JPH09227495A - Phenol derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a novel phenol derivative which has excellent lipid peroxidation-inhibitory action, macrophage-foaming inhibitory action and oxidized low-density lipoprotein formation-inhibitory action with toxicity reduced, and is useful as a preventive or therapeutic agent for ischemic diseases, arteriosclerosis and inflammation. SOLUTION: This phenol derivative is represented by formula I [OR<0> is a (protected)OH; R<1> is H, a lower alkyl; R<2> is H, a (substituted) lower alkyl; R<3> is a (substituted) phenyl; X is O, S; as for R<4> -R<7> , R<4> is H, R<5> -R<7> are each H, an alkoxy, or R<6> is H and R<4> is an alkoxy and R<5> and R<7> are each H or an alkoxy] and its salts, from which 2-(3-phenylureido)-4-methoxyphenol and 2-[(3-(3,4-dichlorophenyl)-ureido]-4-methoxyphenol are excluded, typically 2-[(3-(4- chlorophenyl)ureido]-4-methoxyphenol. The compound of formula I is prepared by reaction of a compound of formula H(OR<00> is OR<0> ) with (tri)phosgene or thiophosgene followed by reaction of the product with a compound of formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel phenol derivative useful as a medicine and a method for producing the same.

[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.

Further, 2- (3-phenylureido) -4-methoxyphenol having an antioxidant effect and having a phenol skeleton is described in Japanese Patent Publication No. 49-13785, and Swiss Patent No. 509754 discloses: 2- {3-
Although (3,4-dichlorophenyl) ureido} -4-methoxyphenol is described, it is not described that it is effective for ischemic diseases, arteriosclerosis and the like.

By the way, the foam cells, which play an important role in the formation of atherosclerotic plaque, are LDs that have undergone oxidative alteration.
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.

On the other hand, the mechanism by which the lipid peroxidation reaction leads to cell membrane damage and eventually cell death has not been completely clarified, but enhancement of production of active oxygen plays an important role in such cell damage process. Is understood as a common perception. 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.

[0009]

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

[0010]

According to the present invention, there is provided a compound represented by the general formula [I]:

[0011]

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(Wherein OR ⁰ is a hydroxyl group which may be protected, R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom or a lower alkyl group which may have a substituent, and R ³ is a substituent). A phenyl group which may have a group, X is O, S or NR ⁸ , R ⁸ is a hydrogen atom, a lower alkyl group,
Aryl group, hydroxyl group or lower alkoxy group, R ⁴ ,
R ⁵ , R ⁶ and R ⁷ are (1) R ⁴ is a hydrogen atom,
R ⁵ , R ⁶ and R ⁷ are a hydrogen atom, an alkoxy group or a lower alkylthio group, or (2) R ⁴ is an alkoxy group or a lower alkylthio group, and R ⁵ and R ⁷ are a hydrogen atom, an alkoxy group or a lower alkylthio group. Base,
R ⁶ represents a hydrogen atom. The present invention relates to a therapeutic agent for ischemic disease and / or arteriosclerosis, which comprises as an active ingredient a phenol derivative or a pharmacologically acceptable salt thereof represented by

Furthermore, the present invention provides a novel compound, a phenol derivative represented by the general formula [I] (provided that 2- (3-
Phenylureido) -4-methoxyphenol and 2-
{3- (3,4-dichlorophenyl) ureido} -4-
Excludes methoxyphenol. ) Or a pharmacologically acceptable salt thereof.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION In the phenol derivative [I], as the hydroxyl group-protecting group for OR ⁰ , any of the conventional protecting groups which can be a hydroxyl group-protecting group can be used. For example, an acyl group or a lower alkoxy lower alkyl group. Examples thereof include a group, a lower alkoxycarbonyl group, an aralkyl group and the like, and an acyl group or a lower alkoxycarbonyl group is particularly preferable.

When the protecting group is an acyl group, examples of the acyl group include an aliphatic acyl group and an aromatic acyl group, and a lower alkanoyl group or a cycloalkanoyl group is particularly preferable as the aliphatic acyl group.

Here, the acyl group may have a substituent, and examples of such a substituent include alanine, valine, glycine, lysine and the like α-amino acid having a hydroxyl group removed. Can be mentioned. In addition, the amino group of a group obtained by removing a hydroxyl group from an α-amino acid may be protected. Examples of this protecting group include an acyl group such as an acetyl group, a lower alkanoyl group such as a propionyl group, a lower alkoxycarbonyl group or a phenyl lower alkoxycarbonyl group such as a benzyloxycarbonyl group.

The substituent on the lower alkyl group of R ² may be an optionally esterified carboxyl group, halogen atom, hydroxyl group, aryl group, amino group, cyano group,
Examples thereof include a nitro group, a sulfonyl group, a carbamoyl group, a lower alkoxy group, a lower alkylthio group, and a formyl group. Among them, an optionally esterified carboxyl group is preferable.

The substituent on the phenyl group of R ³ may be an esterified carboxyl group-substituted lower alkenyl group, an esterified carboxyl group, a halogen atom, a hydroxyl group, a lower alkoxy group or an esterified carboxyl group. Optionally substituted carboxyl-substituted lower alkoxy group, trihalogeno-substituted lower alkyl group, lower alkyl group, lower cycloalkyl group, amino group, nitro group, cyano group, formyl group, sulfonyl group, carbamoyl group, lower alkylthio group, mercapto Group, a hydrazino group, an aryl group and the like, but especially, a carboxyl group-substituted lower alkenyl group which may be esterified, a carboxyl group which may be esterified, a halogen atom, a hydroxyl group, a lower alkoxy group, esterified Carboxyl group which may be換低 grade alkoxy group, a trihalogeno-substituted lower alkyl group or a lower alkyl group is preferred.

The substituents on the phenyl group of R ³ may have the same or different 1 to 4 substituents. When the substituent on the phenyl group of R ³ is a hydroxyl group, the hydroxyl group may be protected, and examples of the protecting group include those defined for R ⁰ .

R ² is an esterified carboxyl group-substituted lower alkyl group, R ³ is an esterified carboxyl group-substituted lower alkenyl group, an esterified carboxyl group, or an esterified carboxyl group-substituted lower alkoxy group. In the case of a phenyl group which may be substituted with a group represented by the above formula, examples of the ester group include a lower alkyl group and an aralkyl group.

Examples of the aryl group for R ⁸ when X is represented by NR ⁸ include a phenyl group and a naphthyl group. As X, an oxygen atom or a sulfur atom is preferable, and an oxygen atom is particularly preferable.

Among the phenol derivatives [I] of the present invention, preferred compounds are those represented by the formula (1)
R ⁴ is a hydrogen atom, R ⁵ , R ⁶ and R ⁷ are hydrogen atoms,
An alkoxy group or a lower alkylthio group, or (2) R ⁴ is an alkoxy group or a lower alkylthio group, R ⁵ and R ⁷ are hydrogen atoms, an alkoxy group or a lower alkylthio group, and R ⁶ is a hydrogen atom Compounds.

Further, among the compounds of the present invention, as a compound preferable in terms of efficacy, in the general formula [I], OR ⁰ is a hydroxyl group which may be protected by an acyl group or a lower alkoxycarbonyl group, and R ² is A hydrogen atom, a lower alkyl group or an optionally esterified carboxyl group-substituted lower alkyl group, wherein R ³ is a phenyl group, or an optionally esterified carboxyl group-substituted lower alkenyl group, optionally esterified A phenyl group substituted with a carboxyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, an optionally esterified carboxyl-substituted lower alkoxy group, a trihalogeno-substituted lower alkyl group and a lower alkyl group, and X is O
Another example is a compound which is S.

Among the phenol derivatives [I] of the present invention,
Other preferred compounds include those represented by the general formula [I]:
Examples include compounds in which OR ⁰ is a hydroxyl group, R ¹ is a hydrogen atom, and X is an oxygen atom.

The phenol derivative [I] of the present invention may have an optically active substance based on asymmetric carbon, but the present invention includes any of these optical isomers and mixtures thereof.

The phenol derivative [I] of the present invention can be used in medicinal use either in a free form or in the form of a pharmaceutically acceptable salt. Examples of such pharmacologically acceptable salts include inorganic acid salts such as hydrochloride, sulfate and hydrobromide, acetate, fumarate, oxalate, maleate and methanesulfonate. Examples include organic acid salts. 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 phenol derivative [I] of the present invention or a salt thereof can be administered orally or parenterally,
In addition, according to a conventional method, it can be used as an appropriate pharmaceutical preparation such as a tablet, a granule, a capsule, a powder, an injection and an inhalant.

The dose of the phenol derivative [I] of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, age, weight and condition of the patient, but in the case of oral administration per day, It is preferably 5 to 50 mg / kg, and 0.1 to 10 mg / kg for parenteral administration.

The compound represented by the general formula [I] of the present invention can be prepared by various methods, for example, [method A] and [method B] shown below.
Alternatively, it can be produced by [Method C].

[Method A] The phenol derivative [I] of the present invention in which X is O or S has the general formula [c]

[0031]

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(In the formula, OR ⁰⁰ represents an optionally protected hydroxyl group, and other symbols have the same meanings as described above.)
An aniline derivative or a salt thereof, and phosgene,
Reacting with triphosgene or thiophosgene, and then reacting with the general formula [b]

[0033]

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(Wherein the symbols have the same meanings as described above), the compound is reacted with an amine derivative or a salt thereof, and when OR ⁰⁰ is a protected hydroxyl group, the protecting group for the hydroxyl group is optionally removed. It can be manufactured by

[Method B] The phenol derivative [I] of the present invention, in which R ² is a hydrogen atom, has the general formula [c]

[0036]

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(Wherein the symbols have the same meanings as described above) and an aniline derivative or a salt thereof, and a general formula [d]

[0038]

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(Wherein the symbols have the same meanings as described above), the isocyanate derivative represented by
When R ⁰⁰ is a protected hydroxyl group, it can be produced by removing the protective group for the hydroxyl group, if desired.

[Method C] Further, the phenol derivative [I] of the present invention comprises (1) an aniline derivative [c] or a salt thereof and a general formula [e].

[0041]

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(Wherein the symbols have the same meanings as described above) or by reacting with a carbamic acid ester derivative, or (2) general formula [f]

[0043]

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(Wherein the symbols have the same meanings as described above), the phenylcarbamic acid ester derivative is reacted with the amine derivative [b], and when OR ⁰⁰ is a protected hydroxyl group, it is optionally selected. It can be produced by removing the protective group for the hydroxyl group.

Examples of the salt of the amine derivative [b] or the aniline derivative [c] include salts with inorganic acids such as hydrochlorides and sulfates and salts with inorganic bases such as alkali metal salts and alkaline earth metal salts. Can be used.

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

[Method A]: The reaction of aniline derivative [c] or its salt with phosgene, triphosgene or thiophosgene and the subsequent reaction with amine derivative [b] or its salt are carried out 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 and the like, and as a solvent, dichloromethane, dimethyl sulfoxide, chloroform, diethyl ether, tetrahydrofuran, toluene, benzene, dioxane. , Dimethylformamide, ethylene glycol dimethyl ether, 1,2-dichloroethane and the like can be preferably used. The present reaction suitably proceeds at -30 to 100 ° C, especially 0 to 50 ° C.

[Method B]: The reaction of the aniline derivative [c] or its salt with the isocyanate derivative [d] is carried out by using dimethyl sulfoxide, dimethylacetamide, dimethylformamide, hexamethylphosphoramide, sulfolane,
It can be carried out in a suitable solvent such as 1,3-dimethyl-2-imidazolidinone, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, dichloromethane or diethyl ether or without solvent. This reaction is -30 to 100 ° C, especially 0 to 50 ° C.
The process proceeds favorably.

[Method C]: (1) The reaction of aniline derivative [c] or a salt thereof with compound [e] is carried out by reacting benzene, cyclohexane, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran. It can be carried out in a suitable solvent. In addition, this reaction is from 50 ℃
It proceeds suitably at 150 ° C, especially 50 to 100 ° C.

(2) The reaction of the phenylcarbamic acid ester derivative [f] 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. Further, this reaction is carried out at 50 ° C to 150 ° C.
In particular, it proceeds suitably at 50 to 100 ° C.

In the above [Method A], [Method B] and [Method C], when OR ⁰⁰ is a protected hydroxyl group, the protecting group for the hydroxyl group may be removed by a known method, if desired. Removal of the protecting group depends on the type of the protecting group,
It can be carried out by a usual method such as hydrolysis, acid treatment, reduction and the like according to a conventional method.

The phenol derivative [I] thus obtained
When OR ^{0 of} is a hydroxyl group, the hydroxyl group can be further protected, if desired, by a known method, for example, by acylation. The acylation reaction is carried out according to a conventional method,
For example, it can be carried out using a free acid such as cyclo-lower alkanoic acid, a lower alkanoic acid which may have a substituent, and a reactive derivative thereof. Examples of the reactive derivative include acid halides, acid anhydrides, activated amides and activated esters. The reaction can be carried out according to a conventional method, but in the presence of a base (triethylamine, pyridine, dimethylaminopyridine, sodium hydride, hexamethylphosphoric triamide, etc.) as an acylating agent, for example, when an acid halide is used. , In a suitable solvent (methylene chloride, tetrahydrofuran, etc.) or without solvent. When a free acid is used as the acylating agent, it is preferable to carry out the reaction in the presence of a conventional condensing agent.

The reaction of acylating with a lower alkoxycarbonyl group may be carried out in the same manner as the above-mentioned acylation reaction using a lower alkyl carbonate, and other conventional protecting groups may be introduced into the hydroxyl group by a conventional method. it can.

The phenol derivative [I] of the present invention can also be produced by interconverting the desired product obtained as described above into another phenol derivative. Such an interconversion reaction may be appropriately selected according to the kind of the substituent that the compound has, and can be carried out, for example, as in the following methods (a) to (d).

Method (a): R ² is a carboxyl-substituted lower alkyl group and / or R ³ is a phenyl group substituted with a carboxyl-substituted lower alkenyl group, a carboxyl group or a carboxyl-substituted lower alkoxy group. A phenol derivative [I] has a corresponding R ² esterified carboxyl group-substituted lower alkyl group and /
Alternatively, a compound in which the corresponding R ³ is a phenyl group substituted with a group selected from an esterified carboxyl group-substituted lower alkenyl group, an esterified carboxyl group or an esterified carboxyl group-substituted lower alkoxy group is used as an inorganic base. Alternatively, it can be produced by hydrolysis in the presence of an inorganic acid. As the inorganic base,
Potassium hydroxide and the like can be preferably used, and as the inorganic acid, hydrochloric acid, hydrobromic acid and the like can be preferably used. The reaction using an inorganic base suitably proceeds at 0 ° C to 100 ° C, and the reaction using an inorganic acid suitably proceeds at 0 ° C to 50 ° C.

[0056] (b) Method: R ² is a phenol derivative is a lower alkyl group which may have a substituent (I) can be prepared by the corresponding R ² is alkyl the compound is a hydrogen atom . Alkylation can be carried out by reacting a lower alkyl halide (lower alkyl chloride, lower alkyl bromide, etc.) or lower alkyl sulfonate (methane sulfonate, toluene sulfonate, etc.) in the presence of a deoxidizing agent. As the deoxidizing agent, an alkali metal hydroxide, an alkali metal hydrogencarbonate, an alkali metal carbonate, an organic base (such as triethylamine and pyridine) can be preferably used. This reaction is 0-5
Properly proceeds at 0 ° C.

[0057] (c) a phenol derivative wherein R ³ is hydroxy-substituted phenyl group (I) is prepared by hydrolyzing a hydroxy-substituted phenyl group where the corresponding R ³ protected compound in the presence of an inorganic acid be able to. Hydrochloric acid, hydrobromic acid and the like can be preferably used as the inorganic acid. This reaction suitably proceeds at 0 ° C to 50 ° C.

(D) The phenol derivative [I] in which X is NR ⁸ is the same as the corresponding phenol derivative [I] in which X is a sulfur atom, and is represented by the general formula R ⁸ NH ₂ (wherein R ⁸ is the same as above). It has a meaning.) It can manufacture by reacting the compound shown.

The solvent used in the reactions described in the above (a) to (d) is not particularly limited as long as it is an inert solvent for the reaction, and examples thereof include dioxane, ethylene glycol dimethyl ether, dimethylacetamide, dimethylformamide, hexamethyl. Phosphoramide, benzene, tetrahydrofuran, toluene, ethyl acetate, lower alcohol, methylene chloride, chloroform, carbon tetrachloride, 1,3-dimethyl-2-imidazolidinone, acetic acid, diethyl ether, dimethoxyethane, dimethyl sulfoxide, acetone water or A mixed solvent thereof can be appropriately used.

Amine derivative [b] of the raw material compound of the present invention
Is, for example, the general formula [h]

[0061]

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(However, Z ¹ represents an amino-protecting group,
Other symbols have the same meaning as described above. ) And a compound represented by the general formula [i]

[0063]

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(Wherein Y ² is a halogen atom and other symbols have the same meanings as described above), and then the protective group is removed to produce the compound.

In the starting compound [c], the aniline derivative [c] in which R ¹ is a hydrogen atom has the general formula [g]

[0066]

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(Where the symbols have the same meanings as described above), the compound can be produced by reducing the compound after azidation. Further, the aniline derivative [c] in which R ¹ is a lower alkyl group is prepared by introducing one protecting group into the amino group of the aniline derivative [c] in which R ¹ is a hydrogen atom, and then the compound represented by the general formula [n]

[0068]

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(Wherein Y represents a halogen atom and other symbols have the same meanings as described above), and then the protective group is removed.

The carbamic acid ester derivative [e] or the phenylcarbamic acid ester derivative [f] can be produced, for example, by a method of reacting an amine derivative [b] or an aniline derivative [c] with phenyl chloroformate.

In the present invention, examples of the alkoxy group include those having 1 to 16 carbon atoms, and examples of the lower alkyl group and the lower alkoxy group include those having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms. Also, a lower alkenyl group,
The lower alkanoyl group has 2 to 7 carbon atoms, especially 2
~ 5 are mentioned. Furthermore, examples of the cycloalkyl group include those having 3 to 8 carbon atoms, particularly those having 3 to 6 carbon atoms.
Halogen atoms include chlorine, bromine, fluorine or iodine. Examples of the aryl group include a phenyl group, a lower alkoxyphenyl group and a naphthyl group.

Specific synthetic methods for the compounds of the present invention will be shown below as examples.

[0073]

【Example】

Example 1 (1) 1.5 g of (2-amino-4-methoxyphenoxy) methoxymethane and 1.26 g of N- (4-chlorophenyl) isocyanate were added to tetrahydrofuran (25 m).
l) After stirring in a solvent at room temperature for 1.5 hours, the solvent is distilled off under reduced pressure. Water is added to the residue, extracted with ethyl acetate, washed and dried, and the solvent is evaporated under reduced pressure. The obtained crystalline residue was recrystallized from a mixed solution of isopropyl ether-ethyl acetate to give [2- {3- (4-chlorophenyl) ureido} -4-methoxyphenoxy] methoxymethane as shown in Table 1 below.
87 g (yield 69%) are obtained.

Melting point (° C.): 128-130 (2) [2- {3- (4-chlorophenyl) ureido}
-4-Methoxyphenoxy] methoxymethane 1.75 g
Concentrated hydrochloric acid (3 ml) is added to a methanol (50 ml) solution of and the mixture is stirred at room temperature for 6 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. The obtained crystals were recrystallized from ethyl acetate to give 1.07 g of 2- [3- (4-chlorophenyl) ureido] -4-methoxyphenol shown in Table 2 below (yield 70
%).

Melting point (° C.): 184-186 Examples 2 to 11 Corresponding aniline derivative [c] and phenyl (or 4-chlorophenyl) isothiocyanate or phenyl isocyanate were treated in the same manner as in Example 1 to give the following 1st And the compounds listed in Table 2 are obtained.

[0076]

[Table 1]

[0077]

[Table 2]

Example 12 (1) Triphosgene 1.9 g of dichloromethane (10 m
1) The solution was cooled to −78 ° C. and 2.4 g of (2-amino-4-methoxyphenoxy) methoxymethane and triethylamine (2.7 ml) in dichloromethane (10 ml).
After dropping the solution, the temperature is raised to 0 ° C., and the solvent is distilled off under reduced pressure. Dichloromethane (10 ml) was added to the residue to give a solution, and at room temperature (2-amino-4-methoxyphenoxy) methoxymethane 2.4 g and triethylamine (2.7 m).
A solution of l) in dichloromethane (10 ml) is added dropwise, and the mixture is further stirred for 1.5 hours. The solvent was distilled off under reduced pressure, the residue water was added The crystals were collected by filtration, the washed and dried, the recrystallized following Table 3, wherein the ethyl acetate N, N ^'- bis (2-methoxymethoxy -5 -Methoxyphenyl) urea 3.4 g
(Yield 67%) is obtained.

[0079] mp: 183-185 ℃ (2) N, N '- bis (2-methoxymethoxy-5-methoxyphenyl) urea 3.0g methanol (20 m
l) and acetone (20 ml) solution in concentrated hydrochloric acid (2 ml)
And stir at room temperature for 18 hours. The solvent was distilled off under reduced pressure,
The residue is extracted with ethyl acetate, washed and dried, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform: ethanol = 20: 1), recrystallized from ethyl acetate and described in Table 2 below.
1.5 g of {N- (2-hydroxy-5-methoxyphenyl) ureido} -4-methoxyphenol (yield 65
%).

Melting point (° C.): 164-166 Examples 13 to 18 The corresponding aniline derivative [c] and phosgene or triphosgene and the corresponding amine derivative [b] were treated in the same manner as in Example 12 to give the following third and third examples. 4 Obtain the compounds listed in Table.

[0081]

[Table 3]

[0082]

[Table 4]

Example 19 (1) Phosgene 2.4 g of dichloromethane (30 ml)
The solution was cooled to −78 ° C., a solution of 3.0 g of 3-methoxycarbonylaniline hydrochloride and triethylamine (7 ml) in dichloromethane (100 ml) was added dropwise, and then 0 ° C.
The temperature is raised to and the solvent is distilled off under reduced pressure. Dichloromethane (80 ml) was added to the residue, and a mixed solution of (2-amino-4-methoxyphenoxy) methoxymethane (2.52 g), triethylamine (2 ml) and dichloromethane (20 ml) was added dropwise at room temperature, and the mixture was further stirred at room temperature for 1 hour. To do. After washing and drying the reaction solution, the solvent was distilled off under reduced pressure, the residue was recrystallized from ethyl acetate, and {2- [3- (3-
Methoxycarbonylphenyl) ureido] -4-methoxyphenoxy} methoxymethane 4.3 g (yield 85%)
Get.

(2) {2- [3- (3-methoxycarbonylphenyl) ureido] -4-methoxyphenoxy}
Methoxymethane 3.6 g, 85% potassium hydroxide 2.0
g, a mixed solution of 2 ml of water and 200 ml of methanol,
Heat to reflux for 4 hours. After distilling off methanol under reduced pressure, water is added and the mixture is washed with ether. The pH of the aqueous layer is adjusted to 1 with 10% hydrochloric acid, and the precipitated crystals are collected by filtration. This was purified by silica gel column chromatography (solvent; chloroform: methanol = 3: 1) and {2- [3 shown in Table 6 below.
-(3-Carboxyphenyl) ureido] -4-methoxyphenoxy} methoxymethane 2.76 g (yield 80
%).

(3) {2- [3- (3-Carboxyphenyl) ureido] -4-methoxyphenoxy} methoxymethane 2.7 g of a mixed solution of methanol (60 ml) and chloroform (30 ml) was added with 10% hydrochloric acid (20 ml). )
And stir overnight at room temperature. The solvent is distilled off under reduced pressure, and the precipitated crystals are collected by filtration. This was subjected to silica gel column chromatography (solvent; chloroform: ethanol = 5:
Purified in 1), recrystallized from an acetone-ether mixed solution, and 2- {3- (3-carboxyphenyl) ureido} -4-methoxyphenol 1.06 g shown in Table 7 below.
(Yield 45%) is obtained.

Melting point: 173-175 ° C. Example 20 Corresponding aniline derivative [c], phosgene and amine derivative [b] were treated in the same manner as in Example 19 to give the following 5th and 6th components.
And the compounds listed in Table 7 are obtained.

[0087]

[Table 5]

[0088]

[Table 6]

[0089]

[Table 7]

Example 21 (1) Phosgene (3.97 g) in dichloromethane (100 m)
l) The solution was cooled to −78 ° C. and 4.90 g of (2-amino-4-methoxyphenoxy) methoxymethane and 11.19 ml of triethylamine in dichloromethane (100 m
l) After dropping the solution, the temperature is raised to 0 ° C., and the solvent is distilled off under reduced pressure. Dichloromethane (100 ml) was added to the residue,
N-5- (tert-butoxycarbonyl) pentyl-N-phenylamine at room temperature 7.05 g, triethylamine (5.60 ml) and dichloromethane (100 ml).
The mixed solution of is added dropwise, and the mixture is further stirred at room temperature overnight. After washing and drying the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1) and shown below {2- [3-phenyl-3-. 10.53 g (yield 83%) of [5- (tert-butoxycarbonyl) pentyl] ureido] -4-methoxyphenoxy} methoxymethane is obtained.

[0091]

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(2) {2- [3-phenyl-3- [5-
(Tert-Butoxycarbonyl) pentyl] ureido] -4-methoxyphenoxy} methoxymethane 2.8
A mixture of 0 g, 0.64 g of anisole, 0.5 ml of water and 15 ml of a 4N hydrogen chloride-dioxane solution was cooled with ice,
Stir for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, washed and dried, the solvent was distilled off, the residue was purified by silica gel column chromatography (solvent; chloroform: ethanol = 15: 1), and crystallized with isopropyl ether. Therefore, 2- [3-phenyl-
0.72 g (yield 33%) of 3- (5-carboxypentyl) ureido] -4-methoxyphenol is obtained.

Melting point: 131-134 ° C.

[0094]

[Chemical 21]

Example 22 A mixed solution of 2.6 g of 2- (3-phenylureido) -4-methoxyphenol, triethylamine (1.7 ml) and dichloromethane (30 ml) was cooled to -50 ° C, and ethyl chlorocarbonate (1 0.15 ml) is added dropwise. After stirring at the same temperature for 1.5 hours, 10% hydrochloric acid is added and the temperature is returned to room temperature. The organic layer is separated, washed with water and dried, and then the solvent is distilled off under reduced pressure. An ether-hexane mixture was added to the crystalline residue, which was collected by filtration and recrystallized from a mixture of ethyl acetate-hexane to give O-ethoxycarbonyl-2- as shown in Table 8 below.
2.3 g (yield: 70%) of (3-phenylureido) -4-methoxyphenol is obtained.

Melting point (° C): 149-151 Examples 23 to 28 2- (3-phenylureido) -4-methoxyphenol and the corresponding starting compound were treated in the same manner as in Example 22 to give the compounds shown in Table 8 below. To get

[0097]

[Table 8]

Reference Example 1 A suspension of 2.13 g of sodium hydride (62%) in dimethylformamide (DMF) (100 ml) was cooled with ice.
A solution of 11.38 g of N-benzyloxycarbonylaniline in DMF (70 ml) is added dropwise. After stirring at room temperature for 30 minutes, the mixture was ice-cooled again, and a solution of 6-bromohexanoic acid tert-butyl ester 13.20 g in DMF (30 ml) was added dropwise. After stirring overnight at room temperature, the solvent is distilled off under reduced pressure, water is added to the residue and the mixture is extracted with ethyl acetate, washed and dried, and then the solvent is distilled off. Dissolve the residue in methanol (180 ml) 1
2% of 0% palladium-carbon is added and catalytic reduction is performed at room temperature and atmospheric pressure for 2 hours. The catalyst was filtered off, and the filtrate was concentrated and purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1) to give N-5- (tert-butoxycarbonyl) pentyl-N-phenylamine 11.16.
g (yield: 85%) are obtained.

Melting point (° C.): 32-34 Reference Example 2 Sodium hydride (62%) 426 mg DMF (10
ml) suspension under ice cooling with 4-aminophenol 1.09
g in small portions. After stirring at room temperature for 20 minutes, the mixture is ice-cooled again, and 1.22 ml of ethyl bromoacetate is added dropwise. After stirring at room temperature for 30 minutes, the solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. The extract was washed and dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (solvent; chloroform: ethyl acetate = 4: 1) to give 4-ethoxycarbonylmethyloxyphenylamine (1.11 g, yield). : 57%) as a syrup.

Reference Example 3 (1) Sodium hydride (62%) 4.22 g of DMF
A DMF solution (20 ml) of 12.41 g of 4-methoxyphenol was added dropwise to the suspension (100 ml) under ice cooling.
After stirring at room temperature for 30 minutes, the mixture is ice-cooled again and 8.86 g of methoxymethane chloride is added dropwise. After further stirring at room temperature for 1 hour, the solvent is distilled off under reduced pressure, water is added to the residue for extraction with ether, washing and drying, and then the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; methyl acetate: hexane =
1:20) to obtain 13.57 g (yield: 81%) of O-methoxymethyl-4-methoxyphenol.

(2) A solution of 11.86 g of O-methoxymethyl-4-methoxyphenol in THF (50 ml) was added to
After cooling to 78 ° C., 91 ml of 1N sec-butyllithium hexane solution is added dropwise. After stirring for another 15 minutes, p
-Toluenesulfonyl azide 15 g THF (30 m
l) Add the solution dropwise and stir for a further 2 hours. The above reaction solution was cooled with ice to give 0.3N sodium pyrophosphate (Na ₄ P ₂
It is poured into 253 ml of O ₇ ) aqueous solution, stirred for 1 hour, added with water, extracted with ether, washed and dried, and then the solvent is distilled off. The residue is subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1), and the eluate is concentrated to obtain 13.75 g of a residue. Add this to THF (10
0 ml) and was added dropwise to 150 ml of a THF suspension of 5 g of lithium aluminum hydride under ice cooling.
After stirring for 2 hours, water (5 ml), 15% aqueous sodium hydroxide solution (5 ml) and water (15 ml) were sequentially added, the insoluble matter was filtered off, the filtrate was concentrated, extracted with ether, washed and dried, The solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate =
4: 1) and purified (2-amino-4) shown in Table 9 below.
1.80 g (yield: 14%) of (methoxyphenoxy) methoxymethane are obtained as a colorless syrup.

Reference Examples 4 to 9 The corresponding starting compounds were treated in the same manner as in Reference Example 3 to obtain the compounds shown in Table 9 below.

[0103]

[Table 9]

Reference Example 10 (1) A solution of 3-methoxyphenol (25.0 g) in carbon disulfide (100 ml) was added dropwise to a solution of bromine (10.3 ml) in carbon disulfide (20 ml) under ice cooling. After stirring for 30 minutes at room temperature, water is added to extract with ether, and after washing and drying,
The solvent is distilled off. The residue was distilled off under reduced pressure to give 3-methoxy-6.
34.8 g (yield: 85%) of bromophenol are obtained.

Boiling point (° C.): 96-98 ° C./4 mmHg (2) Sodium hydride (60%) 1.9 g DMF
Under ice cooling, a DMF solution (20 ml) of 9.5 g of 3-methoxy-6-bromophenol was added to the (100 ml) suspension little by little. After stirring at room temperature for 30 minutes, the mixture was ice-cooled again and 3.7 ml of methoxymethane chloride was added. After further stirring at room temperature for 1 hour, the solvent is distilled off under reduced pressure, water is added to the residue for extraction with ether, washing and drying, and then the solvent is distilled off. The residue is purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 9: 1) to give a colorless syrup. This THF solution (100 ml) was cooled to -78 ° C and 2.
20 ml of 34N n-butyllithium hexane solution is added dropwise little by little. After stirring for further 30 minutes, a THF solution (20 ml) of 9.2 g of p-toluenesulfonyl azide was gradually added dropwise, and the mixture was further stirred for 2 hours. Next, 142 ml of a 0.3 N sodium pyrophosphate (Na ₄ P ₂ O ₇ ) aqueous solution is poured into the above reaction solution, and the mixture is stirred at 0 to 5 ° C. for 2 hours.
The insoluble matter was filtered off, the filtrate was extracted with ethyl acetate, washed and dried, the solvent was evaporated, the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 9: 1), and the eluate was removed. After concentration, it is dissolved in THF (20 ml) and added dropwise to a THF suspension (80 ml) of 3.2 g of lithium aluminum hydride under ice cooling. After stirring for 1 hour,
Water (3.2 ml), 15% aqueous sodium hydroxide solution (3.2 ml) and water (9.6 ml) are added successively, and the insoluble matter is filtered, extracted with ether, washed and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1) and 2.2 g of (2-amino-5-methoxyphenoxy) methoxymethane shown in Table 10 below (yield: 26%). As a colorless syrup.

[0106]

[Table 10]

[0107]

INDUSTRIAL APPLICABILITY The phenol derivative [I] of the present invention or a pharmacologically acceptable salt thereof has an excellent lipid peroxidation inhibitory action, macrophage foaming inhibitory action, oxidized LDL production inhibitory action, ACAT inhibitory action, mouse antioxidant. Since it has an action, a reperfusion-induced arrhythmia inhibitory action, etc., it is useful as a preventive or therapeutic drug for ischemic diseases (myocardial infarction, cerebral infarction, reperfusion injury, etc.), arteriosclerosis, inflammation 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 C07C 277/08 9451-4H C07C 277/08 279/18 9451-4H 279/18 335/18 7106- 4H 335/18 (72) Inventor Hitoshi Kubota 3-39-6 Shirokane, Inagawa-cho, Kawabe-gun, Hyogo Prefecture (72) Inventor Keiko Saito 166 Enshoji Temple 2 Urawa-shi, Saitama Prefecture

Claims (12)

[Claims] 1. A compound of the general formula [I] (Wherein OR ⁰ is a hydroxyl group which may be protected, R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom or a lower alkyl group which may have a substituent, and R ³ has a substituent. Optionally a phenyl group, X is O, S or NR ⁸ , R ⁸ is a hydrogen atom, a lower alkyl group, an aryl group,
Hydroxyl group or lower alkoxy group, R ⁴ , R ⁵ , R ⁶ and R ⁷
(1) R ⁴ is a hydrogen atom, R ⁵ , R ⁶ and R ⁷ are a hydrogen atom, an alkoxy group or a lower alkylthio group, or (2) R ⁴ is an alkoxy group or a lower alkylthio group, R ⁵ and R ⁷ represent a hydrogen atom, an alkoxy group or a lower alkylthio group, and R ⁶ represents a hydrogen atom. ) Phenol derivative (provided that 2- (3-
Phenylureido) -4-methoxyphenol and 2-
{3- (3,4-dichlorophenyl) ureido} -4-
Excludes methoxyphenol. ) Or a pharmacologically acceptable salt thereof. 2. The compound according to claim 1, wherein R ⁴ is a hydrogen atom, and R ⁵ , R ⁶ and R ⁷ are a hydrogen atom, an alkoxy group or a lower alkylthio group. 3. The compound according to claim 1, wherein R ⁴ is an alkoxy group or a lower alkylthio group, R ⁵ and R ⁷ are hydrogen atoms, an alkoxy group or a lower alkylthio group, and R ⁶ is a hydrogen atom. Wherein OR ⁰ is hydroxyl group which may be protected with an acyl group or a lower alkoxycarbonyl group, R ²
Is a hydrogen atom, a lower alkyl group or an optionally esterified carboxyl group-substituted lower alkyl group,
R ³ is a phenyl group, or an optionally esterified carboxyl group-substituted lower alkenyl group, an optionally esterified carboxyl group, a halogen atom, a hydroxyl group,
A phenyl group substituted with a group selected from a lower alkoxy group, an optionally esterified carboxyl group-substituted lower alkoxy group, a trihalogeno-substituted lower alkyl group and a lower alkyl group, and X is O or S. The compound of 2 or 3. 5. The compound according to claim 1, 2, 3 or 4, wherein OR ⁰ is a hydroxyl group, R ¹ is a hydrogen atom and X is an oxygen atom. 6. A compound represented by the general formula [c]: (However, OR ⁰⁰ is a hydroxyl group which may be protected, R ¹ is a hydrogen atom or a lower alkyl group, and R ⁴ , R ⁵ , R ⁶ and R ⁷ are (1) R ⁴ is a hydrogen atom and R ^{5 is} , R ⁶ and R ⁷
Is a hydrogen atom, an alkoxy group or a lower alkylthio group, or (2) R ⁴ is an alkoxy group or a lower alkylthio group, R ⁵ and R ⁷ are hydrogen atoms, an alkoxy group or a lower alkylthio group, and R ⁶ is Represents a hydrogen atom. ) Is reacted with aniline derivative or a salt thereof and phosgene, triphosgene or thiophosgene,
Then, the general formula [b] (Wherein R ² represents a hydrogen atom or a lower alkyl group which may have a substituent, and R ³ represents a phenyl group which may have a substituent). When OR ⁰⁰ is a protected hydroxyl group, the protecting group for the hydroxyl group is optionally removed, and if necessary, the product is converted into a pharmacologically acceptable salt thereof. (However, OR ⁰ is a hydroxyl group which may be protected, X ¹ is O
Alternatively, it represents S, and other symbols have the same meanings as described above. ) Phenol derivative (provided that 2- (3-
Phenylureido) -4-methoxyphenol and 2-
{3- (3,4-dichlorophenyl) ureido} -4-
Excludes methoxyphenol. ) Or a method for producing a pharmacologically acceptable salt thereof. 7. A compound represented by the general formula [c]: (However, OR ⁰⁰ is a hydroxyl group which may be protected, R ¹ is a hydrogen atom or a lower alkyl group, and R ⁴ , R ⁵ , R ⁶ and R ⁷ are (1) R ⁴ is a hydrogen atom and R ^{5 is} , R ⁶ and R ⁷
Is a hydrogen atom, an alkoxy group or a lower alkylthio group, or (2) R ⁴ is an alkoxy group or a lower alkylthio group, R ⁵ and R ⁷ are hydrogen atoms, an alkoxy group or a lower alkylthio group, and R ⁶ is Represents a hydrogen atom. ) An aniline derivative or a salt thereof and a compound represented by the general formula [d] (However, R ³ is a phenyl group which may have a substituent,
X represents O, S or NR ⁸ , and R ⁸ represents a hydrogen atom, a lower alkyl group, an aryl group, a hydroxyl group or a lower alkoxy group. ), An isocyanate derivative represented by
When R ⁰⁰ is a protected hydroxyl group, the protecting group for the hydroxyl group is optionally removed, and if necessary, the product is converted into its pharmacologically acceptable salt.
A]. Embedded image (However, OR ⁰ represents an optionally protected hydroxyl group,
Other symbols have the same meaning as described above. ) Phenol derivative (provided that 2- (3-phenylureido)-
Excludes 4-methoxyphenol and 2- {3- (3,4-dichlorophenyl) ureido} -4-methoxyphenol. ) Or a method for producing a pharmacologically acceptable salt thereof. 8. A compound represented by the general formula [I]: (Wherein OR ⁰ is a hydroxyl group which may be protected, R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom or a lower alkyl group which may have a substituent, and R ³ has a substituent. Optionally a phenyl group, X is O, S or NR ⁸ , R ⁸ is a hydrogen atom, a lower alkyl group, an aryl group,
Hydroxyl group or lower alkoxy group, R ⁴ , R ⁵ , R ⁶ and R ⁷
(1) R ⁴ is a hydrogen atom, R ⁵ , R ⁶ and R ⁷ are a hydrogen atom, an alkoxy group or a lower alkylthio group, or (2) R ⁴ is an alkoxy group or a lower alkylthio group, R ⁵ and R ⁷ represent a hydrogen atom, an alkoxy group or a lower alkylthio group, and R ⁶ represents a hydrogen atom. ) A therapeutic agent for ischemic diseases and / or arteriosclerosis, which comprises a phenol derivative or a pharmacologically acceptable salt thereof represented by the formula (1) as an active ingredient. 9. The therapeutic agent according to claim 8, wherein R ⁴ is a hydrogen atom, and R ⁵ , R ⁶ and R ⁷ are a hydrogen atom, an alkoxy group or a lower alkylthio group. 10. The therapeutic agent according to claim 8, wherein R ⁴ is an alkoxy group or a lower alkylthio group, R ⁵ and R ⁷ are hydrogen atoms, an alkoxy group or a lower alkylthio group, and R ⁶ is a hydrogen atom. 11. OR ⁰ is a hydroxyl group which may be protected by an acyl group or a lower alkoxycarbonyl group, and R
² is a hydrogen atom, a lower alkyl group or an optionally esterified carboxyl group-substituted lower alkyl group, and R ³ is a phenyl group, or an optionally esterified carboxyl group-substituted lower alkenyl group, an esterified A phenyl group substituted with a group selected from an optionally carboxyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, an optionally esterified carboxyl group-substituted lower alkoxy group, a trihalogeno-substituted lower alkyl group and a lower alkyl group. , X is O or S, The therapeutic agent according to claim 8, 9 or 10. 12. The therapeutic agent according to claim 8, 9, 10 or 11, wherein OR ⁰ is a hydroxyl group, R ¹ is a hydrogen atom and X is an oxygen atom.