JPH11171844A - Aryloxyaniline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having high affinity for MDR (Mitchondrial Diazepam Binding Inhibitor Receptor), effective even on such symptoms as not be cured with benzodiazepines with no side effects, and having therapeutic and preventive effects on anxiety and associated diseases and central nervous diseases. SOLUTION: This new compound is an aryloxyaniline derivative of formula I (Ar<1> and Ar<2> are each phenyl, pyridyl or naphthyl; R<1> is H, a 1-10C alkyl, 1-10C alkoxy or the like; X<1> is H, a 1-5C alkyl, phenoxy or the like; Y<1> is a 1-6C alkylene or single bond) or a pharmaceutically acceptable salt thereof, e.g. N-acetyl-N-(2-isopropoxybenzyl)-2-phenoxyaniline. The compound of formula I is obtained, for example, by reaction between an ailine derivative of formula II and a carbonyl derivative of formula III (Y<2> is a single bond or the like; R<5> is a 1-3C alkyl or H) in an inert solvent followed by reduction of the reaction product to form a compound of formula IV which, in turn, is reacted with an N-carbonylating agent in an inert solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicine, and more particularly to a medicine having a high affinity for MDR.

[0002]

BACKGROUND OF THE INVENTION At present, benzodiazepine (BZ) receptors are located on the GABA _A receptor / ion channel complex, the Central Benzodiazepine Receptor (CBR).
And M present in the central nervous system (glial cells) and adrenal glands
itochondrial DBI Receptor (MDR, DBI; Diazepam B
inding Inhibitor: Neuropharmacol., 30,1425-1433,199
(1) (Clin.Neuro
pharmacol., 16,401-417,1993).

MDR agonists indirectly act on the GABA _A / ion channel complex through endogenous neurosteroids to exert an anxiolytic effect.
May be useful for symptoms for which a satisfactory therapeutic effect has not been obtained (obsessive-compulsive disorder, panic disorder) and may reduce the side effects such as excessive sedation or mental dependence observed in BZs. In addition, MDR ligands are indirectly mediated by GABA _A receptors, thereby causing sleep disorders,
May be a treatment for epilepsy, movement disorders associated with muscle stiffness, eating disorders, circulatory disorders, cognitive learning disorders, and drug dependence (Progress in Neurobiology, 38,379-395,1992; ib
it, 49, 73-97, 1996, J. Neurochem. 58, 1589-1601; Neuroph
armacol.30,1435-1440,1991)). In addition, ligands for MDR are cancer (Biochimica et BIOphysica Acta, 1241,453-4).
70,1995), lipid metabolism disorder (Eur. J. Pharmacol., 294, 601-6)
07,1995), schizophrenia (Neuropharmacology, 35, 1075-107)
9, 1996), cerebral infarction (J. Neurosci., 15,5263-5274, 1995),
AIDS (Abstracts of the fifth international conf
erence on AIDS, P458, 1989), Alzheimer's disease (Alzhe
mer Dis. Assoc. Disotd., 2,331-336, 1988) and Huntington's disease (Brain Res., 248, 396-401, 1982). Phenoxyaniline derivatives include WO9533715, JP61040249, JP
57208295 etc. are reported. However, there are no reports of derivatives having a hydrogen atom or an alkyl group as a substituent on the nitrogen atom of aniline and a carbonyl group as a substituent. Further, the applications of the patent are anti-inflammatory drugs based on the action on arachidonic acid system, anti-atherosclerotic drugs based on increased PGI ₂ production, and heat-sensitive recording materials. There is no description of anxiety effects.

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a treatment which is effective against symptoms for which a satisfactory therapeutic effect has not been obtained with the conventional BZs, and which has an effect such as excessive sedation or mental dependence observed in the BZs. An object of the present invention is to provide a drug having a high affinity for MDR, which has a therapeutic effect and a preventive effect on central diseases such as anxiety and related diseases, depression, epilepsy, etc., which do not show side effects. Furthermore, sleep disorders, movement disorders associated with muscle stiffness, eating disorders, circulatory disorders, cognitive learning disorders, drug dependence, cancer, lipid metabolism disorders, schizophrenia, cerebral infarction, AID
An object of the present invention is to provide a remedy for S, Alzheimer's disease and Huntington's disease.

[0005]

The present inventors have made intensive studies on aryloxyaniline derivatives and found that MDR
A novel aryloxyaniline derivative exhibiting high affinity for was found, and the present invention has been completed.

Hereinafter, the present invention will be described. The present invention provides a compound of the formula [I]

[0007]

Embedded image

[In the formula, Ar ¹ and Ar ² are the same or different and represent a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group or a naphthyl group, and R ¹ is a hydrogen atom, a substituted or unsubstituted group. An alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted phenyl group, or a formula -NR ² (R ³ ) (wherein R ² and R ³ are the same or different and are a hydrogen atom Or 1 to 1 carbon atoms
It represents an alkyl group of 0 or a group showing a 4- to 10-membered cyclic amino group together with an adjacent nitrogen atom. X ¹ represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a phenoxy group, a halogen atom, a trifluoromethyl group, a carbamoyl group or an aminosulfonyl group. And Y ¹ represents an alkylene group having 1 to 6 carbon atoms with or without a branched chain or a single bond. Or a pharmaceutically acceptable salt thereof.

In the present invention, the term "substituted phenyl group" means an alkyl group having 1 to 10 carbon atoms, "halogen atom, hydroxyl group,
1 carbon atom substituted by an alkanoyloxy group, a carboxyl group or an alkoxycarbonyl group having 1 to 10 carbon atoms
An alkyl group of 10 to 10, an alkenyl group having 2 to 10 carbon atoms,
An alkoxy group having 1 to 10 carbon atoms, an alkylthio group having 1 to 10 carbon atoms, a formula -OZR ⁴ (wherein Z represents an alkylene group having 1 to 10 carbon atoms having or not having a branched chain; ,
R ⁴ represents an amino group, an amino group substituted with one or two alkyl groups having 1 to 7 carbon atoms, a cyclic amino group having 2 to 7 carbon atoms, a hydroxyl group, a carboxyl group or an alkoxycarbonyl group. ), An alkanoyl group having 2 to 10 carbon atoms or a ketal thereof, a formyl group or an acetal thereof, a carboxyl group, an alkoxycarbonyl group having 2 to 10 carbon atoms, a carbamoyl group, and a nitrogen atom having 1 to 1 carbon atoms. A carbamoyl group, an aminosulfonyl group substituted by one or two alkyl groups of 10; an aminosulfonyl group substituted by one or two alkyl groups having 1 to 10 carbon atoms; a halogen atom and a nitro group A phenyl group substituted by 1 to 3 arbitrarily selected groups, such as 2-methylphenyl group, 2-propylphenyl group, 2-isopropylphenyl group, 2-cyclopentylphenyl group, 2- (1- (Hydroxyethyl) phenyl group, 2-carboxymethylphenyl group, 2-methoxycarbonylphenyl group, 2- Nirufeniru group, 2-
Methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-ethoxyphenyl group, 2-hexyloxyphenyl group, 2-isopropoxyphenyl group, 2-cyclopentoxyphenyl group, 2,5-dimethoxyphenyl Group, 2,4,6-trimethoxyphenyl group,
4-methylthiophenyl group, 2-isopropylthiophenyl group, 4-cyclohexylthiophenyl group, 2- (2
-Dimethylaminoethoxy) phenyl group, 2- (2-hydroxyethoxy) phenyl group, 2-carboxymethoxyphenyl group, 2-methoxycarbonylmethoxyphenyl group, 2-acetylphenyl group, 2- (2-methyl-1,3
-Dioxolan-2-yl) phenyl group, 2-formylphenyl group, 2- (1,3-dioxolan-2-yl) phenyl group, 2-carboxylphenyl group, 2- (N-methylaminocarbonyl) phenyl group, 2- (N, N-dimethylaminocarbonyl) phenyl group, 2-aminocarbonylphenyl group, 2-aminosulfonylphenyl group, 4
-Aminosulfonylphenyl group, 2-methylaminosulfonylphenyl group, 2-dimethylaminosulfonylphenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2
-Bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2,4-difluorophenyl group, 2-nitrophenyl group, 2-aminophenyl group, 2-pyrrolidinophenyl group, 4-dimethylaminophenyl group And so on. The substituted pyridyl group refers to a pyridyl group substituted with a linear or branched alkoxy group having 1 to 10 carbon atoms,
For example, 2-methoxy-3-pyridyl group, 3-methoxy-
Examples thereof include a 2-pyridyl group and a 4-methoxy-3-pyridyl group. The alkyl group having 1 to 10 carbon atoms means a linear, branched or cyclic alkyl group, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, and a cyclobutyl group. Group, cyclopropylmethyl group, pentyl group, isopentyl group, cyclopentyl group, cyclobutylmethyl group, 1-ethylpropyl group, hexyl group, isohexyl group, cyclohexyl group, cyclopentylmethyl group, 1-ethylbutyl group, heptyl group, isoheptyl group , Cyclohexylmethyl group,
Examples include an octyl group, a nonyl group, and a decyl group. Carbon number 1
The substituted alkyl group of 10 to 10 represents an alkyl group substituted by "hydroxyl group, alkanoyloxy group, alkanoyl group, alkoxy group, halogen atom, azido group, amino group, carboxyl group", for example, hydroxymethyl group, acetyloxymethyl A methoxymethyl group, a chloromethyl group, a trifluoromethyl group, an azidomethyl group, an aminomethyl group, a dimethylaminomethyl group, a pyrrolidinomethyl group, and the like. The alkoxy group having 1 to 10 carbon atoms represents a linear, branched or cyclic alkoxy group, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, cyclopropylmethoxy group, Pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and the like. R ²
And an alkyl group having 1 to 10 carbon atoms represented by R ³
Straight, branched or cyclic alkyl group, thus when R ² and R ³ is an alkyl group having 1 to 10 carbon atoms of the formula -
The group represented by NR ² (R ³ ) is, for example, a methylamino group,
Ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, cyclopropylmethylamino group, pentylamino group, isopentylamino group, cyclopentylamino group, cyclobutylmethylamino group, 1-ethylpropylamino Group, hexylamino group, isohexylamino group, cyclohexylamino group, cyclopentylmethylamino group, 1-ethylbutylamino group, heptylamino group, isoheptylamino group, cyclohexylmethylamino group, octylamino group, nonylamino group, decylamino group , Dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group, dipentylamino group, dihexylamino group,
N-methylethylamino group, N-methylpropylamino group, N-methylbutylamino group, N-methylpentylamino group, N-methylhexylamino group, N-ethylpropylamino group, N-ethylbutylamino group, N -Ethylpentylamino group and the like. Further, the 4- to 10-membered cyclic amino group represented by the formula -NR ² (R ³ ) refers to a cyclic amino group which may contain a nitrogen atom or an oxygen atom, for example, a pyrrolidino group, a piperidino group, a piperazino group. Group, N-methylpiperazino group, morpholino group and the like. The alkyl group having 1 to 5 carbon atoms represented by X ¹ represents a “linear, branched or cyclic” alkyl group, such as methyl, ethyl, propyl, isopropyl, cyclopropyl, and butyl. Group, isobutyl group, cyclobutyl group, cyclopropylmethyl group and the like, and the alkoxy group having 1 to 5 carbon atoms means a "linear, branched or cyclic" alkoxy group, for example, methoxy group, ethoxy group Group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, cyclopropylmethoxy group and the like. The alkylene group having 1 to 6 carbon atoms having or not having a branched chain represented by Y ¹ is, for example, a methylene group, an ethylene group, a propylene group, a methylmethylene group, a dimethylmethylene group and the like. A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The pharmaceutically acceptable salts in the present invention include, for example, salts with mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, Salts with organic acids such as benzenesulfonic acid, salts with metal ions such as sodium ion, potassium ion and calcium ion, salts with organic bases such as diethanolamine, and ammonium salts.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the formula [I] can be produced by the following general production methods 1 to 6 (in the following reaction schemes, Ar ¹ , Ar ² , R ¹ , X ¹ and Y ¹ is the same as described above, Y ² represents a single bond or an alkyl group having 1 to 5 carbon atoms, which is substituted or unsubstituted with an alkyl group having 1 to 3 carbon atoms, and R ⁵ is an alkyl group having 1 to 3 carbon atoms. Or a hydrogen atom, X ² represents an acyloxy group having 1 to 10 carbon atoms, a chlorine atom, a bromine atom, a hydroxyl group or an alkoxy group having 1 to 5 carbon atoms, and X ³ represents a chlorine atom, a bromine atom or an iodine atom. [General production method 1]

[0012]

Embedded image

The aniline derivative (1) is reacted with the carbonyl derivative (2) in an inert solvent in the presence or absence of an acid catalyst and then reduced, or the aniline derivative is used in an inert solvent in the presence or absence of an acid catalyst. The compound (3) can be obtained by reducing a mixture of (1) and the carbonyl derivative (2). The compound (4) of the present invention can be obtained by reacting the compound (3) with an N-carbonylating agent in the presence or absence of a base in an inert solvent. Further, the compound (4) of the present invention can also be obtained by reacting phosgene with the compound (3) as an N-carbonylating agent to form a chlorocarbonyl derivative, and then reacting with an alcohol or an amine in the presence or absence of a base. ) Can be obtained.

Here, the acid catalyst is, for example, a hydrogen halide such as hydrogen chloride or hydrogen bromide; an inorganic acid such as hydrochloric acid or sulfuric acid; an organic acid such as acetic acid or tosylic acid;
TS is piperidine hydrochloride.

The reduction may be, for example, sodium borohydride,
This is performed by using a boron-based reducing agent such as lithium borohydride or sodium cyanoborohydride, an aluminum-based reducing agent such as lithium aluminum hydride, or by hydrogenation using palladium, platinum dioxide, Raney nickel, or the like as a catalyst. The N-carbonylating agent includes, for example, acyl halide, organic acid anhydride, alkoxycarbonyl halide, carbamoyl halide, cyanic acid (produced from potassium cyanate and acetic acid in a reaction solution), isocyanate and the like. The base is an organic amine such as triethylamine, diisopropylethylamine and pyridine, and an inorganic base such as potassium carbonate, sodium hydroxide, sodium hydride and sodium metal. Examples of the inert solvent include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, toluene,
Examples thereof include hydrocarbons such as benzene, halogenated hydrocarbon solvents such as chloroform and dichloromethane, acetonitrile, water, and a mixed solvent thereof.

[General Production Method 2]

[0017]

Embedded image

The compound (7) in which R ² of the compound (3) is a hydrogen atom can be obtained by reacting the aniline derivative (1) with the carboxylic acid anhydride, acyl halide, carboxylic acid or carboxylic acid ester represented by the compound (5) and a base. The amide compound (6) is reacted in an inert solvent in the presence or absence of amide compound (6), and then reacted with a reducing agent in an inert solvent.

[General Production Method 3]

[0020]

Embedded image

The aniline derivative (1) is reacted with an N-carbonylating agent in the presence or absence of a base in an inert solvent to give a compound (8), and then, if necessary, in the presence of a halide (9) and a base. The compound of the present invention (10) is reacted in an inert solvent using a phase transfer catalyst, copper powder, cuprous halide, etc.
Can be obtained. Compound (8) can also be obtained by reacting phosgene with compound (1) as an N-carbonylating agent to form a chlorocarbonyl derivative, and then reacting with an alcohol or amine in the presence of a base. .

Here, the N-carbonylating agent includes, for example, acyl halide, organic acid anhydride, alkoxycarbonyl halide, carbamoyl halide, cyanic acid (in the reaction solution,
(Formed from potassium cyanate and acetic acid) or isocyanate. Bases include organic amines such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium hydroxide, sodium hydride and sodium metal; potassium t-butoxide;
And alcoholates such as sodium ethoxide. Phase transfer catalysts include quaternary ammonium salts such as benzyltriethylammonium bromide, 18-crown-
And crown ethers such as 6 ethers. Examples of the inert solvent include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, hydrocarbons such as toluene and benzene, halogenated hydrocarbon solvents such as dichloromethane and chloroform, ketone solvents such as acetone, and acetonitrile. , N, N-dimethylformamide, nitrobenzene, water or a mixed solvent thereof.

[General Production Method 4] When one or both of Ar ¹ and Ar ² contain a nitro group, this nitro group can be converted to an amino group by hydrogenation or metal reduction. This amino group is reacted with a halogenated compound in an inert solvent using a phase transfer catalyst as necessary in the presence of a base, and is substituted with a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms. Is converted to the base.

Here, hydrogenation refers to hydrogenation using palladium, platinum dioxide, Raney nickel or the like as a catalyst, and metal reduction refers to divalent tin salts such as tin and stannous chloride, iron and ferrous chloride. This shows the reduction under acidic, neutral or basic conditions usually using a metal or metal salt such as divalent iron salt, zinc or the like. Examples of the base include organic amines such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium hydroxide, sodium hydride and metallic sodium; and alcoholates such as potassium t-butoxide and sodium ethoxide.
Phase transfer catalysts include quaternary ammonium salts such as benzyltriethylammonium bromide, and crown ethers such as 18-crown-6 ether. Examples of the inert solvent include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, hydrocarbons such as toluene and benzene, halogenated hydrocarbon solvents such as dichloromethane and chloroform, acetonitrile, and N, N-dimethylformamide. , Water or a mixed solvent thereof.

[General Production Method 5] When one or both of Ar ¹ and Ar ² contain an acyloxy group, this acyloxy group can be converted to a hydroxyl group by hydrolysis under acidic or basic conditions. This hydroxyl group is reacted with a halogenated compound in an inert solvent using a phase transfer catalyst as necessary in the presence of a base to form a linear or branched alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted amino group. Is converted into a C1 to C10 linear or branched alkoxy group, a carboxyl group or a C1 to C10 alkoxy group substituted with an alkoxycarbonyl group.

Here, the acidic or basic condition means that an inorganic acid such as hydrochloric acid or sulfuric acid, or an inorganic base such as sodium hydroxide or potassium hydroxide is converted to an alcohol such as methanol or ethanol, an ether such as tetrahydrofuran or dioxane, or the like. Ketones such as acetone, acetonitrile,
It shows that it is used in N, N-dimethylformamide, water or a mixed solvent thereof. Examples of the base include organic amines such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium hydroxide, sodium hydride and metallic sodium; and alcoholates such as potassium t-butoxide and sodium ethoxide. Examples of the phase transfer catalyst include quaternary ammonium salts such as benzyltriethylammonium bromide and crown ethers such as 18-crown-6 ether. Examples of the inert solvent include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, hydrocarbons such as toluene and benzene, halogenated hydrocarbon solvents such as dichloromethane and chloroform,
Examples include acetonitrile, N, N-dimethylformamide, water, and a mixed solvent thereof.

[General Production Method 6] When one or both of Ar ¹ and Ar ² contain an alkoxycarbonyl group, the alkoxycarbonyl group is converted into a carboxyl group by the usual ester hydrolysis conditions. Further, a carboxyl group is an alkoxycarbonyl group having 1 to 10 carbon atoms by esterification, and a primary or
It is converted to a primary alkylaminocarbonyl group and an aminocarbonyl group.

Here, the hydrolysis conditions include, for example, a base such as sodium hydroxide, potassium hydroxide and sodium carbonate, or an inorganic acid such as hydrochloric acid and sulfuric acid, an alcoholic solvent such as methanol and ethanol, and acetone and the like. In an inert solvent such as a ketone solvent. Esterification refers to an alkyl compound or dialkyl sulfate substituted with a chlorine atom, a bromine atom or an iodine atom, for example, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, for example, sodium methoxide. Reacting with an alcoholate such as potassium t-butoxide, for example, an organic base such as triethylamine or diisopropylethylamine, or reacting an alcohol with an acid such as hydrogen chloride or sulfuric acid. Amidation means that a carboxyl group is converted to thionyl chloride, triphenylphosphine-
After conversion into an acid halide with carbon tetrachloride or the like, the compound reacts with a corresponding amine derivative or shows a commonly used amidation such as a mixed acid anhydride method and a dicyclohexylcarbodiimide method.

[General Production Method 7] When one or both of Ar ¹ and Ar ² contains a formyl group or an acyl group, the carbonyl group of the formyl group or the acyl group is reacted with a Wittig reagent to be converted to an alkenyl group. . Further, the alkenyl group is converted to an alkyl group by reduction.

Here, the Wittig reagent is a compound having 1 to 1 carbon atoms.
9 represents a triphenylalkylphosphonium halide or diethylalkylphosphonate having an alkyl group of 9, for example, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, toluene,
Hydrocarbons such as benzene, halogenated hydrocarbons such as methylene chloride and chloroform, acetonitrile, N,
In an inert solvent such as N-dimethylformamide, a base such as sodium hydride, potassium t-butoxide, sodium ethoxide, n-butyllithium and, if necessary, a quaternary ammonium salt such as benzyltriethylammonium bromide, 18-crown Used with a phase transfer catalyst such as crown ethers such as -6 ether. Reduction refers to hydrogenation using palladium, platinum dioxide, Raney nickel, or the like as a catalyst.

[General Production Method 8] When one or both of Ar ¹ and Ar ² contain a formyl group or an acyl group, the carbonyl group of the formyl group or the acyl group reacts with a Grignard reagent to form a secondary or tertiary alcohol. Converted to body. Further, the secondary alcohol is converted to an acyl group by oxidation with various oxidizing agents.

Here, the Grignard reagent is a compound having 1 to 1 carbon atoms.
9 represents an alkyl or alkenyl magnesium halide, for example, methyl magnesium bromide, ethyl magnesium bromide and the like. The various oxidizing agents include metal oxidizing agents such as swan oxidation using oxalyl chloride-dimethyl sulfoxide, chromium oxidizing agents, and manganese dioxide.

In order to use the compound of the present invention as a medicament, the compound of the present invention is used in combination with a conventional bulking agent, binder, disintegrant,
A tablet, pill, capsule, granule, powder, liquid, emulsion, suspension, injection and the like can be prepared by a conventional formulation technique by adding a pH adjuster, a dissolving agent and the like.

The compound of the present invention can be orally or parenterally administered to an adult patient at a dose of 0.1 to 500 mg / day once or several times a day. This dose can be appropriately increased or decreased depending on the type of disease, age, weight, and symptoms of the patient.

[0035]

According to the present invention, a drug having a high affinity for MDR is provided. Therefore, these include anxiety and its related diseases, depression, epilepsy, sleep disorders, cognitive learning disorders, central disorders such as schizophrenia, movement disorders associated with muscle stiffness, eating disorders, circulatory disorders, drug dependence, cancer , Lipid metabolism disorders, cerebral infarction, AIDS, Alzheimer's disease and Huntington's disease.

[0036]

The present invention will be specifically described below with reference to examples and test examples. Example 1 N-acetyl-N- (2-isopropoxybenzyl)-
Synthesis of 2-phenoxyaniline (1) 1.64 g of 2-isopropoxybenzaldehyde
Was dissolved in 10 ml of methanol, and 1.85 g of 2-aminodiphenyl ether was added. After stirring at room temperature for 30 minutes, the mixture was cooled with ice water. To the cooled reaction solution, 1.50 g of sodium borohydride was added little by little, and the mixture was stirred for 30 minutes under ice-cooling and then at room temperature for 30 minutes. An aqueous acetic acid solution (1.5 ml of acetic acid-30 ml of water) was added dropwise to the reaction solution, and 10
After stirring at room temperature for minutes, the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, and then dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 25) to give an oily N- (2-isopropoxybenzyl) -2-phenoxy. 2.65 g of aniline were obtained.

(2) 2.65 g of N- (2-isopropoxybenzyl) -2-phenoxyaniline and 1.5 ml of triethylamine are dissolved in 30 ml of tetrahydrofuran, and 0.8 ml of acetyl chloride is added dropwise to this solution with stirring. Stirred for minutes. The reaction mixture was poured into water, extracted with ethyl acetate, washed with 0.5 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and subsequently with a saturated saline solution, and dried over anhydrous sodium sulfate. After the desiccant is filtered off, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 4) to give oily N-acetyl-N- (2-isopropoxybenzyl). 2.92 g of -2-phenoxyaniline was obtained. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 2 N-acetyl-N- (2,4-dimethoxybenzyl)-
Synthesis of 2-phenoxyaniline (1) 3.70 g of 2-aminodiphenyl ether and 2,4
3.70 g of dimethoxybenzaldehyde was dissolved in 60 ml of methanol, and 70 mg of platinum oxide was added thereto, followed by stirring overnight at room temperature under a stream of hydrogen. 30 ml of chloroform was added to the reaction mixture, and after the precipitate was dissolved, the catalyst was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol.
5.06 g of-(2,4-dimethoxybenzyl) -2-phenoxyaniline were obtained.

(2) N- (2,4-dimethoxybenzyl) -2-phenoxyaniline 1.00 g of pyridine 1.
0.76 g of acetic anhydride was added to 18 g of the solution,
Stirred for a day. The reaction mixture was poured into water, extracted with ethyl acetate, washed with 0.5 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and subsequently with a saturated saline solution, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 3) to give oily N-acetyl-N- (2,4- 1.09 g of dimethoxybenzyl) -2-phenoxyaniline were obtained. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 3 Synthesis of N-acetyl-N- (2-chlorobenzyl) -2-phenoxyaniline (1) A solution of 28.5 g of 2-phenoxyaniline and 25.8 ml of triethylamine in 250 ml of methylene chloride was added with acetyl chloride. 11.5 ml was added dropwise under ice cooling. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure, the residue was poured into water, and extracted with ethyl acetate. Extract solution is 0.5
The extract was washed sequentially with normal hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate. After the desiccant is filtered off, the filtrate is concentrated under reduced pressure, and the residue is subjected to silica gel chromatography (developing solvent: ethyl acetate-hexane = 1:
Purification was performed in 4) to obtain 33.7 g of N-acetyl-2-phenoxyaniline.

(2) Sodium hydride (60% in oi
l) N-acetyl-2-phenoxyaniline 2.00 was added to a suspension of 400 mg of dimethylformamide in 30 ml.
g was added at room temperature, and the mixture was further stirred at room temperature for 30 minutes. To this solution, 1.64 g of 2-chlorobenzyl chloride was added dropwise with stirring at room temperature. After stirring for 30 minutes, ice water was added to the reaction mixture, and the mixture was extracted with ether. The extract was diluted with 0.5N hydrochloric acid,
The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and subsequently with a saturated saline solution, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent is concentrated under reduced pressure, and the residue is subjected to silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 4).
To give 2.92 g of oily N-acetyl-N- (2-chlorobenzyl) -2-phenoxyaniline.
Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 4 N-aminocarbonyl-N- (2-methoxybenzyl)
Synthesis of 2-phenoxyaniline 1.54 g of N- (2-methoxybenzyl) -2-phenoxyaniline synthesized in the same manner as in (1) of Example 1 was dissolved in 20 ml of acetic acid, and an aqueous solution of potassium cyanate ( After dropwise addition of potassium cyanate (1.23 g-water 10 ml), the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 3) to give oily N-aminocarbonyl-N- (2-methoxy). 1.69 g of (benzyl) -2-phenoxyaniline were obtained.

Tables 1 and 2 show the structures and physical property data of this compound and the compound obtained in the same manner.

Example 5 Synthesis of N- (2-methoxybenzyl) -N- (N-methylaminocarbonyl) -2-phenoxyaniline 14 ml of a solution of 751 mg of triphosgene in methylene chloride
Then, 2.03 g of N- (2-methoxybenzyl) -2-phenoxyaniline and 1.03 of diisopropylethylamine were added.
g of methylene chloride (25 ml) was added dropwise with stirring, and the mixture was stirred at room temperature for 5 minutes. An excess amount of methylamine was wiped into the solution with stirring, stirred at room temperature for 5 minutes, and concentrated under reduced pressure. The reaction mixture was poured into ethyl acetate, washed successively with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent was concentrated under reduced pressure, and the precipitated crystals were recrystallized from ethyl acetate to give N- (2-methoxybenzyl) -N- (N-methylaminocarbonyl) -2-phenoxyaniline 2 .02
g was obtained. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 6 Synthesis of N- (2,5-dimethoxybenzyl) -N- (N-methylaminocarbonyl) -2-phenoxyaniline Diphenylphosphoryl was added to a solution of 3.43 ml of acetic acid and 8.36 ml of triethylamine in 90 ml of benzene. Azide 1
2.9 ml was added, and the mixture was heated under reflux for 2 hours. To this reaction solution was added N- (2,5-
Dimethoxybenzyl) -2-phenoxyaniline 2.0
1 g was added, and the mixture was heated under reflux for 6 hours. The reaction mixture was poured into water, the organic phase was separated, washed sequentially with 5% hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated saline, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent is concentrated under reduced pressure, and the residue is subjected to silica gel chromatography (developing solvent:
Purified with ethyl acetate-hexane = 1: 2), recrystallized from diethyl ether, and N- (2,5-dimethoxybenzyl) -N- (N-methylaminocarbonyl) -2-phenoxyaniline 1.20 g I got Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 7 Synthesis of N- (2-methoxybenzyl) -N-methoxycarbonyl-2-phenoxyaniline (1) A solution of 775 mg of triphosgene in methylene chloride 14
In ml, N- (2-methoxybenzyl) -2-phenoxyaniline 2.16 g and diisopropylethylamine 1.
25 ml of methylene chloride in which 10 g was dissolved was slowly added dropwise with stirring, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure, poured into ethyl acetate, washed successively with 5% hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 15).
-Chlorocarbonyl-N- (2-methoxybenzyl)-
2.57 g of 2-phenoxyaniline were obtained.

(2) A solution of 226 mg of sodium methoxide in 5 ml of tetrahydrofuran under ice-cooling was dissolved in 5 ml of tetrahydrofuran.
1.22 g of (2-methoxybenzyl) -2-phenoxyaniline was added dropwise with stirring, and the mixture was stirred at room temperature for 20 minutes.
The reaction mixture was concentrated under reduced pressure, poured into water, extracted with ethyl acetate, washed sequentially with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate. After the desiccant is filtered off, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 6), recrystallized from ethyl acetate, and purified by N-
(2-methoxybenzyl) -N-methoxycarbonyl-
1.18 g of 2-phenoxyaniline were obtained. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 8 N-aminoacetyl-N- (2-methoxybenzyl)-
Synthesis of 2-phenoxyaniline (1) N-chloroacetyl-synthesized in the same manner as in Example 1
1.51 g of N- (2-methoxybenzyl) -2-phenoxyaniline and 10 ml of a dimethylformamide solution of 770 mg of sodium azide were stirred at room temperature overnight. After the reaction mixture was poured into water, it was extracted with ethyl acetate. The extract was washed successively with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate.
After the desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 4) to give oily N-azidoacetyl-
1.55 g of N- (2-methoxybenzyl) -2-phenoxyaniline were obtained.

(2) N-azidoacetyl-N- (2-methoxybenzyl) -2-phenoxyaniline 647 mg
Was dissolved in 7 ml of methanol, 20 mg of platinum oxide was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through celite, concentrated under reduced pressure, and then subjected to silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 1).
After purification in 6), recrystallization from ethyl acetate-isopropyl ether gave 0.24 g of N-aminoacetyl-N- (2-methoxybenzyl) -2-phenoxyaniline. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 9 Synthesis of N-hydroxyacetyl-N- (2-methoxybenzyl) -2-phenoxyaniline (1) 1.01 g of N-chloroacetyl-N- (2-methoxybenzyl) -2-phenoxyaniline , 1.30 g of sodium acetate and 170 mg of tetra-n-butylammonium bromide were stirred in 10 ml of benzene at 80 ° C. for 5 hours. The reaction mixture was poured into ethyl acetate, washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 3) to give oily N-acetoxyacetyl-N- (2-methoxy). 1.03 g of (benzyl) -2-phenoxyaniline were obtained.

(2) N-acetoxyacetyl-N- (2
-Methoxybenzyl) -2-phenoxyaniline 525
mg was dissolved in 6 ml of methanol, and potassium carbonate 537 was dissolved.
After stirring at 50 ° C. for 7 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent is concentrated under reduced pressure, and the residue is subjected to silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 3).
After leaving at room temperature, 450 mg of crystalline N-hydroxyacetyl-N- (2-methoxybenzyl) -2-phenoxyaniline was obtained. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 10 N-acetyl-N- (2-pyrrolidinobenzyl) -2-
Synthesis of phenoxyaniline monohydrochloride (1) N-acetyl-N- synthesized in the same manner as in Example 3
(2-nitrobenzyl) -2-phenoxyaniline 8.
Was dissolved in 80 ml of methanol.
The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. After adding 40 ml of chloroform to the reaction mixture to dissolve the precipitate,
The catalyst was filtered off. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to obtain 6.88 g of N-acetyl-N- (2-aminobenzyl) -2-phenoxyaniline.

(2) N-acetyl-N- (2-aminobenzyl) -2-phenoxyaniline 1.00 g, 1, 4
-680 mg of dibromobutane, 1.03 of potassium carbonate
g and 50 mg of potassium iodide were stirred at 70 ° C. for 3 days in 10 ml of N, N-dimethylformamide solution. The reaction mixture was poured into water, extracted with ethyl acetate, washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 3). The product obtained is treated with ether 5
in 4 ml of a 4N hydrogen chloride-ethyl acetate solution.
After adding 9 ml, the solution was concentrated, recrystallized from ethyl acetate-ether, and N-acetyl-N- (2-pyrrolidinobenzyl) -2-phenoxyaniline monohydrochloride 0.49 was added.
g was obtained. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 11 Synthesis of N-acetyl-N- (2-carboxymethoxybenzyl) -2-phenoxyaniline (1) 1.74 g of 2-acetoxybenzaldehyde and 2
1.85 g of phenoxyaniline in 30 ml of methanol
After stirring at room temperature for 1 hour, 3.00 g of sodium borohydride was added, and the mixture was stirred at the same temperature for 30 minutes. An aqueous acetic acid solution (3.0 ml of acetic acid-60 ml of water) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 10 minutes and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, and then dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent was concentrated under reduced pressure. Residue and triethylamine 4
50 ml of a methylene chloride solution was cooled to 0 ° C., and 2.00 ml of acetyl chloride was added dropwise with stirring. After stirring at room temperature for 20 minutes, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 0.5N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent was concentrated under reduced pressure to obtain crude N-acetyl-N- (2-acetyloxybenzyl) -2-phenoxyaniline.

This was dissolved in 40 ml of a methanol solution,
14 ml of a 5% aqueous potassium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, poured into water, extracted with ethyl acetate, and the extract was washed successively with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether to obtain 1.86 g of N-acetyl-N- (2-hydroxybenzyl) -2-phenoxyaniline.

(2) A solution of 666 mg of N-acetyl-N- (2-hydroxybenzyl) -2-phenoxyaniline in 10 ml of N, N-dimethylformamide at 60%
80 mg of NaH / oil was added, and the mixture was stirred at room temperature for 30 minutes. To this was added 0.3 ml of methyl bromoacetate, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into 0.5N hydrochloric acid, extracted with ethyl acetate, washed with 0.5N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, and subsequently with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and filtered. Was concentrated under reduced pressure to obtain crude N-acetyl-N- (2-methoxycarbonylmethoxybenzyl) -2-phenoxyaniline.

This was dissolved in 10 ml of methanol, and 5%
5 ml of an aqueous potassium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was acidified by adding 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether.
745 mg of N-acetyl-N- (2-carboxymethoxybenzyl) -2-phenoxyaniline were obtained. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 12 Synthesis of N-acetyl-N- (2-propylbenzyl) -2-phenoxyaniline (1) N-acetyl-N-synthesized in the same manner as in Example 3
(2- (1,3-dioxolan-2-yl) benzyl)
2.8 g of 2-phenoxyaniline in 40 m of acetone
and p-toluenesulfonic acid monohydrate 0.10
g was added and stirred at room temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and acetone was concentrated under reduced pressure.
The residue was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. After the desiccant is filtered off, the filtrate is concentrated under reduced pressure, the residue is purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 3), dried, and allowed to stand. 2.12 g of N- (2-formylbenzyl) -2-phenoxyaniline were obtained as crystals.

(2) Under a nitrogen stream, 4.34 g of ethyltriphenylphosphonium bromide in tetrahydrofuran 2
To a 0 ml suspension, 6.63 ml of a 1.63 M n-butyllithium / hexane solution was added dropwise while maintaining the reaction solution temperature at -15 to -10 ° C. The reaction solution was slowly warmed to room temperature, stirred at room temperature for 20 minutes, and then N-acetyl-N- (2
-Formylbenzyl) -2-phenoxyaniline 1.0
A solution of 1 g of tetrahydrofuran (10 ml) was added dropwise, and the mixture was further stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, washed with a saturated saline solution, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure to give oily N-acetyl-N-
859 mg of (2- (propen-1-yl) benzyl) -2-phenoxyaniline were obtained as a mixture of approximately 3: 2 geometric isomers.

(3) 757 mg of N-acetyl-N- (2- (propen-1-yl) benzyl) -2-phenoxyaniline (a mixture of geometric isomers of about 3: 2) was dissolved in 7 ml of ethanol and oxidized. 15 mg of platinum was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The catalyst in the reaction solution was separated by filtration, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 4) to give oily N-acetyl-N- (2-propyl). 647 mg of (benzyl) -2-phenoxyaniline were obtained. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 13 Synthesis of N-acetyl-N- (2-acetylbenzyl) -2-phenoxyaniline (1) An ice-cooled 1M methylmagnesium chloride / tetrahydrofuran solution (5.25 ml) was added to a diluted solution of tetrahydrofuran (15 ml) in a solution of N-acetyl-N- (2-acetylbenzyl) -2-phenoxyaniline. -Acetyl-N- (2-formylbenzyl) -2-phenoxyaniline 1.20 g
Was added dropwise and further stirred at room temperature for 1 hour. The reaction solution was ice-cooled again, a saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 1) to give oily N-acetyl-N
1.19 g of-(2- (1-hydroxyethyl) benzyl) -2-phenoxyaniline was obtained.

(2) A solution of 0.22 ml of oxalyl chloride in 13.5 ml of dichloromethane was cooled to -70 ° C. or less with dry ice-acetone, and a solution of 0.24 ml of dimethyl sulfoxide in 0.9 ml of dichloromethane was added dropwise. And further stirred for 10 minutes. N-acetyl-N
-(2- (1-hydroxyethyl) benzyl) -2-phenoxyaniline 0.48 g of dichloromethane 4.5 ml
Solution was added dropwise, and the reaction solution temperature was gradually raised to -45 ° C.
The mixture was further stirred at the same temperature for 1 hour. To this reaction solution, 1.34 ml of triethylamine was added dropwise at -40 ° C or lower, and the mixture was further stirred at 0 ° C for 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, washed with a saturated saline solution, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent is concentrated under reduced pressure, and the residue is subjected to silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 1).
And recrystallized from ethyl acetate-hexane.
0.41 g of acetyl-N- (2-acetylbenzyl) -2-phenoxyaniline was obtained. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 14 Synthesis of N-acetyl-N- (2-dimethylaminocarbonylbenzyl) -2-phenoxyaniline (1) N-acetyl-N-synthesized in the same manner as in Example 2
2.26 g of (2-methoxycarbonylbenzyl) -2-phenoxyaniline was added to a mixed solution of 23 ml of methanol and 3.6 ml of 2N potassium hydroxide aqueous solution, and the mixture was added at 60 ° C.
For 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was acidified with 2N hydrochloric acid, extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 1) to give oily N-acetyl-N- (2-carboxybenzyl). ) -2-phenoxyaniline 2.01 g was obtained.

(2) 0.50 g of N-acetyl-N- (2-carboxybenzyl) -2-phenoxyaniline was dissolved in a mixed solvent of 10 ml of tetrahydrofuran and 0.1 ml of hexamethylphosphoramide, and 0.2 m of thionyl chloride was dissolved.
was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the residue was dissolved in tetrahydrofuran (10 ml).
A 2% aqueous solution of dimethylamine was added dropwise with stirring. The reaction mixture was poured into water, extracted with ethyl acetate, washed successively with 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent is concentrated under reduced pressure, and the residue is subjected to silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 1).
Purification was performed in 3) to obtain 0.49 g of oily N-acetyl-N- (2-dimethylaminocarbonylbenzyl) -2-phenoxyaniline. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 15 Synthesis of N-acetyl-N- (2-ethoxycarbonylbenzyl) -2-phenoxyaniline N-acetyl-N- (2-carboxybenzyl) -2-
Phenoxyaniline 0.50 g, anhydrous potassium carbonate 0.2
0 g and 0.22 ml of diethyl sulfate were stirred in 10 ml of N, N-dimethylformamide for 3 hours at room temperature. The reaction mixture was poured into water, extracted with ethyl acetate, 1N hydrochloric acid,
The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent is concentrated under reduced pressure, and the residue is subjected to silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 7).
And purified by oily N-acetyl-N- (2-ethoxycarbonylbenzyl) -2-phenoxyaniline 0.5.
0 g was obtained. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 16 Synthesis of N-acetyl-N- (2-methoxyphenyl) -2-phenoxyaniline 2.27 g of N-acetyl-2-phenoxyaniline
-1.3 ml of iodoanisole, 1.38 potassium carbonate
g, copper powder 133 mg and copper bromide 200 mg were refluxed with heating in 20 ml of nitrobenzene for 8 hours. After cooling the reaction solution to room temperature, ethyl acetate was added, and the insolubles were filtered off. The filtrate was washed with 0.5N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and subsequently with a saturated saline solution, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 4) to give oily N-acetyl-N- (2
-Methoxyphenyl) -2-phenoxyaniline 660
mg was obtained. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

Example 17 Synthesis of N-acetyl-N- (2- (2-methoxyphenyl) ethyl) -2-phenoxyaniline (1) 4.98 g of 2-methoxyphenylacetic acid and 0.1 mol of N, N-dimethylformamide 5 ml was dissolved in 30 ml of toluene, 4 ml of thionyl chloride was added, and the mixture was stirred at 70 ° C. for 1 hour and concentrated under reduced pressure. The residue was dissolved in methylene chloride (20 ml), and this was cooled with ice-cooled 2-phenoxyaniline 5.55.
g and 4.6 ml of triethylamine in 30 m of methylene chloride
Then, the solution was added dropwise to the solution under stirring with stirring, and further stirred at room temperature for 1 hour.
The reaction solution was concentrated under reduced pressure, added with ice water, extracted with ethyl acetate, washed with 0.5 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and subsequently with a saturated saline solution, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent was concentrated under reduced pressure.

The residue was dissolved in 40 ml of tetrahydrofuran, added dropwise to a suspension of 1.70 g of lithium aluminum hydride in 40 ml of tetrahydrofuran, and heated under reflux for 30 minutes. The reaction mixture was cooled with ice water, and a saturated aqueous sodium sulfate solution was added dropwise with stirring. After the insolubles in the reaction solution were filtered off through an anhydrous magnesium sulfate plate, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 10) to give oily N- 8.23 g of (2- (2-methoxyphenyl) ethyl) -2-phenoxyaniline was obtained.

(2) Using 3.19 g of N- (2- (2-methoxyphenyl) ethyl) -2-phenoxyaniline, the reaction was carried out in the same manner as in (2) of Example 1, followed by post-treatment and then crystallization with hexane. , N-acetyl-N- (2- (2-methoxyphenyl) ethyl) -2-phenoxyaniline 2.9
5 g were obtained. Tables 1 and 2 show the structure and physical property data of this compound and the compound obtained in the same manner.

[0070]

[Table 1]

[0071]

[Table 2]

[0072]

[Table 3]

[0073]

[Table 4]

[0074]

[Table 5]

[0075]

[Table 6]

[0076]

[Table 7]

[0077]

[Table 8]

[0078]

[Table 9]

[0079]

[Table 10]

[0080]

[Table 11]

[0081]

[Table 12]

[0082]

[Table 13]

[0083]

[Table 14]

[0084]

[Table 15]

[0085]

[Table 16]

[0086]

[Table 17]

[0087]

[Table 18]

[0088]

[Table 19]

[0089]

[Table 20]

[0090]

[Table 21]

[0091]

[Table 22]

[0092]

[Table 23]

[0093]

[Table 24]

Test Example [MDR Receptor Binding Experiment] A crude mitochondrial fraction prepared from rat cerebral cortex was used as a receptor preparation.

[0095] ^[3 H] as labeled ligand ^[3 H] PK1
1195 was used. Binding experiments using [ ³ H] -labeled ligands are described in the Journal of Pharmacology and Experimental T
The following method described in herapeutics, 262, 971 (1992) was used.

Preparation of Receptor Standard: Rat cerebral cortex was treated with a Teflon homogenizer to a volume of 0.1 times the wet weight of a rat.
10 mM Hepes buffer containing 32 M sucrose (pH
Homogenized in 7.4). Homogenate 900x
g, and centrifuged for 10 minutes.
Centrifuged at g for 10 minutes. The precipitate was suspended in Hepes buffer to a protein concentration of 1 mg / ml,
Centrifuged at 000 × g for 10 minutes. 5
The crude mitochondrial fraction was suspended in 0 mM Hepes buffer (pH 7.4).

MDR binding experiment: mitochondrial preparation (1.0 mg protein / ml), [ ³ H] PK1119
5 (2 nM) and the test drug were reacted at 4 ° C. for 90 minutes.

After completion of the reaction, the solution was suction-filtered through a glass filter (GF / B) treated with 0.3% polyethyleneimine.
The radioactivity of the filter paper was measured with a liquid scintillation spectrometer. The binding when reacted in the presence of 10 μMPK11195 was defined as nonspecific binding of [ ³ H] PK11195, and the difference between total binding and nonspecific binding was defined as specific binding. The ^[3 H] PK11195 (2nM) and the test drug with varying concentrations of certain concentrations give inhibition curves by reacting the above conditions, from the inhibition curves ^[3 H] PK11195 binding of 50% inhibition test drug The concentration (IC ₅₀ ) was determined, and the results are shown in Table 3.

[0099]

[Table 25]

[0100]

[Table 26]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/24 ADN A61K 31/24 ADN ADR ADR ADU ADU 31/27 31/27 31/335 31/335 31/40 31/40 31/44 31/44 C07C 235/16 C07C 235/16 A 271/28 271/28 275/34 275/34 C07D 207/16 C07D 207/16 213/64 213/64 213/65 213/65 (72) Inventor Toshio Nakamura 3-24-1, Takada, Toshima-ku, Tokyo Inside Taisho Pharmaceutical Co., Ltd. (72) Inventor Shigeyuki Chaki 3- 24-1-1 Takada, Toshima-ku, Tokyo Taisho Seiyaku Co., Ltd. (72) Invention Person Kazuki Tomizawa 3-24-1, Takada, Toshima-ku, Tokyo Inside Taisho Pharmaceutical Co., Ltd. (72) Inventor Masashi Nagamine 345 Koyamada, Kawachinagano-shi, Osaka Prefecture Japan Agrochemicals Research Institute (72) Inventor Kenji Yamamoto 345 Koyamada, Kawachinagano City, Osaka Prefecture Japan Inside the Pharmaceutical Company Research Institute (72) Koichiro Harada, Inventor 345 Koyamada, Kawachinagano-shi, Osaka Prefecture Japan Agrochemical Company Research Institute (72) Inventor Masanori Yoshida 345 Koyamada, Kawachinagano-shi, Osaka Japan Agrochemical Company Research Inside

Claims (4)

[Claims] (1) Formula (1) [Wherein, Ar ¹ and Ar ² are the same or different and each represent a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group or a naphthyl group, and R ¹ represents a hydrogen atom, a substituted or unsubstituted carbon atom of 1 An alkyl group having 10 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted phenyl group, or a formula -NR ² (R ³ ) wherein R ² and R ³ are the same or different and are each a hydrogen atom or a carbon atom X ¹ represents a hydrogen atom, a carbon atom or a carbon atom, which represents a 1 to 10 alkyl group or a group showing a 4- to 10-membered cyclic amino group together with an adjacent nitrogen atom. Represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a phenoxy group, a halogen atom, a trifluoromethyl group, a carbamoyl group or an aminosulfonyl group, and Y ¹ is a carbon atom having or not having a branched chain. Al of 1-6 It represents a kylene group or a single bond. Or a pharmaceutically acceptable salt thereof. 2. A compound having 1 to 10 carbon atoms in which a substituted phenyl group is substituted by an alkyl group having 1 to 10 carbon atoms, "a halogen atom, a hydroxyl group, a carboxyl group or an alkoxycarbonyl group".
Alkyl group, an alkenyl group having 2 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, an alkylthio group having 1 to 10 carbon atoms, wherein -O-Z-R ⁴ (wherein either Z is a branched chain Represents an alkylene group having 1 to 10 carbon atoms, R ⁴ is an amino group, an amino group substituted with one or two alkyl groups having 1 to 7 carbon atoms, a cyclic amino group having 2 to 7 carbon atoms,
It represents a hydroxyl group, a carboxyl group or an alkoxycarbonyl group. ), An alkanoyl group having 2 to 10 carbon atoms or a ketal thereof, a formyl group or an acetal thereof, a carboxyl group, an alkoxycarbonyl group having 2 to 10 carbon atoms, a carbamoyl group, and a nitrogen atom having 1 to 1 carbon atoms. A carbamoyl group, an aminosulfonyl group substituted with one or two alkyl groups of 10; an aminosulfonyl group substituted with one or two alkyl groups having 1 to 10 carbon atoms; a halogen atom and a nitro group The phenyl group substituted with 1 to 3 of the arbitrarily selected groups, and the substituted pyridyl group is a pyridyl group substituted with 1 to 3 of an alkoxy group having 1 to 10 carbon atoms. An aryloxyaniline derivative or a pharmaceutically acceptable salt thereof. 3. A pharmaceutical comprising the aryloxyaniline derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 4. A ligand of MDR comprising the aryloxyaniline derivative or the pharmaceutically acceptable salt thereof according to claim 1 or 2 as an active ingredient.