JPH11236375A - 1,2-dihydro-2-oxoquinoline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having high affinity for MDR (mitochondrial diazepam binding inhibitor receptor) and useful for treating and preventing anxiety or its related diseases, depression, epilepsy, etc. SOLUTION: A 1,2-dihydro-2-oxoquinoline derivative of formula I [Ar is pyridyl or a group of formula II (R<3> and R<4> are each H, a halogen, a 1-5C alkyl or the like); Y is N atom, CH or C(OH); R<1> and R<2> are each H, a 1-10C alkyl, a 3-15C alkoxyalkyl or the like; (n) is an integer of 1-3], for example, N,N-dihexyl-1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxamide. The compound of formula I can be synthesized by reacting a 1,2-dihydro-2- oxoquinolinecarboxylic acid ester derivative with an arylalkyl halide derivative in the presence of a base in an inert solvent, hydrolyzing the obtained compound and further reacting the reaction product through an acid halide or a mixed acid anhydride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a mitochondrial di
The present invention relates to a compound having high affinity for azepam binding inhibitor receptor (MDR).

[0002]

2. Description of the Related Art _A benzodiazepine (BZ) receptor, one of the sites of action of anxiolytics, is a central benzodiazepine present on the GABA _A receptor / chloride channel complex.
azepinereceptor (CBR) and two subtypes of MDR present in the central nervous system (glial cells), adrenal glands, etc. (Clin. Neuropharmacol., 16, 401-417, 1
993). At present, CBR agonists represented by diazepam are widely used as anxiolytics. However, since CBR agonists act directly on GABA _A receptor / chloride channel complex, they have anxiolytic effects and side effects as well. Develop dependence and excessive sedation. On the other hand, MDR
Since an agonist acts indirectly on the GABA _A receptor / chloride channel complex through the synthesis of a neurosteroid which is an endogenous neuroactive steroid (endogenous anxiolytic substance), an anxiolytic effect appears. But
The side effects of psychodependence and excessive sedation do not occur (J.
Pharmacol. Exp. Ther., 267, 462-471, 1993; ibid.,
265, 649-656, 1993).

[0003] Therefore, a symptom in which a satisfactory therapeutic effect is not obtained with conventional BZs (obsessive-compulsive disorder, panic disorder)
It has been desired to develop MDR agonists as remedies for the drug and as anxiolytics with reduced side effects observed in conventional BZs.

[0004] The compound acting on MDR is GAB.
It may be a therapeutic agent for sleep disorders, epilepsy, dyskinesias associated with muscle stiffness, eating disorders, circulatory disorders, cognitive learning disorders, and drug dependence through A _A receptors (Progress
in Neurobiology, 38, 379-395, 1992; ibid, 49, 73-9
7, 1996, J.A. Neurochem. 58, 1589-1601; Neuropharmaco
l. 30, 1435-1440, 1991)). Furthermore, from the viewpoint of the physiological function of MDR, cancer (Biochimica et BIOphysica Acta, 124
1, 453-470, 1995), disorders of lipid metabolism (Eur. J. Pharmaco
l. , 294, 601-607, 1995), schizophrenia (Neuropharmacol)
ogy, 35, 1075-1079, 1996), cerebral infarction (J. Neurosci., 15,
5263-5274, 1995), AIDS (Abstracts of thefifth in
ternational conference on AIDS, P458, 1989), Alzheimer's disease (Alzheimer Dis. Assoc. Disotd. 2, 331-336, 1)
988) or Huntington's chorea (Brain Res., 248, 396-40)
1,1982). At present, compounds having affinity for MDR are disclosed in JP-A-6-501030.
The indole compound disclosed in Japanese Patent Application Laid-Open Publication No. H10-209,043 is known.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide an MD
An object of the present invention is to provide a novel compound having a high affinity for R.

[0006]

Means for Solving the Problems As a result of intensive studies on compounds having high affinity for MDR, the present inventors have found that a specific 1,2-dihydro-2-oxoquinoline derivative achieves the object. Thus, the present invention has been completed. As described above, indole compounds having an affinity for MDR are known, but there is no report that the 1,2-dihydro-2-oxoquinoline derivative of the present invention has a high affinity for MDR.

That is, the present invention provides a compound of the formula [I]

[0008]

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Wherein Ar is a pyridyl group or a formula

[0010]

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(Wherein X ³ and X ⁴ are the same or different and represent a hydrogen atom, a halogen atom, a C _1-5 alkyl group, a C _1-5 alkoxy group, a hydroxyl group or a trifluoromethyl group). And Y represents a nitrogen atom, CH, or C (OH). R ¹ and R ² are the same or different and represent a hydrogen atom, a C _1-10 alkyl group, a C _3-15 alkoxyalkyl group or a C _3-15 alkylaminoalkyl group, or R ¹ and R ² are Form a cyclic amino group with an adjacent nitrogen atom. X ¹ and X ² are the same or different and each represent a hydrogen atom, a C _1-5 alkyl group, a C _1-5 alkoxy group or a halogen atom, or X ¹ and X ² are taken together to form an alkylenedioxy group To form n shows the integer of 1-3. And a pharmaceutically acceptable salt thereof.

In the present invention, X^Three, X^FourHalogen atom of
Is a fluorine, chlorine, bromine or iodine atom
is there. X^Three, X^FourC_1-5The alkyl group of
Shows a branched alkyl group, for example, methyl group, ethyl
Group, propyl group, isopropyl group, etc.
You. X^Three, X^FourC_1-5The alkoxy group is a linear or branched
Represents an alkoxy group on the branch, such as a methoxy group,
Xyl groups and the like can be mentioned. R¹, R^TwoC_1-10No
A alkyl group is a linear, branched or cyclic alkyl group.
Represents, for example, methyl, ethyl, propyl, isop
Ropyl, cyclopropyl, butyl, isobutyl
Group, cyclobutyl group, cyclopropylmethyl group, pliers
Group, isopentyl group, cyclopentyl group, cyclobutyl
Methyl group, 1-ethylpropyl group, hexyl group, iso
Hexyl group, cyclohexyl group, cyclopentylmethyl
Group, 1-ethylbutyl group, heptyl group, isoheptyl
Group, cyclohexylmethyl group, octyl group, nonyl group,
Decyl group and the like. R¹, R^TwoC _3-15The alkoxyal
A kill group is defined as a linear, branched or cyclic C_1-13Arco
Kishi-C_2-14Represents an alkyl group, for example, methoxyethyl
Group, methoxypropyl group, methoxybutyl group, ethoxy
Ethyl group, ethoxypropyl group, ethoxybutyl group,
Toxylpentyl, ethoxyhexyl, ethoxyhep
Tyl group, propoxyethyl group, propoxypropyl group,
Propoxybutyl group, isopropoxyethyl group, cyclo
And a propylmethoxyethyl group. R¹, R^TwoC_3-15
Alkylaminoalkyl groups are linear, branched or
Is a cyclic C_1-13Alkylamino-C_2-14Represents an alkyl group
For example, methylaminoethyl group, dimethylaminoethyl
Group, methylaminopropyl group, dimethylaminopropyl
Group, methylaminobutyl group, ethylaminoethyl group,
Ethylaminopropyl group, ethylaminobutyl group, ethyl
Laminopentyl group, ethylaminohexyl group, ethyl
Aminoheptyl group, ethylaminooctyl group, propyl
Aminoethyl group, propylaminopropyl group, propyl
Aminobutyl group, isopropylaminoethyl group, cyclo
Propylmethylaminoethyl group, pyrrolidinoethyl group, etc.
It is. R¹, R^TwoAnd with adjacent nitrogen atoms
Cyclic amino groups include, for example, pyrrolidino group, piperidino
Group, homopiperidino group, morpholino group, piperazino group,
N-methylpiperazino group, 3,5-dimethylpiperazino
And the like. X¹, X^TwoC_1-5Is an alkyl group
, Branched or cyclic alkyl groups, such as methyl
Group, ethyl group, propyl group, isopropyl group, butyl
Group, isobutyl group, pentyl group and the like. X¹, X^TwoC
_1-5The alkoxy group is a linear, branched or cyclic
Represents an alkoxy group, for example, a methoxy group, an ethoxy group,
Propoxy, isopropoxy, butoxy, isobut
Toxic group, cyclopropylmethoxy group, pentoxy group,
And an isopentoxy group. X¹, X^TwoAnd the halogen atom
Is a fluorine, chlorine, bromine or iodine atom
is there. X¹Is X^TwoC formed together_1-5Archille
A dioxy group is, for example, a methylenedioxy group,
Dioxy group, n-propylene dioxy group, etc.
Can be. Also, the pharmaceutically acceptable salt in the present invention
For example, salts with mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid, and vinegar
Acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic
Organic acids such as acid, methanesulfonic acid and benzenesulfonic acid
And the like.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the formula [I] can be produced by the following general production methods 1 to 3 (where Ar, Y, R ¹ , R ² , X ¹ , X ² and n are the same as above, Y ¹ represents a nitrogen atom or CH, and R ³ , R ⁴
_Represents the same or different and represents a C _1-5 alkyl group or a benzyl group, and X ⁵ represents a chlorine atom, a bromine atom or an iodine atom. ).

[General Production Method 1]

[0015]

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Step A: 1,2-Dihydro-2-oxoquinoline carboxylic acid ester derivative (1) is prepared by using an arylalkyl halide derivative (2) and an inert solvent, if necessary, using a phase transfer catalyst, in the presence of a base. By reacting, 1-arylalkyl-1,2-dihydro-2-oxoquinoline carboxylic acid ester derivative (3) can be obtained. Here, the inert solvent includes, for example, alcohols such as methanol and ethanol, ethers such as 1,2-dimethoxyethane and tetrahydrofuran, hydrocarbons such as toluene and benzene, chloroform, halogen solvents such as dichloromethane, acetonitrile, N, N-
Examples include dimethylformamide, water or a mixed solvent thereof. Examples of the phase transfer catalyst include quaternary ammonium salts such as benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether.
The base includes, for example, inorganic bases such as potassium carbonate, sodium hydroxide, sodium hydride, and sodium metal, and alcoholates such as potassium t-butoxide and sodium ethoxide.

Step B: 1-arylalkyl-1,2-
The dihydro-2-oxoquinoline carboxylic acid ester derivative (3) is hydrolyzed with a base or an acid in an inert solvent to give a 1-arylalkyl-1,2-dihydro-2-oxoquinoline carboxylic acid derivative (4). . Here, the inert solvent includes, for example, alcohols such as methanol and ethanol, ketones such as acetone, ethers such as 1,2-dimethoxyethane and tetrahydrofuran, hydrocarbons such as toluene and benzene, chloroform, and dichloromethane. Halogen solvent, acetonitrile, N, N-
It is dimethylformamide or the like, or a mixed solvent of these solvents and water. The base refers to an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like, and the acid refers to, for example, hydrochloric acid, sulfuric acid, phosphoric acid and the like. Step C: The compound of the present invention (6) is obtained from a 1-arylalkyl-1,2-dihydro-2-oxoquinolinecarboxylic acid derivative (4) via an acid halide or a mixed acid anhydride,
Can be synthesized.

Here, the acid halide refers to acid chloride, acid bromide, etc., for example, thionyl chloride, thionyl bromide,
It is obtained by reacting a halogenating agent such as oxalyl chloride, carbon tetrachloride-triphenylphosphine, carbon tetrabromide-triphenylphosphine in an inert solvent. The inert solvent shown here, for example, ethers such as tetrahydrofuran, hydrocarbons such as toluene and benzene,
Examples thereof include halogen solvents such as chloroform and dichloromethane, acetonitrile, N, N-dimethylformamide and the like.

The mixed acid anhydride is, for example, an anhydride of carboxylic acid and carbonic acid. For example, a halocarbonate such as ethyl chlorocarbonate and isobutyl chlorocarbonate is converted to triethylamine,
Diisopropylethylamine, N-methylmorpholine,
It is obtained by reacting in an inert solvent in the presence of an organic base such as pyridine or an inorganic base such as sodium hydride. The inert solvent shown here is, for example, ethers such as tetrahydrofuran, hydrocarbons such as toluene and benzene, halogen solvents such as chloroform and dichloromethane, acetonitrile, N, N-dimethylformamide and the like.

The compound (6) of the present invention can also be obtained by reacting a 1-arylalkyl-1,2-dihydro-2-oxoquinolinecarboxylic acid derivative with an amine (5) together with a condensing agent in an inert solvent. Obtainable. Here, the condensing agent indicates a commonly used amidating reagent,
Examples include carbodiimides represented by diphenylphosphoryl azide, diethyl cyanophosphate, carbonyldiimidazole, N, N'-dicyclohexylcarbodiimide, N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride, and the like. Examples of the inert solvent include ethers such as 1,2-dimethoxyethane and tetrahydrofuran, hydrocarbons such as toluene and benzene, halogen solvents such as chloroform and dichloromethane, acetonitrile, and N, N-dimethylformamide. Can be. In addition, this reaction may be carried out with N if necessary.
-Hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine and the like can also be added as an activator.

[General Production Method 2]

[0022]

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The 1,2-dihydro-2-oxoquinoline carboxylic acid derivative (7) is amidated in Step C to give the compound (8) of the present invention, and further subjected to 1-arylalkylation in Step A to give The present compound (6) is obtained.

[General Production Method 3]

[0025]

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Step D: The isatoic anhydride derivative (9) is reacted with the malonic ester (10) in an inert solvent in the presence of a base to give 4-hydroxy-1,2-dihydro-2-oxoquinoline carboxylic acid. Acid ester derivative (1
1) is obtained.

Here, the inert solvent includes, for example, alcohols such as methanol and ethanol, ethers such as 1,2-dimethoxyethane and tetrahydrofuran, hydrocarbons such as toluene and benzene, and halogenated solvents such as chloroform and dichloromethane. , Acetonitrile, N, N-
Examples include dimethylformamide, water or a mixed solvent thereof. The base includes, for example, inorganic bases such as potassium carbonate, sodium hydroxide, sodium hydride, and sodium metal, and alcoholates such as potassium t-butoxide and sodium ethoxide.

Step E: 4-hydroxy-1,2-dihydro-2-oxoquinolinecarboxylic acid ester derivative (1
The compound (12) of the present invention can be obtained by reacting 1) with the amine derivative (5) in an inert solvent. Here, the inert solvent includes, for example, alcohols such as methanol and ethanol, ethers such as 1,2-dimethoxyethane and tetrahydrofuran, hydrocarbons such as toluene and benzene, chloroform, halogen solvents such as dichloromethane, acetonitrile, N, N-dimethylformamide, water or a mixed solvent thereof.

[0029]

The compound of the present invention has a high affinity for MDR. Therefore, anxiety or its related disorders, depression, epilepsy, sleep disorders, cognitive learning disorders, central disorders such as schizophrenia, motor disorders associated with muscle stiffness, eating disorders, circulatory disorders, drug dependence, cancer, lipids Metabolic disorders, cerebral infarction, AID
S, treatment of Alzheimer's disease or Huntington's disease.
Useful as a prophylactic.

[0030]

The present invention will be specifically described below with reference to examples and test examples.

Example 1 (1) Production of N, N-dihexyl-1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxamide 1,2-dihydro-2-oxoquinoxaline-3-carboxylic acid 3.90 g of ethyl ester was dissolved in 25 ml of N, N-dimethylformamide, and this was added dropwise to a suspension of 0.79 g of 60% sodium hydride / oil in 10 ml of N, N-dimethylformamide at room temperature for 30 minutes. After stirring at room temperature for another 30 minutes, benzyl bromide 3.36
g was added dropwise over 10 minutes, and the mixture was further stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue.
The extract was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was chromatographed (silica gel: Wako gel C200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: hexane-ethyl acetate = 10: 1 to 1).
2: 1), recrystallized from ethyl acetate-hexane, and 3.77 g of 1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxylic acid ethyl ester.
I got

(2) 1-benzyl-1,2-dihydro-
10 ml of ethanol and 20 ml of a 10% aqueous sodium hydroxide solution were added to 2.00 g of ethyl 2-oxoquinoxaline-3-carboxylate, and the mixture was stirred at room temperature for 1 hour. 3N hydrochloric acid was added dropwise to the reaction solution, and the mixture was acidified (pH = 3.
0), and the precipitated crystals were collected by filtration. The crystals are washed with water and diethyl ether, and 1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxylic acid 1.7 is obtained.
3 g were obtained.

(3) 1-benzyl-1,2-dihydro-
0.50 g of 2-oxoquinoxaline-3-carboxylic acid and 0.87 ml of triethylamine were added to tetrahydrofuran 3
It was dissolved in 0 ml, cooled to -40 ° C, and 0.19 ml of ethyl chlorocarbonate was added dropwise over 5 minutes. After stirring at -40 ° C for 10 minutes, 0.46 ml of dihexylamine was added dropwise over 5 minutes. After stirring at −40 ° C. for 1 hour, the temperature was raised to room temperature over 1 hour, and further stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous sodium sulfate, and the desiccant was filtered off. Was concentrated under reduced pressure. The residue was purified by chromatography (silica gel: Wako gel C200 (manufactured by Wako Pure Chemical Industries, Ltd., developing solvent: chloroform)), and recrystallized from hexane to give N, N
-Dihexyl-1-benzyl-1,2-dihydro-2-
0.53 g of oxoquinoxaline-3-carboxamide 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, N-dihexyl-1- (3-picolyl) -1,2-
Production of dihydro-2-oxoquinoline-3-carboxamide (1) 9.46 g of 1,2-dihydro-2-oxoquinoline-3-carboxylic acid and 5.06 g of N-methylmorpholine
Was dissolved in a mixed solvent of 50 ml of tetrahydrofuran and 250 ml of N, N-dimethylformamide, cooled to −15 ° C., and 6.83 g of isobutyl chlorocarbonate was added dropwise over 10 minutes. After stirring at −15 ° C. for 10 minutes, 9.73 g of dihexylamine was added dropwise over 5 minutes. After stirring at −15 ° C. for 4 hours and further at room temperature overnight, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated saline solution. After drying over sodium, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 13.51 g of N, N-dihexyl-1,2-dihydro-2-oxoquinoline-3-carboxamide.

(2) N, N-dihexyl-1,2-dihydro-2-oxoquinoline-3-carboxamide 1.0
To a solution of 1 g of N, N-dimethylformamide (13 ml) was added 136 mg of 60% sodium hydride / oil, and the mixture was stirred at room temperature for 1 hour. To this reaction solution, 434 mg of 3-picolyl chloride was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by chromatography (silica gel: Wako gel C200 (manufactured by Wako Pure Chemical Industries, Ltd., developing solvent: hexane-ethyl acetate = 7: 13 to 1:19), recrystallized from ethyl acetate, and N, N-dihexyl- 0.47 g of 1- (3-picolyl) -1,2-dihydro-2-oxoquinoline-3-carboxamide 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 3 N, N-dihexyl-1-benzyl-4-hydroxy-
Production of 1,2-dihydro-2-oxoquinoline-3-carboxamide (1) Dissolve 4.50 g of diethyl malonate in 20 ml of N, N-dimethylformamide and add 1.10 g of 62.4% sodium hydride to room temperature. And added little by little. After stirring at room temperature until hydrogen generation ceased, the reaction solution was heated to 80 ° C., and a solution of 6.70 g of N-benzyl isatoic anhydride dissolved in 20 ml of N, N-dimethylformamide was added dropwise. After the dropwise addition, the reaction mixture was heated and stirred at 120 ° C. for 7 hours. After cooling to room temperature, the reaction mixture was poured into ice water and washed with ethyl acetate. The aqueous phase was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding ethanol to obtain 5.88 g of 1-benzyl-4-hydroxy-1,2-dihydro-2-oxoquinoline-3-carboxylic acid ethyl ester.

(2) 1-benzyl-4-hydroxy-
0.30 g of 1,2-dihydro-2-oxoquinoline-3-carboxylic acid ethyl ester and dihexylamine 2
The mixture was heated and stirred at 130 ° C. for 2 hours. After cooling to room temperature, chloroform and 1N hydrochloric acid were added to the reaction solution, and the separated organic phase was washed with 1N hydrochloric acid and water. After drying the organic phase over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue is purified by chromatography (silica gel: Merck silica gel 230-4000 mesh (Merck), developing solvent: chloroform), and left to crystallize as N, N-dihexyl-1-benzyl-4-hydroxy-1,2. 0.36 g of -dihydro-2-oxoquinoline-3-carboxamide was obtained.

Table 2 shows the structure and physical properties data of this compound and the compound obtained in the same manner.

[0041]

[Table 1]

[0042]

[Table 2]

[Test Example] MDR receptor binding experiment Crude mitochondrial fraction prepared from rat cerebral cortex was used as a receptor preparation.

[0044] ^[3 H] as labeled ligand ^[3 H] PK1
1195 was used.

The binding experiment using the [ ³ H] -labeled ligand was carried out in the Journal of Pharmacology and Experimental Thera.
The following method described in peutics, 262, 971 (1992) was used.

Preparation of Receptor Standard: Rat cerebral cortex was treated with a Teflon homogenizer to a volume of 10 times the wet weight of 0.1 ml.
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 a Hepes buffer at 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] PK111
95 (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 non-specific 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, the ^[3 H] PK11195 binding from the inhibition curves 5
The concentration (IC ₅₀ ) of the test drug that inhibits 0% was determined, and the results are shown in Table 3.

[0050]

[Table 3]

────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification symbol FI A61K 31/00 626 A61K 31/00 626K 626H 643 643D 31/47 601 31/47 601 603 603 (72) Inventor Toshihito Kumagai Tokyo 3-24-1, Takada, Toshima-ku Taisho Pharmaceutical Co., Ltd. (72) Inventor Shigeyuki Chaki 3-24-1, Takada, Toshima-ku, Tokyo Inside Taisho Seiyaku Co., Ltd. (72) Kazuyuki Tomizawa Toshima, Tokyo 3-24-1, Takada-ku Taisho Pharmaceutical Co., Ltd. (72) Inventor Masashi Nagamine 345 Koyamadacho, Kawachinagano-shi, Osaka Prefecture Japan Agrochemicals Co., Ltd. (72) Inventor Makoto Goto Koyamadacho, Kawachinagano-shi, Osaka Prefecture 345 Nippon Agrochemicals Co., Ltd. (72) Inventor Masanori Yoshida 345 Koyamada-cho, Kawachinagano-shi, Osaka Pref. Research house

Claims (1)

[Claims] (1) Formula (1) Wherein Ar is a pyridyl group or a compound of the formula (Wherein X ³ and X ⁴ are the same or different and are a hydrogen atom, a halogen atom, a C _1-5 alkyl group, a C _1-5 alkoxy group,
Shows a hydroxyl group or a trifluoromethyl group. ), And Y represents a nitrogen atom, CH, or C (OH). R ¹ and R ² may be the same or different and each represent a hydrogen atom, a C _1-10 alkyl group, a C _3-15 alkoxyalkyl group,
_Represents an alkylaminoalkyl group of _3-15 , or R ¹ and R ² together with an adjacent nitrogen atom form a cyclic amino group. X ¹ and X ² are the same or different and each represent a hydrogen atom, a C _1-5 alkyl group, a C _1-5 alkoxy group or a halogen atom, or X ¹ and X ² are taken together to form an alkylenedioxy group To form n shows the integer of 1-3. A 1,2-dihydro-2-oxoquinoline derivative or a pharmaceutically acceptable salt thereof.