JP2840796B2 - Novel condensed indane derivative and pharmaceutically acceptable salt thereof - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel condensed indane derivative and a pharmaceutically acceptable salt thereof, a method for producing the same, a composition and an antitumor agent containing the derivative, and a method for treating a tumor in a mammal. About. The compounds of the present invention have excellent antitumor activity and are useful as antitumor agents.

BACKGROUND ART Conventionally, as an indeno [2,1-c] quinoline derivative,
For example, a compound in which a piperazinyl group is substituted at the 6-position described in Med. Chem. Res., 3 , 44-51 (1993) is known. However, although this document describes that the compound has an anti-serotonin effect, it does not report or describe any anti-tumor effect. Therefore, it has not been known that the condensed indane derivative of the present invention has an antitumor effect.

An object of the present invention is to provide a compound having excellent antitumor activity and useful as a therapeutic agent for tumors.

DISCLOSURE OF THE INVENTION As a result of intensive studies, the present inventors have found that condensed indane derivatives exhibit excellent antitumor activity and are useful as antitumor agents, and have completed the present invention.

That is, the present invention provides the following general formula (1) (In the formula, ring A represents a benzene ring or naphthalene ring optionally having a substituent, or a benzene ring having a lower alkylenedioxy group, and ring B represents a benzene ring optionally having a substituent or A benzene ring having a lower alkylenedioxy group, Y represents -N = CR- or -CR = N-, R represents a -NR ₁ R ₂ group, and a nitrogen-containing heterocyclic ring which may have a substituent. Or a —OR ₃ group, wherein R ₁ and R ₂ are the same or different and each represent a hydrogen atom, a phenyl group, a nitrogen-containing heterocyclic group which may have a substituent or a lower alkyl group (the lower alkyl group); The group is substituted with at least one selected from the group consisting of an optionally substituted amino group, a lower alkoxy group, a phenyl group, a nitrogen-containing heterocyclic group, an amine oxide group substituted with a lower alkyl group, and a hydroxyl group. May be)
And R ₃ represents a lower alkyl group which may be substituted with a substituted amino group. However, this excludes the case where R is a nitrogen-containing heterocyclic group which may have a substituent, and the rings A and B are unsubstituted benzene rings. ) And a pharmaceutically acceptable salt thereof.

The compound of the present invention represented by the general formula (1) has excellent antitumor activity and is effective for treating various tumors.

Accordingly, the present invention provides a composition comprising an effective amount of the compound of the general formula (1) and a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

In particular, the present invention provides an antitumor agent comprising an effective amount of the compound of the general formula (1) and a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

The present invention also provides a method for treating a tumor in a mammal, which comprises administering to the mammal an effective amount of the compound represented by the general formula (1) and a pharmaceutically acceptable salt thereof.

In the general formula (1), the groups defined by R ₁ , R ₂ and R ₃ and other groups described in the present specification are more specifically as follows.

Examples of the substituent on the benzene ring and naphthalene ring represented by ring A and ring B include a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, an amino group, a lower acyloxy group, a benzyloxy group, and a lower acylamino. Group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, and the like, preferably a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, an amino group, a lower acyloxy group, a benzyloxy group, a lower acylamino group. No.

Such a substituent may be substituted at any position of each ring and may be substituted with 1 to 4 identical or different each other. Among them, a preferred position in the case of ring A is indeno [2, 1 -C] quinoline ring and indeno [2,1
-C-] at positions 8, 9 and 10 of the isoquinoline ring;
In the case of ring B, it is also at the 2-, 3- and 4-positions. Also, A
The preferred number of substituents on the ring and the B ring is 1-2 each.

In addition, the structure of the indeno [2,1-c] quinoline ring and its substitution position are shown in Table 1 below, and the indeno [2,1-c] quinoline ring is shown in Table 1.
c] The structure of the isoquinoline ring and its substitution position are shown in Table 5 below.

As the lower alkylenedioxy group, for example, methylenedioxy, ethylenedioxy, trimethylenedioxy,
Examples thereof include an alkylenedioxy group having 1 to 4 carbon atoms of a tetramethylenedioxy group. In the case of ring A, the position of such a substituent is an 8,9-substituted or 9,10-substituted indeno [2,1-c] quinoline ring and an indeno [2,1-c] insoquinoline ring.
Substituted, and in the case of ring B, 2,3-substituted or 3,4
-Preferably substituted. When the ring A is a naphthalene ring which may have a substituent, the substitution positions of the other benzene rings of the naphthalene ring bonded to the benzene ring of the indenone skeleton are 8-9, 9-10 and There are three types at positions 10-11, and any of these substitution positions may be used.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of the lower alkyl group include methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as sec-butyl, tert-butyl, pentyl, and hexyl groups.

Examples of the lower alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Examples thereof include linear or branched alkoxy groups having 1 to 6 carbon atoms such as isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy groups.

Examples of the lower acyloxy group include formyloxy, acetoxy, propionyloxy, butyryloxy, 2-methylpropionyloxy, pivaloyloxy, pentanoyloxy, 3-methylbutyryloxy,
A linear or branched acyloxy group having 1 to 6 carbon atoms such as a hexanoyloxy group is exemplified.

Examples of the lower acylamino group include formylamino, acetylamino, propionylamino, butyrylamino, 2-methylpropionylamino, pivaloylamino, pentanoylamino, 3-methylbutyrylamino,
Examples thereof include a linear or branched acylamino group having 1 to 6 carbon atoms such as a hexanoylamino group.

Examples of the lower alkoxycarbonyl group include a methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl group Etc. carbon number 2
To 7 straight-chain or branched alkoxycarbonyl groups.

Examples of the substituent on the nitrogen-containing heterocyclic ring represented by R, R ₁ and R ₂ include a lower alkyl group and a lower alkyl group having a hydroxyl group, and preferably a lower alkyl group.

Examples of the substituent of the substituted amino group of the `` amino group which may be substituted '' represented by R <sub>1</sub> and R <sub>2</sub> and the `` lower alkyl group which may be substituted by the substituted amino group '' represented by R ₃ For example, a lower alkyl group, a lower cycloalkyl group, a di-lower alkylaminoalkyl group, a hydroxy lower alkyl group, a benzyloxycarbonyl group, a lower acyl group, and the like are preferable, and a lower alkyl group, a di-lower alkylaminoalkyl group, and a hydroxy lower group are preferable. Alkyl group,
Examples include a benzyloxycarbonyl group, which may be mono- or di-substituted, and more preferably a di-substituted product.

Examples of the lower alkyl group having a substituted amino group include methylaminomethyl, ethylaminomethyl, methylaminoethyl, ethylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,
Mono- or dialkylaminoalkyl in which the alkyl portion such as diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, diethylaminobutyl, diethylaminopent-2-yl, dipropylaminoethyl, dibutylaminoethyl, dibutylaminohexyl has 1 to 6 carbon atoms Group, N-dimethylaminoethyl-N-
An alkyl group substituted by an acylamino group having 2 to 6 carbon atoms such as a methylaminoethyl group, acetylaminoethyl, acetylaminopropyl, propionylaminoethyl, propionylaminopropyl, pivaloylaminoethyl, pivaloylaminopropyl group, cycloalkyl Propylaminomethyl, cyclopentylaminomethyl, cyclopentylaminoethyl, cyclohexylaminomethyl, an alkyl group substituted by a cycloalkylamino group having 3 to 6 carbon atoms such as cyclohexylaminoethyl group, hydroxymethylaminomethyl, 2-hydroxyethylaminomethyl, 3-hydroxypropylaminomethyl, hydroxymethylaminoethyl, 2-hydroxyethylaminoethyl, 3-hydroxypropylaminoethyl, 4-hydroxybutylaminoethyl and the like An alkyl group substituted by a benzyloxycarbonylamino group such as an alkyl group substituted by a hydroxyalkylamino group having a prime number of 1 to 4, benzyloxycarbonylaminomethyl, benzyloxycarbonylaminoethyl, and N-benzyloxycarbonyl-N-methylaminoethyl group; And the like.

As a lower alkyl group having a lower alkoxy group,
For example, a linear or branched alkyl group having 1 to 6 carbon atoms substituted by an alkoxy group having 1 to 6 carbon atoms such as methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, and methoxypropyl groups is exemplified. Can be

Examples of the lower alkyl group having a phenyl group include a phenyl group such as benzyl, phenethyl, 2-phenethyl, phenylpropyl, benzhydryl and trityl.
And a straight-chain or branched alkyl group having 1 to 4 carbon atoms containing 1 to 3 carbon atoms.

The nitrogen-containing heterocyclic group represented by R, R ₁ and R ₂ is a 5- to 6-membered monocyclic heterocyclic group having 1 to 4 nitrogen atoms and 0 or 1 oxygen atom or sulfur atom. Are preferred, for example, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxatriazolyl, thiatriazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, imidazolidinyl, imidazolidinyl , Pyrazolinyl, piperidyl,
Piperidino, piperazinyl, morpholinyl, morpholino group and the like, preferably a 5- to 6-membered monocyclic heterocyclic group having 1 to 3 nitrogen atoms and 0 or 1 oxygen atom, particularly pyridyl, pyrrolidinyl, Piperidyl, piperidino, piperazinyl, morpholinyl, morpholino, 1,
And a 2,4-triazolyl group.

Examples of the nitrogen-containing heterocyclic group having a substituent include, for example, 4-
Methylpiperazinyl, 4-ethylpiperazinyl, 4-methylpiperidino, 4-ethylpiperidino, 2-hydroxymethylpyrrolidinyl, 2- (2-hydroxyethyl)
And a pyropidinyl group.

Examples of the lower alkyl group having a nitrogen-containing heterocyclic group represented by R ₁ and R ₂ include, for example, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylethyl, 4-pyridyl C1-C6 linear chain containing nitrogen-containing heterocyclic group such as ethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinomethyl, piperidinoethyl, piperazinylmethyl, piperazinylethyl, morpholinomethyl, morpholinoethyl group Or a branched alkyl group.

Examples of the amine oxide group substituted with a lower alkyl group include, for example, methyl amino oxide, ethyl amino oxide, butyl amino oxide, dimethyl amino oxide,
Examples thereof include a mono- or di-alkyl amino oxide group in which the alkyl portion such as a diethyl amino oxide and a dibutyl amino oxide group has 1 to 4 carbon atoms.

Examples of the lower alkyl group having an amine oxide group substituted with a lower alkyl group include methylamino oxide methyl, methyl amino oxide ethyl, ethyl amino oxide methyl, ethyl amino oxide ethyl, dimethyl amino oxide methyl, diethyl amino oxide ethyl, diethyl amino oxide Alkyl moieties such as methyl, diethylaminooxideethyl, and dibutylaminooxidepropyl groups are straight-chain or branched alkyl groups having 1 to 4 carbon atoms including mono- or dialkylaminooxide groups each having 1 to 4 carbon atoms. No.

Examples of the lower alkyl group having a hydroxyl group include, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 2,3-dihydroxy Hydroxyl groups such as butyl, 5-hydroxypentyl, 2,3-dihydroxypentyl, 6-hydroxyhexyl, and 2,3-dihydroxyhexyl;
And a linear or branched alkyl group having 1 to 6 carbon atoms containing 1 or 2 carbon atoms.

The salt of the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt.For example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, tartaric acid, malic acid, maleic acid, fumaric acid, succinic acid, oxalic acid Salts with organic acids such as acid, methanesulfonic acid and P-toluenesulfonic acid, and salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like are included.

In the compound of the above general formula (1), it is preferable that the ring A is a benzene ring which is unsubstituted or substituted with a hydroxyl group or a halogen atom, or a benzene ring having a lower alkylenedioxy group. A benzene ring substituted with a hydroxyl group and / or a halogen atom and a benzene ring having a lower alkylenedioxy group are more preferable.

Ring B is preferably a benzene ring substituted with a hydroxyl group, and more preferably a bezen ring substituted with one or two hydroxyl groups.

 Y is preferably -CR = N-.

R is -NR ₁ R ₂ group, is preferably a piperazinyl group or a -OR ₃ group substituted with a lower alkyl group, and more preferably -NR ₁ R ₂ group.

R ₁ and R ₂ are the same or different and are a hydrogen atom, a phenyl group or an amino group which may be substituted, a nitrogen-containing heterocyclic group,
It is preferably an amine oxide group substituted with a lower alkyl group or a lower alkyl group optionally substituted with a hydroxyl group, and may be substituted with a hydrogen atom or a di-lower alkyl-substituted amino group or a nitrogen-containing heterocyclic group. It is more preferably a lower alkyl group, particularly preferably R ₁ is a lower alkyl group substituted by a dimethylamino group, a diethylamino group or a pyrrolidinyl group, and R ₂ is a hydrogen atom.

R ₃ is preferably a lower alkyl group optionally substituted with a di-lower alkyl-substituted amino group.

A preferred compound of the present invention is a compound represented by the general formula (1)
A benzene ring in which the ring is unsubstituted or substituted with one or two hydroxyl groups and / or halogen atoms, a benzene ring having a lower alkylenedioxy group, a benzene ring in which ring B is substituted with one or two hydroxyl groups, Y Is -CR = N-, R is -NR ₁ R ₂ group (where R ₁ and R ₂ are the same or different and are substituted by a hydrogen atom, or a di-lower alkyl-substituted amino group or a nitrogen-containing heterocyclic group. A lower alkyl group, a piperazinyl group substituted with a lower alkyl group or an —OR ₃ group (where R
₃ is a lower alkyl group which may be substituted with a di-lower alkyl-substituted amino group).
It is a quinoline derivative.

Still more preferred compounds are those represented by A in the general formula (1).
A benzene ring in which the ring is unsubstituted or substituted with one or two hydroxyl groups and / or halogen atoms, a benzene ring having a lower alkylenedioxy group, a benzene ring in which ring B is substituted with one or two hydroxyl groups, Y Is -CR = N-, R is -NR ₁ R ₂ group (where R ₁ is a di-lower alkyl-substituted amino group or a lower alkyl group substituted with a nitrogen-containing heterocyclic group, particularly dimethylamino, diethylamino, pyrrolidinyl A lower alkyl group substituted with a group, wherein R ₂ is a hydrogen atom).

The compound of the present invention represented by the general formula (1) can be produced, for example, according to the following reaction scheme 1.

(Wherein A ring, B ring and Y are the same as above. Z is -CX = N
-Or -N = CX-, and X represents a halogen atom. [Step A] 6-halogenoindeno [2,1] represented by the general formula (2)
-C] quinoline derivative or 5-halogenoindeno [2,1-c] isoquinoline derivative and amine (NH (R ₁ ) (R ₂ ) represented by RH or a nitrogen-containing heterocyclic ring optionally having a substituent The compound of the present invention represented by the general formula (1) can be obtained by amination or alkoxylation of the compound) or an alcohol (R ₃ OH) without a solvent or in an appropriate solvent. In the amination reaction, in a suitable solvent,
Sodium hydride, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, triethylamine, and the like may be used. In the alkoxylation reaction, the alcohol may be alcohol itself or an alcoholate prepared by adding sodium, sodium hydride, potassium tert-butoxide, or the like in an appropriate solvent.

Examples of the solvent include alcohols such as methanol, ethanol, propanol and tert-butanol, dimethylformamide, dimethylacetamide, pyridine, toluene, benzene, acetonitrile, tetrahydrofuran, water and the like, and these may be used alone or in combination of two or more. May be used.

The reaction may be carried out in such a manner that the amine or alcohol is used in an amount of 0.1 to 100 times, preferably 1 to 10 times the amount of the compound of the formula (2). The reaction temperature is 0 to 200 ° C., preferably 50 to 150 ° C., and the reaction time is 0.1 to 100 hours, preferably 1 to 60 hours, and the reaction proceeds advantageously.

In the case where the compound of the general formula (1) obtained in the reaction step formula 1 has a lower alkoxy group or a benzyloxy group as a substituent on the ring A or the ring B, if necessary, this may be carried out, for example, without solvent or in a suitable solvent. By reacting with hydrobromic acid, hydroiodic acid, hydrochloric acid, sulfuric acid or the like, it can be converted to a hydroxyl group. Examples of the solvent include acetic acid, water and the like, and these may be used alone or as a mixture of two or more. The reaction rate is 1 to 1000 times (v / w), preferably 5 to 100 times (v / w) hydrobromic acid, hydroiodic acid, hydrochloric acid, sulfuric acid, etc., based on the lower alkoxy group or benzyloxy group. w)
Good to use. The reaction temperature is 0 to 200 ° C, preferably 5
0 to 150 ° C, and the reaction time is 0.1 to 100 hours, preferably
The reaction advantageously proceeds in 0.5 to 60 hours.

When the compound of the general formula (1) obtained in the reaction step formula 1 has a nitro group as a substituent on the ring A or the ring B, if necessary, it can be converted into an amino group by reducing it. This reduction reaction can be performed, for example, using tin chloride or the like in a suitable solvent in the presence of hydrogen chloride. Examples of the solvent include alcohols such as methanol and ethanol, and dimethylformamide. The reaction rate is preferably 1 to 100 times the molar amount of hydrogen chloride and 1 to 10 times the molar amount of tin chloride based on the nitro group. Reaction temperature is 0
To 50 ° C, and the reaction time is 0.1 to 100 hours, preferably 1 to 100 hours.
The reaction proceeds advantageously in ~ 12 hours.

When the compound of the general formula (1) obtained in the reaction step formula 1 has a hydroxyl group as a substituent on the ring A or the ring B, if necessary, this is alkylated, benzylated or acylated to give an alkoxy group. , A benzyloxy group or an acyloxy group. The alkylation reaction or benzylation reaction is carried out in a suitable solvent in the presence of a base.
It is carried out by reacting with an alkylating agent or a benzylating agent. Examples of the solvent include dimethoxyethane, dioxane, tetrahydrofuran, dimethylformamide,
Acetone can be exemplified. Examples of the base include potassium carbonate, sodium carbonate, potassium hydroxide and the like. Examples of the alkylating agent include, for example, an optionally substituted alkane halide, a sulfate or a sulfonate, and examples of the benzylating agent include a benzyl halide. The ratio of the reaction is 1 for the base to 1 for the hydroxyl group.
1 to 5 times the molar amount of the alkylating agent or benzylating agent.
It is preferable to use a double molar amount. The reaction temperature is 0 to 80 ° C. and the reaction time is 0.1 to 24 hours, preferably 0.5 to 10 hours, and the reaction proceeds advantageously.

When R has an amino group substituted with a lower alkyl group in the compound of the general formula (1) obtained in the reaction step formula 1, if necessary, this may be reacted with an oxidizing agent in an appropriate solvent to obtain a lower alkyl group. It can also be converted to an amine oxide group substituted with an alkyl group. The solvent is not particularly limited as long as it does not participate in the reaction.Examples include ethers, ethers such as tetrahydrofuran, methylene chloride, halogenated hydrocarbons such as chloroform, acetone, alkyl ketones such as methyl ethyl ketone, methanol, ethanol and the like. Examples thereof include aprotic polar solvents such as alcohols, N, N-dimethylformamide, dimethylsulfoxide, and acetonitrile, acetic acid, and water. These may be used alone or in combination of two or more. The oxidizing agent is not particularly limited, but includes manganese dioxide,
Sodium hypochlorite, CAN (ceric ammonium sulphate), DDQ (2,3-dichloro-5,6-dicyano-1,4-)
Benzoquinone), chloranil (2,3,5,6-tetrachloro-1,4-benzoquinone), DMSO-pyridine sulfur trioxide complex, Jones reagent, pyridinium crochromate, pyridinium dichromate, dimethyl sulfoxide-oxalyl chloride, peroxide Examples include hydrogen, peroxides such as tert-butyl hydroperoxide, peracids such as formic acid, peracetic acid, and metachloroperbenzoic acid, and their combined use.

In this reaction, the oxidizing agent is used in an amount of 1 to 100 equivalents, preferably about 1 to 10 equivalents, relative to the compound represented by the general formula (1). The reaction temperature is under ice cooling to about the boiling point of the solvent, and the reaction time is about 0.1 to 96 hours, preferably
The reaction advantageously proceeds in about 0.1 to 1 hour.

The acylation reaction is performed by reacting a desired carboxylic acid or a reactive derivative thereof. When a reactive derivative is used, this reaction is carried out in an appropriate solvent, depending on the type and the type of the starting phenolic derivative, and an appropriate base may be added to promote the reaction. Such reactive derivatives include, for example, acid anhydrides, mixed acid anhydrides, acid halides and the like. Examples of the solvent include chloroform, dichloromethane, dioxane, tetrahydrofuran, dimethylformamide, pyridine and the like.
Examples of the base include sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine, 4-dimethylaminopyridine and the like. The ratio of the reaction is preferably such that the base is used in a molar amount of 1 to 5 times and the acylating agent is used in a molar amount of 1 to 5 times with respect to the hydroxyl group. The reaction temperature is 0 to 50 ° C. and the reaction time is 0.1 to 24 hours, preferably 0.5 to 3 hours, and the reaction proceeds advantageously.

When the compound of the general formula (1) obtained in the reaction step formula 1 has an amino group as a substituent on the A ring or the B ring, it can be converted to an acylamino group by acylation if necessary. . This acylation reaction is carried out by reacting a desired carboxylic acid or a reactive derivative thereof. When using reactivity inducibility, the reaction
The reaction is carried out in an appropriate solvent, depending on the type of the starting aniline derivative, and an appropriate base may be added to promote the reaction. Such reactive derivatives include, for example, acid anhydrides, mixed acid anhydrides, acid halides and the like. Examples of the solvent include chloroform, dichloromethane, odioxane, tetrahydrofuran, dimethylformamide, pyridine and the like. Examples of the base include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine, 4-dimethylaminopyridine and the like. The reaction rate is 1-5 bases based on amino groups.
It is preferable to use a 1- to 5-fold molar amount of the acylating agent. The reaction temperature is 0 to 50 ° C. and the reaction time is 0.1 to 100 hours, preferably 0.5 to 10 hours, and the reaction proceeds advantageously.

A nitro group can also be introduced by subjecting the compound of the general formula (1) obtained in the reaction step formula 1 to a nitration reaction, if necessary. This nitration reaction is carried out without solvent or in sulfuric acid.
It can be performed using a nitrating agent such as fuming nitric acid or nitric acid. The reaction rate is based on the compound of the general formula (1).
The nitrating agent is preferably used in a molar amount of 1 to 100 times. The reaction temperature is 0 to 30 ° C. and the reaction time is 0.1 to 20 hours, preferably 0.5 to 5 hours, and the reaction proceeds advantageously.

When R has a protecting group such as a benzyloxycarbonyl group or a lower acyl group in the compound of the general formula (1) obtained in the reaction step formula 1, if necessary, the compound may be brominated in, for example, no solvent or an appropriate solvent. The deprotected product can also be obtained by reacting with hydroic acid, hydroiodic acid, hydrochloric acid, sulfuric acid or the like. Examples of the solvent include acetic acid and water, and these may be used alone or as a mixture of two or more. The reaction rate is based on the protecting group, hydrobromic acid, hydroiodic acid,
1 to 1000 times (v / w) hydrochloric acid, sulfuric acid, etc., preferably 5 to 1
It is better to use 00 times (v / w). Reaction temperature is 0 to 200 ° C
Degree, preferably about 50 to 150 ° C., and the reaction time is 0.1
The reaction proceeds advantageously for 100100 hours, preferably 0.5-60 hours.

The compound of the present invention obtained by the above reaction can be converted into a salt form by a conventionally known method such as reacting the compound with the above-mentioned organic acid or inorganic acid in an appropriate solvent. Examples of the solvent include water, methanol, ethanol, dichloromethane, tetrahydrofuran and the like. The reaction temperature is preferably from 0 to 50 ° C.

The 6-halogenoindeno [2,1-c] quinoline derivative represented by the general formula (2) used as a raw material in the reaction step formula 1 can be prepared by the method described in, for example, J. Heterocyclic Chem., 28 1809 (1991). Although it can be produced, for example, it can also be produced according to the following reaction process formulas 2 to 3.

(In the formula, A ring, B ring and X are the same as described above. R ₄ represents a lower alkyl group.) [Step B] The compound represented by the general formula (3) is usually dissolved in a suitable solvent,
The carboxylic acid represented by the general formula (4) is produced by hydrolysis with a basic compound.

The compound represented by formula (3) can be produced by the method described in JP-A-3-223254.

The solvent is not particularly limited as long as it does not take part in the reaction. For example, methanol, ethanol, alcohols such as propanol, dioxane, tetrahydrofuran,
Examples thereof include ethers such as dimethoxyethane, water and the like, and these may be used alone or as a mixture of two or more. Examples of the basic compound include hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide and barium hydroxide.

The reaction ratio is preferably 1 to 10 times the molar amount of the basic compound with respect to the compound of the formula (3). Reaction temperature is 0
-100 ° C, preferably 50-100 ° C, and the reaction time is 0.5
The reaction proceeds advantageously within 〜100 hours, preferably 15050 hours.

[Step C] The compound represented by the general formula (3) or (4) is reacted with a halogenating agent in a solvent-free state and, if necessary, in an inert solvent, if necessary, to give a compound represented by the general formula (5) or the general formula (4). A compound represented by the formula (6) is produced.

The inert solvent for this reaction is not particularly limited as long as it does not participate in the reaction, and examples thereof include chloroform, benzene, toluene, and xylene. Examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide and the like. Further, pyridine, dimethylformamide and the like may be added to accelerate the reaction.

The ratio of the reaction is preferably such that the halogenating agent is used in a molar amount of 1 to 100 times the compound of the general formula (3) or (4). The reaction temperature is 0 to 200 ° C, preferably 50 to 150 ° C, and the reaction time is 0.5 to 100 hours, preferably 0.5 to 10 hours, and the reaction proceeds advantageously.

The compound of the general formula (5) or (6) obtained by this reaction can be isolated and purified as necessary, but can be used in the next step without purification.

[Step D] The compound represented by Formula (5) or (6) obtained in Step C is reacted with a protonic acid or a Lewis acid in a solvent-free or, if necessary, an inert solvent, to give a compound of the general formula (2a) ) Is produced.

The inert solvent for this reaction is not particularly limited as long as it does not participate in the reaction, and examples thereof include nitrobenzene, xylene, dichloromethane, carbon tetrachloride and the like. Examples of the protic acid include sulfuric acid, phosphoric acid, polyphosphoric acid, and hydrobromic acid, and examples of the Lewis acid include aluminum chloride, tin chloride, and iron chloride.

The ratio of the reaction is such that the protonic acid or Lewis acid is used in a molar amount of 1 to 1000 times, preferably 1 to 100 times the molar amount of the compound of the general formula (5) or (6). The reaction proceeds at a reaction temperature of 0 to 200 ° C and a reaction time of 0.5 to 50 hours, preferably 0.5 to 20 hours.

(In the formula, A ring, B ring, X and R are the same as above, and R ₅ is a lower alkyl group.) [Step E] A compound represented by the general formula (7) and a compound represented by the general formula (8) The compound represented by the general formula (9) is usually produced by reacting the compound in an appropriate solvent.

The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include alcohols such as methanol, ethanol, and propanol, benzene, toluene, xylene, dioxane, and tetrahydrofuran.

The reaction ratio is preferably 0.5 to 2 times the molar amount of the compound of the general formula (8) with respect to the compound of the general formula (7).
The reaction temperature is 20 to 150 ° C, preferably 90 to 130 ° C, and the reaction time is 0.1 to 50 hours, preferably 0.1 to 2 hours, and the reaction proceeds advantageously.

[Step F] The compound represented by the general formula (9) obtained by reacting the compound represented by the general formula (9) obtained in the step E with a protonic acid, usually without a solvent and optionally in an inert solvent, is used. A compound is produced.

The inert solvent for this reaction is not particularly limited as long as it does not participate in the reaction, and examples thereof include nitrobenzene and xylene. Examples of the protic acid include sulfuric acid, phosphoric acid, polyphosphoric acid, and hydrobromic acid.

The ratio of the reaction is such that the protonic acid is used in a solvent amount, preferably 5 to 15 times the amount of the compound of the general formula (9).
The reaction temperature is 90 to 150 ° C., and the reaction time is 0.5 to 50 hours, preferably 1 to 10 hours, and the reaction proceeds advantageously.

[Step G] The compound represented by the general formula (10) is obtained by reacting the compound represented by the general formula (3) or (4) represented by the reaction step formula 2 usually without a solvent, and optionally in an inert solvent. , Also produced by reacting with a protonic acid.

The inert solvent for this reaction is not particularly limited as long as it does not participate in the reaction, and examples thereof include nitrobenzene and xylene. Examples of the protic acid include sulfuric acid, phosphoric acid, polyphosphoric acid, and hydrobromic acid.

The ratio of the reaction is such that the protonic acid is used in a solvent amount, preferably 5 to 15 times the amount of the compound of the general formula (3) or (4). The reaction temperature is 50 to 200 ° C., and the reaction time is 0.5 to 50 hours, preferably 0.5 to 10 hours, and the reaction proceeds advantageously.

[Step H] The compound represented by general formula (2a) obtained by reacting the compound represented by the general formula (10) obtained in the step F or G with a halogenating agent is usually used without a solvent and, if necessary, in an inert solvent.
Is produced.

The inert solvent for this reaction is not particularly limited as long as it does not participate in the reaction, and examples thereof include chloroform, benzene, toluene, and xylene. Examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide and the like. Further, pyridine, dimethylformamide and the like may be added to accelerate the reaction.

The reaction ratio is preferably such that the halogenating agent is used in an amount of 1 to 100 moles per mole of the compound of the general formula (10). The reaction temperature is 0 to 200 ° C, preferably 50 to 150 ° C, and the reaction time is 0.
The reaction proceeds advantageously in 5 to 50 hours, preferably 0.5 to 10 hours.

The 5-halogenoindeno [2,1-c] isoquinoline derivative represented by the general formula (2) used as a raw material in the reaction scheme 1 can be produced, for example, according to the following reaction scheme 4.

(In the formula, the A ring, the B ring and X are the same as described above.) [Step I] The compound represented by the general formula (12) is obtained by treating the compound represented by the general formula (11) with ammonia in an inert solvent. A carboxylic acid is produced.

This reaction is carried out by a known method, for example, Bolletino Chimico Farm
aceutico 125 437 (1986).

The compound of the general formula (11) is, for example, Boll. Sedute
Accad.Gioenia Sci.Nat.Catania 6 606 (1960), as described in JP-A-5-132463, JP-can be synthesized.

The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include alcohols such as methanol, ethanol, and propanol.

The reaction may be carried out in an amount of 1 to 1000 times, preferably 10 to 100 times, the molar amount of ammonia to the compound of the formula (11). The reaction temperature is 0 to 100 ° C, preferably around room temperature, and the reaction time is 0.5 to 100 hours, preferably 2 to 100 hours.
The reaction advantageously proceeds in 2020 hours.

[Step J] The compound represented by the general formula (12) obtained in the step I is reacted with a protonic acid or a Lewis acid in an inert solvent, if necessary, usually in a solvent-free state to form an intramolecular closed form. A compound represented by the formula (13) is produced.

The inert solvent for this reaction is not particularly limited as long as it does not participate in the reaction, and examples thereof include nitrobenzene, carbon disulfide, nitroparaffin, ethylene chloride, and methylene chloride. Examples of the protic acid include hydrogen fluoride, sulfuric acid, phosphoric acid, phosphorus pentoxide, and polyphosphoric acid. Examples of the Lewis acid include aluminum chloride, iron chloride, stannic chloride, zinc chloride, boron fluoride and the like.

The reaction ratio is preferably 5 to 15 times the amount of the protonic acid and 1 to 10 times the amount of the Lewis acid with respect to the compound of the formula (12). The reaction proceeds at a reaction temperature of 0 to 200 ° C and a reaction time of 0.5 to 50 hours, preferably 0.5 to 20 hours.

[Step K] The compound represented by the general formula (2b) is obtained by reacting the compound represented by the general formula (13) obtained in the step J with a halogenating agent, usually without a solvent and, if necessary, in an inert solvent. Compound is produced.

The inert solvent for this reaction is not particularly limited as long as it does not participate in the reaction, and examples thereof include chloroform, benzene, toluene, and xylene. Examples of the halogenating agent include, for example, thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide and the like. Further, pyridine, dimethylformamide and the like may be added to accelerate the reaction.

The reaction ratio is preferably 1 to 100 times the molar amount of the halogenating agent to the compound of the formula (13). The reaction temperature is 0 to 200 ° C, preferably 50 to 150 ° C, and the reaction time is 0.
The reaction proceeds advantageously in 5 to 50 hours, preferably 0.5 to 10 hours.

The compound of the present invention and each compound obtained by the above method are generally separated and purified by known means, for example, concentration, solvent extraction,
It can be isolated and purified by using filtration, recrystallization, various types of chromatography and the like.

When the compound of the present invention is used as a therapeutic agent for malignant tumors in mammals including humans, various pharmaceutical administration forms can be widely adopted depending on the purpose. Examples include oral preparations such as tablets, pills, powders, granules, capsules, solutions, suspensions, and emulsions, and parenteral preparations such as injections, suppositories, ointments, and patches. These administration agents are formulated by conventional formulation methods generally known in the art.

In the case of molding into a tablet form, for example, lactose, sucrose, sodium chloride, fructose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, a simple syrup, glucose solution, starch solution are used as carriers. ,
Gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrants such as sodium, monoglyceride stearate, starch, lactose, sucrose,
Disintegration inhibitors such as stearic acid, cocoa butter, hydrogenated oil, etc., absorption promoters such as quaternary ammonium bases, sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid And a lubricant such as purified talc, stearate, boric acid powder, polyethylene glycol and the like. Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, multilayer tablets and the like.

When molded into the form of pills, as a carrier, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil,
Excipients such as kaolin and talc, binders such as gum arabic powder, tragacanth powder and gelatin, and disintegrants such as laminaran and agar can be used.

Capsules are usually prepared by mixing the compound of the present invention with the various carriers exemplified above and filling into hardened gelatin capsules, soft capsules and the like according to a conventional method.

When molded into the form of suppositories, carriers such as polyethylene glycol, cocoa butter, higher alcohols,
Esters of higher alcohols, gelatin, semi-synthetic glycerides and the like can be used.

When prepared as an injection, the liquid preparations, emulsions and suspensions are preferably sterilized and isotonic with blood, and when formed into these forms, diluents such as water, ethyl alcohol, macrogol , Propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and a usual solubilizing agent, a buffer, a soothing agent and the like may be added. You may.

When preparing an ointment, a base, a stabilizer, a lubricant, a preservative, and the like, which are usually used for the compound of the present invention, are blended as necessary, and mixed and formulated by a conventional method. Examples of the base include liquid paraffin, white petrolatum, beeswax, paraffin and the like. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.

In the case of producing a patch, the above-mentioned ointment, paste, cream, gel and the like may be applied to a usual support in a conventional manner. As the support, a woven or nonwoven fabric made of cotton, cloth, or synthetic fiber, a film of soft vinyl chloride, polyethylene, polyurethane, or the like, or a foam sheet is suitable.

Further, in each of the above-mentioned preparations, a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be contained in the pharmaceutical preparation as necessary.

The amount of the compound of the present invention to be contained in the pharmaceutical preparation of the present invention is not particularly limited and may be appropriately selected in a wide range, but is usually preferably 1 to 70% by weight in the pharmaceutical preparation.

The administration method of the above pharmaceutical preparation is not particularly limited, and is appropriately determined according to various preparation forms, patient age, gender and other conditions, degree of disease, and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are administered orally. The injection is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acid, and further administered intramuscularly, intradermally, subcutaneously or intraperitoneally as needed. Suppositories are administered rectally. The ointment is applied to skin, oral mucosa, and the like.

The amount of the compound of the present invention to be incorporated in each of the above-mentioned dosage unit forms is not fixed depending on the condition of the patient to which this compound is to be applied or on its dosage form. The dose is preferably about 0.1 to 500 mg for injections and about 5 to 1000 mg for suppositories. Further, the daily dose of the drug having the above-mentioned dosage form varies depending on the patient's condition, body weight, age, sex and the like and cannot be determined unconditionally, but is usually about 0.1 to 5000 mg, preferably 1 to 1000 mg per adult day. It is preferable to administer this once or in 2 to 4 divided doses.

The malignant tumor that can be treated by administering a preparation containing the compound of the present invention is not particularly limited, and examples thereof include head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gall bladder and bile duct cancer, and pancreatic cancer. Lung cancer, breast cancer, ovarian cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, malignant lymphoma, leukemia, cervical cancer, skin cancer, brain tumor and the like.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail with reference to Reference Examples, Examples, Pharmacological Test Examples and Formulation Examples.

Reference Example 1 Synthesis of 1,2-dihydro-4- (3,4-methylenedioxyphenyl) -2-oxo-3-quinolinecarboxylic acid 1,2-dihydro-4- (3,4-methylenedioxyphenyl ) A mixture of 40 g (118.6 mmol) of 2-oxo-3-quinolinecarboxylic acid ethyl ester, 200 ml of methanol, 300 ml of water, and 33.3 g (593.5 mmol) of potassium hydroxide was heated to reflux for 40 hours. After the reaction, 110 ml of 6N hydrochloric acid was added to the reaction solution to make it acidic, and the precipitated crystals were collected by filtration. The obtained crystals were washed with diethyl ether to obtain 35 g (yield 95.4%) of the title compound.

Melting point: 247 to 250 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 7.45 (1 H, m), 7.35 (1 H, d, J = 8 Hz), 7.13 (1 H, m), 7.
06 (1H, d, J = 8Hz), 6.98 (1H, d, J = 8Hz), 6.87 (1H,
s), 6.76 (1H, d, J = 8 Hz), 6.08 (2H, s) IR (KBr) cm ^-1 : 3440,1646,1577,1486,1441,1395,1238,1039 Reference Example 2 6-chloro- Synthesis of 9,10-methylenedioxy-7H-indeno [2,1-c] quinolin-7-one 1,2-dihydro-4- (3,4-methylenedioxyphenyl)-obtained in Reference Example 1 10 g (32.3 mmol) of 2-oxo-3-quinolinecarboxylic acid and 100 ml of phosphorus oxychloride (1.07 mol
The mixture of l) was heated at reflux for 4 hours. After the reaction, the reaction solution was evaporated to dryness and washed several times with n-hexane. 50 g of polyphosphoric acid was added to the obtained residue, and the mixture was heated at 90 ° C. for 2 hours. After the reaction, the reaction solution was added to ice water, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in tetrahydrofuran, the insolubles were removed by filtration, and the residue was purified by silica gel chromatography (developing solvent: chloroform) to give the title compound (6.0 g).
(59.9% yield).

Melting point: 265-270 ° C ¹ H-NMR (CDCl ₃ ) δ: 8.34 (1 H, d, J = 8 Hz), 8.04 (1 H, d, J = 8 Hz), 7.84 (1
H, d−d, J = 8,7Hz), 7.66 (1H, d−d, J = 8,7Hz), 7.58 (1
H, s), 7.23 (1H, s), 6.17 (2H, s) IR (KBr) cm ^-1 : 3450,1713,1556,1504,1478,1420,1384,1335,1266,103
7 Reference Example 3 Synthesis of 1,2-dihydro-4-phenyl-2-oxo-3-quinolinecarboxylic acid 5 g (17 mmol) of 1,2-dihydro-4-phenyl-2-oxo-3-quinolinecarboxylic acid ethyl ester A mixture of 20 ml of ethanol, 40 ml of water and 5 g (89 mmol) of potassium hydroxide was heated under reflux for 1.5 hours.

After the reaction, 60 ml of 2N hydrochloric acid was added to the reaction solution to make it acidic, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain 4.2 g (yield 92.9%) of the title compound.

Melting point: 246-254 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 13.10 (1H, brs), 12.28 (1H, s), 7.60-7.05 (9H, m) IR (KBr) cm ^{− 1} : 3000,2970,2950,2880,2850,2840,2790,1699,1653,160
8,1598,1557,1506,1488,1435,1411,1262,1100,753,709,
Reference Example 4 Synthesis of 5H-indeno [2,1-c] quinoline-6,7-dione 1,2-dihydro-4-phenyl-2- obtained in Reference Example 3
A mixture of 2 g (7.5 mmol) of oxo-3-quinoline carboxylic acid and 20 g of polyphosphoric acid was reacted at 130 ° C. for 4 hours. After the reaction,
The reaction solution was added to ice water, and the precipitated crystals were collected by filtration. The obtained crystals were reprecipitated with methanol to obtain 1.7 g (yield: 91.2%) of the title compound.

Melting point:> 290 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 12.12 (1 H, brs), 8.55 (1 H, d, J = 8 Hz), 8.40 (1 H, d, J)
= 8Hz), 7.78−7.33 (6H, m) IR (KBr) cm ^-1 : 2860,1724,1652,1618,1601,1585,1503,1484,1404,76
Reference Example 5 3-Methyl-5H-indeno [2,1-c] quinoline-6,7
Synthesis of -dione 2.5 g of ethyl 1,2-dihydro-4-phenyl-7-methyl-2-oxo-3-quinolinecarboxylate (8.
1 mmol) and 20 ml of concentrated sulfuric acid were heated and stirred at 95 ° C. for 10 hours. After the reaction, the reaction solution was added to ice water, and the precipitated crystals were collected by filtration. The obtained crystals were sequentially washed with water and methanol to obtain 1.5 g (yield: 70.6%) of the title compound.

Melting point:> 290 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 12.03 (1 H, brs), 8.41 (1 H, d, J = 8 Hz), 8.36 (1 H, d, J
= 7Hz), 7.70-7.17 (5H, m), 2.44 (3H.s) IR (KBr) cm ^-1 : 3440,1711,1643,1599,1580,1543,1481,1465,1437,140
4 Reference Example 6 6-chloro-3-methyl-7H-indeno [2,1-c]
Synthesis of quinolin-7-one 3-methyl-5H-indeno [2,1-
c] A mixture of 700 g (2.7 mmol) of quinoline-6,7-dione and 10 ml (107 mmol) of phosphorus oxychloride was heated under reflux for 1.5 hours. After the reaction, the reaction solution was evaporated to dryness, water was added to the residue, and the precipitated crystals were collected by filtration. After the obtained crystals were washed with water, they were dissolved in chloroform, and the insoluble matter was removed by filtration. Recrystallization from benzene gave 550 mg (yield: 73.4%) of the title compound.

Melting point: 208-211 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.38 (1 H, d, J = 9 Hz), 8.13 (1 H, d, J = 7 Hz), 7.85 (1
H, s), 7.80 (1H, d, J = 6Hz), 7.64 (1H, d-dd, J = 8,
8,1Hz), 7.56-7.50 (2H, m), 2.60 (3H, s) IR (KBr) cm ^-1 : 1718,1623,1557,1494,1460,1413,1064,915,867,755,7
15 Reference Example 7 Synthesis of 1,3-dioxo-3'-methoxy-2-indanecarboxyanilide 2.7 g of 2-ethoxycarbonyl-1,3-indandione
To a suspension of (12.5 mmol) in 100 ml of toluene was added 1.7 g (13.8 mmol) of m-anisidine, and the mixture was refluxed for 0.5 hour. After the reaction, about half of the solvent was distilled off, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain 1.7 g (yield 46.0%) of the title compound.

Melting point: 128-138 ° C ¹ H-NMR (CDCl ₃ ) δ: 9.52 (1H, drs), 7.70-7.55 (4H, m), 7.31 (1H, d, J =
8Hz), 7.17 (1H, d−d, J = 2, 2Hz), 7.10−6.74 (2H, m),
3.84 (1H, s) IR (KBr) cm ^-1 : 1658,1604,1584,1563,1537,1496,1455,1416 Reference Example 8 3-Methoxy-5H-indeno [2,1-c] quinoline-
Synthesis of 6,7-dione 1,3-dioxo-3'-methoxy-2 obtained in Reference Example 7
-A mixture of 1.6 g (5.4 mmol) of indane carboxyanilide and 18 g of polyphosphoric acid was reacted at 120 ° C for 1.5 hours. After the reaction, the reaction solution was added to ice water, and the precipitated crystals were collected by filtration.
The obtained crystals were washed with tetrahydrofuran to obtain 1.0 g (yield 66.6%) of the title compound.

Melting point: 236 to 246 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.48 (1 H, d, J = 9 Hz), 8.35 (1 H, d, J = 7 Hz), 7.71-7.
55 (3H, m), 6.99-6.92 (2H, m), 3.90 (3H.s) IR (KBr) cm ^-1 : 1705,1640,1621,1585,1480,1415,1394 Reference Example 9 6-chloro- 3-methoxy-7H-indeno [2,1-
c] Synthesis of quinolin-7-one 3-methoxy-5H-indeno [2,1-
c] A mixture of 550 mg (2.0 mmol) of quinoline-6,7-dione and 20 ml (214 mmol) of phosphorus oxychloride was heated under reflux for 4 hours in the presence of a catalytic amount of N, N-dimethylformamide. After the reaction, the reaction solution was evaporated to dryness, water was added to the residue, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in chloroform,
The insoluble material was removed by filtration. Wash with benzene to give the title compound 460m
g (78.4% yield) was obtained.

Melting point: 261 to 266 ° C ¹ H-NMR (CDCl ₃ ) δ: 8.39 (1 H, d, J = 9 Hz), 8.11 (1 H, d, J = 8 Hz), 7.81 (1
H, m), 7.64 (1H, d-dd, J = 8, 8, 1 Hz), 7.53 (1H, m),
7.41 (1H, d, J = 2 Hz), 7.33 (1H, d-d, J = 9.2 Hz), 4.00
(3H, s) IR (KBr) cm ^-1 : 1706,1618,1564,1496,1474,1464,1428,1208,1186,115
7,1122,1060,1012 Reference Example 10 1,2-dihydro-7-methoxy-4-phenyl-2-phenyl
Synthesis of ethyl oxo-3-quinolinecarboxylate 2-amino-4-methoxybenzophenone 20 g (88 mmo
l), diethyl malonate 26.7 ml (176 mmol), 1,8-diazabicyclo [5,2,0] -undec-7-ene (DBU) 0.66
ml (4.4 mmol) of the mixture was heated and stirred at 160 ° C. for 2 hours.
After the reaction, the reaction solution was air-cooled, 30 ml of ethanol was added, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol to give the title compound (25.7 g, yield 90.2%).

Melting point: 175-177 ° C ¹ H-NMR (CDCl ₃ ) δ: 12.60 (1H, brs), 7.48-7.35 (5H, m), 7.18 (1H, d, J
= 9Hz), 6.91 (1H, d, J = 3Hz), 6.72 (1H, d-d, J = 9.3H)
z), 4.08 (2H, q, J = 7 Hz), 3.90 (3H, s), 0.97 (3H, t, J
= 7 Hz) IR (KBr) cm ^-1 : 2980,2940,1735,1642,1597,1516,1238,1213,1094 Reference Example 11 1,2-dihydro-7-methoxy-4-phenyl-2-phenyl
Synthesis of oxo-3-quinolinecarboxylic acid 1,2-dihydro-7-methoxy-4- obtained in Reference Example 10
The same reaction treatment as in Reference Example 1 was carried out using 3.0 g of phenyl-2-oxo-3-quinolinecarboxylic acid ethyl ester, washed with ethanol, and 2.7 g of the title compound (yield 99.0)
%).

Melting point: 229-294 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 13.23 (1 H, s), 12.25 (1 H, s), 7.54-7.44 (3 H, m),
7.31-7.27 (2H, m), 6.99-6.90 (2H.m), 6.80 (1H, m)
3.83 (3H, s) IR (KBr) cm ^-1 : 3170,1731,1625,1476,1403,1243,1212,847 Reference Example 12 6-Chloro-3-methoxy-7H-indeno [2,1-
c] Synthesis of quinolin-7-one (alternative method) 1,2-dihydro-7-methoxy-4- obtained in Reference Example 11
The same reaction as in Reference Example 2 was performed using phenyl-2-oxo-3-quinolinecarboxylic acid to obtain the title compound. In addition, the physical property values corresponded to the values of the compound of Reference Example 9.

Reference Example 13 6-chloro-3-hydroxy-7H-indeno [2,1-
c] Synthesis of quinolin-7-one 10.0 g (33.8 mmol) of 6-chloro-3-methoxy-7H-indeno [2,1-c] quinolin-7-one obtained in Reference Example 9.
l) A mixture of 100 ml of concentrated sulfuric acid was heated and stirred at 160 ° C. for 2 hours. After the reaction, the reaction solution was added to ice water, and the precipitated crystals were collected by filtration. The obtained crystals are washed sequentially with water and ethanol,
8.5 g (89.4% yield) of the title compound was obtained.

Melting point:> 300 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 11.18 (1 H, brs), 8.66 (1 H, d, J = 9 Hz), 8.43 (1 H, d, J
= 8Hz), 7.77-7.59 (3H, m), 7.35 (1H, d-d, J = 9.2H)
z), 7.23 (1H, d, J = 2 Hz) IR (KBr) cm ^-1 : 3110,1711,1623,1610,1461,1435,1398,1179,1067,750 Reference Example 14 3-benzyloxy-6- Chloro-7H-indeno [2,
Synthesis of 1-c] quinolin-7-one 500 mg (1.8 mmol) of 6-chloro-3-hydroxy-7H-indeno [2,1-c] quinolin-7-one obtained in Reference Example 13.
l), 247 mg (2.0 m2) of benzyl chloride was added to a suspension of potassium carbonate (300 mg, 2.1 mmol) in N, N-dimethylformamide (5 ml).
mol) and stirred at 90 ° C. for 3 hours. After the reaction, the reaction solution was added to ice water, and the precipitated crystals were collected by filtration. The obtained crystals were washed successively with water and 2-propanol to give the title compound 61
0 mg (92.4% yield) was obtained.

Melting point: 212-214 ° C ¹ H-NMR (CDCl ₃ ) δ: 8.40 (1 H, d, J = 9.5 Hz), 8.10 (1 H, d, J = 7.5 Hz), 7.80
(1H, d, J = 7.5Hz), 7.67−7.31 (9H, m), 5.24 (2H, s) IR (KBr) cm ^-1 : 3090,1711,1623,1570,1461,1435,1397,1179, Reference Example 15 Synthesis of 1,2-dihydro-4-phenyl-1-oxo-3-isoquinolinecarboxylic acid 36.2 g of 4-phenylisocoumarin-3-carboxylic acid (1
To a solution of 36 mmol) in 50 ml of methanol was added 100 ml of a saturated solution of ammonia in methanol and stirred at room temperature for 8 hours. After the reaction, the solvent was distilled off, and 300 ml of methanol was added.
Further, 100 ml of a 4N hydrochloric acid-ethyl acetate solution was added to make the solution acidic.
The solvent was distilled off, water was added, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol-water to give the title compound
32.0 g (88.7% yield) was obtained.

Melting point:> 300 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 13.53 (1H, brs), 11.11 (1H, brs), 8.32 (1H, d, J = 8H)
z), 7.72-7.26 (7H, m), 7.10 (1H, d, J = 8Hz) IR (KBr) cm ^-1 : 3160,1704,1656,1643,1622,1606,1598,1468,1446,130
7,761,706 Reference Example 16 Synthesis of 6H-indeno [2,1-c] isoquinoline-5,7-dione 1,2-dihydro-4-phenyl-1- obtained in Reference Example 15
Oxo-3-isoquinoline carboxylic acid 32 g and polyphosphoric acid 3
00g of the mixture was reacted at 100 ° C for 5 hours. After the reaction, the reaction solution was added to water, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate to give the title compound (26.6 g, yield 89.2 g).
%).

Melting point:> 300 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 12.18 (1H, brs), 8.40-8.35 (2H, m), 7.94-7.88 (2
H, m), 7.73 (1H, d-d, J = 8.8Hz), 7.54-7.46 (2H, m),
7.24 (1H, d-d, J = 7,7 Hz) IR (KBr) cm ^-1 : 3060,1716,1681,1645,1620,1604,1598,1588,1462,132
8,716 Reference Example 17 Synthesis of 5-chloro-7H-indeno [2,1-c] isoquinolin-7-one 26.6 g of 6H-indeno [2,1-c] isoquinolin-5,7-dione obtained in Reference Example 16 (108 mmol), phosphorus oxychloride 300
ml of the mixture in the presence of 1 ml of N, N-dimethylformamide.
Heated to reflux for an hour. After the reaction, the reaction solution was evaporated to dryness, ice water was added to the residue, and the precipitated crystals were collected by filtration. The obtained crystals were washed with water and recrystallized from toluene to give the title compound 22.5.
g (78.7% yield) was obtained.

Melting point: 242 to 244 ° C ¹ H-NMR (CDCl ₃ ) δ: 8.51 to 8.47 (2H, m), 7.99 to 7.82 (3H, m), 7.74 (1H,
d, J = 7 Hz), 7.59 (1H, d-d, J = 8.8 Hz), 7.40 (1H, d-d,
J = 8,7Hz) IR (KBr) cm ^-1 : 1738,1722,1615,1602,1461,1412,1347,1253,765,713,
682,616 Reference Example 18 Using Reference Examples 1 to 17, the following compounds were synthesized.

・ 2,6-dichloro-7H-indeno [2,1-c] quinoline-
7-one Melting point: 282 to 284 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.46 (1 H, d, J = 8 Hz), 8.11 (1 H, d, J = 7 Hz), 8.03 (1
H, d, J = 9Hz), 7.84-7.79 (2H, m), 7.69 (1H, d-dd,
J = 8,8,1 Hz), 7.57 (1H, d-d, J = 7.7 Hz) 6-chloro-2-methoxy-7H-indeno [2,1-
c] Quinolin-7-one Melting point: 261 to 262 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.06 (1 H, d, J = 8 Hz), 8.00 (1 H, d, J = 9 Hz), 7.82 (1
H, d, J = 7Hz), 7.68-7.50 (4H, m), 4.06 (3H, s) 6-chloro-2-nitro-7H-indeno [2,1-c]
Quinoline-7-one Melting point:> 300 ° C. ¹ H-NMR (CDCl ₃ ) δ: 9.47 (1 H, d, J = 2 Hz), 8.64 (1 H, d-d, J = 9.2 Hz), 8.2
5 (1H, d, J = 8Hz), 8.24 (1H, d, J = 9Hz), 7.88 (1H, d, J
= 7Hz), 7.78 (1H, d-dd, J = 8, 8, 1Hz), 7.64 (1H, d
−d, J = 8.8 Hz) 6-chloro-2,3-methylenedioxy-7H-indeno [2,1-c] quinolin-7-one Melting point:> 300 ° C. ¹ H-NMR (CDCl ₃ ) Δ: 8.02 (1H, d, J = 8 Hz), 7.81 (1H, d, J = 7 Hz), 7.72 (1
H, s), 7.64 (1H, d-dd, J = 8, 8, 1 Hz), 7.52 (1H, d-
d, J = 8.8 Hz), 7.37 (1H, s), 6.23 (2H, s) 6-chloro-2,3-dimethoxy-7H-indeno [2,1-
c] Quinolin-7-one Melting point: 300-302 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.00 (1 H, d, J = 7 Hz), 7.82 (1 H, d, J = 7 Hz), 7.65 (1
H, d−d, J = 8,8Hz), 7.61 (1H, s), 7.52 (1H, d−d, J = 8,
7Hz), 7.41 (1H, s) 4,14 (3H, s), 4.07 (3H, s) 6-chloro-3-fluoro-7H-indeno [2,1-
c] Quinolin-7-one Melting point: 257-259 ° C ¹ H-NMR (CDCl ₃ ) δ: 8.55 (1H, m), 8.12 (1H, d, J = 7 Hz), 7.84 (1H, d, J = 7
Hz), 7.76-7.47 (4H, m) 6-chloro-3,9-dimethoxy-7H-indeno [2,1-
c] Quinolin-7-one Melting point: 298-300 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.31 (1 H, d, J = 9 Hz), 7.98 (1 H, d, J = 9 Hz), 7.37 (1
H, d, J = 3Hz), 7.33 (1H, d, J = 3Hz), 7.29 (1H, d−d, J =
9,3Hz), 7.08 (1H, d-d, J = 8.3Hz), 3.99 (3H, s), 3.94
(3H, s) ・ 3,6-dichloro-7H-indeno [2,1-c] quinoline-
7-one Melting point: 250-252 ° C ¹ H-NMR (CDCl ₃ ) δ: 8.40 (1 H, d, J = 9 Hz), 8.07 (1 H, d, J = 9 Hz), 8.05 (1
H, s), 7.80 (1H, d, J = 7 Hz), 7.69-7.52 (3H, m) 3-benzyloxy-6-chloro-9,10-methylenedioxy-7H-indeno [2,1- c] Quinolin-7-one Melting point: 241-243 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.19 (1H, d, J = 9 Hz), 7.60-7.31 (8H, m), 7.19 (1H,
s), 6.15 (2H, s), 5.21 (2H, s) 6-chloro-3-methoxy-9,10-methylenedioxy-7H-indeno [2,1-c] quinolin-7-one : <300 ° C ¹ H-NMR (CDCl ₃ ) δ: 8.22 (1 H, d, J = 9 Hz), 7.53 (1 H, s), 7.36 (1 H, d, J = 3)
Hz), 7.30 (1H, d, J = 3Hz), 7.23 (1H, s), 6.16 (2H,
s), 3.98 (3H, s) 6-chloro-8-methoxy-7H-indeno [2,1-
c] Quinolin-7-one Melting point: 259-260 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.48 (1 H, d, J = 8 Hz), 8.08 (1 H, d, J = 8 Hz), 7.84 (1
H, d−d−d, J = 8,7,1Hz), 7.77 (1H, d, J = 8Hz), 7.67
(1H, d−d−d, J = 8, 7, 1 Hz), 7.60 (1H, d−d, J = 9.8H)
z), 7.09 (1H, d, J = 9 Hz), 4.04 (3H, s) 6-chloro-8-hydroxy-7H-indeno [2,1-
c] Quinolin-7-one Melting point: 240-241 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.38 (1H, s), 8.46 (1H, d, J = 9 Hz), 8.09 (1H, d, J = 9
Hz), 7.88 (1H, d-dd, J = 7, 7, 1 Hz), 7.73-7.65 (2
H, m), 7.52 (1H, d-d, J = 9.7 Hz), 7.03 (1H, d, J = 9 Hz)-6-chloro-9-methoxy-7H-indeno [2,1-
c] Quinolin-7-one Melting point: 210-212 ° C ¹ H-NMR (CDCl ₃ ) δ: 8.39 (1H, d, J = 8 Hz), 8.04-7.97 (2H, m), 7.83 (1H,
d−d−d, J = 9, 7, 1 Hz), 7.65 (1H, d−d−d, J = 8, 7, 1H)
z), 7.29 (1H, d, J = 3 Hz), 7.07 (1H, d-d, J = 8,3 Hz),
3.93 (3H, s) 6-chloro-10-methoxy-7H-indeno [2,1-
c] Quinolin-7-one Melting point: 255-256 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.43 (1 H, d, J = 9 Hz), 8.08 (1 H, d, J = 9 Hz), 7.86 (1
H, d−d−d, J = 9,7,1Hz), 7.76 (1H, d, J = 8Hz), 7.69
(1H, d−d−d, J = 8, 7, 1 Hz), 7.65 (1H, d, J = 2 Hz), 6.9
4 (1H, d-d, J = 8.2 Hz), 3.99 (3H, s) 6-chloro-10-hydroxy-7H-indeno [2,1-
c] Quinolin-7-one Melting point:> 300 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 8.64 (1H, d, J = 8 Hz), 8.05-7.81 (4H, m), 7.63 (1H,
d, J = 8 Hz), 6.95 (1H, d-d, J = 8.2 Hz) 2-aza-1-chloro-13H-dibenzo [c, i] fluoren-13-one Melting point: 258 to 261 ° C. ¹ H-NMR (CDCl ₃ ) δ: 9.00 (1H, d, J = 8 Hz), 8.53 (1H, d, J = 9 Hz), 8.22 (1
H, d, J = 9Hz), 8.09 (1H, d, J = 8Hz), 8.03 (1H, d, J = 9H)
z), 7.81 (1H, d, J = 8 Hz), 7.71-7.47 (4H, m) Example 1 6-(((dimethylamino) ethyl) amino) -3-methoxy-7H-indeno [2,1- c] Synthesis of quinolin-7-one (compound 1) 2 g (6.8 mmol) of 6-chloro-3-methoxy-7H-indeno [2,1-c] quinolin-7-one obtained in Reference Example 9 in pyridine (20 ml) N, N-dimethylethylenediamine 3g in suspension
(33.8 mmol), and the mixture was heated and stirred at 100 ° C. for 24 hours. After the reaction, the reaction solution was evaporated to dryness, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over magnesium sulfate and evaporated, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform: ethanol = 10: 1).
(V / v)). Crystallized from ethanol,
1.3 g (yield 55.3%) of the title compound was obtained. Table 1 shows the physical property values.

Next, this compound was dissolved in a mixed solution of chloroform-methanol, and insolubles were removed by filtration. The filtrate was acidified with 4N hydrochloric acid-ethyl acetate, and the precipitated crystals were collected by filtration and dried under reduced pressure to quantitatively obtain the salt of Compound 1 (Compound 1-a). Table 1 shows the physical properties
Shown in

Example 2 Synthesis of 6-(((dimethylamino) ethyl) amino) -3-fluoro-7H-indeno [2,1-c] quinolin-7-one dihydrochloride (Compound 2) 6-chloro-3 -Fluoro-7H-indeno [2,1-
c] 860 mg (3.0 mmol) of quinolin-7-one pyridine 10
N, N-dimethylethylenediamine 800mg (9.0m
mol), and the mixture was heated and stirred at 90 ° C. for 12 hours. After the reaction, the reaction solution was evaporated to dryness, water was added to the residue, and the mixture was extracted with chloroform. After drying the chloroform layer with magnesium sulfate,
The residue was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform: ethanol = 10: 1 (v /
Purified by v)). Next, it was dissolved in 20 ml of tetrahydrofuran, and 2 ml of 4N hydrochloric acid / dioxane was added. After concentration under reduced pressure, the obtained residue was crystallized from diethyl ether to obtain 420 mg (yield: 34.3%) of the title compound. Table 1 shows the physical property values.

Example 3 Synthesis of 6 (((dimethylamino) ethyl) amino) -3-hydroxy-7H-indeno [2,1-c] quinolin-7-one (Compound 3) 6-((obtained in Example 1 (Dimethylamino) ethyl)
Amino) -3-methoxy-7H-indeno [2,1-c] quinolin-7-one 47% in a solution of 3 g (8.6 mmol) in 40 ml of acetic acid.
Hydrogen bromide (40 ml) was added, and the mixture was heated under reflux for 60 hours. After the reaction,
The reaction solution is evaporated to dryness, water is added to the residue, and
The pH was adjusted to about 8 and extracted with chloroform. The chloroform layer was dried over magnesium sulfate and evaporated, and the residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol: water = 8: 3: 1 (v / v / v)). Crystallized from cyclohexane, 2.1 g of the title compound
(73.0% yield). Table 1 shows the physical property values.

Next, this compound was dissolved in a mixed solution of chloroform-methanol, and insolubles were removed by filtration. The filtrate was acidified with 4N hydrochloric acid-ethyl acetate, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain a salt of compound 3 (compound 3-a) in a yield of 89.4%. Table 1 shows the physical property values.

Example 4 6-(((dimethylamino) ethyl) amino) -3-
Synthesis of (pivaloyloxy) -7H-indeno [2,1-c] quinolin-7-one (compound 4) 6-(((dimethylamino) ethyl) obtained in Example 3
Amino) -3-hydroxy-7H-indeno [2,1-c]
100 mg (0.3 mmol) of quinolin-7-one in dichloromethane
4-dimethylaminopyridine 100mg (0.8mmo
l), pivaloyl chloride 37 μl (0.3 mmol) was added,
Stir at room temperature for 3 hours. After the reaction, water was added to the reaction solution to wash the organic layer, followed by drying over magnesium sulfate, and the solvent was distilled off. The obtained residue is subjected to silica gel column chromatography (developing solvent; chloroform: ethanol = 10: 1).
(V / v)) and crystallized from hexane to obtain 105 mg (yield: 80.0%) of the title compound. Table 1 shows the physical property values.

Example 5 Synthesis of 6-(((dimethylamino) ethyl) amino) -3-hydroxy-4-nitro-7H-indeno [2,1-c] quinolin-7-one (Compound 5) Obtained in Example 3. 6-(((dimethylamino) ethyl)
Amino) -3-hydroxy-7H-indeno [2,1-c]
A mixture of 100 mg (0.3 mmol) of quinolin-7-one, 1 ml of concentrated sulfuric acid and 1 ml of nitric acid was stirred at 5 ° C for 2 hours. After the reaction, the reaction solution was added to ice water, and the precipitated crystals were collected by filtration. The obtained crystals were purified by silica gel column chromatography (developing solvent; lower layer solution of chloroform: methanol: water = 9: 3: 1 (v / v / v)) and crystallized from ethanol-diethyl ether to give the title compound (60 mg). (52.9% yield).
Table 1 shows the physical property values.

Example 6 6-((aminoethyl) amino) -3-hydroxy-7H
Synthesis of -indeno [2,1-c] quinolin-7-one dihydrochloride (Compound 59) To Compound 56 (1.1 g) obtained in the same manner as in Example 1, 20 ml of concentrated hydrochloric acid was added, and the mixture was heated to an external temperature of 100 g. The reaction was performed at 12 ° C. for 12 hours. After the reaction,
After adding isopropanol and allowing to cool, the precipitated crude crystals were collected by filtration. The obtained crude crystals were subjected to a high-porous polymer gel column chromatography (MCI gel, manufactured by Mitsubishi Kasei Co., Ltd.), and the fraction eluted with methanol: water (1:10) (1 drop of concentrated hydrochloric acid) was concentrated under reduced pressure. The crystals were washed with ethanol, and the filtered crystals were dried under reduced pressure to give the title compound (524 mg, yield 63.7
%).

Example 7 Synthesis of 6-(((methylamino) ethyl) amino) -3-hydroxy-7H-indeno [2,1-c] quinolin-7-one trihydrochloride (Compound 60) As in Example 1. Concentrated hydrochloric acid-dioxane (10 ml-10 ml) was added to Compound 57 (1.0 g) obtained by
Reacted for hours. After the reaction, after concentration under reduced pressure,
10 ml was added, and the mixture was reacted at an external temperature of 100 ° C. for 2 hours. After the reaction, 30 ml of isopropanol was added, and the precipitated crude crystals were collected by filtration. The obtained crude crystals were dissolved in water, concentrated hydrochloric acid (0.5 ml) and isopropanol (30 ml) were added, and the mixture was stirred under ice cooling and crystallized to obtain the title compound (560 mg, yield 68.8%).

Example 8 6-(((dimethylaminooxide) ethyl) amino)
Synthesis of -3-hydroxy-7H-indeno [2,1-c] quinolin-7-one dihydrochloride (Compound 61) Compound 53 (2.0 g) obtained in the same manner as in Example 1 was added to 10 ml of chloroform. After melting and stirring under ice-cooling, a solution of m-chloroperbenzoic acid (1.2 g) in chloroform (10 ml) was added dropwise,
The reaction was performed at room temperature for 3 hours. After the reaction, alumina column chromatography (developing solvent; chloroform: methanol =
40: 1) to give 6-(((dimethylaminooxide) ethyl) amino) -3-benzyloxy-7H-indeno [2,1-c] quinolin-7-one. Next, 7.5 ml of concentrated hydrochloric acid was added to this compound and reacted at an external temperature of 100 ° C. for 1.5 hours. After the reaction, 12 ml of ethanol was added and the mixture was allowed to cool, and the precipitated crude crystals were collected by filtration. The obtained crude crystals are ethanol 15
The resulting suspension was stirred under heating, and allowed to cool. The suspension was further suspended in 15 ml of dichloromethane, heated and stirred, allowed to cool, and the crystals were collected by filtration to obtain 1.34 g (yield: 84.1%) of the title compound.

Example 9 Synthesis of 6- (2-dimethylaminoethoxy) -9,10-methylenedioxy-7H-indeno [2,1-c] quinolin-7-one (Compound 64) 6- obtained in Reference Example 2 8 g of chloro-9,10-methylenedioxy-7H-indeno [2,1-c] quinolin-7-one (25.
(8 mmol) was added to a solution prepared with 1.78 g (77.4 mmol) of sodium and 80 ml (796 mmol) of 2-dimethylaminoethanol, and the mixture was heated with stirring at 60 ° C. for 24 hours. After the reaction, the reaction solution was added to ice water and extracted with chloroform. The chloroform layer was dried over magnesium sulfate and evaporated, and the residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 10: 1 (v / v)), crystallized from ethyl acetate, and the title compound 6.37 was obtained. g (68.1% yield) was obtained. Table 2 shows the physical property values.

Next, this compound was dissolved in chloroform, and insolubles were removed by filtration. The filtrate was acidified with 4N hydrochloric acid-ethyl acetate, and the precipitated crystals were collected by filtration and dried under reduced pressure to give the salt of compound 64 (compound 64
-A) was obtained quantitatively. Table 2 shows the physical property values.

Examples 10 to 74 Compounds 6 to 58 and 62 to 63 shown in Table 1, compounds 65 to 72 shown in Table 2, compounds 73 and 73 shown in Table 3, and The compound 74 shown was synthesized.

The compounds 9-a, 23-a, 26-a were prepared in the same manner as in the method for producing the hydrochloride of the compounds 1-a, 3-a, 64-a in Example 1.
a, 28-a, 31-a, 41-a, 47-a, 49-a, 50-
a, 66-a and 73-a were prepared.

Example 75 Synthesis of 6- (1- (4-methylpiperazinyl))-7H-indeno [2,1-c] isoquinolin-7-one (compound 75) 5-chloro-7H obtained in Reference Example 17 −Indeno [2,1−
c] -isoquinolin-7-one 1.0 g (3.7 mmol), N-
A mixture of 2 ml (18 mmol) of methylpiperazine and 10 ml of N, N-dimethylformamide was stirred at 100 ° C. for 4 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and evaporated, and the residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 100: 1 (v / v)), crystallized from ethanol, and 400 mg of the title compound. (32.3% yield). Table 5 shows the physical property values.

Examples 76 to 80 Compounds 76 to 80 shown in Table 5 were synthesized from the corresponding raw materials in the same manner as in Example 75.

Hereinafter, the test results of the antitumor effect of the compound of the present invention are shown, and the usefulness of the compound of the present invention will be described.

Pharmacological Test Example 1 Cell Killing Action p388 mouse leukemia cells were seeded at 2 × 10 ³ cells / well in a 96-well plate. After dissolving the compound of the present invention in purified water or dimethyl sulfoxide, the compound was diluted to various concentrations with a medium, added to each well, and cultured. After three days of contact, the plate was fixed with glutaraldehyde, and the number of cells was counted by crystal violet staining.

Control the cell killing of each compound by 50%
Expressed as decreasing drug concentration (IC ₅₀ ). Table 6 shows the results
Shown in

Pharmacological Test Example 2 Antitumor Activity CDF ₁ strain mice were treated with p388 mouse leukemia cells (1 × 10 ⁶ cells)
/ mouse) was intraperitoneally inoculated, and 1 and 5 days after transplantation, the compound of the present invention dissolved in 5% glucose or 5% dimethyl sulfoxide at each concentration was injected intraperitoneally, and the number of survival days was observed. The life extension rate of the group to which the compound of the present invention was administered was determined by comparison with the control group. Table 7 shows the results.

Formulation Example 1 Capsule A capsule was prepared according to a conventional method at the following mixing ratio.

Compound 3-a 200 mg Lactose 30 mg Maize starch 50 mg Crystalline cellulose 10 mg Magnesium stearate 3 mg 293 mg per capsule Formulation Example 2 Tablets Tablets were prepared according to a conventional method at the following compounding ratio.

Compound 7 100mg Lactose 47mg Maize starch 50mg Crystalline cellulose 50mg Hydroxypropylcellulose 15mg Talc 2mg Magnesium stearate 2mg Ethyl cellulose 30mg Unsaturated fatty acid glyceride 2mg Titanium dioxide 2mg 300mg per tablet Formulation example 3 Granules Prepared.

Compound 28-a 200mg Mannitol 540mg Corn starch 100mg Crystalline cellulose 100mg Hydroxypropylcellulose 50mg Talc 10mg 1000mg per packet Formulation Example 4 Fine granules Fine granules were prepared according to a conventional method in the following mixing ratio.

Compound 64-a 200 mg Mannitol 520 mg Corn starch 100 mg Crystalline cellulose 100 mg Hydroxypropylcellulose 70 mg Talc 10 mg 1000 mg per packet Formulation Example 5 Injections Injections were prepared according to a conventional method in the following mixing ratio.

Compound 41-a 100 mg distilled water for injection qs 2 ml in one tube Formulation Example 6 Suppositories Suppositories were prepared according to a conventional method in the following mixing ratio.

Compound 73-a 200 mg Huy step tetrazole S-55 1300 mg (mono saturated fatty acids from lauric acid to stearic acid -, di -, tri - glycerides mixed compound, manufactured by Dynamit Nobel Co.) per 1500mg

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Masato Washinasu 621-2-A-201, Iwasawa, Hanno City, Saitama (72) Inventor Teruhiro Utsugi 1-29-15-1304, Kamiikebukuro, Toshima-ku, Tokyo (72) Inventor Yuji Yamada 2-2953-21 Higashisayamagaoka, Tokorozawa-shi, Saitama (56) References Heterocyclic Chem, (1991), 28 (7) 1809-12 (58) Fields investigated (Int. Cl. ⁶ , DB) (Name) C07D 221/18

Claims (14)

(57) [Claims] 1. The general formula (1) (In the formula, ring A represents a benzene ring or naphthalene ring optionally having a substituent, or a benzene ring having a lower alkylenedioxy group, and ring B represents a benzene ring optionally having a substituent or .Y showing a benzene ring having a lower alkylenedioxy group -N = CR- or -CR = N-a shows, R represents shows the -NR ₁ R ₂ group or -OR ₃ group. wherein R ₁ and R _Two
Are the same or different and are a hydrogen atom, a phenyl group, a nitrogen-containing heterocyclic group which may have a substituent or a lower alkyl group (the lower alkyl group is an optionally substituted amino group, a lower alkoxy group, Phenyl group, nitrogen-containing heterocyclic group,
R ₃ represents a lower alkyl group which may be substituted with a substituted amino group, which may be substituted with at least one selected from the group consisting of an amine oxide group and a hydroxyl group substituted with a lower alkyl group. . And the pharmaceutically acceptable salts thereof. 2. The ring substituents represented by rings A and B comprise a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, an amino group, a lower acyloxy group, a benzyloxy group and a lower acylamino group. The condensed indane derivative according to claim 1, which is selected from the group and a pharmaceutically acceptable salt thereof. (3) R ₁ and R ₂ are the same or different and each represent a hydrogen atom,
3. A phenyl group or an optionally substituted amino group, a nitrogen-containing heterocyclic group, an amine oxide group substituted with a lower alkyl group or a lower alkyl group optionally substituted with a hydroxyl group. And the pharmaceutically acceptable salts thereof. Wherein Y is represented by -CR = N-, even R is substituted with a hydrogen atom or a di-lower alkyl-substituted amino group or nitrogen-containing heterocyclic group R ₁ and R ₂ are the same or different A preferred lower alkyl group-NR ₁ R ₂ group, a piperazinyl group substituted with a lower alkyl group or a lower alkyl group in which R ₃ may be substituted with a di-lower alkyl-substituted amino group-
_3. The condensed indane derivative according to claim 1, which has an indeno [2,1-c] quinoline skeleton that is an OR3 group, and a pharmaceutically acceptable salt thereof. 5. The fused indane derivative according to claim 4, wherein R _{1 is a} di-lower alkyl-substituted amino group or an alkyl group substituted with a nitrogen-containing heterocyclic ring, and R ₂ is a hydrogen atom. salt. 6. The condensed indane derivative according to claim 5, wherein R ₁ is an alkyl group substituted with a dimethylamino group, a diethylamino group or a pyrrolidinyl group, and a pharmaceutically acceptable salt thereof. 7. The fused indane derivative according to claim 1, wherein ring B is a benzene ring substituted with a hydroxyl group, and a pharmaceutically acceptable salt thereof. 8. The condensed indane derivative according to claim 1, wherein ring A is a benzene ring which is unsubstituted or substituted with a hydroxyl group or a halogen atom, and a pharmaceutically acceptable salt thereof. 9. The fused indane derivative according to claim 1, wherein ring A is a benzene ring having a lower alkylenedioxy group, and a pharmaceutically acceptable salt thereof. 10. Y is represented by -CR = N-, R is R ₁ and R ₂
Is the same or different and is a lower alkyl group which may be substituted with a hydrogen atom or a di-lower alkyl-substituted amino group or a nitrogen-containing heterocyclic group -NR ₁ R ₂ group, a piperazinyl group substituted with a lower alkyl group or R ₃ is a —OR ₃ group which is a lower alkyl group which may be substituted with a di-lower alkyl-substituted amino group, wherein the benzene ring A is unsubstituted or substituted with one or two hydroxyl groups and / or halogen atoms. A benzene ring having a lower alkylenedioxy group, wherein the B ring is 1 to
The condensed indane derivative according to claim 1, which has an indeno [2,1-c] quinoline skeleton which is a benzene ring substituted with two hydroxyl groups, and a pharmaceutically acceptable salt thereof. 11. Y is represented by -CR = N-, wherein R is an alkyl group in which R ₁ is substituted by a di-lower alkyl-substituted amino group or a nitrogen-containing heterocyclic group, and R ₂ is a hydrogen atom. A benzene ring having a ₁ R ₂ group, wherein the A ring is unsubstituted or substituted by 1 to 2 hydroxyl groups and / or halogen atoms, a benzene ring having a lower alkylenedioxy group, and the B ring has 1 to 2 The condensed indane derivative according to claim 1, which has an indeno [2,1-c] quinoline skeleton which is a benzene ring substituted with a hydroxyl group, and a pharmaceutically acceptable salt thereof. 12. Y is -CR = N-, R is -NR wherein R ₁ is an alkyl group substituted by a dimethylamino group, a diethylamino group or a pyrrolidinyl group, and R ₂ is a hydrogen atom.
₁ is R ₂ groups, the benzene ring to which ring A is unsubstituted or substituted with one to two hydroxyl and / or halogen atoms, with a benzene ring having a lower alkylenedioxy group, B ring is 1-2
Is a benzene ring substituted with two hydroxyl groups [2,
1-c] The fused indane derivative according to claim 1, which has a quinoline skeleton, and a pharmaceutically acceptable salt thereof. 13. An antitumor agent comprising an effective amount of the condensed indane derivative according to claim 1 and a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier. 14. The method for producing a condensed indane derivative according to claim 1, wherein the compound of the following general formula (2) is reacted with a compound represented by RH. (Wherein A ring, B ring, R and Y are the same as above. Z is -CX
= N- or -N = CX-, and X represents a halogen atom. )