ethyl acetate = 10: 1) to give 5-hydroxy-.
1.287 g of 2,3-dihydrobenzofuran (yield: 3
6%, melting point: 110-112 ° C).

(4) This product (2.00 g) and p-anisidine (1.90 g) were treated in the same manner as in Reference Example 2 (1) to give 6- (4).
-Methoxyphenyl) azo-5-hydroxy-2,3-
3.52 g of dihydrobenzofuran (yield: 89%, melting point: 113-116 ° C.) are obtained.

(5) This product (3.05 g) was treated in the same manner as in Reference Example 2 (2) to give 6- (4-methoxyphenyl) azo-5.
3.13 g (yield: 88%, melting point: 89-91 ° C.) of -methoxymethoxy-2,3-dihydrobenzofuran are obtained.

(6) This product (3.13 g) was treated in the same manner as in Reference Example 2 (3) to give 6-amino-5-methoxymethoxy-.
1.33 g of 2,3-dihydrobenzofuran (yield: 68
%, Properties: brown oil, IR: 3450, 3369, 2
950, 2896, 1629, 1503 cm ^-1 ).

Reference Example 4 A mixture of 24.80 g of dicyclohexylamine, 27.86 g of benzaldehyde, 0.1 g of p-toluenesulfonic acid and 250 ml of toluene was added to Dean-Stark.
Heat to reflux for 3 hours using the equipment. The solvent is distilled off, the residue is dissolved in 250 ml of methanol, 0.5 g of 10% palladium-carbon (Pd-C) is added, and the mixture is subjected to medium pressure catalytic reduction for 2 hours at room temperature using a Parr reduction device. After removing the catalyst by filtration, the filtrate is concentrated, the residue is dissolved in 5% hydrochloric acid, and washed with hexane. The aqueous layer is made alkaline with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract is washed and dried, then the solvent is evaporated to remove N-cyclohexyl-N-
46.93 g of benzylamine (yield: 99%, property: oily substance) are obtained.

Reference Example 5 To a mixed solution of 8.30 g of N-benzyloxycarbonylaniline and 75 ml of dimethylformamide (DMF) was added 1.56 g of 62% sodium hydride under ice cooling, and the mixture was stirred at room temperature for 1 hour. Under ice cooling, a mixed solution of 7.48 g of ethyl 4-bromobutyrate and 25 ml of DMF was added dropwise, and the mixture was stirred overnight at room temperature. DMF was distilled off under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate, washed and dried, and then the solvent was distilled off.
The residue is purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1). The eluate is dissolved in 60 ml of methanol, 1 g of 10% palladium-carbon (Pd-C) is added, and catalytic reduction is carried out at room temperature and atmospheric pressure for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated and purified by silica gel chromatography (solvent; hexane: ethyl acetate = 4: 1) to give N- (3-ethyloxycarbonylpropyl) -N.
-3.2 g of phenylamine (yield: 42%, property: oily substance) are obtained.

Reference Example 6 1- (N-benzyloxycarbonylamino) naphthalene was treated in the same manner as in Reference Example 5 to obtain N- (3-ethyloxycarbonylpropyl) -N- (1-naphthyl) amine.

Reference Example 7 To a solution of 13.23 g of diisopropylamine in 250 ml of tetrahydrofuran (THF) was added 72 ml of 1.6 M butyllithium-hexane solution at -50 ° C, and the temperature was raised to -10 ° C. After cooling to −50 ° C. again, a mixed solution of 17.81 g of ethylcyclohexyl acetate and 75 ml of THF was dropped, and then the temperature was raised to −30 ° C. Hexamethylphosphoramide (HMPA) (20 ml) is added, benzyl bromide (13.7 ml) is added dropwise at the same temperature, and then the mixture is stirred at the same temperature overnight. After concentrating THF under reduced pressure, a saturated aqueous ammonium chloride solution is added to the residue, and the mixture is extracted with ethyl acetate. The extract is washed and dried, the solvent is evaporated, and the residue is subjected to a silica gel column to give a colorless oil.

This product was dissolved in 150 ml of ethanol,
Add 70 ml of 10% sodium hydroxide aqueous solution, and add 12
Heat to reflux for hours. After distilling off ethanol, add water and add 10
Adjust the pH to 1 with% hydrochloric acid. After extraction with ethyl acetate, washing and drying, the solvent was evaporated, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 2:
1) 9.57 g of purified 2-cyclohexyl-3-phenylpropionic acid (yield: 39%, melting point: 70-73)
° C).

[0105]

INDUSTRIAL APPLICABILITY The phenol derivative (1) of the present invention or a pharmacologically acceptable salt thereof has excellent lipid peroxidation inhibitory action, macrophage foaming inhibitory action, oxidized LDL production inhibitory action, ACAT inhibitory action, mouse antioxidant. Action, reperfusion-induced arrhythmia inhibitory action, cerebral edema inhibitory action, carbon tetrachloride-induced liver injury inhibitory action, etc. It is useful as a preventive or therapeutic drug for disorders and the like. In addition, the object of the present invention has low toxicity and high safety when used as a pharmaceutical compound.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/34 A61K 31/34 31/36 31/36 31/44 31/44 31/66 31 / 66 C07C 257/14 9451-4H C07C 257/14 275/32 9451-4H 275/32 279/18 9451-4H 279/18 327/40 7106-4H 327/40 335/18 7106-4H 335/18 C07D 213 / 40 C07D 213/40 307/79 307/79 317/66 317/66 405/12 213 405/12 213 (72) Inventor Hitoshi Kubota 3-39-6 (72) Inventor, Inagawa, Kawabe-gun, Hyogo Prefecture Keiko Saito 166 Enshoji Temple 2 Urawa City, Saitama Prefecture

Claims (6)

[Claims] 1. A compound of the general formula (1) (In the formula, R ⁰ represents a hydrogen atom, an alkyl group or an alkyloxy group, ^one of R ¹ and R ³ represents a hydrogen atom, and the other represents a naphthalene ring or an oxygen-containing bicyclic ring together with R ² and a benzene ring. Form a heterocyclic ring, W represents an oxygen atom, a sulfur atom or NR ⁷ , R ⁷ represents a hydrogen atom, an alkyl group,
R represents an aryl group, a hydroxyl group or an alkyloxy group, and R
⁴ represents a substituted or unsubstituted amino group or a substituted or unsubstituted alkyl group, and OR ⁵ represents an optionally protected hydroxyl group. ) And a pharmacologically acceptable salt thereof. 2. R ⁰ is a hydrogen atom, R ¹ is a hydrogen atom,
R ² and R ³ form a naphthalene ring together with a benzene ring,
W is an oxygen atom, and R ⁴ is mono- or di-substituted by a substituent selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group and a substituted or unsubstituted heterocyclic group. The compound according to claim 1, wherein the compound is an amino group. 3. R ⁰ is a hydrogen atom, R ³ is a hydrogen atom,
R ¹ and R ² together with the benzene ring form a dihydrobenzofuran ring or a 1,3-benzo [d] dioxole ring,
⁴ is (1) a mono- or di-substituted amino group having a substituent selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group and a substituted or unsubstituted heterocyclic group, or ( 2) The compound according to claim 1, which is a substituted alkyl group having a substituent selected from a substituted or unsubstituted alkyl group and a substituted or unsubstituted cycloalkyl group. 4. R ⁴ is a lower alkyl group substituted with a pyridyl group,
Lower alkyloxycarbonyl lower alkyl group, phenyl group-substituted lower alkyl group, cycloalkyl group, phenyl group which may be mono- or di-substituted by lower alkyl group, naphthyl group which may be substituted by hydroxyl group, hydroxyl group-substituted 2, A mono- or di-substituted amino group having a substituent selected from a 3-dihydrobenzofuranyl group and a lower alkylenedioxyphenoxy group, or a mono- or di-substituted lower alkyl group having a substituent selected from a phenyl group and an unsubstituted cycloalkyl group The compound according to claim 1, 2 or 3, which is 5. R ⁴ is a pyridylmethyl group, an ethoxycarbonylpropyl group, a phenylmethyl group, a cyclohexyl group, a phenyl group, a 2,6-diisopropyl phenyl group,
Mono or di having a substituent selected from naphthyl group, 2-hydroxynaphthyl group, 5-hydroxy- (2,3-dihydrobenzofuran) -6-yl group and 4,5-methylenedioxyphenol-2-yl group. Substituted amino group or 1-cyclohexyl-2-phenylethyl group, OR
The compound according to claim 1, 2 or 3, wherein ⁵ is a hydroxyl group. 6. 2- [3- (3-Pyridylmethyl) ureido] -4,5-methylenedioxyphenol, 2-
[3- (2,6-diisopropylpyrphenyl) ureido]
-4,5-Methylenedioxyphenol, 1- [3-
(3-Ethoxycarbonylpropyl) -3-phenylureido] -2-naphthol, 1- [3- (3-pyridylmethyl) ureido] -2-naphthol, 6- [3- (5
-Hydroxy-2,3-dihydrobenzofuran-6-yl) ureido] -5-hydroxy-2,3-dihydrobenzofuran, 2- [3- (4,5-methylenedioxyphenol-2-yl) ureido]- 4,5-methylenedioxyphenol, 2- [3- (3-ethoxycarbonylpropyl) -3- (1-naphthyl) ureido] -4,
5-methylenedioxyphenol, 1- (3-phenylureido) -2-naphthol, 1- [3- (2-hydroxynaphthalen-1-yl) ureido] -2-naphthol, 2- (3-phenylthioureido) ) -4,5-Methylenedioxyphenol, 2- (3-cyclohexyl-)
The compound according to claim 1, which is selected from 3-phenylmethylureido) -4,5-methylenedioxyphenol and 2- (2-cyclohexyl-3-phenylpropionylamino) -4,5-methylenedioxyphenol.