JPH11228539A - Nitrogen-containing tetracyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having high affinity for MDR (mitochondrial diazepam binding inhibitor receptor), and useful as a therapeutic/ preventive agent for anxiety or related diseases, depression or the like. SOLUTION: This new compound is shown by formula I [Y<1> to Y<3> are each N-C=N or C=C-NR<3> (R<3> is H, a 1-5C alkyl or the like); Y<4> is S, SO, SO2 or the like; R<1> and R<2> are each H, a 1-12C alkyl, 3-15C alkoxyalkyl or the like; X<1> and X<2> are each H, a 1-5C alkyl, 1-5C alkoxy or the like; (n) is 0, 1 or 2], e.g. N-2-(propylamino)ethyl-N-hexyl-6,11-dihydro-5-thia-11-aza- benzo[a]fluorene-6-carboxamide. It is recommended that this new compound is obtained, for example, by reaction of a ketocarboxylic acid derivative of formula II with a phenylhydrazine derivative of formula III to form a tetracyclic indole derivative of formula IV which, in turn, is reacted with a halogenating agent such as thionyl chloride in an inert solvent such so toluene.

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). Currently, excessive but CBR agonists represented by diazepam are widely used as anxiolytics, CBR agonists to act directly on GABA _A receptor / chloride channel complex, at the same time side effects and anxiolytic effects Expresses sedation and mental dependence. On the other hand, MDR
Since an agonist acts indirectly on GABA _A receptor / chloride channel through the synthesis of a neurosteroid which is an endogenous neuroactive steroid (endogenous anxiolytic substance), an anxiolytic effect is expressed. Does not exhibit the side effects of excessive sedation or mental dependence (J. Pharm
acol. 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 The present inventors have conducted intensive studies on compounds having a high affinity for MDR, and as a result, have found that a specific nitrogen-containing tetracyclic compound achieves the object, and completed the present invention. did. As described above, indole compounds having an affinity for MDR are known, but there is no report that the nitrogen-containing tetracyclic compound of the present invention has high affinity for MDR.

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

[0008]

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[Wherein, Y ¹ -Y ² -Y ³ is NC = N,
Or (wherein, R ³ is a hydrogen atom,. Represents an alkyl group containing nitrogen alkyl or C _2-10 of C _1-5) wherein C = C-NR ³ represents a group represented by. Y ⁴ is S, SO, SO ₂ , C
H ₂ or a group represented by the formula NR ⁴ (wherein R ⁴ represents a C _1-5 alkanoyl group or a C _1-5 alkyl group). 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, and n represents 0, 1 or 2. Or a pharmaceutically acceptable salt thereof.

In the present invention, C ³ of R ³ , R ⁴ , X ¹ and X ² is
The alkyl group of _1-5 represents a linear, branched or cyclic alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a cyclopropylmethyl group, a pentyl group And an isopentyl group. Examples of the C _2-10 nitrogen-containing alkyl group of R ³ include a methylaminopropyl group, a dimethylaminoethyl group, a pyrrolidinoethyl group, and a 4-methylpiperazinoethyl group. The C _1-5 alkanoyl group for R ⁴ includes, for example, formyl group, acetyl group,
And a propionyl group. The C _1-10 alkyl group of R ¹ and R ^{2 represents} a linear, branched or cyclic alkyl group;
For example, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, cyclopentyl, cyclobutylmethyl, 1-ethylpropyl , Hexyl group, isohexyl group, cyclohexyl group, cyclopentylmethyl group, 1-
Examples thereof include an ethylbutyl group, a heptyl group, an isoheptyl group, a cyclohexylmethyl group, an octyl group, a nonyl group, and a decyl group. The C _3-15 alkoxyalkyl group of R ¹ and R ² represents a linear, branched or cyclic C _1-13 alkoxy-C _2-14 alkyl group, such as a methoxyethyl group and a methoxypropyl group. , Methoxybutyl group, ethoxyethyl group, ethoxypropyl group, ethoxybutyl group, ethoxypentyl group, ethoxyhexyl group, ethoxyheptyl group, propoxyethyl group, propoxypropyl group, propoxybutyl group, isopropoxyethyl group,
Examples thereof include a cyclopropylmethoxyethyl group. The C _3-15 alkylaminoalkyl group of R ¹ and R ² represents a linear, branched or cyclic C _1-13 alkylamino-C _2-14 alkyl group, and includes a methylaminoethyl group and a dimethyl group. Aminoethyl, methylaminopropyl, dimethylaminopropyl, methylaminobutyl, ethylaminoethyl, ethylaminopropyl, ethylaminobutyl, ethylaminopentyl, ethylaminohexyl, ethylaminoheptyl, ethyl Examples include aminooctyl, propylaminoethyl, propylaminopropyl, propylaminobutyl, isopropylaminoethyl, cyclopropylmethylaminoethyl, and pyrrolidinoethyl. The cyclic amino group formed by R ¹ , R ² and the nitrogen atom adjacent thereto is, for example, a pyrrolidino group, a piperidino group, a homopiperidino group, a morpholino group, a piperazino group, an N-methylpiperazino group, a 3,5-dimethylpiperazine And the like. The C _1-5 alkoxy group for X ¹ and X ² is
It represents a linear, branched or cyclic alkoxy group, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, cyclopropylmethoxy, pentoxy, isopentoxy and the like. X ¹ and X ² represent 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 and methanesulfonic acid. And salts with organic acids such as benzenesulfonic acid.

[0012]

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 scheme, Y ¹ , Y ² , Y ³ , Y ⁴ , R ¹ , R ² , X ¹ , X ² and n are the same as described above, R ⁵ represents a hydrogen atom or a C _1-5 alkyl group, and R ⁶ represents a C _1-5 alkyl group or C _2-10 R ⁷ and R ⁸ are the same or different and represent a C _1-5 alkyl group or a benzyl group, X ³ represents a chlorine atom, a bromine atom or an iodine atom, and X ⁴ represents a fluorine atom , Chlorine, bromine or iodine, Boc
Represents a t-butoxycarbonyl group. ).

[General Production Method 1]

[0014]

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Step A: Tetracyclic indole derivative (3)
Is obtained by a Fischer indole synthesis method using a ketocarboxylic acid derivative (1) and a phenylhydrazine derivative (2). R of tetracyclic indole derivative (3)
^{When 5} is a C _1-5 alkyl group, the ester can be converted to a carboxylic acid derivative (R ⁵
= H).

Step B: The compound (5) of the present invention can be synthesized from the tetracyclic indole derivative (3) via an acid halide or a mixed acid anhydride. Here, acid chloride and acid halide, it represents an acid bromide or the like, the tetracyclic indole derivative ^{(3) (R 5 = H} ), for example thionyl chloride, thionyl bromide, oxalyl chloride, carbon tetrachloride - triphenylphosphine And a halogenating agent such as carbon tetrabromide-triphenylphosphine in an inert solvent. The inert solvent shown here includes 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 mixed acid anhydride refers to an anhydride of a carboxylic acid derivative (3) (R ⁵ ＨH) with a carbonate or a carboxylic acid, for example, a halocarbonate such as ethyl chlorocarbonate or isobutyl chlorocarbonate. Alternatively, for example, carboxylic acids such as acetic acid, propionic acid, benzoic acid, and naphthoic acid are reacted in an inert solvent in the presence of an organic base such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or an inorganic base such as sodium hydride. Obtained by: 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 (5) of the present invention can also be obtained by reacting the tetracyclic indole derivative (3) with an amine (4) together with a condensing agent in an inert solvent. Here, the condensing agent indicates a commonly used amidating reagent, for example, diphenylphosphoryl azide, diethyl cyanophosphate, carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, N-ethyl-N′-dimethylaminopropylcarbodiimide hydrochloride And the like. The inert solvent is, for example, ethers such as 1,2-dimethoxyethane and tetrahydrofuran, hydrocarbons such as toluene and benzene, for example, chloroform,
Halogen-based solvents such as dichloromethane, acetonitrile,
N, N-dimethylformamide and the like. This reaction may be carried out, if necessary, with N-hydroxysuccinimide, 1-hydroxybenzotriazole or 3-hydroxy-4-
Oxo-3,4-dihydro-1,2,3-benzotriazine and the like can be added as an activator.

[General Production Method 2]

[0020]

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The compound (5) of the present invention can also be obtained by amidating the ketocarboxylic acid (6) in the step B and then reacting the obtained ketoamide derivative (7) under the Fischer's indole synthesis conditions in the step A.

[General Production Method 3]

[0023]

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Step C: The compound (9) of the present invention is obtained by reacting the tetracyclic compound (5) with a halogenated compound (8) in an inert solvent in the presence or absence of a phase transfer catalyst together with a base. 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, and halogenated solvents such as chloroform and dichloromethane. , Acetonitrile, N, N-
Dimethylformamide and the like. Phase transfer catalysts, for example, benzyltriethylammonium bromide, quaternary ammonium salts such as tetrabutylammonium 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.

[General Production Method 4]

[0027]

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Step D: 2-cyanobenzyl halide (1
The benzylmalonic acid derivative (12) can be obtained by reacting 0) with the 2-aminomalonic acid diester derivative (11) with a base in an inert solvent in the presence or absence of a phase transfer catalyst.

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. Solvent, acetonitrile,
N, N-dimethylformamide and the like. Examples of the phase transfer catalyst include quaternary ammonium salts such as benzyltriethylammonium bromide and tetrabutylammonium bromide, and crown ethers such as 18-crown-6-ether. The base is, for example, potassium carbonate,
Inorganic bases such as sodium hydroxide, sodium hydride and sodium metal; and alcoholates such as potassium t-butoxide and sodium ethoxide.

Step E: Benzylmalonic acid derivative (12)
The phenylalanine derivative (13) can be obtained by hydrolyzing an ester with a base or an acid in an inert solvent, followed by decarboxylation. Here, the inert solvent is, 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, halogen solvents such as chloroform and dichloromethane, acetonitrile, N, N-dimethylformamide, water and the like Is a mixed solvent. 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.

Further, a phenylalanine derivative (13)
Is deprotected by reacting with an organic acid such as trifluoroacetic acid and formic acid or an inorganic acid such as hydrogen chloride, hydrochloric acid, hydrobromic acid and sulfuric acid after the reaction in step B, and is led to an amide (14). .

Step F: The amide derivative (14) is reacted with a nitrobenzene derivative (15) in an inert solvent in the presence or absence of a base to give an aniline derivative (1).
It can lead to 6).

Here, the base includes, for example, potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydride,
Inorganic bases such as metallic sodium; alcoholates such as potassium t-butoxide and sodium ethoxide; and organic bases such as triethylamine, diisopropylethylamine and pyridine. Examples of the inert solvent include alcohols such as methanol and ethanol, ethers such as 1,2-dimethoxyethane, tetrahydrofuran and dioxane, hydrocarbons such as toluene and benzene, halogen solvents such as chloroform and dichloromethane, and acetonitrile. , N, N-dimethylformamide and the like.

Step G: The nitro group of the aniline derivative (16) is reduced in an inert solvent and then treated with an acid in an inert solvent to obtain the compound (17) of the present invention.

The term "reduction" used herein refers to hydrogenation using platinum dioxide, palladium or the like, or acid, neutral or basic conditions using a metal such as tin, iron or zinc or a metal salt such as stannous chloride. Shows metal reduction at The inert solvent at this time is, for example, alcohols such as methanol and ethanol,
Ethers such as diethyl ether and tetrahydrofuran; hydrocarbons such as toluene and benzene; halogenated carbon solvents such as dichloromethane and chloroform; organic carboxylic acids such as acetonitrile, N, N-dimethylformamide and acetic acid; water; Solvents. Acid treatment in an inert solvent, for example, methanol, in a single solvent of alcohols such as ethanol, or diethyl ether,
In a mixed solvent of ethers such as tetrahydrofuran, hydrocarbons such as toluene and benzene, halogenated solvents such as dichloromethane and chloroform, and a mixed solvent of N, N-dimethylformamide and alcohol with hydrogen chloride, hydrogen bromide, sulfuric acid, This indicates that the reaction is performed using an acid such as fluoroacetic acid.

[General Production Method 5]

[0037]

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Step H: Sulfur atom-containing tetracyclic compound (1
8) treatment with an oxidizing agent in an inert solvent to give a racemic or optically active sulfoxide derivative (19)
Or a sulfone derivative (20) is obtained.

Here, the inert solvent includes, for example, alcohols such as methanol and ethanol, diethyl ether,
Ethers such as tetrahydrofuran; hydrocarbons such as toluene and benzene; halogenated solvents such as dichloromethane and chloroform; organic carboxylic acids such as acetonitrile, N, N-dimethylformamide and acetic acid; water; and mixed solvents thereof. The oxidizing agent, for example, m- chloroperbenzoic acid, percarboxylic acids such as peracetic acid, or hydrogen peroxide, oxone _{(OXONE, 2KSO 5 · KHSO 4} · K
Inorganic peroxides such as ₂ SO ₄ ).

[General Production Method 6]

[0041]

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Step I: The optically active compound (22) was prepared by converting the racemic compound (21) of the present invention into H using a chiral stationary phase.
It can also be obtained by dividing by PLC. Here, the chiral stationary phase is a derivative such as cellulose ester, cellulose carbamate, amylose carbamate, crown ether, polymethacrylate and the like.

Step J: Racemic carboxylic acid derivative (2
By converting 3) into a salt with a chiral amine, it can be resolved into an optically active form (24). Here, the chiral amine means (+) or (−)-1-phenylethylamine, (+) or (−)-2-amino-1-butanol, (+) or (−)-alaninol, brucine, cinchonidine. , Cinchonine, quinine, quinidine, dehydroabiethylamine and the like. The optically active substance (22) is obtained by amidating the optically active substance (24) in Step B.

[General Production Method 7] One or both of R ¹ and R ² of the compound (21) or (22) of the present invention contains a nitrogen atom protected by an acyl group, an alkoxycarbonyl group or the like. In these cases, these protecting groups are deprotected with an acid or a base to give the compound of the present invention.

Here, the acid is, for example, trifluoroacetic acid,
Formic acid, hydrogen chloride, hydrogen bromide, hydrochloric acid, hydrobromic acid and the like, and the base is, for example, potassium carbonate, sodium carbonate,
Potassium hydroxide, sodium hydroxide, lithium hydroxide,
Indicates barium hydroxide and the like.

[0046]

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

[0047]

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

Example 1 N-2- (propylamino) ethyl-N-hexyl-
Preparation of 6,11-dihydro-5-thia-11-aza-benzo [a] fluorene-6-carboxamide (1) 22.54 g of (4-oxo-thiochroman-2-yl) -carboxylic acid and phenylhydrazine 7ml
15 ml of sulfuric acid was added to a solution of 100 ml of ethanol of
The mixture was refluxed for 5 hours. The reaction solution is cooled to room temperature, and ice water 5
Poured into 00 ml and extracted with ether. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol-hexane to give 6,11-dihydro-5. -Thia-11-aza-benzo [a] fluorene-6-carboxylic acid ethyl ester 21.85 g was obtained.

(2) 19.46 g of potassium hydroxide was added to water 4
0, and dissolve in 6,11-dihydro-5-thia-11.
-Aza-benzo [a] fluorene-6-carboxylic acid ethyl ester 21.63 g was added to a solution of ethanol 100 ml. After heating under reflux for 2 hours, concentrated hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 3, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol-hexane to give 6,11-dihydro-
5-thia-11-aza-benzo [a] fluorene-6
19.94 g of carboxylic acid were obtained. m. p. 141.5-142.5 ° C.

(3) 6,11-dihydro-5-thia-1
1-aza-benzo [a] fluorene-6-carboxylic acid 8
To a solution of 44 mg of N-2- (Nt-butoxycarbonylpropylamino) ethyl-hexylamine and 1.66 g of 44 ml of dichloromethane was added 552 mg of 1-hydroxybenzotriazole monohydrate and N-ethyl-N′-dimethylaminopropyl. 863 mg of carbodiimide hydrochloride
Was added and stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, a 5% aqueous solution of potassium hydrogen sulfate, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution, dried over anhydrous sodium sulfate, and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica gel: Chromatorex NHDM10).
20 (manufactured by Fuji Devison Chemical Co., Ltd.), developing solvent: hexane-ethyl acetate = 2: 1 to 3: 2) to give amorphous N-2- (Nt-butoxycarbonylpropylamino) ethyl-N- Hexyl-6,11-dihydro-5
1.35 g of -thia-11-aza-benzo [a] fluorene-6-carboxamide were obtained.

(4) N-2- (Nt-butoxycarbonylpropylamino) ethyl-N-hexyl-6,11
600 mg of -dihydro-5-thia-11-aza-benzo [a] fluorene-6-carboxamide was stirred in 4.2 ml of 99% formic acid for 5 hours. The reaction solution is concentrated under reduced pressure, dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, the desiccant is filtered off, and the filtrate is concentrated under reduced pressure. Was recrystallized from ethyl acetate to give N-2- (propylamino) ethyl-N-hexyl-6,11-dihydro-5-thia-1.
406 mg of 1-aza-benzo [a] fluorene-6-carboxamide were obtained.

Table 1 shows the structure and physical property data of this compound and the compound obtained in the same manner.

Example 2 N, N-dihexyl-6,11-dihydro-5-thia-
Production of 11-aza-benzo [a] fluorene-6-carboxamide (1) 14.0 ml of thionyl chloride was added to a solution of 20.00 g of (4-oxo-thiochroman-2-yl) -carboxylic acid in 200 ml of benzene, and 3 Heated to reflux for an hour. The reaction solution was concentrated under reduced pressure. Dichloromethane 1 of this residue
00 ml of the solution were mixed with 24.6 ml of dihexylamine and 20.0 ml of triethylamine in 200 ml of dichloromethane.
The mixture was added dropwise with stirring to 1 under ice cooling. After stirring at room temperature overnight, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and water, 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate,
After washing with saturated saline and drying over anhydrous sodium sulfate,
The drying agent was removed by filtration, and the filtrate was 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 = 5: 1 to 1: 1.
3: 1), recrystallized from hexane, and N, N-dihexyl- (4-oxo-thiochroman-2-yl)-
29.22 g of carboxamide were obtained.

(2) N, N-dihexyl- (4-oxo-thiochroman-2-yl) -carboxamide 1.00
g and phenylhydrazine 0.26 ml at 100 ° C. for 30 minutes.
After stirring for minutes, the reaction mixture was dried at 50 ° C. under reduced pressure for 30 minutes. 1.44 g of anhydrous zinc chloride was added to the residue,
And cooled to room temperature. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. . The residue was recrystallized from ethyl acetate-hexane to give N,
N-dihexyl-6,11-dihydro-5-thia-11
0.79 g of -aza-benzo [a] fluorene-6-carboxamide was obtained.

(3) Racemic N, N-dihexyl-
6,11-dihydro-5-thia-11-aza-benzo [a] fluorene-6-carboxamide was obtained by high-performance liquid chromatography (chiralpak AD (manufactured by Daicel), 2Φ × 25 cm, mobile phase: hexane-ethanol = 3). : 7, flow rate: 5 ml / min).

(-)-N, N-dihexyl-6,11-
Dihydro-5-thia-11-aza-benzo [a] fluorene-6-carboxamide [α] _D ²⁶ -25.9 (c
= 0.180, EtOH), retention time: 20 min. (+)-N, N-dihexyl-6,11-dihydro-5
-Thia-11-aza-benzo [a] fluorene-6-carboxamide [α] _D ²⁶ +25.9 (c = 0.20
7, EtOH), retention time: 37 min.

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-6,11-dihydro-11-methyl-5-thia-11-aza-benzo [a] fluorene-
Preparation of 6-carboxamide N, N-dihexyl-6,11-dihydro-5-thia-
11-aza-benzo [a] fluorene-6-carboxamide 200 mg of N, N-dimethylformamide 10 m
To the solution (1), 21 mg of 60% sodium hydride / oil was added, and the mixture was stirred at room temperature for 1 hour. To this solution was added 33 μl of methyl iodide, and the mixture was stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction solution, 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, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure.
The residue was recrystallized from hexane to give N, N-dihexyl-
6,11-dihydro-11-methyl-5-thia-11
Aza-benzo [a] fluorene-6-carboxamide 1
55 mg were obtained.

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

Example 4 N, N-dihexyl-5,6-dihydro-benzo [4,
5] Imidazo [2,1-a] isoquinoline-6-carboxamide (1) Dissolve 0.49 g of sodium in 20 ml of ethanol, and add 5.90 g of diethyl 2-Nt-butoxycarbonylaminomalonate to ethanol 10
ml of the solution were added dropwise with stirring at room temperature. After stirring for 20 minutes, 2-cyanobenzyl bromide 4.00 was added to the reaction solution.
g of ethanol (10 ml) was added, and the mixture was stirred at room temperature for 10 minutes, and further stirred under heating and reflux for 3.5 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and water, a 5% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution,
After washing with saturated saline and drying over anhydrous sodium sulfate,
The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue is chromatographed (silica gel: Wako gel C200 (manufactured by Wako Pure Chemical Industries, Ltd., developing solvent: hexane-ethyl acetate = 5: 1)).
2- (2-cyanobenzyl) -2-N
7.86 g of -t-butoxycarbonylaminomalonic acid diethyl ester was obtained.

(2) 2- (2-cyanobenzyl) -2-
To 1.17 g of Nt-butoxycarbonylaminomalonic acid diethyl ester, 20 ml of ethanol and an aqueous sodium hydroxide solution (0.36 g of sodium hydroxide / 0.5 of water)
ml), and the mixture was stirred under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and a 5% aqueous potassium hydrogen sulfate solution was added to the residue, followed by extraction with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and the desiccant was filtered off.
The filtrate was concentrated under reduced pressure to obtain 0.81 g of crude Nt-butoxycarbonyl- (2-cyanophenyl) alanine as an oil. This compound was used for the next step without purification.

(3) Crude Nt-butoxycarbonyl-
0.81 g of (2-cyanophenyl) alanine and 0.67 g of dihexylamine were added to N, N-dimethylformamide 8
was dissolved in 0.5 ml of 1-hydroxybenzotriazole monohydrate and 0.69 g of N-ethyl-N′-dimethylaminopropylcarbodiimide hydrochloride were added thereto.
Stirred overnight at room temperature. The reaction mixture was poured into water, extracted with ethyl acetate, washed with a 5% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, 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: hexane-ethyl acetate = 4: 1), and Nt-butoxycarbonyl- (2-cyanophenyl) alanine dihexylamide was used. 01 g was obtained.

(4) Nt-butoxycarbonyl- (2
-Cyanophenyl) alanine dihexylamide 0.9
8 g was dissolved in 1.7 ml of dichloromethane, 1.7 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1.5 hours.
The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with dichloromethane, washed with saturated saline, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. Concentration gave 0.76 g of crude (2-cyanophenyl) alanine dihexylamide. This compound was used for the next step without purification.

(5) 0.76 g of crude (2-cyanophenyl) alanine dihexylamide, 0.30 g of 2-fluoronitrobenzene and 0.36 g of anhydrous potassium carbonate were heated and refluxed in 8 ml of N, N-dimethylformamide for 2.5 hours. did. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. Chromatography of the residue (silica gel: Wako gel C20)
0 (manufactured by Wako Pure Chemical Industries), developing solvent: hexane-ethyl acetate =
5: 1) to give N- (2-nitrophenyl)-(2
-Cyanophenyl) alanine dihexylamide 0.4
2 g were obtained.

(6) N- (2-nitrophenyl)-(2
-Cyanophenyl) alanine dihexylamide 95 m
g and 10 mg of platinum dioxide were stirred in 3 ml of methanol for 2 hours in a hydrogen atmosphere. After filtering off the insolubles using a celite plate, the filtrate was concentrated under reduced pressure.

The residue was dissolved in 5 ml of ethanol, and hydrogen chloride gas was blown into the solution to obtain a saturated solution. Reaction solution 4
After stirring for an hour, the mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel: Wako gel C200 (manufactured by Wako Pure Chemical Industries), developing solvent: hexane-ethyl acetate = 2: 1), recrystallized from ethyl acetate, and N, N-dihexyl-5,6-dihydro. -Benzo [4,5] imidazo [2,1-a] isoquinoline-
24 mg of 6-carboxamide was obtained.

Table 3 shows the structure and physical properties data of this compound and the compound obtained in the same manner.

Example 5 N, N-dipropyl-6,11-dihydro-5-thia-
Preparation of 11-aza-benzo [a] fluorene-6-carboxamide 5,5-dioxide N, N-dipropyl-6,11-dihydro-5-thia-
11-Aza-benzo [a] fluorene-6-carboxamide To a solution of 500 mg of dichloromethane in 30 ml of dichloromethane,
Under ice cooling, a solution of 710 mg of m-chloroperbenzoic acid (containing 70% or more) in 30 ml of dichloromethane was added dropwise over 20 minutes while stirring. After further stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel: Wakogel C200 (manufactured by Wako Pure Chemical Industries, Ltd., developing solvent: hexane-ethyl acetate = 3: 1 to 1: 1), and recrystallized from ethyl acetate-hexane to give N, N- Dipropyl-
230 mg of 6,11-dihydro-5-thia-11-aza-benzo [a] fluorene-6-carboxamide 5,5-dioxide were obtained.

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

[0070]

[Table 1]

[0071]

[Table 2]

[0072]

[Table 3]

Test Example [MDR Receptor Binding Experiment] A crude mitochondrial fraction prepared from rat cerebral cortex was used as a receptor preparation. As ^[3 H] labeled ligand ^[3 H] PK
11195 was used. Binding experiments using [ ³ H] -labeled ligands were performed in the Journal of Pharmacology and Experimental
The following method described in Therapeutics, 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 0.
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 mixture 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 suppressed 0% was determined, and the results are shown in Table 4.

[0078]

[Table 4]

Continuation of the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/00 625 A61K 31/00 625B 626 626N 626K 635 635 637 637C 643 643D 31/40 605 31/40 605 609 609 31/435 605 31 / 435 605 31/47 610 31/47 610 C07D 471/04 102 C07D 471/04 102 495/04 111 495/04 111 (72) Inventor Toshihito Kumagai 3-24-1, Takada, Toshima-ku, Tokyo Taisho Seiyaku Co., Ltd. Inside the company (72) Inventor Shigeyuki Chaki 3- 24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Kazuki Tomizawa 3- 24-1, Takada, Toshima-ku, Tokyo Taisho Seiyaku Co., Ltd. (72) Inventor Masashi Nagamine 345 Koyamada-cho, Kawachinagano City, Osaka Prefecture Nippon Agrochemicals Co., Ltd. (72) Inventor Makoto Goto 345 Koyamadacho, Kawachinagano City, Osaka Prefecture Nippon Agrochemicals Co., Ltd. Kuniaki Kondo Osaka 345 Koyamada-cho, Kawachi Nagano-shi, Japan Nippon Agrochemicals Co., Ltd. (72) Inventor Masanori Yoshida 345 Koyamada-cho, Kawachinagano-shi, Osaka Japan Nippon Agrochemicals Co., Ltd.

Claims (1)

[Claims] (1) Formula (1) [Wherein, Y ¹ -Y ² -Y ³ is NC = N or a formula C = C
—NR ³ (wherein, R ³ represents a hydrogen atom, a C _1-5 alkyl group or a C _2-10 nitrogen-containing alkyl group). Y ⁴ is S, SO, SO ₂ , CH ₂ or a formula N
And a group represented by R ⁴ (wherein R ⁴ represents a C _1-5 alkanoyl group or a C _1-5 alkyl group). R ¹ and R ²
_Are the same or different and represent a hydrogen atom, a C _1-10 alkyl group,
_{It represents a 3-15} alkoxyalkyl group or a C _3-15 alkylaminoalkyl group, 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, and n represents 0, 1 or 2. Or a pharmaceutically acceptable salt thereof.