JPH05306284A - Indoloquinoline derivative - Google Patents

Abstract

PURPOSE:To provide the subject new compound having high antitumor activity and low toxicity and useful as an antitumor agent. CONSTITUTION:The compound of formula I (R<1> and R<2> are H, OH or lower alkoxy provided that R<1> and R<2> are not H at the same time) or its salt, e.g. N-[4-N-(4-methoxy-10H-indolo[3,2-b]quinolin-11-yl)amino-3-methoxyphenyl) methanesulfonamide. The compound can be produced e.g. by reacting 2-amino-3- methoxybenzoic acid of formula II with chloroacetyl chloride in dry benzene at 80-90 deg.C, aminating the product with aniline, subjecting the produced intermediate of formula III to intramolecular condensation under heating in the presence of a polyphosphoric acid, reacting the resultant intermediate with phosphorus oxychloride under refluxing and aminating the obtained intermediate of formula IV with N-(4-amino-2-methoxyphenyl)methanesulfonamide hydrochloride of formula V.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is an invention useful in the field of medicine, and more particularly to a novel indoloquinoline derivative having antitumor activity and low toxicity.

[0002]

2. Description of the Related Art Conventionally, various drugs such as antibiotics, hormones, and nucleic acid metabolism inhibitors have been used as antitumor agents. However, although many of these antitumor agents exert a tentative antitumor effect by attacking cancer cells, they are difficult to use for a long period of time due to their strong toxicity, and if complete treatment of tumors is not possible. If not, there are many cases.

For example, as a compound having an antitumor activity by intercalating deoxyribonucleic acid (DNA), indolo [3,2-
b] Quinoline derivative (II):

[0004]

[Chemical 3]

Has been reported (Chem. Pharm.Bul
l.), 38 , 3048 (1990) and journals
Of Medicinal Chemistry (J.Med. Chem.), 3
2 , 1295 (1989)).

However, the antitumor activity of this compound (II) is not sufficient, and there is a problem in terms of toxicity, so that it is not effective yet.

[0007] Therefore, today, with satisfactory efficacy, there is no problem in terms of toxicity, that is, there is a sufficiently large difference between the dose at which antitumor activity is expressed and the dose at which toxicity is expressed, and a complete cure is achieved. The development of new antitumor agents that can bring about the above is awaited.

The present inventors have conducted extensive studies to solve the above-mentioned problems, and as a result, the indoloquinoline derivative (II)
It was found that, surprisingly, a novel compound in which a lower alkoxy group or a hydroxyl group is introduced shows remarkable antitumor activity and a high cure rate as compared with conventional indoloquinoline derivatives, and is extremely useful clinically. The present invention has been completed.

[0009]

The present invention has the general formula (I):

[0010]

[Chemical 4]

(In the formula, R ¹ and R ² are each independently a hydrogen atom, a hydroxyl group or a lower alkoxy group;
R ¹ and R ² are not both hydrogen atoms) or a pharmacologically acceptable salt thereof.

The present invention also relates to an antitumor agent containing the above compound as an active ingredient.

[0013]

EXAMPLES In the indoloquinoline derivative represented by the general formula (I) of the present invention, R ¹ and R ² are each independently a hydrogen atom, a hydroxyl group or a lower alkoxy group.
Neither ¹ nor R ² becomes a hydrogen atom. The lower alkoxy group has 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group and a propoxy group.

The substitution positions of R ¹ and R ² are not particularly limited, but it is preferable that R ¹ is substituted at the 4-position and R ² is substituted at the 7-position.

Among the compounds of the present invention represented by the general formula (I), a particularly preferred compound is N- [4-N-
(4-Methoxy-10H-indolo [3,2-b] quinolin-11-yl) amino-3-methoxyphenyl] methanesulfonamide, N- [4-N- (4-hydroxy-10-indolo [3,3. 2-b] quinolin-11-yl) amino-3-methoxyphenyl] methanesulfonamide, N- [4-N- (7-methoxy-10H-indolo [3,2-b] quinolin-11-yl) amino. -3-
Methoxyphenyl] methanesulfonamide, N- [4-
N- (7-hydroxy-10-indolo [3,2-b]
And quinolin-11-yl) amino-3-methoxyphenyl] methanesulfonamide.

The compound of the present invention represented by the general formula (I) may be in the form of a pharmacologically acceptable salt. The salt is not particularly limited, but hydrochloric acid, hydrobromic acid,
Acid addition salts of mineral acids such as hydroiodic acid and sulfuric acid, acid addition salts of sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid and benzenesulfonic acid, or acetic acid, phosphoric acid, oxalic acid, maleic acid , Acid addition salts of organic acids such as tartaric acid, citric acid, gluconic acid, and lactic acid.

The compound of the present invention represented by the general formula (I) is produced, for example, by the following method.

Process A Of the compounds of the present invention represented by the general formula (I), N-
[4-N- (4-methoxy-10H-indoloquinolin-11-yl) amino-3-methoxyphenyl] methanesulfonamide hydrochloride (Compound of Example 1), N- [4
-N- (4-hydroxy-10H-indolo [3,2-
b] Quinolin-11-yl) amino-3-methoxyphenyl] methanesulfonamide hydrochloride (Compound of Example 2) and its intermediate can be produced by the method shown in the following figure.

[0019]

[Chemical 5]

The intermediate 3-methoxy-2 [(N-phenylamino) acetamido] benzoic acid is 2-amino-3-
Obtained by chloroacetylation of methoxybenzoic acid, followed by amination with aniline. The intermediate 11-chloro-4-methoxy-10H-indolo [3,2-b] quinoline was prepared by converting the intermediate 3-methoxy-2-[(N-phenylamino) acetamido] benzoic acid into polyphosphoric acid (PP).
It can be produced by intramolecular condensation with A) under heating and then treatment with phosphorus oxychloride. Intermediate 11-
Chloro-4-hydroxy-10H-indolo [3,2-
b] quinoline is 11-chloro-4-methoxy-10H
It can be prepared by heating indolo [3,2-b] quinoline with 47% hydrobromic acid.

The compounds of Examples 1 and 2 correspond to the intermediates 11-chloro-4-methoxy-10H-indolo [3,2-b] quinoline and 11-chloro-4-hydroxy-10H-indolo [3. 2-b] Quinoline is N
It can be produced by amination with-(4-amino-2-methoxyphenyl) methanesulfonamide hydrochloride.

That is, the intermediate 3-methoxy-2 [(N-
Phenylamino) acetamido] benzoic acid can be obtained by refluxing 2-amino-3-methoxybenzoic acid in chloroacetyl chloride and dry benzene for 4 hours to obtain 2-chloroacetamido-3-methoxybenzoic acid in dry dimethylformamide. It can be produced by reacting at 80 to 90 ° C. for 6 hours.

Intermediate 11-chloro-4-methoxy-10
H-indolo [3,2-b] quinoline is obtained by reacting 3-methoxy-2 [(N-phenylamino) acetamido] benzoic acid with polyphosphoric acid at 120 ° C. for 2 hours.
It can be produced by refluxing methoxy-5H, 10H-indolo [3,2-b] quinolin-11-one with phosphorus oxychloride for 2 hours.

Intermediate 11-chloro-4-hydroxy-1
OH-indolo [3,2-b] quinoline is produced by refluxing 11-chloro-4-methoxy-10H-indolo [3,2-b] quinoline with a 47% aqueous hydrobromic acid solution for 10 hours. You can The compounds of Examples 1 and 2 are intermediates 11-chloro-4-methoxy-
10H-indolo [3,2-b] quinoline and 11-
Chloro-4-hydroxy-10H-indolo [3,2-
b] It can be produced by refluxing quinoline and N- (4-amino-2-methoxyphenyl) methanesulfonamide hydrochloride in ethoxyethanol for 4 hours.

Process B Of the compounds of the present invention represented by the general formula (I), N-
[4-N- (7-methoxy-10H-indolo [3,2
-B] quinolin-11-yl) amino-3-methoxyphenyl] metalsulfonamide hydrochloride (compound of Example 3), N- [4-N- (7-hydroxy-10H-indolo [3,2-b] ] Quinoline-11-yl) amino-3
-Methoxyphenyl] metalsulfonamide hydrochloride (Compound of Example 4) and its intermediate can be produced by the method shown in the following figure.

[0026]

[Chemical 6]

Intermediate 2-{[N-benzyl-N- (4-
Methoxyphenyl) amino] acetamido} benzoic acid is a combination of 2-chloroacetamidobenzoic acid and N-benzyl-benzoic acid.
Obtained by heating p-anisidine in dimethylformamide. The intermediate 11-chloro-7-methoxy-10H-indolo [3,2-b] quinoline is an intermediate 2-{[N-benzyl-N- (4-methoxyphenyl)
Amino] acetamide} benzoic acid to polyphosphoric acid (PP
It can be produced by intramolecular condensation with A) under heating and then treatment with thionyl chloride or phosphorus oxychloride. Intermediate 11-chloro-7-hydroxy-10H-
Indolo [3,2-b] quinoline is 11-chloro-7
It can be produced by heating -methoxy-10H-indolo [3,2-b] quinoline and pyridinium chloride.

The compounds of Examples 3 and 4 are intermediates 11-chloro-7-methoxy-10H-indolo [3,2-b] quinoline and 11-chloro-7-hydroxy-10H-indolo [3,3. 2-b] Quinoline is N
It can be produced by amination with-(4-amino-2-methoxyphenyl) methanesulfonamide hydrochloride.

That is, the intermediate 2-{[N-benzyl-N
-(4-Methoxyphenyl) amino] acetamide} benzoic acid is obtained by mixing 2-chloroacetamidobenzoic acid and N-benzyl-p-anisidine in dry dimethylformamide.
It can be produced by reacting at 80 to 90 ° C. for 6 hours.

Intermediate 11-chloro-7-methoxy-10
H-indolo [3,2-b] quinoline is an intermediate 2-
{[N-benzyl-N- (4-methoxyphenyl) amino] acetamido} benzoic acid was added to polyphosphoric acid at 120-15.
7-Methoxy-5H, 10H-indolo [3,2-b] quinoline-1 obtained by reacting at 0 ° C. for 5 hours
It can be prepared by reacting 1-one with thionyl chloride or phosphorus oxychloride in dry dimethylformamide for 10 hours at room temperature.

Intermediate 11-chloro-7-hydroxy-1
OH-indolo [3,2-b] quinoline is produced by reacting 11-chloro-7-methoxy-10H-indolo [3,2-b] quinoline with pyridinium chloride at 170 to 180 ° C for 3 hours. You can

The compounds of Examples 3 and 4 are intermediates 11-chloro-7-methoxy-10H-indolo [3,2-b] quinoline and 11-chloro-7-hydroxy-10H-indolo [3,3. 2-b] quinoline and N
It can be produced by refluxing-(4-amino-2-methoxyphenyl) methanesulfonamide hydrochloride in ethoxyethanol for 4 hours.

The compounds of the present invention have good antitumor activity (deoxyribonucleic acid (DNA)), as shown in the Examples below.
Intercalating property). The dose may be administered to patients in need of treatment (animals and humans) as long as it does not show toxicity, but it is preferably in the range of 1 to 500 mg / kg, and generally in the range of several doses. It can be administered once and thus in a total daily dose of 10-200 mg / kg per day. The dose can be changed depending on factors such as symptoms.

The antitumor agent of the present invention is prepared as a solid preparation or a liquid preparation and administered orally or parenterally.
Solid formulations for oral administration include powders, granules, tablets, pills,
Liquid formulations for parenteral and oral use, such as capsules,
It can be used in the form of elixirs, suspensions, emulsions, syrups, alcohol solutions, oil solutions and the like.

Examples of solid pharmaceutical carriers include lactose, starch, sucrose, mannitol, sorbit, dextrin, cellulose, calcium carbonate, etc., and if necessary, suitable lubricants, binders and other auxiliary agents are added. can do. Pharmaceutical liquid carriers include water, ethanol, glycerin, propylene glycol, vegetable oils, common solvents such as oily esters, and if necessary, suitable wetting agents, suspending agents, emulsifiers, sweeteners, flavors, preservatives, etc. Auxiliary agents can be added.

Hereinafter, the pharmacological action and synthesis of the compound of the present invention will be described in detail with reference to specific examples, but the present invention is not limited to such examples.

Test Example 1 In the test of antitumor activity, the effect on p-388 mouse leukemia was determined by the protocol (Cancer) of the US National Cancer Institute.
The test was performed according to the Chemotherapy Report (Cancer Chemother Rep.), Part 3, 3, 11, and 1972). p
-388 murine leukemia cells 10 ⁶ cells were implanted into the abdominal cavity of CDF1 mice, and the test compound was administered intraperitoneally the day after tumor implantation and 5 days later. The effect was determined by the median survival of each of the administration group (T) and the control group (C).
time) was calculated and expressed as T / C, and T / C of 1.25 or higher was regarded as effective. The cured animals were determined on the 30th day of tumor implantation. As a control compound, N- [4-N-
Similar tests were conducted for (10H-indolo [3,2-b] quinolin-11-yl) amino-3-methoxyphenyl] methanesulfonamide hydrochloride and amsacrine. The results are shown in Table 1.

[0038]

[Table 1]

Among the six compounds tested this time, the highest activity was observed for the compound of Example 4.

The compound of the present invention showed a far superior therapeutic effect than the control compound, and 3 to 5 out of 6 treated animals which were not observed with amsacrine were observed.

From these results, it was shown that the compound of the present invention has remarkably high activity and high cure rate.

The toxicity of the compound of the present invention was reduced to 1/4 or less of that of the control compound.

The production examples of the compound of the present invention will be described below.
In each of the examples, the melting point was measured with a Yanagimoto micro melting point measuring instrument and is uncorrected. ¹ H-nuclear magnetic resonance ( ¹ H-NMR) spectrum is Hitachi R-24 spectrometer (60 MHz)
Was measured using Me ₄ Si as an internal standard. FAB-
MS is a VG-70SE spectrometer (VG Analyti
The infrared (IR) absorption spectrum is JA
It was measured with a SCOA-102 spectrometer (manufactured by JASCO Corporation).

Reference Example 1 11-chloro-4-methoxy-
10H-indolo [3,2-b] quinoline (1) 2-chloroacetamido-3-methoxybenzoic acid

[0045]

[Chemical 7]

Chloroacetyl chloride (0.4 ml, 20 mm
2-amino-3-methoxybenzoic acid (3.50 g, 20
mmol) in dry benzene (40 ml) was added dropwise at room temperature. The reaction mixture was heated to reflux for 4 hours. After cooling to room temperature, the formed precipitate was collected by filtration and recrystallized from a mixed solution of n-hexane and benzene to obtain 4.80 g (90%) of the title compound as a yellow crystal.

Melting point: 131-132 ° C. ¹ H-NMR (CDCl ₃ + DMSO-d ₆ ) δ _ppm :
3.83 (3H, s, OCH ₃ ), 4.20 (2H, s, CH ₂
Cl), 6.97 to 7.60 (3H, m), 9.33 (1H, br,
NH), 10.41 (1H, br, COOH) Elemental analysis: Calculated value (C ₁₀ H ₁₀ ClNO ₄ ) Actual value C, 49.30 C, 49.19 H, 4.14 H, 4.05 N, 5.75 N, 5.48 (2) 3-methoxy -2-[(N-phenylamino) acetamide] benzoic acid

[0048]

[Chemical 8]

2-chloroacetamido-3-methoxybenzoic acid (4.5 g, 19 mmol), distilled aniline (6 ml, 50 mm)
ol) and dry dimethylformamide (DMF) (6 m
The mixture of l) was heated and reacted at 80 to 90 ° C. for 4 hours. The reaction mixture is cooled to room temperature and poured into ice water, then 10%
It was made alkaline with KOH solution and extracted with methylene chloride. The aqueous layer was neutralized with a 10% hydrochloric acid solution, and the formed precipitate was collected by filtration to obtain 3.1 g (56%) of the title compound as yellow crystals.

Melting point: 125 to 127 ° C. IR (nujol): 3300, 1680 cm ^{−1 1} H-NMR (CDCl ₃ + DMSO-d ₆ ) δ _ppm :
3.67 (3H, s, OCH ₃ ), 3.76 (2H, s, C
_{H 2), 6.43~6.74 (3H,} m), 6.85~7.44 (5H,
m), 9.10 (1 H, br, NH) Elemental analysis value: Calculated value (C ₁₆ H ₁₆ N ₂ O ₄ ) Actual value C, 63.99 C, 63.93 H, 5.37 H, 5.19 N, 9.33 N, 9.09 (3) 11-chloro-4-methoxy-10H-indolo [3,2-b] quinoline (V)

[0051]

[Chemical 9]

3-Methoxy-2-[(N-phenylamino) acetamido] benzoic acid (1.50 g, 5.00 mmol) and P
The mixture of PA (50 g) was stirred mechanically with 120-13
The mixture was heated and reacted at 0 ° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into ice water, and made alkaline with a saturated potassium bicarbonate solution. The precipitate formed is filtered off, then washed with water,
Dried to 4-methoxy-5H, 10H-indolo [3,3
0.72 g (50%) of 2-b] quinolin-11-one was obtained.

4-Methoxy-5H, 10H-indolo [3,2-b] quinolin-11-one (0.72 g, 2.45 mm)
ol) and phosphorus oxychloride (7 ml) were heated to reflux for 2 hours. Excess phosphorus oxychloride was removed, then the residue was made alkaline with saturated potassium bicarbonate solution and extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. After evaporation of the solvent, 350 mg (61%) of the title compound was obtained.

Melting point: 220-224 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 4.03 (3 H, s,
_{OCH 3), 6.75~7.93 (6H,} m), 8.45 (1H,
d, J = 8 Hz), 11.68 (1H, br, NH) FAB-MS (positive ion mode) m / z: 285 [(M +
1) ⁺ +2], 283 [(M + 1) ⁺ ] Elemental analysis: Calculated value (C ₁₆ H ₁₁ ClN ₂ O) Measured value C, 67.97 C, 67.99 H, 3.92 H, 3.95 N, 9.91 N, 9.95 Reference Example 2 11-chloro-4-hydroxy-10H-indolo [3,2-b] quinoline

[0055]

[Chemical 10]

11-chloro-4-methoxy-10H-indolo [3,2-b] quinoline (200 mg, 0.71 mmol) and 47
A mixture of% hydrobromic acid aqueous solution (10 ml) was heated under reflux for 10 hours and evaporated to dryness under reduced pressure. The remaining solid was dissolved in boiling water and made alkaline with saturated potassium bicarbonate solution. The precipitate was collected by filtration and recrystallized from a mixed solution of methylene chloride and methanol to give 180 mg (94%) of the title compound.

Melting point: 181-183 ° C. (decomposition) IR (nujol): 3400, 3340 cm ^{-1 1} H-NMR (DMSO-d ₆ + CDCl ₃ ) δ: 7.00
~ 7.87 (6H, m), 8.42 (1H, d, J = 8Hz),
9.20 (1H, br, OH), 11.50 (1H, br, N)
H) FAB-MS (positive ion mode) m / z: 271 [(M +
1) ⁺ +2], 269 [(M + 1) ⁺ ] Elemental analysis: Calculated value (C ₁₅ H ₉ ClN ₂ O) Measured value C, 67.05 C, 67.01 H, 3.38 H, 3.39 N, 10.43 N, 10.64 Reference Example 3 11-chloro-7-methoxy-10H-indolo [3,2-b] quinoline (1) 2-{[N-benzyl-N- (4-methoxyphenyl) amino] acetamide} benzoic acid

[0058]

[Chemical 11]

2-chloroacetamide benzoic acid (5.33
g, 25 mmol), N-benzyl-p-anisidine (6.50
g, 50 mmol) and dry DMF (6 ml) 100
The mixture was heated at 12 ° C for 12 hours. The reaction mixture was cooled to room temperature, poured into ice water, then made alkaline with 10% KOH solution and extracted with methylene chloride. The aqueous layer was neutralized with a 10% hydrochloric acid solution. The precipitate formed was collected and recrystallized from a mixed solution of chloroform and methanol to give the title compound as yellow crystals.
4.8 g (56%) was obtained.

Melting point: 153-155 ° C. ¹ H-NMR (CDCl ₃ + DMSO-d ₆ ) δ _ppm :
3.67 (3H, s, OCH ₃ ), 4.12 (2H, s, COC
_{H 2), 4.76 (2H,} s, Ar-CH 2), 6.76 (4
H, s), 6.98 to 7.68 (7H, m), 7.87 to 8.26 (1
H, m), 8.50 to 8.86 (1H, m) Elemental analysis: Calculated value (C ₂₃ H ₂₂ N ₂ O ₄ ) Measured value C, 70.75 C, 70.77 H, 5.68 H, 5.44 N, 7.17 N, 7.04 (2 ) 11-Chloro-7-methoxy-10H-indolo [3,2-b] quinoline

[0061]

[Chemical formula 12]

2-{[N-benzyl-N- (4-methoxyphenyl) amino] acetamido} benzoic acid (1.50
A mixture of g, 2.5 mmol) and PPA (50 g) was heated and reacted at 120 to 150 ° C. for 5 hours while stirring. The reaction mixture was poured into ice water and made alkaline with saturated potassium bicarbonate solution. The precipitate formed is filtered off, then washed with water,
After drying 7-methoxy-5H, 10H-indolo [3,2
-B] 0.72 g (50%) of quinolin-11-one was obtained.

7-Methoxy-5H, 10H-indolo [3,2-b] quinolin-11-one (0.72 g, 2.45 mm)
ol), thionyl chloride (2 ml) and dry DMF (8
The reaction mixture was stirred at room temperature for 10 hours to react. Excess thionyl chloride was removed, the reaction mixture was poured into ice water,
It was then made alkaline with saturated potassium bicarbonate solution and extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. After removing the solvent, the residue was chromatographed on silica gel (ethyl acetate: n-hexane =
1: 4) to give 200 mg (61%) of the title compound.

Melting point: 220-224 ° C. ¹ H-NMR (DMSO-d ₆ + D ₂ O) δ _ppm : 3.88
_{(3H, s, OCH 3)} , 7.36~7.79 (5H, m), 7.
94 to 8.42 (2H, m) FAB-MS (positive ion mode) m / z; 285 [(M +
1) ⁺ +2], 283 [(M + 1) ⁺ ] Elemental analysis: Calculated value (C ₁₆ H ₁₁ ClN ₂ O) Measured value C, 69.99 C, 69.97 H, 3.92 H, 3.55 N, 9.91 N, 9.65 Reference Example 4 11-chloro-7-hydroxy-10H-indolo [3,2-b] quinoline

[0065]

[Chemical 13]

A mixture of 11-chloro-7-methoxy-10H-indolo [3,2-b] quinoline (200 mg, 0.71 mmol) and dry pyridinium chloride (1.50 g) was added to the mixture.
Heated at 0-180 ° C for 3 hours. The reaction solution was poured into ice water.
The precipitate formed was collected by filtration and then recrystallized from a mixed solution of methylene chloride and methanol to give 180 mg (94%) of yellow crystals.
%) Of the title compound.

Melting point: 190 to 192 ° C. (decomposition) IR (nujol): 3400 cm ^{−1 1} H-NMR (DMSO-d ₆ + CDCl ₃ ) δ _ppm :
7.17 to 7.56 (5H, m), 7.74 to 8.23 (2H, m) FAB-MS (positive ion mode) m / z; 271 [(M +
1) ⁺ +2], 269 [(M + 1) ⁺ ] Elemental analysis: Calculated value (C ₁₅ H ₉ ClN ₂ O) Measured value C, 67.05 C, 67.24 H, 3.38 H, 3.26 N, 10.43 N, 10.43 Example 1 N- [4-N- (4-methoxy-10H-indolo [3,2-b] quinolin-11-yl) amino-
3-Methoxyphenyl] methanesulfonamide / hydrochloride

[0068]

[Chemical 14]

11-chloro-4-methoxy-10H-indolo [3,2-b] quinoline (480 mg, 1.7 mmol) and 4
-(Methylsulfonyl) amino-2-methoxyaniline
A mixture of (430 mg, 1.87 mmol) was reacted in 2-ethoxyethanol (20 ml) under reflux for 4 hours. After cooling to room temperature, the precipitate was collected by filtration and recrystallized from methanol,
The title compound was obtained as yellow crystals (410 mg, 45
%). The physical properties of the title compound in the free form were as follows.

Melting point: 223-225 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ + CDCl ₃ ) δ _ppm :
2.94 (3H, s, SO ₂ CH ₃ ), 3.89, 4.08 (6H,
S, OCH ₃ × 2), 6.25 to 6.83 (2H, m), 6.
96 to 7.84 (8H, m), 8.54 (1H, d, J = 8Hz) FAB-MS (positive ion mode) m / z; 463 [(M +
1) ⁺ ] Elemental analysis: Calculated value (C ₂₄ H ₂₂ N ₄ O ₄ S) Measured value C, 62.32 C, 62.68 H, 4.80 H, 4.57 N, 12.11 N, 12.32 Example 2 N- [4-N- (4-hydroxy-10H-
Indolo [3,2-b] quinolin-11-yl) amino-3-methoxyphenyl] methanesulfonamide hydrochloride

[0071]

[Chemical 15]

11-chloro-4-hydroxy-10H-
Indolo [3,2-b] quinoline (455mg, 1.7mmol)
And 4- (methylsulfonyl) amino-2-methoxyaniline (430 mg, 1.87 mmol) were reacted in 2-ethoxyethanol under reflux for 4 hours. After cooling to room temperature, the precipitate was collected by filtration and recrystallized from methanol to give the title compound as yellow crystals (434 mg, 57
%). The physical properties of the title compound in the free form were as follows.

Melting point: 178-180 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ + D ₂ O) δ _ppm : 2.90
(3H, s, SO ₂ CH ₃ ), 3.92 (3H, s, OCH
₃ ), 6.35 to 6.79 (2H, m), 6.85 to 7.89 (8H,
m), 8,37 (1 H, d, J = 8 Hz) FAB-MS (positive ion mode) m / z; 448 (M ⁺ ) Elemental analysis: Calculated value (C ₂₃ H ₂₀ N ₄ O ₄ S) Measured value C, 61.59 C, 61.46 H, 4.49 H, 4.57 N, 12.49 N, 12.37 Example 3 N- [4-N- (7-methoxy-10H-indolo [3,2-b] quinolin-11-yl) amino −
3-Methoxyphenyl] methanesulfonamide hydrochloride

[0074]

[Chemical 16]

11-chloro-7-methoxy-10H-indolo [3,2-b] quinoline (485 mg, 1.7 mmol) and 4
-(Methylsulfonyl) amino-2-methoxyaniline
A mixture of (430 mg, 1.87 mmol) was reacted in 2-ethoxyethanol under reflux for 4 hours. After cooling to room temperature,
The precipitate was collected by filtration and recrystallized from methanol to give the title compound as yellow crystals (338 mg, 43%). The physical properties of the title compound in the free form were as follows.

Melting point: 223-225 ° C. IR (nujol): 3460, 3350 cm ^{−1 1} H-NMR (DMSO-d ₆ + CDCl ₃ ) δ _ppm :
2.91 (3H, s, SO ₂ CH ₃ ), 3.96, 3.99 (6H,
s, OCH ₃ × 2), 6.37 (1H, d, J = 8Hz),
6.76 (1H, dd, J = 8.2 Hz), 7.14 (1H, d,
J = 2Hz), 7.22 ~ 7.70 (5H, m), 7.77 ~ 8.28
(2H, m), 8.45 (1H, br, NH), 9.27 (1
H, br, NH) FAB-MS (positive ion mode) m / z; 463 [(M +
1) ⁺ ] Elemental analysis: Calculated value (C ₂₄ H ₂₂ N ₄ O ₄ S) Measured value C, 62.32 C, 62.32 H, 4.80 H, 4.57 N, 12.11 N, 11.87 Example 4 N- [4-N- (7-hydroxy-10H-
Indolo [3,2-b] quinolin-11-yl) amino-3-methoxyphenyl] methanesulfonamide hydrochloride

[0077]

[Chemical 17]

11-chloro-7-hydroxy-10H-
Indolo [3,2-b] quinoline (459mg, 1.7mmol)
And 4- (methylsulfonyl) amino-2-methoxyaniline (430 mg, 1.87 mmol) were reacted in 2-ethoxyethanol under reflux for 4 hours. After cooling to room temperature, the precipitate was collected by filtration and recrystallized from methanol to give the title compound as yellow crystals (343 mg, 45
%). The physical properties of the title compound in the free form were as follows.

Melting point: 178-180 ° C. ¹ H-NMR (DMSO-d ₆ + D ₂ O) δ _ppm : 2.58
(3H, s, SO ₂ CH ₃ ), 3.89 (3H, s, OCH
₃ ), 6.12 (1H, d, J = 8Hz), 6.49 (1H, d
d, J = 8.2 Hz), 6.90 (1H, d, J = 2 Hz),
7.62 ~ 7.91 (2H, m), 8.20 (1H, br, NH),
9.01 (1 H, br, NH) FAB-MS (cation mode) m / z; 448 (M ⁺ ) Elemental analysis: Calculated value (C ₂₃ H ₂₀ N ₄ O ₄ S) Measured value C, 61.59 C, 63.12 H , 4.50 H, 4.32 N, 12.49 N, 12.46

[0080]

The present invention has high antitumor activity,
An indoloquinoline derivative having low toxicity is provided.

Claims (2)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ and R ² are each independently a hydrogen atom, a hydroxyl group, or a lower alkoxy group, provided that R ¹ and R ² are not both hydrogen atoms.) Or an indoloquinoline derivative thereof A pharmacologically acceptable salt. 2. General formula (I): (In the formula, R ¹ and R ² are each independently a hydrogen atom, a hydroxyl group, or a lower alkoxy group, provided that R ¹ and R ² are not both hydrogen atoms.) Or an indoloquinoline derivative thereof An antitumor agent comprising a pharmacologically acceptable salt as an active ingredient.