Condensed-Indan derivatives and pharmaceutically acceptable salts thereof

A condensed-indan derivative represented by formula (1) and a pharmaceutically acceptable salt thereof: ##STR1## wherein ring A represents an optionally substituted benzene ring or naphthalene ring, or a benzene ring having a lower alkylenedioxy group, ring B represents an optionally substituted benzene ring or a benzene ring having a lower alkylenedioxy group. Y represents --N.dbd.CR-- or --CR=N--, R represents a --NR.sub.1 R.sub.2 group, an optionally substituted nitrogen-containing heterocyclic group or a --OR.sub.3 group, wherein R.sub.1 and R.sub.2 are the same or different and each is a hydrogen atom; a phenyl group; an optionally substituted nitrogen-containing heterocyclic group; or a lower alkyl group which may be substituted by 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 by a lower alkyl group or a hydroxyl group(s); R.sub.3 represents a lower alkyl group optionally substituted by a substituted amino group, except when R represents an optionally substituted nitrogen-containing heterocyclic group; ring A and ring B are a benzene ring having no substituent group.

TECHNICAL FIELD 
The present invention relates to novel condensed-indan derivatives, 
pharmaceutically acceptable salts thereof, a method for producing the 
derivatives, composition and antitumor agent containing the derivatives 
and a method for treating tumor of mammal. The compounds of the invention 
have excellent antitumor activities, thereby useful as antitumor agent. 
BACKGROUND ART 
As indeno2,1-c!quinoline derivatives, for example, compounds substituted 
at 6-position by a piperazinyl group described in Med. Chem. Res., 3, 
44-51 (1993) are known. Although the document discloses antiserotonin 
activities thereof, antitumor activities of the compounds are in no way 
reported and described in the document. The antitumor activities of the 
condensed-indan derivatives of the invention are, hence, unknown. 
It is an object of the invention to provide compounds which have excellent 
antitumor activities and are useful as medicament for treatment of tumor. 
DISCLOSURE OF THE INVENTION 
The present inventors have conducted research and found that 
condensed-indan derivatives demonstrate excellent antitumor activities and 
are useful as antitumor agent. Thus, the present invention has been 
accomplished. 
The present invention provides condensed-indan derivatives represented by 
the formula (1) or pharmaceutically acceptable salts thereof: 
##STR2## 
wherein ring A represents an optionally substituted benzene ring or 
naphthalene ring, or a benzene ring having a lower alkylenedioxy group, 
ring B represents an optionally substituted benzene ring or a benzene ring 
having a lower alkylenedioxy group. Y represents --N.dbd.CR-- or 
--CR.dbd.N--, R represents a --NR.sub.1 R.sub.2 group, an optionally 
substituted nitrogen-containing heterocyclic group or a --OR.sub.3 group, 
wherein R.sub.1 and R.sub.2 are the same or different and each is a 
hydrogen atom; a phenyl group; an optionally substituted 
nitrogen-containing heterocyclic group; a lower alkyl group which may be 
substituted by 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 
by a lower alkyl group or a hydroxyl group; R.sub.3 represents a lower 
alkyl group optionally substituted by a substituted amino group, provided 
that ring A and ring B are not a benzene ring having no substituent when R 
represents an optionally substituted nitrogen-containing heterocyclic 
group. 
The compounds of the present invention represented by said formula (1) has 
excellent antitumor activities, and are effective for treatment of a 
variety of tumors. 
Accordingly, the invention provides a composition comprising an effective 
amount of the compound of said formula (1) or a pharmaceutically 
acceptable salt thereof and a pharmaceutically acceptable carrier 
therefor. 
The present invention, in particular, provides an antitumor agent 
comprising an effective amount of the compound of said formula (1) or a 
pharmaceutically acceptable salt thereof and a pharmaceutically acceptable 
carrier therefor. 
The present invention further provides a method for treating tumor of 
mammal which comprises administering an effective amount of the compound 
of said formula (1) or a pharmaceutically acceptable salt thereof to 
mammal. 
In said formula (1), examples of groups as defined in R.sub.1, R.sub.2 and 
R.sub.3 and the other groups described in the specification are shown 
below. 
Examples of substituent groups included in benzene ring and naphthalene 
ring represented by ring A and ring B are halogen atom, lower alkyl group, 
lower alkoxy group, hydroxyl group, nitro group, amino group, lower 
acyloxy group, benzyloxy group, lower acylamino group, cyano group, 
carboxyl group, lower alkoxycarbonyl group, preferably halogen atom, lower 
alkyl group, lower alkoxy group, hydroxyl group, nitro group, amino group, 
lower acyloxy group, benzyloxy group and lower acylamino group. 
Said substituent groups may be placed at any position of each ring which 
may have the same or different 1-4 substituent groups. With respect to 
ring A, preferable positions are 8-, 9- and 10-position of 
indeno2,1-c!quinoline ring and indeno2,1-c!isoquinoline ring. With 
respect to ring B, preferable positions are similarly 2-, 3- and 
4-position. The number of substituent group in each ring are preferably 1 
and 2, respectively. 
Structure and substitution position of indeno2,1-c!quinoline are shown in 
table 1 below, and structure and substitution position of 
indeno2,1-c!isoquinoline are shown in table 5 below. 
Examples of lower alkylenedioxy group are methylenedioxy, ethylenedioxy, 
trimethylenedioxy, tetramethylenedioxy group and like alkylenedioxy group 
having 1-4 carbon atoms. The substitution positions of lower alkylenedioxy 
group are preferably 8,9-position or 9,10-position of 
indeno2,1-c!quinoline ring and indeno2,1-c!isoquinoline ring in the case 
of ring A; and similarly 2,3-position or 3,4-position in the case of ring 
B. When ring A is an optionally substituted naphthalene ring, substitution 
positions of the other benzene ring which is a part of naphthalene ring 
combined with benzene ring in indenone skeleton are any of three cases, 
i.e., 8-9 position, 9-10 position and 10-11 position of ring A. 
Example of halogen atoms are fluorine atom, chlorine atom, bromine atom and 
iodine atom. 
Example of lower alkyl group are straight or branched alkyl groups having 1 
to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. 
Example of lower alkoxy group are straight or branched alkoxy groups having 
1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, 
n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc. 
Example of lower acyloxy groups are straight or branched acyloxy groups 
having 1 to 6 carbon atoms, such as formyloxy, acetoxy, propionyloxy, 
butyryloxy, 2-methylpropionyloxy, pivaloyloxy, pentanoyloxy, 
3-methylbutyryloxy, hexanoyloxy, etc. 
Example of lower acylamino groups are straight or branched acylamino groups 
having 1 to 6 carbon atoms, such as formylamino, acetylamino, 
propionylamino, butyrylamino, 2-methylpropionylamino, pivaloylamino, 
pentanoylamino, 3-methylbutyrylamino, hexanoylamino, etc. 
Examples of the lower alkoxycarbonyl group are straight or branched 
alkoxycarbonyl groups having 2 to 7 carbon atoms, such as methoxycarbonyl, 
ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, 
pentyloxycarbonyl, hexyloxycarbonyl, etc. 
Examples of substituent groups included in nitrogen-containing heterocycles 
represented by R, R.sub.1 and R.sub.2 are lower alkyl groups, lower alkyl 
groups having hydroxyl group(s), preferably lower alkyl groups. 
Examples of substituent groups of substituted amino groups referred to as 
"optionally substituted amino group" represented by R.sub.1 and R.sub.2 
and referred to as "lower alkyl group optionally substituted by a 
substituted amino group" represented by R.sub.3, are lower alkyl group, 
lower cycloalkyl group, di-loweralkylamino-alkyl group, hydroxyloweralkyl 
group, benzyloxycarbonyl group, lower acyl group, preferably lower alkyl 
group, di-loweralkylamino-alkyl group, hydroxyloweralkyl group and 
benzyloxycarbonyl group. Said substituted amino groups may be 
mono-substituted or di-substituted, preferably di-substituted. 
Examples of lower alkyl group having substituted amino group are 
methylaminomethyl, ethylaminomethyl, methylaminoethyl, ethylaminoethyl, 
dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, 
diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, 
diethylaminobutyl, diethylaminopenta-2-yl, dipropylaminoethyl, 
dibutylaminoethyl, dibutylaminohexyl and like mono- or di-alkylamino-alkyl 
groups having 1 or 2 C.sub.1 -C.sub.6 alkyl moieties; 
N-dimethylaminoethyl-N-methylaminoethyl group, acetylaminoethyl, 
acetylaminopropyl, propionylaminoethyl, propionylaminopropyl, 
pivaloylaminoethyl, pivaloylaminopropyl and like alkyl group substituted 
by C.sub.2 -C.sub.6 acylamino group; cyclopropylaminomethyl, 
cyclopentylaminomethyl, cyclopentylaminoethyl, cyclohexylaminomethyl, 
cyclohexylaminoethyl and like alkyl group substituted by C.sub.3 -C.sub.6 
cycloalkylamino group; hydroxymethylaminomethyl, 
2-hydroxyethylaminomethyl, 3-hydroxypropylaminomethyl, 
hydroxymethylaminoethyl, 2-hydroxyethylaminoethyl, 
3-hydroxypropylaminoethyl, 4-hydroxybutylaminoethyl group and like alkyl 
group substituted by C.sub.1 -C.sub.4 hydroxyalkylamino group; 
benzyloxycarbonylaminomethyl, benzyloxycarbonylaminoethyl, 
N-benzyloxycarbonyl-N-methylaminoethyl group and like alkyl group 
substituted by benzyloxycarbonylamino group. 
Examples of lower alkyl group having lower alkoxy group are methoxymethyl, 
ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl 
group and like straight or branched C.sub.1 -C.sub.6 alkyl group 
substituted by C.sub.1 -C.sub.6 alkoxy group. 
Examples of lower alkyl group substituted by a phenyl group are benzyl, 
phenethyl, 2-phenethyl, phenylpropyl, benzhydryl, trityl group and like 
straight or branched C.sub.1 -C.sub.4 alkyl group substituted by 1-3 
phenyl groups. 
Examples of nitrogen-containing heterocyclic group represented by R, 
R.sub.1 and R.sub.2 are preferably 5- or 6-membered monocyclic-type 
heterocyclic group having 1-4 nitrogen atoms and 0 or 1 oxygen atom or 
sulfur atom, specifically pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, 
isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 
oxatriazolyl, thiatriazolyl, tetrazolyl, pyridyl, pyridazinyl, 
pyrimidinyl, pyrazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, 
imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperidino, 
piperazinyl, morpholinyl, morpholino group, etc., more preferably 5- or 
6-membered monocyclic-type heterocyclic group having 1-3 nitrogen atoms 
and 0 or 1 oxygen atom, in particular, pyridyl, pyrrolidinyl, piperidyl, 
piperidino, piperazinyl, morpholinyl, morpholino, 1,2,4-triazolyl group. 
Examples of substituted nitrogen-containing heterocyclic group are 
4-methylpiperazinyl, 4-ethylpiperazinyl, 4-methylpiperidino, 
4-ethylpiperidino, 2-hydroxymethylpyrrolidinyl, 
2-(2-hydroxyethyl)pyrrolidinyl, etc. 
Examples of lower alkyl group having nitrogen-containing heterocyclic group 
represented by R.sub.1 and R.sub.2 are 2-pyridylmethyl, 3-pyridylmethyl, 
4-pyridylmethyl, 2-pyridylethyl, 3-pyridylethyl, 4-pyridylethyl, 
pyrrolidinylmethyl, pyrrolidinylethyl, piperidinomethyl, piperidinoethyl, 
piperazinylmethyl, piperazinylethyl, morpholinomethyl, morpholinoethyl and 
like straight or branched C.sub.1 -C.sub.6 alkyl group having 
nitrogen-containing heterocyclic group. 
Examples of amine oxide group substituted by lower alkyl group are 
methylamino oxide, ethylamino oxide, butylamino oxide, dimethylamino 
oxide, diethylamino oxide, dibutylamino oxide and like mono- or 
di-alkylamino oxide group in which alkyl moieties have 1-4 carbon atoms. 
Examples of lower alkyl group having an amine oxide group substituted by 
lower alkyl group are methylamino oxide methyl, methylamino oxide ethyl, 
ethylamino oxide methyl, ethylamino oxide ethyl, dimethylamino oxide 
methyl, dimethylamino oxide ethyl, diethylamino oxide methyl, diethylamino 
oxide ethyl, dibutylamino oxide propyl and like straight or branched 
C.sub.1 -C.sub.4 alkyl group having mono- or di-alkylamino oxide group in 
which alkyl moieties have 1-4 carbon atoms. 
Examples of lower alkyl group having hydroxyl groups are hydroxymethyl, 
1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 
2,3-dihydroxypropyl, 4-hydroxybutyl, 2,3-dihydroxybutyl, 5-hydroxypentyl, 
2,3-dihydroxypentyl, 6-hydroxyhexyl, 2,3-dihydroxyhexyl group and like 
straight or branched C.sub.1 -C.sub.6 alkyl group having 1 or 2 hydroxyl 
groups. 
Examples of the salts of the compounds of the invention are not 
specifically limited to, as long as the salts are pharmaceutically 
acceptable salts, which include salts formed with organic acids, such as 
formic acid, acetic acid, propionic acid, trifluoroacetic acid, tartric 
acid, malic acid, maleic acid, fumaric acid, succinic acid, oxalic acid, 
methansulfonic acid, p-toluenesulfonic acid; and inorganic acids such as 
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid. 
With respect to the compound represented by formula (1): 
ring A preferably represents a benzene ring optionally substituted by 
hydroxyl group(s) or halogen atom(s), or a benzene ring having a lower 
alkylenedioxy group, more preferably represents a benzene ring optionally 
substituted by 1 or 2 hydroxyl groups and/or halogen atoms, or a benzene 
ring having a lower alkylenedioxy group; 
ring B preferably represents a benzene ring substituted by hydroxyl 
group(s), more preferably represents a benzene ring substituted by 1 or 2 
hydroxyl groups; 
Y preferably represents --CR.dbd.N--; 
R preferably represents a --NR.sub.1 R.sub.2 group, piperazinyl group 
substituted by lower alkyl group, or --OR.sub.3 group, more preferably 
represents a --NR.sub.1 R.sub.2 group. 
R.sub.1 and R.sub.2 are the same or different and each is preferably a 
hydrogen atom, a phenyl group or a lower alkyl group optionally 
substituted by an optionally substituted amino group, a 
nitrogen-containing heterocyclic group, an amine oxide group substituted 
by lower alkyl group or a hydroxy group, more preferably a hydrogen atom 
or a lower alkyl group optionally substituted by a 
diloweralkyl-substituted amino group or a nitrogen-containing heterocyclic 
group, in particular, R.sub.1 is a lower alkyl group substituted by 
dimethylamino group, diethylamino group or pyrrolidinyl group and R.sub.2 
is a hydrogen atom; and 
R.sub.3 preferably represents a lower alkyl group optionally substituted by 
diloweralkyl-substituted amino group. 
The preferred compounds of the invention are indeno2,1-c!quinoline 
derivatives represented by the formula (1), wherein ring A represents 
benzene ring unsubstituted or substituted by 1 or 2 hydroxyl group(s) 
and/or halogen atom(s); or a benzene ring having a lower alkylenedioxy 
group; ring B represents a benzene ring substituted by 1 or 2 hydroxyl 
group(s); Y represents --CR.dbd.N--, R represents a --NR.sub.1 R.sub.2 
group (wherein R.sub.1 and R.sub.2 are the same or different and each is a 
hydrogen atom or a lower alkyl group optionally substituted by a 
diloweralkyl-substituted amino group or a nitrogen-containing heterocyclic 
group), piperazinyl group substituted by lower alkyl group, or --OR.sub.3 
group (wherein R.sub.3 represents a lower alkyl group optionally 
substituted by di-loweralkyl-substituted amino group). 
The more preferred compounds of the invention are indeno2,1-c!quinoline 
derivatives represented by the formula (1), wherein ring A represents a 
benzene ring unsubstituted or substituted by 1 or 2 hydroxyl groups and/or 
halogen atoms, or a benzene ring having a lower alkylenedioxy group; ring 
B represents a benzene ring substituted by 1 or 2 hydroxyl groups; Y 
represents --CR.dbd.N--, R represents a --NR.sub.1 R.sub.2 group (wherein 
R.sub.1 represents a lower alkyl group substituted by a 
diloweralkyl-substituted amino group or a nitrogen-containing heterocyclic 
group, in particular, lower alkyl group substituted by dimethylamino, 
diethylamino or pyrrolidinyl group, R.sub.2 is a hydrogen atom.). 
The compounds of the present invention represented by formula (1) may be 
produced according to the reaction formula 1 below. 
##STR3## 
wherein ring A, ring B and Y are as defined above. Z represents 
--CX.dbd.N-- or --N.dbd.CX--, X represents halogen atom. 
(Step A) 
The desired compound of the invention represented by formula (1) is 
produced by reacting 6-halogeno-indeno2,1-c!quinoline derivative or 
5-halogeno-indeno2,1-c!isoquinoline derivative represented by formula (2) 
with amine represented by RH (which corresponds to NH(R.sub.1)(R.sub.2) or 
optionally substituted nitrogen-containing heterocyclic group) or alcohol 
(R.sub.3 OH) in the presence or absence of suitable solvent for amination 
or alkoxylation. In carrying out the amination reaction, sodium hydride, 
potassium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium 
carbonate, sodium carbonate, sodium bicarbonate, triethylamine, etc., may 
be employed in a suitable solvent. In carrying out the alkoxylation 
reaction, alcohol may be employed in the form of free alcohol or 
alcoholate prepared by adding sodium, sodium hydride, potassium 
tert-butoxide, etc., to a suitable solvent. 
Examples of solvent are methanol, ethanol, propanol, tert-butanol and like 
alcohols, dimethylformamide, dimethylacetoamide, pyridine, toluene, 
benzene, acetonitrile, tetrahydrofuran, water, etc. The solvents are 
employed singly or in a mixture of two or more of them. 
In carrying out the reaction, the amine or alcohol is employed about 
0.1-100 times, preferably 1-10 times as much as the molar amount of 
compound of formula (2). The reaction temperature is within the range of 
0.degree.-200.degree. C., preferably 50.degree.-150.degree. C., and the 
reaction time is within the range of 0.1-100 hours, preferably 1-60 hours. 
These conditions are favorable to the progress of the reaction. 
When ring A or ring B of compound of formula (1) obtained according to 
reaction formula 1 has lower alkoxy groups or benzyloxy groups as 
substituent groups, the substituent groups may be converted into hydroxyl 
group by reacting the compound with hydrobromic acid, hydroiodic acid, 
hydrochloric acid, sulfuric acid etc., in the presence or absence of a 
suitable solvent. Examples of the solvent are acetic acid and water, which 
may be employed singly or in a mixture of two or more of them. In carrying 
out the reaction, hydrobromic acid, hydroiodic acid, hydrochloric acid or 
sulfuric acid is employed in an amount of 0.1-1000 times (v/w), preferably 
5-100 times (v/w) as much as the amount of lower alkoxy groups or 
benzyloxy groups. The reaction temperature is within the range of 
0.degree.-200.degree. C., preferably 50.degree.-150.degree. C., and the 
reaction time is within the range of 0.1-100 hours, preferably 0.5-60 
hours. These conditions are favorable to the progress of the reaction. 
When ring A or ring B of compound of formula (1) obtained according to 
reaction formula 1 has a nitro group as substituent group, the nitro group 
may be converted into amino group by reduction, if desired. The reduction 
reaction may be carried out in a suitable solvent by using tin chloride in 
the presence of hydrochloride. Examples of the solvent are methanol, 
ethanol and like alcohols, dimethylformamide, etc. In carrying out the 
reaction, the molar amount of hydrochloride employed is preferably 1-100 
times as much as the molar amount of nitro group, and the molar amount of 
tin chloride employed is preferably 1-10 times as much as the molar amount 
of nitro group. The reaction temperature is within the range of 
0.degree.-50.degree. C., and the reaction time is within the range of 
0.1-100 hours, preferably 1-12 hours. These conditions are favorable to 
the progress of the reaction. 
When ring A or ring B of compound of formula (1) obtained according to 
reaction formula 1 has hydroxyl group as substituent groups, the hydroxyl 
group may be converted into alkoxy group, benzyloxy group or acyloxy group 
by alkylation, benzylation or acylation, respectively, if desired. 
Alkylation and benzylation reaction may be carried out in a suitable 
solvent by reacting alkylating agent or benzylating agent therewith in the 
presence of base. Examples of the solvent are dimethoxyethane, dioxane, 
tetrahydrofuran, dimethylformamide, acetone, etc. Examples of base are 
potassium carbonate, sodium carbonate, potassium hydroxide, etc. Examples 
of alkylating agent are halide, sulfate ester and sulfonate ester of 
optionally substituted alkanes. Examples of benzylating agent are benzyl 
halides, etc. In carrying out the reaction, the molar amount of base 
employed is preferably 1-5 times, the molar amount of alkylating agent or 
benzylating agent employed is preferably 1-5 times, as much as the molar 
amount of hydroxyl groups. The reaction temperature is within the range of 
0.degree.-80.degree. C., and the reaction time is within the range of 
0.1-24 hours, preferably 0.5-10 hours. These conditions are favorable to 
the progress of the reaction. 
When R of compound of formula (1) obtained according to reaction formula 1 
has an amino group substituted by a lower alkyl group, the amino group 
substituted by a lower alkyl group may be converted into an amineoxide 
group substituted by a lower alkyl group by reacting the amino group with 
an oxidizing agent in a suitable solvent. The solvent is not specifically 
limited to, as long as the solvent does not exert an adverse effect on the 
reaction. Examples of the solvent are ether, tetrahydrofuran and like 
ethers, methylene chloride, chloroform and like halogenated hydrocarbons, 
acetone, methylethylketone and like alkylketones, methanol, ethanol and 
like alcohols, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile and 
like aprotic polar solvents, acetic acid, water, etc., which may be 
employed singly or in a mixture of two or more of them. Oxidizing agents 
are not specifically limited to, but include manganese dioxide, sodium 
hypochlorite, CAN(ammonium cerium (IV) nitrate), 
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 chlorochromate, pyridinium 
dichromate, dimethylsulfoxide-oxalyl chloride, hydrogen peroxide, 
tert-butylhydroperoxide and like peroxides, performic acid, peracetic 
acid, m-chloroperbenzoic acid and like peracids, which may be employed 
singly or in a mixture thereof. 
In carrying out the reaction, an oxidizing agent is employed within about 
1-100 equivalent amount, preferably about 1-10 equivalent amount of the 
compound represented by formula (1). The reaction temperature ranges from 
ice-cooling to about boiling point of the solvent, and reaction time 
ranges from about 0.1-96 hours, preferably about 0.1 to 1 hour. These 
conditions are favorable to the progress of the reaction. 
Acylation reaction is carried out by reacting the compound with a desired 
carboxylic acid or reactive derivatives thereof. When employing the 
reactive derivatives, the reaction is conducted in a suitable solvent 
optionally in the presence of base to accelerate the reaction, although 
the reaction conditions are varied according to kinds of the reactive 
derivatives and of starting phenolic derivatives. Examples of the reactive 
derivatives are acid anhydride, mixed acid anhydride, acid halide, etc. 
Examples of solvent are chloroform, dichloromethane, dioxane, 
tetrahydrofuran, dimethylformamide, pyridine, etc. Examples of base are 
sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, 
4-dimethylaminopyridine, etc. In carrying out the reaction, the molar 
amount employed is preferably 1-5 times in base, 1-5 times in acylating 
agent as much as the molar amount of hydroxyl group. The reaction 
temperature is within the range of 0.degree.-50.degree. C., and the 
reaction time is within the range of 0.1-24 hours, preferably 0.5-3 hours. 
These conditions are favorable to the progress of the reaction. 
When ring A or ring B of compound of formula (1) obtained according to 
reaction formula 1 has an amino group as substituent group, the amino 
group may be converted into acylamino group by acylation, if desired. The 
acylation reaction is carried out by reacting a desired carboxylic acid or 
reactive derivatives therewith. When reactive derivatives are employed, 
the reaction is conducted in a suitable solvent optionally in the presence 
of base to accelerate the reaction, although the reaction conditions are 
varied according to kinds of the reactive derivatives and of starting 
aniline derivatives. Examples of the reactive derivatives are acid 
anhydride, mixed acid anhydride, acid halide, etc. Examples of solvent are 
chloroform, dichloromethane, dioxane, tetrahydrofuran, dimethylformamide, 
pyridine, etc. Examples of base are sodium bicarbonate, sodium carbonate, 
potassium carbonate, triethylamine, pyridine, 4-dimethylaminopyridine, 
etc. In carrying out the reaction, the molar amount employed is preferably 
1-5 times in base, 1-5 times in acylating agent as much as the molar 
amount of amino group. The reaction temperature is within the range of 
0.degree.-50.degree. C., and the reaction time is within the range of 
0.1-100 hours, preferably 0.5-10 hours. These conditions are favorable to 
the progress of the reaction. 
Nitro groups may be introduced to the compound of formula (1) obtained 
according the reaction formula 1 by nitration reaction. The nitration 
reaction is conducted by using nitrating agent such as fuming nitric acid 
and nitric acid in the presence or absence of sulfuric acid. In carrying 
out the reaction, the molar amount of nitrating agent employed is 
preferably 1-100 times as much as the molar amount of compound of formula 
(1). The reaction temperature is within the range of 0.degree.-30.degree. 
C., and the reaction time is within the range of 0.1-20 hours, preferably 
0.5-5 hours. These conditions are favorable to the progress of the 
reaction. 
When R of compound of formula (1) obtained according to reaction formula 1 
has protective groups, such as benzyloxycarbonyl group, lower acyl group, 
etc., the protective groups may be removed by reacting the protective 
group with hydrobromic acid, hydroiodic acid, hydrochloric acid, sulfuric 
acid, etc., in a suitable solvent or without solvent. The solvent includes 
acetic acid, water, etc., which are employed singly or in a mixture of two 
or more of them. 
In carrying out the reaction, hydrobromic acid, hydroiodic acid, 
hydrochloric acid, sulfuric acid, etc., are employed in an amount ranging 
1-1,000 times (v/w), preferably 5-100 (v/w) times as much as the amount of 
protective group. The reaction temperature is within the range of about 
0.degree.-200.degree. C., preferably about 50.degree.-150.degree. C., and 
the reaction time is within the range of 0.1-100 hours, preferably 0.5-60 
hours. These conditions are favorable to the progress of the reaction. 
The compounds of the invention obtained by said reactions may be converted 
into salts thereof according to a conventional method by reacting the 
compounds with said organic acids or inorganic acids in a suitable 
solvent. Examples of solvent are water, methanol, ethanol, 
dichloromethane, tetrahydrofuran, etc. The reaction temperature is 
preferably within the range of 0.degree.-50.degree. C. 
The 6-halogenoindeno2,1-c!quinoline derivatives represented by formula (2) 
employed as a starting material in reaction formula 1 may be produced 
according to the method described in J. Heterocyclic Chem., 28, 1809 
(1991), or e 2 and 3 below. 
##STR4## 
wherein ring A, ring B and X are as defined above. R.sub.4 represents a 
lower alkyl group. 
&lt;Step B&gt; 
The carboxylic acid of formula (4) may be produced by hydrolyzing the 
compound of formula (3) in a suitable solvent with basic compound. 
The compound of formula (3) may be produced according to the method 
disclosed in Japanese Unexamined Patent Publication No. 3-223254. 
Examples of solvent are not specifically limited to, as long as the solvent 
does not exert an adverse effect on the reaction, but include methanol, 
ethanol, propanol and like alcohols, dioxane, tetrahydrofuran, 
dimethoxyethane and like ethers and water, which are employed singly or in 
a mixture of two or more of them. Examples of basic compound are sodium 
hydroxide, potassium hydroxide, barium hydroxide and like alkali metal or 
alkaline earth metal hydroxides. 
In carrying out the reaction, the molar amount of basic compound employed 
is preferably 1-10 times as much as the molar amount of compound of 
formula (3). The reaction temperature is within the range of 
0.degree.-100.degree. C., preferably 50.degree.-100.degree. C., and the 
reaction time is within the range of 0.5-100 hours, preferably 1-50 hours. 
These conditions are favorable to the progress of the reaction. 
&lt;Step C&gt; 
The compounds of formula (5) or formula (6) may be produced by reacting 
halogenating agent with compounds of formula (3) or formula (4) usually 
without solvent, or optionally in an inert solvent, respectively. Examples 
of inert solvent are not specifically limited to, as long as the solvent 
does not exert an adverse effect on the reaction, but include chloroform, 
benzene, toluene, xylene, etc. Examples of halogenating agents are thionyl 
chloride, thionyl bromide, phosphorous oxychloride, phosphorus chloride, 
phosphorus bromide, phosphorus pentachloride, phosphorus pentabromide, 
etc. Pyridine or dimethylformamide may be added to accelerate the 
reaction. 
In carrying out the reaction, the molar amount of halogenating agent 
employed is preferably about 1-100 times as much as the molar amount of 
compound of formula (3) or formula (4). The reaction temperature is within 
the range of 0.degree.-200.degree. C., preferably 50-150.degree. C., and 
the reaction time is within the range of 0.5-100 hours, preferably 0.5-10 
hours. These conditions are favorable to the progress of the reaction. 
The compound of formula (5) or formula (6) is optionally separated and 
purified, but may be employed in the following step without purification. 
&lt;Step D&gt; 
The compound of formula (2a) is produced by reacting compound of formula 
(5) or formula (6) obtained in step C with protonic acid or Lewis acid 
without solvent or optionally in the presence of inert solvent. 
Examples of inert solvent are not specifically limited to, as long as the 
solvent does not exert an adverse effect on the reaction, but include 
nitrobenzene, xylene, dichloromethane, carbontetrachloride, etc. Examples 
of protonic acid are sulfuric acid, phosphoric acid, polyphosphoric acid, 
hydrobromic acid, etc. Examples of Lewis acid are aluminium chloride, tin 
chloride, iron chloride, etc. 
In carrying out the reaction, the molar amount of protonic acid or Lewis 
acid employed is 1-1000 times, preferably 1-100 times as much as the molar 
amount of compound of formula (5) or (6). The reaction temperature is 
within the range of 0.degree.-200.degree. C., and the reaction time is 
within the range of 0.5-50 hours, preferably 0.5-20 hours. These 
conditions are favorable to the progress of the reaction. 
##STR5## 
wherein ring A, ring B, X and R.sub.4 are as defined above. R.sub.5 
represents a lower alkyl group. 
&lt;Step E&gt; 
The compound of formula (9) is produced by reacting compound of formula (7) 
with compound of formula (8) usually in a suitable solvent. 
Examples of solvent are not specifically limited to, as long as the solvent 
does not exert an adverse effect on the reaction, but include methanol, 
ethanol, propanol and like alcohols, benzene, toluene, xylene, dioxane, 
tetrahydrofuran, etc. 
In carrying out the reaction, the molar amount of compound (8) employed is 
preferably 0.5-2 times as much as the molar amount of compound of formula 
(7). The reaction temperature is within the range of 
20.degree.-150.degree. C., preferably 90.degree.-130.degree. C. The 
reaction time is within the range of 0.1-50 hours, preferably 0.1-2 hours. 
These conditions are favorable to the progress of the reaction. 
&lt;Step F&gt; 
The compound of formula (10) is produced by reacting compound of formula 
(9) obtained in step E with protonic acid usually without solvent, 
optionally in the presence of inert solvent. 
Examples of inert solvent of the reaction are not specifically limited to, 
as long as the solvent does not exert an adverse effect on the reaction, 
but include nitrobenzene, xylene, etc. Examples of protonic acid are 
sulfuric acid, phosphoric acid, polyphosphoric acid, hydrobromic acid, 
etc. 
In carrying out the reaction, the amount of protonic acid employed is an 
amount as solvent, preferably 5-15 times as much as the amount of compound 
of formula (9). The reaction temperature is within the range of 
90.degree.-150.degree. C. The reaction time is within the range of 0.5-50 
hours, preferably 1-10 hours. These conditions are favorable to the 
progress of the reaction. 
&lt;Step G&gt; 
The compound of formula (10) is also produced by reacting compound of 
formula (3) or (4) with protonic acid usually without solvent, optionally 
in the presence of inert solvent. 
Examples of inert solvent of the reaction are not specifically limited to, 
as long as the solvent does not exert an adverse effect on the reaction, 
but include nitrobenzene, xylene, etc. Examples of protonic acid are 
sulfuric acid, phosphoric acid, polyphosphoric acid, hydrobromic acid, 
etc. 
In carrying out the reaction, the amount of protonic acid employed is an 
amount as solvent, preferably 5-15 times as much as the amount of compound 
of formula (3) or (4). The reaction temperature is within the range of 
50.degree.-200.degree. C. The reaction time is within the range of 0.5-50 
hours, preferably 0.5-10 hours. These conditions are favorable to the 
progress of the reaction. 
&lt;Step H&gt; 
The compound of formula (2a) is produced by reacting compound of formula 
(10) obtained in step F or step G with a halogenating agent usually 
without solvent, optionally in the presence of inert solvent. 
Examples of inert solvent of the reaction are not specifically limited to, 
as long as the solvent does not exert an adverse effect on the reaction, 
but include chloroform, benzene, toluene, xylene, etc. Examples of 
halogenating agent are thionyl chloride, thionyl bromide, phosphorous 
oxychloride, phosphorus chloride, phosphorus bromide, phosphorus 
pentachloride, phosphorus pentabromide, etc. Pyridine, dimethylformamide, 
etc., may be added to accelerate the reaction. 
In carrying out the reaction, the molar amount of halogenating agent 
employed is preferably 1-100 times as much as the molar amount of compound 
of formula (10). The reaction temperature is within the range of 
0.degree.-200.degree. C., preferably 50.degree.-150.degree. C. The 
reaction time is within the range of 0.5-50 hours, preferably 0.5-10 
hours. These conditions are favorable to the progress of the reaction. 
The 5-halogenoindeno2,1-c!isoquinoline derivatives represented by formula 
(2), which is employed as starting material in reaction formula 1, may be 
produced according to reaction formula 4 shown below. 
&lt;Reaction formula 4&gt; 
##STR6## 
wherein ring A, ring B and X are as defined above. &lt;Step I&gt; 
The carboxylic acid of formula (12) is produced by treating compound of 
formula (11) with ammonia in an inert solvent. 
The reaction may be carried out according to a known method disclosed in 
Bolletino Chimico Farmaceutico, 125, 437 (1986). 
In addition, the compound of formula (11) may be synthesized according to 
the description of Boll. Sedute Accad. Gioenia Sci. Nat. Catania, 6, 606 
(1960), or Japanese Unexamined Patent Publication No. 5-132463. 
Examples of solvent are not specifically limited to, as long as the solvent 
does not exert an adverse effect on the reaction, but include methanol, 
ethanol, propanol and like alcohols, etc. 
In carrying out the reaction, the molar amount of ammonia employed is 
1-1000 times, preferably 10-100 times as much as the molar amount of 
compound of formula (11). The reaction temperature is within the range of 
0.degree.-100.degree. C., preferably about room temperature, and the 
reaction time is within the range of 0.5-100 hours, preferably 2-20 hours. 
These conditions are favorable to the progress of the reaction. 
&lt;Step J&gt; 
The compound of formula (13) is produced by reacting compound of formula 
(12) obtained in step I with protonic acid or Lewis acid without solvent 
or optionally in the presence of inert solvent. 
Examples of inert solvent are not specifically limited to, as long as the 
solvent does not exert an adverse effect on the reaction, but include 
nitrobenzene, carbon disulfide, nitroparaffin, chloroethylene, 
dichloromethane, etc. Examples of protonic acid are hydrogen fluoride, 
sulfuric acid, phosphoric acid, diphosphorous pentaoxide, polyphosphoric 
acid, etc. Examples of Lewis acid are aluminium chloride, iron chloride, 
stannic chloride, zinc chloride, boron fluoride, etc. 
In carrying out the reaction, the molar amount is 5-15 times in protonic 
acid and 1-10 times in Lewis acid as much as the molar amount of compound 
of formula (12). The reaction temperature is within the range of 
0.degree.-200.degree. C., and the reaction time is within the range of 
0.5-50 hours, preferably 0.5-20 hours. These conditions are favorable to 
the progress of the reaction. 
&lt;Step K&gt; 
The compound of formula (2b) is produced by reacting compound of formula 
(13) obtained in step J with halogenating agent usually without solvent, 
optionally in the presence of inert solvent. 
Examples of inert solvent of the reaction are not specifically limited to, 
as long as the solvent does not exert an adverse effect on the reaction, 
but include chloroform, benzene, toluene, xylene, etc. Examples of 
halogenating agent are thionyl chloride, thionyl bromide, phosphorous 
oxychloride, phosphorus chloride, phosphorus bromide, phosphorus 
pentachloride, phosphorus pentabromide, etc. Pyridine, dimethylformamide, 
etc., may be added to accelerate the reaction. 
In carrying out the reaction, the molar amount of halogenating agent 
employed is preferably 1-100 times as much as the molar amount of compound 
of formula (13). The reaction temperature is within the range of 
0.degree.-200.degree. C., preferably 50.degree.-150.degree. C. The 
reaction time is within the range of 0.5-50 hours, preferably 0.5-10 
hours. These conditions are favorable to the progress of the reaction. 
The compounds of the invention and other compounds produced in any of the 
above-mentioned methods may be isolated and purified by conventional 
separation and purification means employed in the relevant field of art, 
for example, by concentration, extraction with solvent, filtration, 
recrystallization, various chromatographic techniques and so forth. 
When the compounds of the invention is employed as medicaments for 
malignant tumor of mammal, the compound may be made into various 
pharmaceutical dosage forms according to therapeutic purpose. Examples of 
pharmaceutical dosage forms are oral preparations, such as tablets, coated 
tablets, pills, powders, granules, capsules, liquids, suspensions, 
emulsions, and parenteral preparations such as injections, suppositories, 
ointments, plasters and so on. Such preparations can be formulated in a 
manner already known or conventional to those skilled in the art. 
When formulated in a form of tablets, employed as carriers are excipients 
such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium 
carbonate, kaolin, crystalline cellulose and silicic acid; binders such as 
simple syrup, glucose solution, starch solution, gelatin solution, 
carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate 
and polyvinyl pyrrolidone; disintegrators such as dried starch, sodium 
alginate, agar powder, powdered laminaran, sodium bicarbonate, calcium 
carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl 
sulfate, stearic acid monoglyceride, cacao butter, hydrogenated oil; 
absorption promoters such as quaternary ammonium base, sodium lauryl 
sulfate; humectants such as glycerine, starch; adsorbent such as starch, 
lactate, kaolin, bentonite, colloidal silicone dioxide; lubricants such as 
purified talc, stearic acid salt, borax and polyethylene glycol. Tablets 
may optionally be formed as tablets to which conventional coating is 
applied, such as sugar-coated tablets, gelatine-coated tablets, 
enteric-coated tablets, film-coating tablets, double-layer tablets, 
milti-layer tablets, etc. 
For the formulation of pills, as carrier are employed excipients such as 
glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, 
talc; binders such as gum arabic powder, tragacanth powder, gelatine; 
disintegrators such as laminaran, agar. 
Capsules may be prepared according to a conventional method, by mixing the 
compound of the invention with said carriers, followed by filling the 
mixture in hard gelatin capsule, soft elastic capsule, etc., 
For the formulation of suppositories, as carriers are employed polyethylene 
glycol, cacao butter, higher alcohols, higher alcohol esters, gelatine, 
semi-synthesized glycerides, etc. 
When prepared as injections, liquids, emulsion and suspensions are 
preferably sterile and isotonic to blood. For the formulation of said 
preparations, employed are diluents such as water, ethanol, macrogol, 
propyleneglycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl 
alcohol, polyoxyethylene sorbitane fatty acid esters, etc. To the 
medicinal preparations are added not only sodium chloride, glucose and 
glycerin in an enough amount to prepare isotonic solution, but also 
conventional solubilizer, buffers, local anesthetic, etc. 
Ointments may be prepared in a conventional manner by optionally blending 
to the compound of the invention base, stabilizer, wetting agent, 
preservative etc., and the resulting composition is admixed to give 
ointment preparations. Examples of base are liquid paraffin, white 
petrolatum, white beeswax, paraffin, etc. Examples of preservative are 
methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl 
parahydroxybenzoate, etc. 
Plasters are prepared by applying said ointments, pastes, creams, gels etc. 
to conventional supports. Examples of supports are suitably woven fabrics 
and unwoven fabrics made of cotton, staple fiber or some other chemical 
fiber, films or foamed sheets made of plasticized polyvinyl chloride, 
polyethylene, polyurethane, etc. 
Coloring agent, preservatives, perfumes, flavors, sweeteners, and other 
medicaments may optionally be added to the medical formulations. 
The amount of the compounds of the invention in medical formulations are 
not specifically limited to, but usually include 1-70% by weight of the 
medicinal preparations. 
The way of administration of said medicinal preparations is not 
specifically limited to, but suitably determined according to the type of 
preparations, age, sex and other factors of patients, severity of 
disorder, etc. For example, tablets, pills, liquids, suspensions, 
emulsions, granules, capsules are orally administered. Injections are 
intravenously administered singly or in a mixture with conventional 
additives, such as glucose, amino acids, etc. Injections may be 
intramuscularly, intracutaneously, subcutaneously or intraperitoneally 
administered in a single form. Suppositories are administered in rectum. 
Ointments are applied to skin, tunica mucosa oris, etc. 
The amount of the compound of the present invention to be incorporated into 
each of the dosage units varies with the symptoms of the patient or with 
the type of the preparations. The preferable amount per administration 
unit is about 1 to 1,000 mg for oral preparations, about 0.1 to 500 mg for 
injections, or about 5 to 1,000 mg for suppositries. The dosage per day of 
the drug in the above dosage form is variable with the symptoms, body 
weight, age, sex and other factors of the patient, but usually ranges from 
about 0.1 to 5,000 mg, preferably from about 1 to 1,000 mg for human 
adult. The preparation is preferably administered in a single dose or in 
two to four divided doses. 
Examples of malignant tumor treated by administering preparations 
containing the compounds of the invention are not specifically limited to, 
but include head and neck cancer, esophageal carcinoma, gastric cancer, 
colon cancer, rectum cancer, cancer of liver, gallbladder cancer or 
cholangioma, pancreatic cancer, pulmonary cartinoma, breast cancer, 
ovarian cancer, bladder cancer, prostatic cancer, testicular tumor, 
osteochondroma, malignant lymphoma, leukemia, cervical cancer, skin 
carcinoma, brain tumor, etc. 
Best Mode for Carrying out the Invention 
Reference examples, examples, pharmacological test examples and dosage form 
examples of the invention are shown below. 
&lt;Reference example 1&gt; 
Synthesis of 1,2-dihydro-4-(3,4-methylenedioxyphenyl)-2-oxo-3-quinoline 
carboxylic acid 
A mixture of 1,2-dihydro-4-(3,4-methylenedioxyphenyl)-2-oxo-3-quinoline 
carboxylic acid ethyl ester (40 g, 118.6 mmol), methanol (200 ml), water 
(300 ml) and potassium hydroxide (33.3 g, 593.5 mmol) was refluxed with 
heat for 40 hours. To the reaction mixture was added 110 ml of 6N-HCl to 
acidify the mixture to obtain a precipitated crystal by filtration. The 
crystal obtained was washed with diethylether to give 35 g (yield: 95.4%) 
of the title compound. 
m.p.: 247.degree.-250.degree. C. (decomp.) 
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 7.45(1H, m), 7.35(1H, d, J=8 Hz), 
7.13(1H, m), 7.06(1H, d, J=8 Hz), 6.98(1H, d, J=8 Hz), 6.87(1H, s), 
6.76(1H, d, J=8 Hz), 6.08(2H, s). 
IR(KBr)cm.sup.-1 : 3440, 1646, 1577, 1486, 1441, 1395, 1238, 1039. 
&lt;Reference example 2&gt; 
Synthesis of 6-chloro-9,10-methylenedioxy-7H-indeno2,1-c!quinoline-7-on 
A mixture of 1,2-dihydro-4-(3,4-methylenedioxyphenyl)-2-oxo-3-quinoline 
carboxylic acid obtained in reference example 1 (10 g, 32.3 mmol) and 
phosphorous oxychloride (100 ml, 1.07 mol) was refluxed with heat for 4 
hours. The reaction mixture was distilled to dryness and washed with 
n-hexane several times. To the residue obtained was added 50 g of 
polyphosphoric acid, and the mixture was heated at 90.degree. C. for 2 
hours. The reaction mixture was poured into ice water to filtrate a 
crystal precipitated. The crystal obtained was dissolved in 
tetrahydrofuran to filter off undissolved substances and purified by 
silica gel column chromatography (eluent: chloroform) to give 6.0 g (yield 
59.9%) of the title compound. 
m.p.: 265.degree.-270.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.34(1H, d, J=8 Hz), 8.04(1H, d, J=8 Hz), 
7.84(1H, d-d, J=8,7 Hz), 7.66(1H, d-d, J=8,7 Hz), 7.58(1H, s), 7.23(1H, 
s), 6.17(2H, s). 
IR(KBr)cm.sup.-1 : 3450, 1713, 1556, 1504, 1478, 1420, 1384, 1335, 1266, 
1037. 
&lt;Reference example 3&gt; 
Synthesis of 1,2-dihydro-4-phenyl-2-oxo-3-quinoline carboxylic acid 
A mixture of 1,2-dihydro-4-phenyl-2-oxo-3-quinoline carboxylic acid ethyl 
ester (5 g, 17 mmol), ethanol (20 ml), water (40 ml) and potassium 
hydroxide (5 g, mmol) was refluxed with heat for 1.5 hours. To the 
reaction mixture was added 60 ml of 2N-HCl to acidify the mixture to 
obtain a precipitated crystal by filtration. The crystal obtained was 
recrystallized from ethanol to give 4.2 g (yield: 92.9%) of the title 
compound. 
m.p.: 246.degree.-254.degree. C. (decomp.) 
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 13.10(1H, brs), 12.28(1H, s), 
7.60-7.05(9H, m), 
IR(KBr)cm.sup.-1 : 3000, 2970, 2950, 2880, 2850, 2840, 2790, 1699, 1653, 
1608, 1598, 1557, 1506, 1488, 1435, 1411, 1262, 1100, 753, 709, 591. 
&lt;Reference example 4&gt; 
Synthesis of 5H-indeno2,1-c!quinoline-6,7-dion 
A mixture of 1,2-dihydro-4-phenyl-2-oxo-3-quinoline carboxylic acid 
obtained in reference example 3 (2 g, 7.5 mmol) and polyphosphoric acid 
(20 g) was reacted at 130.degree. C. for 4 hours. The reaction mixture was 
poured into ice water to obtain a crystal precipitated by filtration. The 
crystal obtained was reprecipitated with methanol to give 1.7 g (yield 
91.2%) of the title compound. 
m.p.: &gt;290.degree. C. 
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 12.12(1H, brs), 8.55(1H, d, J=8 Hz), 
8.40(1H, d, J=8 Hz), 7.78-7.33(6H, m). 
IR(KBr)cm.sup.-1 : 2860, 1724, 1652, 1618, 1601, 1585, 1503, 1484, 1404, 
763, 743, 576. 
&lt;Reference example 5&gt; 
Synthesis of 3-methyl-5H-indeno2,1-c!quinoline-6,7-dion 
A mixture of 1,2-dihydro-4-phenyl-7-methyl-2-oxo-3-quinoline carboxylic 
acid ethyl ester (2.5 g, 8.1 mmol) and conc. sulfuric acid (20 ml) was 
stirred with heat at 95.degree. C. for 10 hours. The reaction mixture was 
poured into ice water to obtain a crystal precipitated by filtration. The 
crystal obtained was washed with water and methanol in this sequence to 
give 1.5 g (yield 70.6 of the title compound. 
m.p.: &gt;290.degree. C. 
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 12.03(1H, brs), 8.41(1H, d, J=8 Hz), 
8.36(1H, d, J=7 Hz), 7.70-7.17(5H, m), 2.44(3H, s) 
IR(KBr)cm.sup.-1 : 3440, 1711, 1643, 1599, 1580, 1543, 1481, 1465, 1437, 
1404. 
&lt;Reference example 6&gt; 
Synthesis of 6-chloro-3-methyl-7H-indeno2,1-c!quinoline-7-on 
A mixture of 3-methyl-5H-indeno2,1-c!quinoline-6,7-dion obtained in 
reference example 5 (700 mg, 2.7 mmol) and phosphorous oxychloride (10 ml, 
107 mmol) was refluxed with heat for 1.5 hours. The reaction mixture was 
distilled to dryness. To the residue was added water to obtain a crystal 
precipitated by filtration. The crystal obtained was washed with water and 
dissolved in chloroform to filter off undissolved substances. 
Recrystallization from benzene to give 550 mg (yield 73.4%) of the title 
compound. 
m.p.: 208.degree.-211.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.38(1H, d, J=9 Hz), 8.13(1H, d, J=7 Hz), 
7.85(1H, s), 7.80(1H, d, J=6 Hz), 7.64(1H, d-d-d, J=8,8,1 Hz), 
7.56-7.50(2H, m), 2.60(3H, s). 
IR(KBr)cm.sup.-1 : 1718, 1623, 1557, 1494, 1460, 1413, 1064, 915, 867, 755, 
715. 
&lt;Reference example 7&gt; 
Synthesis of 1,3-dioxo-3,-methoxy-2-indancarboxyanilide 
To a suspension of 2-ethoxycarbonyl-1,3-indandione (2.7 g, 12.5 mmol) in 
toluene (100 ml) was added m-anisidine (1.7 g, 13.8 mmol) and the mixture 
was refluxed with heat for 0.5 hour. About half amount of the solvent was 
distilled off to obtain a crystal precipitated by filtration. The crystal 
obtained was recrystallized from ethanol to give 1.7 g (yield 46.0%) of 
the title compound. 
m.p.: 128.degree.-138.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 9.52(1H, brs), 7.70-7.55(4H, m), 7.31(1H, 
d, J=8 Hz), 7.17(1H, d-d, J=2, 2 Hz), 7.10-6.74(2H, m), 3,84(1H, s). 
IR(KBr)cm.sup.-1 : 1658, 1604, 1584, 1563, 1537, 1496, 1455, 1416. 
&lt;Reference example 8&gt; 
Synthesis of 3-methoxy-5H-indeno2,1-c!quinoline-6,7-dion 
A mixture of 1,3-dioxo-3'-methoxy-2-indancarboxyanilide (1.6 g, 5.4 mmol) 
obtained in reference example 7 and polyphosphoric acid (18 g) was reacted 
at 120.degree. C. for 1.5 hours. The reaction mixture was poured into ice 
water to obtain a crystal precipitated by filtration. The crystal obtained 
was washed with tetrahydrofuran to give 1.0 g (yield 66.6%) of the title 
compound. 
m.p.: 236.degree.-246.degree. C. (decomp.) 
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 8.48(1H, d, J=9 Hz), 8.35(1H, d, J=7 
Hz), 7.71-7.55(3H, m), 6.99-6.92(2H, m), 3.90(3H, s) 
IR(KBr)cm.sup.-1 : 1705, 1640, 1621, 1585, 1480, 1415, 1394 
&lt;Reference example 9&gt; 
Synthesis of 6-chloro-3-methoxy-7H-indeno2,1-c!quinoline-7-on 
A mixture of 3-methoxy-5H-indeno2,1-c!quinoline-6,7-dion (550 ml, 2.0 
mmol) obtained in reference example 8 and phosphorous oxychloride (20 ml, 
214 mmol) was refluxed with heat in the presence of catalytic amount of 
N,N-dimethylformamide for 4 hours. The reaction mixture was distilled to 
dryness. To the residue was added water to obtain a crystal precipitated 
by filtration. The crystal obtained was dissolved in chloroform to filter 
off undissolved substances. Recrystallization from benzene gave 460 mg 
(yield 78.4%) of the title compound. 
m.p.: 261.degree.-266.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.39(1H, d, J=9 Hz), 8.11(1H, d, J=8 Hz), 
7.81(1H, m), 7.64(1H, d-d-d, 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.sup.-1 : 1706, 1618, 1564, 1496, 1474, 1464, 1428, 1208, 1186, 
1157, 1122, 1060, 1012. 
&lt;Reference example 10&gt; 
Synthesis of 1,2-dihydro-7-methoxy-4-phenyl-2-oxo-3-quinoline carboxylic 
acid ethyl ester 
A mixture of 2-amino-4-methoxybenzophenone (20 g, 88 mmol), diethylmalonate 
(26.7 ml, 176 mmol), 1,8-diazabicyclo5,2,0!-undeca-7-en (DBU) (0.66 ml, 
4.4 mmol) was stirred with heat at 160.degree. C. for 2 hours. The 
reaction mixture was cooled by air. To the cooled mixture was added 
ethanol (30 ml) to obtain a precipitated crystal by filtration. The 
crystal obtained was washed with ethanol to give 25.7 g (yield: 90.2%) of 
the title compound. 
m.p.: 175.degree.-177.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 12.60(1H, brs), 7.48-7.35(5H, m), 
7.18(1H, d, J=9 Hz), 6.91(1H, d, J=3 Hz), 6.72(1H, d-d, J=9,3 Hz), 
4.08(2H, q, J=7 Hz), 3.90(3H, s), 0.97(3H, t, J=7 Hz) 
IR(KBr)cm.sup.-1 : 2980, 2940, 1735, 1642, 1597, 1516, 1238, 1213, 1094. 
&lt;Reference example 11&gt; 
Synthesis of 1,2-dihydro-7-methoxy-4-phenyl-2-oxo-3-quinoline carboxylic 
acid 
A 3.0 g of 1,2-dihydro-7-methoxy-4-phenyl-2-oxo-3-quinoline carboxylic acid 
ethyl ester obtained in reference example 10 was reacted and treated in 
the same procedure as reference example 1, and washed with ethanol to give 
2.7 g (yield: 99.0%) of the title compound. 
m.p.: 292.degree.-294.degree. C. 
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 13.23(1H, s), 12.25(1H, s), 
7.54-7.44(3H, m), 7.31-7.27(2H, m), 6.99-6.90(2H, m), 6.80(1H, m), 
3.83(3H, s). 
IR(KBr)cm.sup.-1 : 3170, 1731, 1625, 1476, 1403, 1243, 1212, 847. 
&lt;Reference example 12&gt; 
Synthesis of 6-chloro-3-methoxy-7H-indeno2,1-c!quinoline-7-on (another 
method) 
Said 1,2-dihydro-7-methoxy-4-phenyl-2-oxo-3-quinoline carboxylic acid 
obtained in reference example 11 was reacted and treated in the same 
procedure as reference example 2 to give the title compound. The 
physicochemical properties of the compound obtained corresponded to those 
of reference example 9. 
&lt;Reference example 13&gt; 
Synthesis of 6-chloro-3-hydroxy-7H-indeno2,1-c!quinoline-7-on 
A mixture of 6-chloro-3-methoxy-7H-indeno2,1-c!quinoline-7-on (10.0 g, 
33.8 mmol) obtained in reference example 9 and 100 ml of conc. sulfuric 
acid was stirred with heat at 160.degree. C. for 2 hours. The reaction 
mixture was poured into ice water to obtain a crystal precipitated by 
filtration. The crystal obtained was washed with water and ethanol in this 
sequence to give 8.5 g (yield 89.4%) of the title compound. 
m.p.: &gt;300.degree. C. 
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 11.18(1H, brs), 8.66(1H, d, J=9 Hz), 
8.43(1H, d, J=8 Hz), 7.77-7.59(3H, m), 7.35(1H, d-d, J=9,2 Hz), 7.23(1H, 
d, J=2 Hz). 
IR(KBr)cm.sup.-1 : 3110, 1711, 1623, 1610, 1461, 1435, 1398, 1179, 1067, 
750. 
&lt;Reference example 14&gt; 
Synthesis of 3-benzyloxy-6-chloro-7H-indeno2,1-c!quinoline-7-on 
To a suspension of 6-chloro-3-hydroxy-7H-indeno2,1-c!quinoline-7-on (500 
mg, 1.8 mmol) obtained in reference example 13 and potassium carbonate 
(300 mg, 2.1 mmol) in N,N-dimethylformamide (5 ml) was added 
benzylchloride (247 mg, 2.0 mmol) and the mixture was stirred at 
90.degree. C. for 3 hours. The reaction mixture was poured into ice water 
to obtain a crystal precipitated by filtration. The crystal obtained was 
washed with water and 2-propanol in this sequence to give 610 mg (yield 
92.4%) of the title compound. 
m.p.: 212.degree.-214.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.40(1H, d, J=9.5 Hz), 8.10(1H, d, J=7.5 
Hz), 7.80(1H, d, J=7.5 Hz), 7.67-7.31(9H, m), 5.24(2H, s) 
IR(KBr)cm.sup.-1 : 3090, 1711, 1623, 1570, 1461, 1435, 1397, 1179, 1067, 
750. 
&lt;Reference example 15&gt; 
Synthesis of 1,2-dihydro-4-phenyl-1-oxo-3-isoquinoline carboxylic acid 
To a methanol (50 ml) solution of 4-phenylisocoumaline-3-carboxylic acid 
(36.2 g, 136 mmol) was added 100 ml of saturated ammonia in methanol 
solution, and the mixture was stirred at room temperature for 8 hours. The 
mixture was distilled to remove solvent. To the residue was added 300 ml 
of methanol and 100 ml of 4N-hydrochloride in ethyl acetate solution to 
acidify the mixture. Solvent was removed by distillation. Water was added 
to the residue to obtain a crystal precipitated by filtration. The crystal 
obtained was recrystallized from ethanol-water to give 32.0 g (yield: 
88.7%) of the title compound. 
m.p.: &gt;300.degree. C. 
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 13.53(1H, brs), 11.11(1H, brs), 
8.32(1H, d, J=8 Hz), 7.72-7.26(7H, m), 7.10(1H, d, J=8 Hz). 
IR(KBr)cm.sup.-1 : 3160, 1704, 1656, 1643, 1622, 1606, 1598, 1468, 1446, 
1307, 761, 706 
&lt;Reference example 16&gt; 
Synthesis of 6H-indeno2,1-c!isoquinoline-5,7-dion 
A mixture of 1,2-dihydro-4-phenyl-1-oxo-3-isoquinoline carboxylic acid (32 
g) obtained in reference example 15 and polyphosphoric acid (300 g) was 
reacted at 100.degree. C. for 5 hours. The reaction mixture was poured 
into ice water to obtain a crystal precipitated by filtration. The crystal 
obtained was washed with ethyl acetate to give 26.6 g (yield 89.2%) of the 
title compound. 
m.p.: &gt;300.degree. C. 
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 12.18(1H, brs), 8.40-8.35(2H, m), 
7.94-7.88(2H, m), 7.73(1H, d-d, J=8,8 Hz), 7.54-7.46(2H, m), 7.24(1H, d-d, 
J=7,7 Hz). 
IR(KBr)cm.sup.-1 : 3060, 1716, 1681, 1645, 1620, 1604, 1598, 1588, 1462, 
1328, 716. 
&lt;Reference example 17&gt; 
Synthesis of 5-chloro-7H-indeno2,1-c!isoquinoline-7-on 
A mixture of 6H-indeno2,1-c!isoquinoline-5,7-dion obtained in reference 
example 16 (26.6 g, 108 mmol) and phosphorous oxychloride (300 ml) was 
refluxed with heat in the presence of 1 ml of N,N-dimethylformamide for 2 
hours. The reaction mixture was distilled to dryness. To the residue was 
added ice water to obtain a crystal precipitated by filtration. The 
crystal obtained was washed with water and recrystallized from toluene to 
give 22.5 g (yield 78.7%) of the title compound. 
m.p.: 242.degree.-244.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.51-8.47(2H, m), 7.99-7.82(3H, m), 
7.74(1H, d, J=7 Hz), 7.59(1H, d-d, J=8,8 Hz), 7.40(1H, d-d, J=8,7 Hz ). 
IR(KBr)cm.sup.-1 : 1738, 1722, 1615, 1602, 1461, 1412, 1347, 1253, 765, 
713, 682, 616. 
&lt;Reference example 18&gt; 
The following compounds were synthesized by employing compounds of 
reference examples 1-17. 
* 2,6-dichloro-7H-indeno2,1-c!quinoline-7-on 
m.p.: 282.degree.-284.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.46(1H, d, J=8 Hz), 8.11(1H, d, J=7 Hz), 
8.03(1H, d, J=9 Hz), 7.84-7.79(2H, m), 7.69(1H, d-d-d, J=8,8,1 Hz), 
7.57(1H, d-d, J=7,7 Hz). 
* 6-chloro-2-methoxy-7H-indeno2,1-c!quinoline-7-on 
m.p.: 261.degree.-262.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.06(1H, d, J=8 Hz), 8.00(1H, d, J=9 Hz), 
7.82(1H, d, J=7 Hz), 7.68-7.50(4H, m), 4.06(3H, s). 
* 6-chloro-2-nitro-7H-indeno2,1-c!quinoline-7-on 
m.p.: &gt;300.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 9.47(1H, d, J=2 Hz), 8.64(1H, d-d, J=9,2 
Hz), 8.25(1H, d, J=8 Hz), 8.24(1H, d, J=9 Hz), 7.88(1H, d, J=7 Hz), 
7.78(1H, d-d-d, J=8,8,1 Hz), 7.64(1H, d-d, J=8,8 Hz). 
* 6-chloro-2,3-methylenedioxy-7H-indeno2,1-c!quinoline-7-on 
m.p.: &gt;300.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.02(1H, d, J=8 Hz), 7.81(1H, d, J=7 Hz), 
7.72(1H, s), 7.64(1H, d-d-d, 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-indeno2,1-c!quinoline-7-on 
m.p.: 300.degree.-302.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.00(1H, d, J=7 Hz), 7.82(1H, d, J=7 Hz), 
7.65(1H, d-d, J=8,8 Hz), 7.61(1H, s), 7.52(1H, d-d, J=8,7 Hz), 7.41(1H, 
s), 4.14(3H, s), 4.07(3H, s). 
* 6-chloro-3-fluoro-7H-indeno2,1-c!quinoline-7-on 
m.p.: 257.degree.-259.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 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-indeno2,1-c!quinoline-7-on 
m.p.: 298.degree.-300.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.31(1H, d, J=9 Hz), 7.98(1H, d, J=9 Hz), 
7.37(1H, d, J=3 Hz), 7.33(1H, d, J=3 Hz), 7.29(1H, d-d, J=9,3 Hz), 
7.08(1H, d-d, J=8,3 Hz), 3.99(3H, s), 3.94(3H, s). 
* 3,6-dichloro-7H-indeno2,1-c!quinoline-7-on 
m.p.: 250.degree.-252.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.40(1H, d, J=9 Hz), 8.07(1H, d, J=9 Hz), 
8.05(1H, s), 7.80(1H, d, J=7 Hz), 7.69-7.52(3H, m). 
* 3-benzyloxy-6-chloro-9,10-methylenedioxy-7H-indeno2,1-c!quinoline-7-on 
m.p.: 241.degree.-243.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 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-indeno2,1-c!quinoline-7-on 
m.p.: &gt;300.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.22(1H, d, J=9 Hz), 7.53(1H, s), 
7.36(1H, d, J=3 Hz), 7.30(1H, d, J=3 Hz), 7.23(1H, s). 6.16(2H, s), 
3.98(3H, s). 
* 6-chloro-8-methoxy-7H-indeno2,1-c!quinoline-7-on 
m.p.: 259.degree.-260.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.48(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz), 
7.84(1H, d-d-d, J=8,7,1 Hz), 7.77(1H, d, J=8 Hz), 7.67(1H, d-d-d, J=8,7,1 
Hz), 7.60(1H, d-d, J=9,8 Hz), 7.09(1H, d, J=9 Hz), 4.04(3H, s). 
* 6-chloro-8-hydroxy-7H-indeno2,1-c!quinoline-7-on 
m.p.: 240.degree.-241.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.83(1H, s), 8.46(1H, d, J=9 Hz), 
8.09(1H, d, J=9 Hz), 7.88(1H, d-d-d, J=7,7,1 Hz), 7.73-7.65(2H, m), 
7.52(1H, d-d, J=9,7 Hz), 7.03(1H, d, J=9 Hz), 
* 6-chloro-9-methoxy-7H-indeno2,1-c!quinoline-7-on 
m.p.: 210.degree.-212.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 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=8,7,1 Hz), 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-indeno2,1-c!quinoline-7-on 
m.p.: 255.degree.-256.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 8.43(1H, d, J=9 Hz), 8.08(1H, d, J=9 Hz), 
7.86(1H, d-d-d, J=9,7,1 Hz), 7.76(1H, d, J=8 Hz), 7.69(1H, d-d-d, J=8,7,1 
Hz), 7.65(1H, d, J=2 Hz) 6.94(1H, d-d, J=8,2 Hz), 3.99(3H, s), 
* 6-chloro-10-hydroxy-7H-indeno2,1-c!quinoline-7-on 
m.p.: &gt;300.degree. C. 
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 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-dibenzoc,i!fluorene-13-on 
m.p.: 258.degree.-261.degree. C. 
.sup.1 H-NMR(CDCl.sub.3) .delta.: 9.00(1H, d, J=8 Hz), 8.53(1H, d, J=9 Hz), 
8.22(1H, d, J=9 Hz), 8.09(1H, d, J=8 Hz), 8.03(1H, d, J=9 Hz), 7.81(1H, d, 
J=8 Hz), 7.71-7.47(4H, m).