JPH05140168A - Indolocarbazole derivative and antitumor agent comprising the same as active ingredient - Google Patents

Abstract

PURPOSE:To obtain an antitumor agent having strongly antitumor action by using a new indolocarbozole derivative. CONSTITUTION:An antitumor agent comprising a derivative of formula I (Y and Z are H or O and Y and Z are not H at the same time; R1 and R2 are H, formyl, nitro, OH, etc.) and its pharmaceutically acceptable salt as an active ingredient. For example, a compound wherein Y=0, Z=H2, R1=H and R2=HA in the compound of formula I. The compound of formula I, for example, is obtained by reacting a compound of formula II (R5 and R6 are H, formyl, etc.; R7 is H or beta,beta,beta-trichloroethoxy carbonyl) as a starting raw material with an excessive amount of a chlorine gas as a reagent at room temperature to give a compound of formula III (R2 and R4 are H or formyl), oxidizing the compound at the position to give an oxo derivative of formula IV, converting the derivative to an acid anhydride type compound and eliminating saccharide part.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the following formula (I) having an antitumor effect.

[0002]

[Chemical 5]

An indolocarbazole derivative represented by
The present invention relates to a salt thereof and an antitumor agent containing them as an active ingredient.

[0004]

PRIOR ART The following formula (V)

[0005]

[Chemical 6]

It is already known that rebeccamycin and its analogues represented by the formula (1) have antitumor activity (Japanese Patent Laid-Open Nos. 59-141597 and 63-1).
98695).

[0007]

DISCLOSURE OF THE INVENTION By creating a novel indolocarbazole derivative, a substance having an antitumor effect far superior to that of a conventional antitumor drug and a clinically useful anti-tumor agent containing the substance as an active ingredient It is intended to provide a tumor drug.

[0008]

As a result of intensive studies to solve the above problems, the present inventors have found that the novel indolocarbazole derivative has a strong antitumor effect, and the present invention Has been completed. That is, the invention has the general formula (I)

[0009]

[Chemical 7]

An indolocarbazole derivative represented by
The present invention relates to a pharmaceutically acceptable salt thereof and an antitumor agent containing them as an active ingredient. In the case of acid addition, examples of pharmaceutically acceptable addition acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid, formic acid, acetic acid, benzoic acid,
There are organic acids such as maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, methanesulfonic acid, toluenesulfonic acid, aspartic acid and glutamic acid.

Various methods are conceivable for producing the compound represented by the general formula (I). For example, it can be easily and efficiently produced from a staurosporine derivative. Further, by a known method, after protecting a highly reactive nitrogen atom of staurosporine (for example, 4′-N-position), a substituent is introduced into an aromatic ring to give a known staurosporine derivative, and then, The compound of the present invention can be produced by chemically converting the γ-lactam ring moiety and eliminating the sugar moiety. The most typical manufacturing method will be described below. Needless to say, the method for producing the staurosporine derivative and the indolocarbazole derivative is merely an example, and the present invention is not limited thereto.

In the production method shown below, when the defined group is changed under the conditions of the method for carrying out the method or is unsuitable for carrying out the method, a method commonly used in synthetic organic chemistry, for example, a functional group is used. Easily implemented by providing means for protecting and deprotecting the group (see, for example, Protective Groups in Organic Synthesis, Green, John Willie & Sons Incorporated (1981)) can do.

The starting material is, for example, the following formula (VI)

[0014]

[Chemical 8]

A compound represented by the formula (Japanese Patent Application Laid-Open No. 3-72485)
(See Japanese Patent Laid-Open Publication) can be used. The general formula (I)
The compound in which R1 and / or R2 of is a halogen atom can be prepared, for example, as follows. Examples of the halogen atom include chlorine atom and bromine atom. A compound in which R7 in the general formula (VI) is a β, β, β-trichloroethoxycarbonyl group and R5 and / or R6 is a hydrogen atom is a halogenated hydrocarbon solvent, for example, a chloroform solvent, and chlorine gas is used as a reaction reagent. At room temperature, or using N-chlorosuccinimide under concentrated hydrochloric acid or concentrated sulfuric acid catalyst at a reaction temperature of 0 to 1
The reaction is carried out at 00 ° C., preferably 40 to 70 ° C., and R5
The hydrogen atom of R6 and / or R6 can be replaced with a chlorine atom, and the hydrogen atom of R5 and / or R6 can be replaced with a bromine atom by using bromine instead of chlorine gas.

For example, the following equation (VII)

[0017]

[Chemical 9]

The compound represented by the formula (VII) is reacted with N-chlorosuccinimide and concentrated hydrochloric acid in a halogenated hydrocarbon solvent, preferably a chloroform solvent, to give a compound of the following formula (VII)
I)

[0019]

[Chemical 10]

It is possible to obtain a chloro derivative represented by:
The N-chlorosuccinimide used is 1 to 2 equivalents, preferably 1 to 1.4 equivalents, and concentrated hydrochloric acid is 0.005 to 0.
2 equivalents, preferably 0.01 to 0.1 equivalents, the reaction temperature is 0 to 100 ° C, preferably 40 to 85 ° C, and the reaction time is 2 to 16 hours, preferably 4 to 6 hours. is there. Further, in the compound of the general formula (VII), when R6 is a hydrogen atom, by using the above-mentioned double reagent, the following formula (IX)

[0021]

[Chemical 11]

The compound represented by can be obtained. When R5 and / or R6 in the general formula (VI) is a hydroxyl group or an amino group, the hydroxyl group can be easily an alkoxy group or a benzyloxy group and the amino group can be a benzyl group or 1 to 4 carbon atoms by the following method. It can be converted to an amino group which is mono- or di-substituted by the alkyl group which it has. Examples of the alkoxy group include methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, n-butoxy group, tert. -Butoxy group, and examples of the substituted amino group include methylamino group, dimethylamino group, ethylamino group, diethylamino group, ethylmethylamino group, n-propylamino group, methyl n-propylamino group, di (n- Propylamino) group, iso-propylamino group, di (iso-propylamino) group, n-butylamino group, di (n-butylamino) group, sec-butylamino group, tert-butylamino group, benzylamino group , A dibenzylamino group and the like.

As a method for converting the above-mentioned alkoxy group, benzyloxy group or benzyl group or an amino group mono- or di-substituted by an alkyl group having 1 to 4 carbon atoms, R5 and / or
Alternatively, a compound having a hydroxyl group or an amino group in R6, or a compound obtained by converting a functional group, if necessary, by a protecting group commonly used in synthetic organic chemistry in an inert solvent, such as N 2 , N-dimethylformamide, tetrahydrofuran, or 1,4-dioxane, preferably N, N-dimethylformamide, a weakly nucleophilic base, that is, an alkali metal hydride such as sodium hydride or potassium hydride, or trimethylamine, triethylamine. Tertiary amine or di (is
2 such as o-propyl) amine and di (n-propyl) amine
In the presence of an organic amine such as a primary amine, preferably sodium hydride, the following formula (X)

[0024]

[Chemical 12]

By reacting with a compound represented by the formula (5), the hydroxyl group and amino group of R5 and / or R6 are respectively OR8 group (alkoxy group, benzyloxy group), NHR8 group (1
(Substituted amino group) or N (R8) ₂ group (disubstituted amino group). For example, for the conversion of an alkoxy group or a monosubstituted amino group, sodium hydride is 1 to 2 equivalents, preferably 1.0 to 1.2 equivalents, based on the reaction substrate, and the compound of formula (X) is 1 equivalent.
To 3 equivalents, preferably 1.5 to 2.0 equivalents, the reaction temperature is 0 to 100 ° C, preferably 20 to 80 ° C,
The reaction time is 2 to 20 hours, preferably 4 to 7 hours. Further, regarding the 2-substituted amino group conversion, sodium hydride is 1 to 5 equivalents, preferably 2 to 3 equivalents, and the compound of the formula (X) is 1 to 5 equivalents, preferably 2 to 3 equivalents, relative to the reaction substrate. The reaction temperature is 0 to 100 ° C., preferably 20 to 80 ° C., and the reaction time is 5 to 40 hours, preferably 7 to 12 hours.

The method for producing the compound described in claim 1, that is, the chemical conversion of the γ-lactam ring and the elimination of the sugar moiety will be illustrated below, but the invention is not limited thereto. First, the following equation (XI) adjusted as described above

[0027]

[Chemical 13]

The following formula (XII) obtained by oxidizing the 7-position of the compound represented by

[0029]

[Chemical 14]

It can be converted to a compound represented by: The compound of the formula (XI) is treated with an alcohol solvent such as methanol, ethanol, propanol or butanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane or a mixed solvent thereof, preferably tert. -Dissolved in a mixed solvent of butyl alcohol and 1,4-dioxane, manganese (III) acetylacetonate and ter
t. -Butyl hydroperoxide at a reaction temperature of -20 to
By reacting at 100 ° C., preferably at 20 to 30 ° C., the 7-oxo compound represented by the general formula (XII) can be obtained.

The manganese (III) acetylacetonate used in the reaction is 0.01 to 3 equivalents, preferably 0.1 to
0.5 eq, tert. -Butyl hydroperoxide is 2 to 20 equivalents, preferably 7 to 10 equivalents, and the reaction time is 5 to 48 hours, preferably 20 to 30 hours. Next, Method 1 and Method 2 show examples of methods for synthesizing acid anhydride type and lactone type aglycone derivatives from imide type.

Method 1: Synthesis of acid anhydride type compound 1-1: Conversion to acid anhydride type compound

[0033]

[Chemical 15]

The compound represented by the general formula (XII) is converted into an alcohol solvent such as methanol, ethanol, propanol or butanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane or a mixed solvent thereof, preferably methanol and 1, It is dissolved in a mixed solvent of 4-dioxane and reacted with aqueous ammonia. Subsequently, the compound represented by the general formula (XIII) can be obtained by adding 3N-sodium hydroxide to a methanol solution and carrying out a reaction. Ammonia water is 5 to 100 equivalents, preferably 10 to 50 equivalents, sodium hydroxide is 0.5 to 3 equivalents,
It is preferably 1.0 to 1.2 equivalents. Reaction time is 2
The reaction temperature is 0 to 2 in 12 hours, preferably 6 to 8 hours.
The temperature is 00 ° C, preferably 50 to 100 ° C.

1-2: elimination of sugar moiety

[0036]

[Chemical 16]

The compound represented by the general formula (XIII) is converted into a mineral acid such as acetic acid, trichloroacetic acid, trifluoroacetic acid or methanesulfonic acid, preferably trifluoroacetic acid, or a mineral acid such as hydrochloric acid or sulfuric acid, or an aqueous solution thereof. , Preferably by reacting with hydrochloric acid to give a compound of general formula (XI
A compound represented by V) can be obtained. Hydrochloric acid is 1
5 normal concentration, preferably 10 at 2.0-3.5 normal concentration
To 70 equivalents, preferably 30 to 60 equivalents, the reaction temperature is 50 to 105 ° C, preferably 70 to 100 ° C, and the reaction time is 4 to 24 hours, preferably 5 to 12 hours.

Method 2: Synthesis of lactone type compound 2-1: Conversion to lactone type compound

[0039]

[Chemical 17]

The compound of the general formula (XII) is methanol,
Ethanol, propanol, alcohol solvent such as butanol, tetrahydrofuran, ether solvent such as 1,4-dioxane, water or a mixed solvent thereof, preferably dissolved in a mixed solvent of 2-propanol and water, sodium borohydride and By reacting and then heating with acetic acid, a mixture of lactone compounds represented by the general formula (XV) and the general formula (XVI) can be obtained. The reaction temperature with sodium borohydride is -10 to 50 ° C, preferably 0 to 25 ° C, and the reaction time is 12 to 48 hours, preferably 24 to 30 hours. The reaction temperature with acetic acid is 25 to 100 ° C, preferably 70 to 80 ° C, and the reaction time is 1 to 10 hours, preferably 3 to 4 hours.
The two lactones (XV) and (X
VI) is not isolated, and the following sugar site elimination step (step 2-2) can be carried out as it is as a mixture.

2-2: Elimination of sugar moiety

[0042]

[Chemical 18]

Removal of the sugar moiety of the mixture of the compound represented by the general formula (XV) and the compound represented by the general formula (XVI) is carried out in the same manner as in the method 1-2, and
A mixture of the compound represented by II) and the compound represented by the general formula (XVIII) is obtained, and each can be isolated. However, R3 and R4 of the compound represented by the general formula (XV) and the compound represented by the general formula (XVI)
Are the same groups, the products are one type.

Further, when R3 and / or R4 in the compound represented by the general formula (II) is a hydroxyl group, a hydroxymethyl group or an amino group, it is easily acylated by a reaction which is usually used, such as the Schotten-Baumann reaction. The compound represented by the general formula (I) can be produced. The antitumor activity of the indolocarbazole derivative according to the present invention was evaluated using p-388 mouse leukemia. 10 to 30 mg / kg for the compounds shown in the examples
When the survival time of leukemia mice was examined in a dose range of / injection, life extension of T / C of 125% or more was observed in all, and it was shown that these indolocarbazole derivatives have useful antitumor activity.

Next, typical examples of compounds represented by the general formula (I) obtained by the above-mentioned production method (compounds 1, 2, 3,
4) is shown in Table 1 and its intermediate is shown in Table 2. In addition, production examples of these compounds 1, 2, 3, 4 will be shown in Examples.

[0046]

EXAMPLES Hereinafter, examples of producing compounds 1 to 4 shown in Table 1 and intermediates a to m shown in Table 2 will be described.

[0047]

Example 1 Production Example of Compound 1 (1-1: Synthesis Example of Compound a) Staurosporine 932
mg (2.0 mmol) was dissolved in 10 ml of dry pyridine, and 0.3 ml (2.2 mmol) of β, β, β-trichloroethyl chloroformate was added dropwise under cooling to 0 ° C.
The reaction was performed for 10 hours. 10 ml of water was added to the reaction solution, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtering off sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography using silica gel (elution solvent: chloroform) to obtain 1052 mg of compound a as pale yellow crystals (yield 82%). .. ¹ H-NMR (CDCl ₃ , δ) 9.40 (d, 1H), 8.00 to 7.20 (m, 7)
H), 6.75 to 6.68 (m, 1H), 6.62 (b
r. s, 1H), 5.00 (s, 2H), 4.77 (b
r. s, 2H), 4.07 (br.s, 1H), 2.8.
5 (s, 3H), 2.70 to 2.55 (m, 1H),
2.60 (s, 3H), 2.50 to 2.40 (m, 2
H) 2.41 (s, 3H) MS m / z 640 (M ⁺ ) (1-2: Synthesis example of compound b) Compound a 256 mg
(0.4 mmol) tert. -Butyl alcohol 2
To a mixed solution of 10 ml of ml-1,4-dioxane, 11 mg of manganese (III) acetylacetonate, 70% t
ert. -Butyl hydroperoxide (0.48 ml) was added, and the reaction was carried out at room temperature for 30 hours. After the reaction was completed, the solvent was concentrated, chloroform was added, and the mixture was passed through Celite.
The chloroform solution was washed with water, dried and concentrated, and the residue was purified by silica gel column chromatography (elution solvent: chloroform-methanol = 5: 1) to obtain 200 mg (0.305 mmo) of compound b, which was a columnar green-yellow crystal.
l) Obtained (77% yield). ¹ H-NMR (CDCl ₃ , δ) 9.97 (d, 1H), 9.24 (d, 1H), 7.8.
0 to 7.20 (m, 6H), 6.71 (dd, 1H),
4.88 (br.s, 2H), 4.84 (br.s, 1
H), 3.98 (br.s, 1H), 2.94 (s, 3)
H), 2.90-2.60 (m, 2H), 2.44
(S, 3H), 2.24 (br.s, 3H) MS m / z 654 (M ⁺ ) (1-3: Synthesis example of compounds c and c ′) Compound b187m
g (0.30 mmol) was added to 2-propanol 10 ml and water 2 ml, sodium borohydride 74.5
mg (1.97 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Then, 1.2 ml of acetic acid was added and heated at 80 ° C. for 3 hours. After the reaction was completed, the solvent was concentrated, water was added, and 10
The mixture was neutralized with aqueous sodium hydrogen carbonate solution and extracted with chloroform. After washing with water and drying with sodium sulfate, chloroform was concentrated under reduced pressure to obtain a crude product. Preparative thin layer chromatography (silica gel, benzene-ethyl acetate = 5:
In 1), 118 mg (0.183 mmol) of pale yellow columnar crystals were obtained as a mixture of lactones c and c '(yield 6
1.0%). MS m / z 641 (M ⁺ ) (1-4: Synthesis example of compound 1) 103 mg (0.161 mmol) of a mixture of compounds c and c ′ was dissolved in 5 ml of trifluoroacetic acid, and 3 ml of 3N-hydrochloric acid was added thereto.
The reaction was carried out at 0 ° C for 5 hours. After completion of the reaction, the mixture was neutralized with 10% aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. After washing with water and drying over anhydrous sodium sulfate, ethyl acetate was concentrated under reduced pressure to obtain 25 mg of compound 1 (yield 50.1
%). ¹ H-NMR (DMSO-d ₆ , δ) 11.72 (br.s, 1H), 11.48 (br.
s, 1H), 9.25 (d, 1H), 8.12 (d, 1)
H), 7.80 to 7.20 (m, 6H), 5.62
(S, 2H) MS m / z 312 (M ⁺ )

[0048]

Example 2 Production Example of Compound 2 (2-1: Synthesis Example of Compound d) Compound b 105 mg
(0.160 mmol) in 3 ml of methanol, 1,4-
It was dissolved in a mixed solvent of 3.0 ml of dioxane, 2.0 ml of 28% -ammonia water was reacted at 50 ° C. for 3 hours, and then 3N was added.
-Add 1.0 ml of sodium hydroxide methanol solution,
The reaction was carried out for 3 hours and 30 minutes at 10 ° C. After completion of the reaction, the solvent was concentrated under reduced pressure, acidified with 10% -hydrochloric acid, and extracted with chloroform. The residue obtained by concentrating chloroform under reduced pressure was purified by silica gel column chromatography (eluting solvent: chloroform) to obtain 35 mg of compound d (yield 33.3%). ¹ H-NMR (CDCl ₃ , δ) 9.16 (d, 1H), 9.04 (d, 1H), 7.7.
0 to 7.40 (m, 6H), 6.70 (m, 1H),
4.90 (br.s, 2H) 4.85 (br.s, 1
H), 3.93 (br.s, 1H), 2.84 (s, 3)
H), 2.70 to 2.50 (m, 2H), 2.32 (b
r. s, 3H), 1.55 (br.s, 3H) MS m / z 655 (M ⁺ ) (2-2: Synthesis example of compound 2) Compound d 30 mg (0.
(038 mmol) was dissolved in 4 ml of trifluoroacetic acid, 1 ml of 3N-hydrochloric acid was added, and the reaction was carried out at 100 ° C. for 5 hours. After completion of the reaction, the mixture was neutralized with 10% aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. After washing with water and drying over sodium sulfate, ethyl acetate was concentrated under reduced pressure to give compound 2 as 5.
1 mg was obtained (yield 41.0%). ¹ H-NMR (DMSO-d ₆ , δ) 11.65 (br.s, 2H), 9.22 (d, 2)
H), 7.80-7.20 (m, 6H) MS m / z 326 (M ⁺ ).

[0049]

Example 3 Production Example of Compound 3 (3-1: Synthesis Example of Compound e) Compound a 846 mg
(1.32 mmol) in 35 ml of 2,6-lutidine
Dissolve, add 12 ml of acetic anhydride dropwise, and heat to 140 ° C.
The reaction was performed for 3 hours below. 40 ml of chloroform in the reaction solution
After adding, the solution was diluted with dilute hydrochloric acid and saturated sodium hydrogen carbonate.
Sequentially wash with aqueous solution of water and water,
After drying, the solvent was removed under reduced pressure and the residue was re-used with acetone.
Crystallization yielded 770 mg of compound e, which was a pale yellow crystal.
(Yield 85%).¹ H-NMR (CDCl₃, Δ) 9.40 (d, 1H), 8.00 to 7.20 (m, 7)
H), 6.73 (m, 1H), 5.00 (s, 2H),
4.80 (s, 2H), 3.95 (br.s, 1H),
2.85 (s, 3H), 2.65 (s, 3H), 2.7
0 to 2.55 (m, 1H), 2.55 (s, 3H),
2.50 to 2.40 (m, 2H), 2.41 (s, 3
H) MS m / z 682 (M⁺) (3-2: Synthesis example of compound f) 1 m of dry dichloromethane
Dissolve 100 mg (0.196 mmol) of compound e in 1
Then, under cooling to 0 ° C., 320 μl of titanium tetrachloride is further added.
Add 130 μl of α, α-dichloromethyl methyl ether
The reaction was carried out at room temperature for 30 hours. Dichlorinated solution
After adding 100 ml of methane, saturated sodium hydrogen carbonate
Washed with aqueous solution and water, dried over anhydrous sodium sulfate
did. After removing sodium sulfate by filtration, remove the solvent under reduced pressure.
As a result, 72 mg of compound f which is a yellow crystal was obtained (yield
67%). ¹ 1 H-NMR (DMSO-d₆, Δ) 10.07 (s, 1H), 9.83 (s, 1H), 9,
23 (s, 1H), 8.29 (s, 1H), 8.02
(D, 1H), 7.93 (d, 1H), 7.73 (d,
1H), 7.60 (d, 1H), 6.91 (br.s,
1H), 5.06 (s, 2H), 4.99 (s, 2)
H), 4.26 (br.s, 1H), 3.10 to 2.1.
0 (m, 3H), 2.73 (s, 3H), 2.53
(S, 3H), 2.52 (s, 3H), 2.41 (s,
3H) MS m / z 738 (M⁺) (3-3: Synthesis example of compound g) Compound f272 mg
(0.37 mmol) was added to 50 ml of dichloromethane.
After dissolution, 346 mg of metachloroperbenzoic acid and charcoal
Add 100 mg of potassium hydrogen sulphate and at room temperature with exclusion of light.
The reaction was carried out for 3.5 hours. Saturated sodium sulfite
50 ml of aqueous solution of sodium, saturated aqueous solution of sodium hydrogen carbonate
Wash with 50 ml and 50 ml of water and dry with anhydrous sodium sulfate.
Dried. After the desiccant was filtered off, the solvent was removed under reduced pressure.
After the residue was dissolved in 45 ml of methyl cellosolve, 4N-
Add 10 ml of sodium hydroxide aqueous solution, and at room temperature 2:00
It was stirred for a while. The reaction completed liquid was neutralized with 50 ml of 1N hydrochloric acid.
Then, extract with dichloromethane and dissolve the dichloromethane.
The solution was washed with water and dried over anhydrous sodium sulfate. Sodium sulfate
After filtering off thorium, the solvent was removed under reduced pressure, and the residue was
Silica gel column chromatography (chloroform-
Compound that is a single yellow crystal after purification by methanol)
196 mg of g was obtained (yield 79%).¹ 1 H-NMR (DMSO-d₆+ D₂O, δ) 8.20 (s, 1H), 7.78 (d, 1H), 7.4
3 (d, 1H), 7.31 (s, 1H), 7.01
(D, 2H), 6.83 (br.s, 1H), 4.93
(S, 2H), 4.91 (s, 2H), 4.23 (b
r. s, 1H), 4.0-2.0 (m, 3H), 2.7
3 (s, 3H), 2.67 (s, 3H), 2.24
(S, 3H) MS m / z 672 (M⁺) (3-4: Synthesis example of compound h) Compound g 269 mg
(0.4 mmol) tert. -Butyl alcohol 2
A solution of manganese (I
II) Acetylacetonate 13 mg, 70% ter
t. -Butyl hydroperoxide 0.48 ml was added
The reaction was carried out at room temperature for 30 hours. After completion of the reaction, solvent
Was concentrated, chloroform was added, and the mixture was passed through Celite. Ku
The loroform solution was washed with water, dried and concentrated, and the residue was
Kagel column chromatography (eluting solvent: chloropho
Purified with rum-methanol = 5: 1)
134 mg (0.19 mmol) of crystalline compound h was obtained.
(Yield 49%).¹ 1 H-NMR (DMSO-d₆+ D₂O, δ) 8.65 (s, 1H), 8.50 (s, 1H), 7.9
2 (d, 1H), 7.58 (d, 1H), 7.27
(D, 2H), 6.77 (br.s, 1H), 4.90
(S, 2H), 4.22 (br.s, 1H), 4.05
˜2.10 (m, 3H), 2.92 (s, 3H), 2.
77 (s, 3H), 2.18 (s, 3H) MS m / z 686 (M⁺(3-5: Synthesis example of compounds i and i ′) Compound h100m
g (0.15 mmol) and 2-propanol (8 ml)
Sodium borohydride 31.4m
g (0.862 mmol) was added and stirred at room temperature for 24 hours
did. Next, add 0.8 ml of acetic acid and stir at 80 ° C for 3 hours.
Heated. After the reaction was completed, the solvent was concentrated, water was added, and 10
Neutralize with aqueous sodium hydrogen carbonate solution and add chloroform.
Extracted. After washing with water and drying over sodium sulfate, chloroform
Was concentrated under reduced pressure to obtain a crude product. Preparative thin layer chromatography
Ruffy (silica gel, chloroform-methanol = 1
5: 1) pale yellow as a mixture of lactones i, i '
Columnar crystals 50.5 mg (0.075 mmol) were obtained.
(Yield 52.0%). MS m / z 673 (M⁺(3-6: Synthesis example of compound 3) Mixing of compounds i and i ′
40 mg (0.059 mmol) of compound is trifluoroacetic acid
Dissolve in 4 ml of acid, add 2 ml of 3N hydrochloric acid, and add 100
The reaction was carried out at 0 ° C for 5 hours. After reaction, 10% carbonated water
It was neutralized with an aqueous solution of sodium and extracted with ethyl acetate.
After washing with water and drying over anhydrous sodium sulfate, concentrate ethyl acetate under reduced pressure.
The product was condensed to obtain 8.9 mg of compound 3 (yield 43.5%).¹ 1 H-NMR (DMSO-d₆, Δ) 11.76 (br.s, 1H), 11.52 (br.
s, 1H), 9.28 (br.s, 1H), 9.07
(Br.s, 1H), 8.80 (s, 1H), 7.76
(D, 1H), 7.70 (d, 1H), 7.34 (s,
1H), 7.10 to 6.80 (m, 2H), 5.68
(S, 2H) MS m / z 344 (M⁺)

[0050]

Example 4 Production Example of Compound 4 (4-1: Synthesis Example of Compound j) 20 ml of dichloromethane
Is cooled to 0 ° C. and trifluoromethanesulfonic acid 75 μ
After adding 1 l, 35 μl of fuming nitric acid was added and stirred for 20 minutes. The reaction solution was cooled to −78 ° C., and compound e885 mg
40 ml of a dichloromethane solution of (0.56 mmol) was added dropwise and the reaction was performed for 30 minutes. The reaction completion liquid was washed with a saturated sodium hydrogen carbonate aqueous solution and water, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure, and the residue was recrystallized from methanol to obtain 373 mg of compound j as pale yellow crystals (yield 91%). ¹ H-NMR (DMSO-d ₆ , δ) 9.85 (s, 1 H), 8.00 to 6.90 (m, 6)
H), 6.75 (br.s, 1H), 5.00 (s, 2)
H), 4.85 (s, 2H), 3.95 (br.s, 1)
H), 2.90 (s, 3H), 2.70 (s, 6H),
2.40 (s, 3H), 2.90 to 2.40 (m, 3
H) MS m / z 727 (M ⁺ ) (4-2: Synthesis example of compound k) Compound j 373 mg
(0.51 mmol) was added to 50 ml of methyl cellosolve, and then 12 ml of hydrazine hydrate (85%) was added dropwise.
The reaction was carried out at room temperature for 3 hours. 500m of water in the reaction completed liquid
After adding l, the mixture was extracted with chloroform, the chloroform solution was washed with water and dried over anhydrous sodium sulfate. After the sodium sulfate was filtered off, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to give compound 274 as yellow crystals.
mg was obtained (yield 78%). ¹ H-NMR (DMSO-d ₆ , δ) 9.86 (d, 1H), 8.00 to 7.25 (m, 6)
H), 7.28 (br.s, 1H), 4.90 (br.
s, 4H), 4.00 (s, 1H), 3.30 to 3.1.
5 (m, 1H), 2.75 (s, 3H), 2.90 ~
2.70 (m, 1H), 2.53 (s, 3H), 2.3
5 to 2.20 (m, 1H), 2.15 (s, 3H) MS
m / z 685 (M ⁺ ) (4-3: Synthesis example of compound l) Compound k 250 mg
(0.365 mmol) tert. -Butyl alcohol 2 ml-1,4-dioxane 20 ml solution to manganese (III) acetylacetonate 10 mg, 70% te
rt. -Butyl hydroperoxide (0.50 ml) was added and the reaction was carried out at room temperature for 30 hours. After the reaction was completed, the solvent was concentrated, chloroform was added, and the mixture was passed through Celite. The chloroform solution was washed with water, dried and concentrated, and the residue was purified by silica gel column chromatography (eluting solvent: chloroform-methanol) to obtain 103 mg (0.147 mmol) of compound 1 that was a green-yellow columnar crystal (yield 40. 3%). ¹ H-NMR (DMSO-d ₆ , δ) 10.21 (s, 1H), 9.29 (d, 1H), 7.
82 (d, 1H), 7.50 to 7.10 (m, 4H),
6.62 (m, 1H), 4.83 (s, 2H), 4.0
2 (m, 1H), 3.30 to 3.15 (m, 1H),
2.90 (s, 3H), 2.90 to 2.70 (m, 2
H), 2.50 (s, 3H), 2.12 (s, 3H) MS m / z 699 (M ⁺ ) (4-4: Synthesis example of compound m) Compound l 95 mg (0.
(136 mmol) was dissolved in a mixed solvent of 3 ml of methanol and 7.0 ml of 1,4-dioxane, 2.0 ml of 28% -ammonia water was reacted at 50 ° C. for 3 hours, and 1.0 ml of 3N-sodium hydroxide methanol solution was added. Addition was continued for 3 hours and 30 minutes at 10 ° C. After completion of the reaction, the solvent was concentrated under reduced pressure, acidified with 10% -hydrochloric acid, and extracted with chloroform. The residue obtained by concentrating chloroform under reduced pressure was purified by silica gel column chromatography (elution solvent: chloroform-methanol) to give compound m of 25
mg was obtained (yield 26.7%). ¹ H-NMR (CDCl ₃ , δ) 9.62 (s, 1H), 9.12 (d, 1H), 7.9.
2 (d, 1H), 7.70 to 7.40 (m, 4H),
6.82 (m, 1H), 4.87 (br.s, 2H)
4.12 (m, 1H), 3.38 (m, 1H), 2.8
0 to 2.50 (m, 2H), 2.88 (s, 3H),
2.62 (s, 3H), 2.22 (s, 3H) MS m / z 700 (M ⁺ ) (4-5: Synthesis example of compound 4) Compound m 20 mg (0.
(029 mmol) was dissolved in 3 ml of trifluoroacetic acid, 1 ml of 3N-hydrochloric acid was added, and the reaction was carried out at 100 ° C. for 5 hours. After completion of the reaction, the reaction mixture was neutralized with a 10% sodium hydrogen carbonate aqueous solution and then with ethyl acetate. After washing with water and drying over sodium sulfate, ethyl acetate was concentrated under reduced pressure to give compound 4.
3 mg (0.010 mmol) was obtained (yield 34.5
%). ¹ H-NMR (DMSO-d ₆ , δ) 11.82 (br.s, 1H), 11.40 (br.
s, 1H) 9.52 (s, 1H), 9.14 (d, 1
H), 7.90-7.20 (m, 5H) MS m / z 371 (M ⁺ ).

[0051]

[Experimental Example] Female CD2F1 (BALB / C × 5 females per group)
DBA / 2) mice were intraperitoneally transplanted with 10 ⁶ P388 mouse leukemia cells. After that, from the day after the transplant, Twee
The indolocarbazole derivative of the present invention dissolved or suspended in a physiological saline solution (dilution solution) containing n80 was intraperitoneally administered once a day for a total of 5 times, and the survival days of each group were observed. The median survival time of the control group (C) similarly administered with only the diluted solution was compared with the median survival time of each drug administration group (T), and T / C
Was determined to be valid when 125% or more, and invalid when 125% or less. The obtained results are shown in Table 3, and it was revealed that the indolocarbazole derivative of the present invention has antitumor activity.

[0052]

[Table 1]

[0053]

[Table 2]

[0054]

[Table 3]

[0055]

INDUSTRIAL APPLICABILITY The compound represented by the general formula (I) and the pharmaceutically acceptable salt thereof of the present invention have antitumor activity and are expected to be useful as an active ingredient of an antitumor agent. ..

Claims (8)

[Claims] 1. A compound represented by the general formula (I): The indolocarbazole derivative represented by and its pharmaceutically acceptable salt. 2. A compound represented by the general formula (II): The compound according to claim 1 and a pharmaceutically acceptable salt thereof. 3. A compound represented by the general formula (III): The compound according to claim 1, which is represented by 4. A compound represented by the general formula (IV): The compound according to claim 1, which is represented by 5. An antitumor agent comprising the compound according to claim 1 represented by the general formula (I) as an active ingredient. 6. An antitumor agent comprising the compound according to claim 2 represented by the general formula (II) as an active ingredient. 7. The method according to claim 3, which is represented by the general formula (III).
An antitumor agent comprising the described compound as an active ingredient. 8. An antitumor agent comprising the compound according to claim 4 represented by the general formula (IV) as an active ingredient.