JPH09194481A - Condensed tetra-and hetyerocyclic derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound derivative which is a specific condensed tetra- and heterocyclic derivative, having a cyclic imide part in the molecule, excellent antitumor activities and low toxicity and useful as an active ingredient, etc., of an antitumor agent. SOLUTION: This new tetra- and heterocyclic derivative (salt) is represented by formula I rings A and B are each a (substituted)monocyclic aromatic ring; X is a bond, O, S or CH=CH; Y is a group represented by the formula e-f [(e) is a lower alkylene; (f) is an amino group which may be substituted with a lower alkyl group]}, has excellent antitumor activities and low toxicity and is useful as an active ingredient, etc., of an antitumor agent. The compound is obtained by reacting a compound represented by formula II [ring Aa is a (protected)ring A; G is O or S] with a compound represented by formula III [ring Ba is a (protected)ring B; K and L are each an eliminable group; R is a lower alkyl], then amidating the resultant compound, providing a condensed tricyclic compound represented by formula IV and further carrying out the cyclizing reaction of the resultant condensed tricyclic compound represented by formula IV with a compound represented by formula V (D and E are each an eliminable group).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel fused tetracyclic heterocyclic derivative, a method for producing the same, and a pharmaceutical composition containing the compound as an active ingredient.

[0002]

2. Description of the Related Art A cyclic imide moiety in a molecule

Embedded image Examples of the fused polycyclic heterocyclic antitumor substance having a compound include tricyclic compound amonafide [5-amino-2- [2-
(Dimethylamino) ethyl] -1H-benz [de] isoquinoline-1,3 (2H) -dione] is the most well known, but it has strong bone marrow toxicity in clinical studies conducted so far and its efficacy rate is high. Reported to be low [Drug
S Fut., 17 , 832 (1992)]. Further, as a tetracyclic compound, azonafide [2- [2 '-(dimethylamino) ethyl] -1, which increased antitumor activity in a preclinical test by converting the aminonaphthalene part of amonafide into anthracene, 2-dihydro-3H-dibenz (d
[eh) -isoquinoline-1,3-dione] has been reported (WO9200281). In addition to the above, condensed polycyclic heterocyclic antitumor substances having a cyclic imide moiety in the molecule include 2- [2- (dimethylamino) ethyl] pyrimido [5,6,1-de] acridine-1, 3,7-Trione [Farmaco, 47 , 1035 (1992)] and 2,3-dihydro-2- [2- (dimethylamino)
Ethyl] -1H, 7H-naphthyridino [3,2,1-i
j] Quinazoline-1,3,7 (2H) -trione [Journal of Medicinal Chemistry (J. Med. Ch
em.), 37 , 593 (1994)], but all have shown weak antitumor activity in preclinical studies.

[0003]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel fused tetracyclic heterocyclic derivative having excellent antitumor activity. Furthermore, it aims at providing the pharmaceutical composition which uses this compound as an active ingredient.

[0004]

[Means for Solving the Problems] In view of the above points, the present inventors have conducted earnest research in search of an excellent antitumor substance, and as a result, the novel fused tetracyclic heterocycle derivative has excellent antitumor properties. The present invention has been completed by finding that it has activity and low toxicity.

That is, the present invention has the general formula (I)

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[In the formula, A ring and B ring are the same or different and each represents a monocyclic aromatic ring which may have a substituent. X is a bond, an oxygen atom, a sulfur atom or -CH = C
Means H-. Y represents a group represented by the formula ef (wherein e represents a lower alkylene group, and f represents an amino group optionally substituted with a lower alkyl group), or a drug thereof. Regarding a salt that is physically acceptable.

In the definition of the A ring and the B ring of the above general formula (I), the monocyclic aromatic ring means an aromatic group 5 or 5 which may contain at least one of a nitrogen atom, an oxygen atom and a sulfur atom. It is a 6-membered ring, and examples thereof include benzene, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, pyrrole, and thiazole. The above rings may each have 1 to 3 substituents,
When there are a plurality of substituents, they may be the same or different. Examples of the substituent include a nitro group, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, a lower acyl group, a lower alkylated, a lower acylated or a lower alkylsulfonylated amino group, an aromatic carboxylic acid. Examples thereof include an amide group and an aromatic sulfonamide group.

In the above general formula (I), ring A and B
The substituent which the ring may have and the lower alkyl group in the definition of f in Y are a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, n
-Propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-
Pentyl group (amyl group), isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2
-Methylbutyl group, 1,2-dimethylpropyl group, n-
Hexyl group, isohexyl group, 1-methylpentyl group,
2-methylpentyl group, 3-methylpentyl group, 1,1
-Dimethylbutyl group, 1,2-dimethylbutyl group, 2,
2-dimethylbutyl group, 1,3-dimethylbutyl group,
2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,
1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1
-Ethyl-2-methylpropyl group and the like can be mentioned. Among these, preferable groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like, and among these, a most preferable group includes a methyl group and an ethyl group. The lower alkylene group in the definition of e in Y means a residue obtained by removing one hydrogen atom from the above lower alkyl group. In the definition of the substituent which ring A and ring B may have and f in Y, when the amino group is substituted with two lower alkyl groups, these alkyl groups are bonded to each other to form 5
Alternatively, a 6-membered ring may be formed.

The lower alkoxy group in the definition of the substituent which ring A and ring B may have is a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, It means a lower alkoxy group derived from the above lower alkyl group such as a tert-butoxy group, and among these, the most preferable group includes a methoxy group and an ethoxy group. Further, examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom. The lower acyl group includes a formyl group having 1 to 6 carbon atoms, an acetyl group, a propionyl group, a butyryl group,
Examples thereof include isobutyryl group and valeryl group. Examples of the lower alkylsulfonylated amino group include a methanesulfonamide group having 1 to 6 carbon atoms, an ethanesulfonamide group, a propanesulfonamide group, a butanesulfonamide group, a pentanesulfonamide group, and a hexanesulfonamide group. To be The aromatic carboxylic acid amide group and the aromatic sulfonamide group may have a substituent, for example, benzene, pyridine, thiophene,
It means a monocyclic aromatic carboxylic acid amide group such as furan and a sulfonic acid amide group. Examples of the substituent include a lower alkyl group, a lower alkoxy group, a hydroxyl group and a halogen atom.

The fused tetracyclic heterocyclic derivative represented by the above general formula (I) may form a salt with an acid. The present invention also includes a salt of compound (I). As the salt with an acid, for example, an inorganic acid salt with hydrochloric acid, hydrobromic acid, sulfuric acid, or acetic acid,
Examples thereof include organic acid salts with lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid and the like. It goes without saying that not only hydrates of these compounds but also all optical isomers are included when they exist. Further, the compound of the present invention also includes a compound which exhibits a strong antitumor activity, but exhibits an antitumor activity by being metabolized in vivo by metabolism such as oxidation, reduction, hydrolysis and conjugation. Furthermore, the present invention also includes a compound which is metabolized in vivo by metabolism such as oxidation, reduction and hydrolysis to produce the compound of the present invention.

The compound (I) of the present invention can be produced by various methods. Among them, typical methods are shown below.

1) General formula (II)

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(In the formulae, Aa ring and Ba ring mean A ring and B ring which may be protected respectively. X, e and f have the same meanings as described above) and a general formula ( III)

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It can be produced by reacting a compound represented by the formula (wherein D and E are the same or different and each represents a leaving group). This reaction is generally carried out by dissolving the compound (II) in an aprotic solvent such as dimethylformamide, tetrahydrofuran or dioxane, and then adding 2-3 equivalents of sodium hydride, and then adding the compound (III). Performed by. Examples of compound (III) include phosgene, ethyl chlorocarbonate, N, N'-carbonyldiimidazole and the like. The reaction is usually performed in the temperature range of -50 to 150 ° C. In the obtained product, when the amino group, hydroxyl group, etc. are protected, by carrying out a usual deprotection method such as acid treatment, alkali treatment, catalytic reduction,
It is possible to obtain the target compound (I).

2) General formula (IV)

[Chemical 6]

Reacting a compound represented by the formula (wherein Ab ring and Bb ring are A ring and B ring having an amino group on either one or both rings) with sodium nitrite under acidic condition To give a diazonium salt, and then reacting with a nucleophile in the presence or absence of a catalyst. This reaction can be carried out under usual Sandmeyer reaction or reaction conditions similar thereto. Examples of the nucleophile include cuprous halide, cuprous cyanide, sulfuric acid-cupric nitrate-cuprous oxide, and the like. Moreover, these can also be used in combination.

Next, the raw material compound (I
The method for producing I) will be described. Raw compound (I
I) includes known compounds and novel compounds. In the case of a new compound, it can be produced by applying a synthetic method of a known compound which has already been reported, or by combining them.

Manufacturing method 1

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(In the formulae, the Ac ring means a monocyclic ring which is not an aromatic ring which may have a substituent. Aa, Ba ring, e
And f have the same meaning as described above. ) The compound represented by the general formula (VII) is
It can be produced by applying the indole synthesis method of Ischer, the tetrahydrocarbazole synthesis method of Borsche [Org. Syn. IV , 884 (1963)], and the like. That is, a cyclic ketone represented by the general formula (V) and an o-represented by the general formula (VI).
The hydrazino aromatic carboxylic acid can be produced, for example, by heating in acetic acid or formic acid or in a neutral solvent such as ethanol in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid or zinc chloride. The compound represented by the general formula (VIII) is
It can be produced by dehydrogenating compound (VII) with a dehydrogenating agent. Examples of the dehydrogenating agent include 2,
3-dichloro-5,6-dicyano-1,4-berezoquinone, chloranil, palladium-carbon and the like can be mentioned. The reaction is usually performed at room temperature or under heating. The target compound (IIa) can be produced by condensing the compound (VIII) and the compound (IX).
Examples of the condensation method include an acid chloride method, an active ester method, a mixed acid anhydride method, and a method using 1,3-dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole, diphenylphosphoryl azide as a condensing agent. .

Manufacturing method 2

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(Wherein G represents an oxygen atom or a sulfur atom. K and L represent a leaving group and R represents a lower alkyl group. Aa, Ba, e and f have the same meanings as described above. The compound represented by the general formula (XII) can be produced by reacting the compound of the general formula (X) with the compound of the general formula (XI). A preferable example of the leaving group K in the compound (XI) is a nitro group, and a preferable example of L is a halogen atom. The reaction can be carried out by heating in the presence or absence of a base such as triethylamine, sodium acetate or sodium hydroxide. The target compound (IIb) is obtained by subjecting the ester of the compound (XII) to alkaline hydrolysis.
III), and in the same manner as in Production method 1, the compound (IX)
It can be produced by condensation with.

When the compound of the present invention is used as a medicine, it is administered orally or parenterally. The dose is not particularly limited, although it varies depending on the degree of symptoms, age of patient, sex, weight, difference in sensitivity, administration method, administration time, administration interval, properties of pharmaceutical preparation, preparation, type, type of active ingredient, etc. Adults 1-3000mg per day, preferably about 10-
The dose is 2000 mg, more preferably 20 to 1000 mg, which is usually administered in 1 to 3 times daily. When preparing a solid preparation for oral use, the main ingredient is an excipient and further a binder, if necessary.
After adding disintegrant, lubricant, coloring agent, flavoring agent, etc.,
Tablets, coated tablets, granules, fine granules, powders, capsules and the like are prepared by a conventional method. Examples of the excipient include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, and the like, and examples of the binder include polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose,
Hydroxypropyl methylcellulose and the like, lubricants such as magnesium stearate, talc, and silica are those that are permitted to be added to pharmaceuticals as coloring agents, and as flavoring agents, cocoa powder, peppermint Brain, aromatic acid, peppermint oil, dragon brain, cinnamon powder and the like are used. Of course, these tablets and granules may be sugar-coated, gelatin-coated and optionally coated as needed. When preparing an injection, p should be added as the main drug if necessary.
H adjusting agent, buffering agent, suspending agent, solubilizing agent, stabilizing agent,
An isotonic agent, a preservative, etc. are added, and an intravenous, subcutaneous or intramuscular injection is prepared by a conventional method. At that time, if necessary, the product may be freeze-dried by a conventional method. Examples of the suspending agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like. Examples of the solubilizing agent include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester. Examples of the stabilizer include sodium sulfite, sodium metasulfite and the like, and examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol and the like.

[0023]

Next, examples of pharmacological experiments for describing the effects of the compounds of the present invention will be shown. Experimental Example 1 in P388 cells (mouse leukemia cells)
In vitro antitumor test 10% fetal bovine serum, penicillin (100 units / ml), streptomycin (100 μg / ml), mercaptoethanol (5
(× 10 ⁻⁵ M) and sodium pyruvate (1 mM) were added to RPMI1640 medium (Sanko Junyaku Co., Ltd.), and P388 cells were suspended in each well of a 96-well U-bottom microplate at 1.25 × 10 ³ cells (0.
1 ml) and seeded at 37 ℃ in an incubator containing 5% carbon dioxide gas.
Cultured for one day.

The compound of the present invention was treated with dimethyl sulfoxide.
Dissolve at a concentration of 10 ^-2 M and 10% fetal bovine serum-RPMI1640
The medium was diluted to a concentration of 10 ⁻⁴ M or 10 ⁻⁵ M. Using this as the highest concentration, 3-fold serial dilution was performed with 10% fetal bovine serum-RPMI 1640 culture solution. This is P388 mentioned earlier.
0.1 ml of each was added to each well of the cell culture plate and cultured at 37 ° C. for 3 days in a culture vessel containing 5% carbon dioxide.

After culturing, 0.05 ml of MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] solution (3.3 mg / ml) was added to each well for another 2 hours. Cultured. After centrifuging the microplate and removing the supernatant by suction from each well, the produced formazan was dissolved in 0.1 ml of dimethyl sulfoxide, and the absorbance at 540 nm was measured with a microplate reader, which was used as an index of the number of viable cells. The inhibition rate was calculated from the following formula, and the concentration of the test compound that inhibited 50% (IC ₅₀ ) was determined.

[0026]

[Equation 1]

T: Absorbance of the hole to which the test compound was added C: Absorbance of the hole to which the test compound was not added The obtained IC ₅₀ values are shown in Table 1.

[0028]

[Table 1]

Experimental Example 2 KB cells (human nasopharyngeal carcinoma cells)
In vitro antitumor test against 10% fetal bovine serum, penicillin (100 units / ml), streptomycin (100 μg / ml), mercaptoethanol (5
KB cells suspended in RPMI1640 medium (Sanko Junyaku Co., Ltd.) containing × 10 ^-5 M) and sodium pyruvate (1 mM)
1.25 x 10 ³ (0.1 m
l), and the cells were cultured at 37 ° C. for 1 day in an incubator containing 5% carbon dioxide. The compound of the present invention was treated with dimethyl sulfoxide to give 10
^It was dissolved at a concentration of ^-2 M and diluted with 10% fetal calf serum-RPMI1640 culture medium to a concentration of 10 ^-4 M or 10 ^-5 M. Using this as the highest concentration, 3-fold serial dilution was performed with 10% fetal bovine serum-RPMI 1640 culture solution. 0.1 ml of this was added to each well of the culture plate of KB cells described above, and the mixture was cultured at 37 ° C. for 3 days in a culture vessel containing 5% carbon dioxide.

After culturing, 0.05 ml of MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] solution (3.3 mg / ml) was added to each well for another 2 hours. Cultured. After removing the supernatant from each well by suction, remove the formed formazan by adding 0.1 ml of dimethyl sulfoxide.
The cells were lysed and the absorbance at 540 nm was measured with a microplate reader and used as an index of the number of living cells. The inhibition rate was calculated from the following formula, and the concentration of the test compound that inhibited 50% (IC
₅₀ ) asked.

[0031]

[Equation 2]

T: Absorbance of the hole to which the test compound was added C: Absorbance of the hole to which the test compound was not added The obtained IC ₅₀ values are shown in Table 2.

[0033]

[Table 2]

Experimental Example 3 In vivo antitumor test against M5076 (mouse reticulosarcoma) BDF1 mice (6 to 7 weeks of age, female) were subcutaneously implanted on the lateral side of the body at 1 × 10 5.
^Six M5076 were transplanted. The compound of the present invention was dissolved in 5% glucose solution, and intraperitoneally administered once a day according to each schedule on and after the day after transplantation. The control group was administered with 5% glucose solution. The experiment was carried out with 10 mice as a control group and 5 mice as a drug administration group. The tumor was excised 21 days after the transplantation and the tumor weight was measured. The tumor growth inhibition rate of the drug-administered group relative to the control group was determined by the following formula. Growth inhibition rate (%) = C−T / C × 100 T; average tumor weight of test compound administration group C: average tumor weight of control group Experimental results are shown in Table 3.

[0035]

[Table 3]

As is clear from the above experimental examples, the compound of the present invention has an excellent antitumor effect and is useful as an antitumor agent.

[0037]

EXAMPLES Next, Production Examples showing production of starting compounds of the compounds of the present invention and Examples of representative compounds of the invention compounds will be shown, but the present invention is not limited thereto.

Production Example 1 9H-carbazole-1-carboxylic acid

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2-hydrazinobenzoic acid hydrochloride 19.8 g (0.
A suspension of 105 mol) of acetic acid (180 ml) is gently boiled and stirred with cyclohexanone 10.4 ml (0.100 mol) of acetic acid (20 ml).
The solution was added dropwise over 10 minutes. After the addition was completed, the mixture was heated under reflux for 6 hours, allowed to cool, and water (1 L) was slowly added. The precipitated product is filtered off with suction, washed with water and dried to give 5, 6, 7, 8
-Tetrahydro-9H-carbazole-1-carboxylic acid
10.0 g (yield 46%) was obtained. Then, 5, 6, 7, 8-
Tetrahydro-9H-carbazole-1-carboxylic acid 4.
Toluene (100 ml) was added 3 g (20 mmol) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (10 g, 44 mmol).
And was heated to reflux for 2 hours. After cooling down, the precipitate that precipitated was collected by suction filtration and purified by silica gel column chromatography (eluting with dichloromethane: methanol = 9: 1) to obtain 2.46 g (yield 58%) of the title compound. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 7.19-7.23 (m, 1H), 7.26 (t, J
= 7.6Hz, 1H), 7.40-7.45 (m, 1H), 7.74 (d, J = 8.0Hz, 1H), 8.00
(dd, J = 0.8,7.6Hz, 1H), 8.17 (d, J = 7.6Hz, 1H), 8.41 (dd, J =
0.8,7.6Hz, 1H), 11.34 (br-s, 1H), 13.18 (br-s, 1H)

Production Example 2 6-Acetyl-9H-carbazole-1-carboxylic acid

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Aluminum chloride, anhydrous 880 mg (6.6 mmol)
0.21 ml of acetic anhydride (2.2 m
mol) was added and the mixture was stirred at room temperature, and then a suspension of 420 mg (2 mmol) of the compound of Production Example 1 in chloroform (20 ml) was added all at once under ice cooling. After the addition was completed, the temperature was slowly returned to room temperature and the mixture was stirred overnight. This was slowly poured into ice and 1N hydrochloric acid was added to decompose aluminum chloride. The mixture was extracted with ethyl acetate and tetrahydrofuran, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: ethanol = 4: 1) to give the title compound (370 mg, yield 75%).
I got ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.68 (s, 3H), 7.34 (t, J = 7.6H
z, 1H), 7.80 (d, J = 8.8Hz, 1H), 8.03-8.06 (m, 1H), 8.06 (dd, J
= 1.6,8.8Hz, 1H), 8.55 (d, J = 7.6Hz, 1H), 8.91 (d, J = 1.6Hz, 1
H), 11.73 (br-s, 1H)

Production Example 3 N- [2- (dimethylamino) ethyl] -6-nitro-
9H-carbazole-1-carboxamide ( 1 ) and N- [2- (dimethylamino) ethyl] -3-nitro-
9H-carbazole-1-carboxamide ( 2 )

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Carbazole-1-carboxylic acid 2.0 g (9.5 m
To a solution of (mol) in acetic acid (250 ml) was added dropwise a solution of 1.01 g (10 mmol) of potassium nitrate in concentrated sulfuric acid (2.5 ml) in a cold water bath with stirring. After stirring overnight at room temperature, slowly add water (500 ml),
The precipitated product was collected by filtration, washed with water and dried to give 2.3 g of a mixture of regioisomers of nitrocarbazole-1-carboxylic acid. This was dissolved in 100 ml of N, N-dimethylformamide, and 2.9 g (18 mmol) of 1,1-carbonyldiimidazole
Was added and stirred for 2 hours. Next, 4 ml (36 mmol) of N, N-dimethylethylenediamine was added and the mixture was stirred overnight. After adding water, the product was extracted with ethyl acetate, and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and concentrated. The residue was separated and purified by silica gel column chromatography (eluting with dichloromethane: ethanol), and N- [2- (dimethylamino) ethyl] -6-nitro-9H-carbazole-1-carboxamide ( 1 ).
Of 1.46 g (yield 47.4%), and N- [2- (dimethylamino) ethyl] -3-nitro-9H-carbazole-1.
-210 mg (yield 6.8%) of carboxamide ( 2 ) was obtained. 6-nitro form ( 1 , as hydrochloride) ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.85 (br-s, 6H), 3.26-3.38
(m, 2H), 3.73 (q, J = 5.6Hz, 2H), 7.38 (t, J = 7.6Hz, 1H), 7.86
(d, J = 9.0Hz, 1H), 8.09 (d, J = 7.6Hz, 1H), 8.32 (dd, J = 2.2,9.
0Hz, 1H), 8.60 (d, J = 7.6Hz, 1H), 9.04 (t, J = 5.6Hz, 1H), 9.22
(d, J = 2.2Hz, 1H), 9.93 (br-s, 1H), 12.14 (s, 1H) 3-nitro compound ( 2 , as hydrochloride) ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.84 (br-s, 6H), 3.20-3.40
(m, 2H), 3.65-3.80 (m, 2H), 7.31 (t, J = 7.6Hz, 1H), 7.52 (t, J
= 7.6Hz, 1H), 7.81 (d, J = 7.6Hz, 1H), 8.41 (d, J = 7.6Hz, 1H),
8.90 (d, J = 2.0Hz, 1H), 9.20-9.28 (m, 1H), 9.35 (d, J = 2.0Hz,
1H), 9.64-9.86 (m, 1H), 12.14 (br-s, 1H)

Example 1 2- [2- (Dimethylamino) ethyl] -1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H)
-Dione hydrochloride

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1.06 g (5 mmol) of the compound of Preparation Example 1 was added to N,
Dissolved in N-dimethylformamide (50 ml) to give N, N '
-Carbonyldiimidazole (1.62 g, 10 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, 2.2 ml (20 mmol) of N, N-dimethylethylenediamine was added and stirred overnight. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (dichloromethane: methanol = 2).
Purification by elution at 0: 1) gave 1.4 g (quantitative) of N- [2- (dimethylamino) ethyl] -9H-carbazole-1-carboxamide. 350 mg (1.24 mmol) of this N- [2- (dimethylamino) ethyl] -9H-carbazole-1-carboxamide was dissolved in N, N-dimethylformamide (20 ml), and 110 mg of sodium hydride (oil-based) under a nitrogen stream. (2.74 mmol) was added, and after 30 minutes, 0.12 ml (1.25 mmol) of ethyl chloroformate was added under ice cooling, and the mixture was stirred for 30 minutes. After 1N hydrochloric acid was added to acidify and the solvent was distilled off under reduced pressure,
A saturated aqueous sodium hydrogen carbonate solution was added to make the mixture weakly alkaline, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. Ethanol + 1N hydrochloric acid was added thereto, and the mixture was stirred overnight. The precipitated crystals were collected by filtration to give the title compound
200 mg (47% yield) were obtained. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.90 (br-s, 6H), 3.44-3.49
(m, 2H), 4.41 (t, J = 5.6Hz, 2H), 7.55-7.60 (m, 1H), 7.67-7.7
2 (m, 2H), 8.10 (dd, J = 0.8,7.6Hz, 1H), 8.34-8.37 (m, 1H), 8.
38-8.41 (m, 1H), 8.58 (dd, J = 0.8,7.6Hz, 1H), 9.62 (br-s, 1
H)

Example 2 8-Acetyl-2- [2- (dimethylamino) ethyl]
-1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

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300 mg (1.2 mmol) of the compound of Preparation Example 2 was added to N,
Dissolved in N-dimethylformamide (20 ml) to give N, N '
-Carbonyldiimidazole (400 mg, 2.4 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, 0.53 ml (4.8 mmol) of N, N-dimethylethylenediamine was added and stirred overnight. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water,
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol, hexane was added for crystallization, and N- [2- (dimethylamino) ethyl]-
180 mg of 8-acetyl-9H-carbazole-1-carboxamide was obtained. This was dissolved in N, N-dimethylformamide (10 ml), and under a nitrogen stream, 56 mg (1.4 mmol) of sodium hydride (oil) was added, and after 30 minutes, 0.14 ml (1.4 mmol) of ethyl chloroformate under ice cooling. Was added and stirred for 10 minutes. 1N
Hydrochloric acid was added to make the mixture acidic, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to make the mixture weakly alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: ethanol = 9: 1). This was suspended in ethanol, 1N hydrochloric acid was added, and the mixture was stirred overnight. The precipitated crystals were collected by filtration to give the title compound (125 mg, yield 27%). Melting point: Wetting started at 240 ° C., coloring started at 258 ° C., 1/2 wet coloring at 270 ° C., whole infiltrated at 281 to 284 ° C., colored brown, and gas was generated to decompose. FAB mass spectrometry m / z; 350 (MH ⁺ ) ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.75 (s, 3H), 2.90-2.94 (m, 6)
H), 3.48-3.52 (m, 2H), 4.42 (t, J = 5.6Hz, 2H), 7.75 (t, J = 8.0
Hz, 1H), 8.16 (d, J = 8.0Hz, 1H), 8.31 (dd, J = 1.6,8.8Hz, 1H),
8.49 (d, J = 8.8Hz, 1H), 8.73 (d, J = 8.0Hz, 1H), 9.05 (d, J = 1.6
Hz, 1H), 9.44 (br-s, 1H)

Example 3 2- [2- (Dimethylamino) ethyl] -8-nitro-
1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

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N- [2- (dimethylamino) of Production Example 3
5.82 g of ethyl] -6-nitro-9H-carbazole-1-carboxamide was added to N, N-dimethylformamide (200
ml), and under a nitrogen stream, sodium hydride (oil-based)
After adding 1.75g (40mmol) and stirring for 1 hour, under ice cooling, ethyl chloroformate 3.8ml (40mmol) in dichloromethane (10ml)
The solution was added and stirred for 30 minutes. 1N Hydrochloric acid was added to acidify, and the deposited precipitate was collected by filtration. Ethanol was added and heated, and after cooling, the precipitate was collected by filtration and the title compound 5.54 g (yield 36%)
I got ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.89 (br-s, 6H), 3.46-3.50
(m, 2H), 4.43 (t, J = 5.6Hz, 2H), 7.76 (t, J = 7.6Hz, 1H), 8.19
(d, J = 7.6Hz, 1H), 8.53-8.60 (m, 2H), 8.80 (d, J = 7.6Hz, 1H),
9.38 (d, J = 2.0Hz, 1H), 10.18 (br-s, 1H)

Example 4 8-Amino-2- [2- (dimethylamino) ethyl]-
1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

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5.54 g (14 mmol) of the compound of Example 3 was suspended in acetic acid (200 ml) and 1N hydrochloric acid, 10% palladium carbon (containing 50% water) (550 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. After removing the catalyst by filtration and distilling off the solvent under reduced pressure, water,
A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness. Ethanol was added and heated, and after cooling, the precipitate was collected by filtration and used as the free base of the title compound.
3.74 g (yield 81%) was obtained. Of this, 430 mg (1.3 mmol)
Was suspended in ethanol (20 ml), 1N hydrochloric acid (1.5 ml) was added, and the mixture was stirred overnight. The precipitated crystals were collected by filtration to give the title compound 480
mg (quantitative) was obtained. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.91 (br-s, 6H), 3.44-3.50
(m, 2H), 4.39 (t, J = 5.6Hz, 2H), 7.04-7.08 (m, 1H), 7.54-7.5
6 (m, 1H), 7.63 (t, J = 7.6Hz, 1H), 8.05 (dd, J = 0.8,7.6Hz, 1
H), 8.12 (d, J = 8.8Hz, 1H), 8.44 (dd, J = 0.8,7.6Hz, 1H), 9.60
(br-s, 1H)

Example 5 8-Acetylamino-2- [2- (dimethylamino) ethyl] -1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

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1.61 g (5 mm) of the free base of the compound of Example 4
ol) was suspended in pyridine (15 ml), acetic anhydride (15 ml) was added and the mixture was stirred at room temperature for 3 hours, ethyl acetate was added and the precipitate was collected by filtration. This was suspended in ethanol, 1N hydrochloric acid was added, and the mixture was stirred, and the precipitated crystals were collected by filtration to give the title compound (1.81 g, yield 90%). Water and saturated aqueous sodium hydrogen carbonate solution were added to this, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness. This was suspended in ethanol, the precipitate was collected by filtration, and then ethanol and 1
N hydrochloric acid was added and stirred, and the precipitated crystals were collected by filtration to give the title compound.
1.37 g (68% yield) was obtained. Melting point: Wet coloring started at 255 ° C., 1/2 at 267 ° C., whole infiltrated at 269 ° C., colored brown and decomposed. FAB mass spectrometry m / z; 365 (MH ⁺ ) ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.12 (s, 3H), 2.92 (br-s, 6)
H), 3.45-3.52 (m, 2H), 4.40 (t, J = 5.6Hz, 2H), 7.67 (t, J = 7.6
Hz, 1H), 7.74 (dd, J = 2.0,8.8Hz, 1H), 8.10 (dd, J = 0.8,7.6H
z, 1H), 8.30 (d, J = 8.8Hz, 1H), 8.53 (dd, J = 0.8,7.6Hz, 1H),
8.62 (d, J = 2.0Hz, 1H), 9.29 (br-s, 1H), 10.32 (s, 1H)

Example 6 2- [2- (Dimethylamino) ethyl] -8-hydroxy-1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

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The title compound was obtained by hydroxylating the sulfate salt of the compound of Example 4 via the diazonium salt. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.87 (br-s, 6H), 3.36-3.48
(m, 2H), 4.32-4.40 (m, 2H), 7.09 (dd, J = 2.4,8.8Hz, 1H), 7.6
2 (t, J = 7.6Hz, 1H), 7.63 (d, J = 2.4Hz, 1H), 8.04 (d, J = 7.6Hz,
1H), 8.15 (d, J = 8.8Hz, 1H), 8.48 (d, J = 7.6Hz, 1H), 9.30 (br-
s, 1H), 9.84 (s, 1H)

Example 7 8-Chloro-2- [2- (dimethylamino) ethyl]-
1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

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The title compound was obtained by subjecting the sulfate salt of the compound of Example 4 to chlorination by a Sandmeyer reaction via a diazonium salt. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.28 (br-s, 6H), 3.42-3.48
(m, 2H), 4.40 (t, J = 5.8Hz, 2H), 7.71 (t, J = 7.6Hz, 1H), 7.73
(dd, J = 2.0,8.6Hz, 1H), 8.13 (dd, J = 0.8,7.6Hz, 1H), 8.36
(d, J = 8.6Hz, 1H), 8.53 (d, J = 2.0Hz, 1H), 8.60 (dd, J = 0.8,7.
6Hz, 1H), 9.89 (br-s, 1H)

Example 8 2- [2- (Dimethylamino) ethyl] -8-methyl-
1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

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The title compound was obtained from 6-methyl-9H-carbazole-1-carboxylic acid in the same manner as in Example 1. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.51 (s, 3H), 2.88 (br-s, 6
H), 3.42-3.47 (m, 2H), 4.38 (t, J = 5.8Hz, 2H), 7.47-7.50 (m,
1H), 7.65 (t, J = 7.6Hz, 1H), 8.05 (dd, J = 0.8,7.6Hz, 1H), 8.1
2-8.14 (m, 1H), 8.23 (d, J = 8.8Hz, 1H), 8.49 (dd, J = 0.8,7.6H
z, 1H), 9.65 (br-s, 1H)

Example 9 2- [2- (Dimethylamino) ethyl] -8-methoxy-1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

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6-methoxy-9H-carbazole-1-
The title compound was obtained from the carboxylic acid in the same manner as in Example 1. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.92 (br-s, 6H), 3.46-3.51
(m, 2H), 3.92 (s, 3H), 4.40 (t, J = 5.6Hz, 2H), 7.27 (dd, J = 2.
6,9.0Hz, 1H), 7.68 (t, J = 7.6Hz, 1H), 7.97 (d, J = 2.6Hz, 1H),
8.09 (dd, J = 0.8,7.6Hz, 1H), 8.26 (d, J = 9.0Hz, 1H), 8.57 (d
d, J = 0.8,7.6Hz, 1H), 9.43 (br-s, 1H)

Example 10 2- [2- (Dimethylamino) ethyl] -5-nitro-
1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

[Chemical 21]

N- [2- (dimethylamino) of Production Example 3
Ethyl] -3-nitro-9H-carbazole-1-cal
The title compound was obtained using voxamide in the same manner as in Example 3. ¹ HNMR (DMSO-d₆) Δ (ppm); 2.83 (br-s, 6H), 3.28-3.46
(m, 2H), 4.36-4.44 (m, 2H), 7.63-7.68 (m, 1H), 7.77-7.82
(m, 1H), 8.41-8.44 (m, 1H), 8.59-8.62 (m, 1H), 8.78 (d, J = 2.
0Hz, 1H), 9.57 (d, J = 2.0Hz, 1H), 9.60-9.88 (m, 1H)

Example 11 5-Amino-2- [2- (dimethylamino) ethyl]-
1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione dihydrochloride

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The title compound was obtained by treating the compound of Example 10 in the same manner as in Example 4. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.84-2.94 (m, 6H), 3.42-3.5
2 (m, 2H), 4.40 (t, J = 5.6Hz, 2H), 7.54-7.59 (m, 1H), 7.67-7.
73 (m, 1H), 7.86 (d, J = 1.6Hz, 1H), 8.23 (d, J = 1.6Hz, 1H), 8.3
2-8.38 (m, 2H), 10.05 (br-s, 1H)

Example 12 5-Acetylamino-2- [2- (dimethylamino) ethyl] -1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

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The title compound was obtained by treating the compound of Example 11 in the same manner as in Example 5. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.15 (s, 3H), 2.89-2.94 (m, 6
H), 3.45-3.51 (m, 2H), 4.40 (t, J = 5.8Hz, 2H), 7.54-7.58 (m,
1H), 7.67-7.72 (m, 1H), 8.30 (d, J = 7.6Hz, 1H), 8.34-8.38
(m, 2H), 8.66 (d, J = 1.6Hz, 1H), 9.57 (br-s, 1H), 10.53 (s, 1
H)

Example 13 2- [2- (Dimethylamino) ethyl] -1H-pyrimido [5,6,1-kl] phenothiazine-1,3 (2
H) -dione hydrochloride

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10H-phenothiazine-1-carboxylic acid
228 mg (0.937 mmol) was suspended in 5 ml of chloroform, and phosphorus trichloride (2 ml) and N, N-dimethylformamide (0.4 ml) were sequentially added dropwise under ice-cooling stirring. After stirring under ice cooling for 30 minutes, the stirring was continued at room temperature for 3.5 hours. The solvent was completely distilled off from the reaction mixture under reduced pressure, the obtained residue was dissolved in 5 ml of toluene, and the mixture was added dropwise to a solution of 1 ml of N, N-dimethylethylenediamine in 20 ml of chloroform under stirring with ice cooling. The reaction mixture was allowed to come to room temperature gradually and stirring was continued overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, the organic layer was separated, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off to give N- [2- (dimethylamino) ethyl] -10H-.
290 mg of phenothiazine-1-carboxamide was obtained. N
-[2- (Dimethylamino) ethyl] -10H-phenothiazine-1-carboxamide 100 mg, triethylamine
0.2 ml was dissolved in 5 ml of dichloromethane, 0.06 ml of ethyl chloroformate was added with stirring at room temperature, and stirring was continued for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the resulting residue was dissolved in 5 ml of N, N-dimethylformamide to give 110-
The mixture was heated and stirred at 120 ° C for 40 minutes. The reaction mixture was returned to room temperature, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 90 mg of the free base of the title compound. This was converted into a hydrochloride by a conventional method and then recrystallized from ethanol to obtain 76 mg of the title compound. FAB mass spectrometry m / z; 342 (MH ⁺ ) ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.90 (s, 6H), 3.48 (br-t, J =
5.6Hz, 2H), 4.34 (t, J = 5.6Hz, 2H), 7.29 (td, J = 1.2,7.6Hz, 1
H), 7.35 (td, J = 1.6,7.6Hz, 1H), 7.41 (t, J = 7.6Hz, 1H), 7.43
(dd, J = 1.6,7.6Hz, 1H), 7.70 (dd, J = 1.6,7.2Hz, 1H), 7.78 (d
d, J = 1.2,8.4Hz, 1H), 7.88 (dd, J = 1.2,8.0Hz, 1H)

Example 14 2- [2- (Dimethylamino) ethyl] -1H-benzo [b] pyrimido [5,6,1-jk] [1] benzazepine-1,3 (2H) -dione hydrochloride

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5H-dibenz [b, f] azepine-4-
The carboxylic acid was treated in the same manner as in Example 1 to obtain the title compound. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.85 (s, 3H), 2.92 (s, 3H), 3.
40-3.50 (m, 2H), 4.26-4.32 (m, 2H), 6.73 (d, J = 11.4Hz, 1H).
6.94 (d, J = 11.4Hz, 1H), 7.28-7.44 (m, 5H), 7.61 (d, J = 8.4H
z, 1H), 7.93 (d, J = 8.4Hz, 1H), 9.84 (br-s, 1H)

Example 15 5-Acetylamino-2- [2- (dimethylamino) ethyl] -1H-pyrido [3,2-b] pyrimido [5,5]
6,1-ed] [1,4] benzoxazine-1,3
(2H) -dione hydrochloride

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10H-pyrido [3,2-b] [1,4]
The title compound was obtained in the same manner as in Examples 1, 11, and 12 using benzoxazine-7-nitro-9-carboxylic acid. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.06 (s, 3H), 2.85 (s, 6H), 3.
37 (q, J = 5.2,11.2Hz, 2H), 4.28 (t, J = 5.6Hz, 2H), 7.28 (dd, J
= 4.4,8.0Hz, 1H), 7.57 (dd, J = 1.2,8.0Hz, 1H), 7.64 (d, J = 2.
4Hz, 1H), 7.91 (d, J = 2.4,1H), 8.10 (dd, J = 1.6,4.4Hz, 1H),
9.82 (br-s, 1H), 10.5 (s, 1H)

Example 16 9-Acetylamino-2- [2- (dimethylamino) ethyl] -1H-pyrimido [5,6,1-kl] phenoxazine-1,3 (2H) dione hydrochloride

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7-Nitro-10H-phenoxazine-1
Using the same carboxylic acid as in Examples 1, 4 and 5, the title compound was obtained. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.06 (s, 3H), 2.88 (s, 6H), 3.
38-3.44 (m, 2H), 4.32 (t, J = 5.6Hz, 2H), 7.19 (dd, J = 1.2,9.6
Hz, 1H), 7.31 (td, J = 1.6,7.6Hz, 1H), 7.39 (dt, J = 1.6,7.6H
z, 1H), 7.55 (d, J = 1.6Hz, 1H), 7.64 (dt, J = 1.6,7.6Hz, 1H),
8.44 (dd, J = 1.6,9.6Hz, 1H), 9.80 (br-s, 1H), 10.30 (s, 1H)

Example 17 2- [2- (Dimethylamino) ethyl] -8-methanesulfonylamino-1H-pyrimido [5,6,1-jk]
Carbazole-1,3 (2H) -dione hydrochloride

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The title compound was obtained in the same manner as in Example 5. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.90 (br-s, 6H), 3.05 (s, 3
H), 3.42-3.52 (m, 2H), 4.35-4.42 (m, 2H), 7.47-7.55 (m, 1
H), 7.67 (t, J = 7.6Hz, 1H), 8.06-8.16 (m, 2H), 8.32 (d, J = 8.8
Hz, 1H), 8.57 (d, J = 7.6Hz, 1H), 9.35 (br-s, 1H), 10.01 (s, 1
H)

Example 18 2- [2- (Dimethylamino) ethyl] -8- (2-thiophenecarbonylamino) -1H-pyrimido [5,5]
6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

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The title compound was obtained in the same manner as in Example 5. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.91 (br-s, 6H), 3.44-3.52
(m, 2H), 4.39 (t, J = 5.6Hz, 2H), 7.25 (dd, J = 4.0,5.0Hz, 1H),
7.68 (t, J = 7.6Hz, 1H), 7.89 (dd, J = 1.2,5.0Hz, 1H), 7.93 (d
d, J = 2.0,8.8Hz, 1H), 8.10 (dd, J = 0.8,7.6Hz, 1H), 8.11 (dd,
J = 1.2,4.0Hz, 1H), 8.34 (d, J = 8.8Hz, 1H), 8.54 (dd, J = 0.8,
7.6Hz, 1H), 8.72 (d, J = 2.0Hz, 1H), 9.42 (br-s, 1H), 10.61
(s, 1H)

Example 19 2- [2- (Dimethylamino) ethyl] -8- (2-thiophenesulfonylamino) -1H-pyrimido [5
6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

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The title compound was obtained in the same manner as in Example 5. (Free base) ¹ HNMR (CDCl ₃ ) δ (ppm); 2.90 (br-s, 6H), 3.
42-3.52 (m, 2H), 4.38 (t, J = 5.6Hz, 2H), 7.09 (dd, J = 3.7,4.9
Hz, 1H), 7.38 (dd, J = 2.2,8.8Hz, 11H), 7.55 (dd, J = 1.3,3.7H
z, 1H), 7.67 (t, J = 7.7Hz, 1H), 7.87 (dd, J = 1.3,4.9Hz, 1H),
8.08 (d, J = 2.2Hz, 1H), 8.11 (dd, J = 0.7,7.7Hz, 1H), 8.27 (d,
J = 8.8Hz, 1H), 8.58 (dd, J = 0.7,7.7Hz, 1H), 9.31 (br-s, 1H),
10.66 (s, 1H)

Example 20 8-Acetylamino-2- [2- (dimethylamino) ethyl] -9-methyl-1H-pyrimido [5,6,1-j
k] carbazole-1,3 (2H) -dione hydrochloride

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The title compound was obtained in the same manner as in Example 5. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.14 (s, 3H), 2.44 (s, 3H), 2.
88-2.96 (m, 6H), 3.46-3.53 (m, 2H), 4.40 (t, J = 5.5Hz, 2H),
7.66 (t, J = 7.6Hz, 1H), 8.07 (d, J = 7.6Hz, 1H), 8.23 (s, 1H),
8.33 (s, 1H), 8.51 (d, J = 7.6Hz, 1H), 9.41 (br-s, 1H), 9.58
(s, 1H)

Example 21 2- [2- (Dimethylamino) ethyl] -8-octanoylamino-1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

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The title compound was obtained in the same manner as in Example 5. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 0.88 (t, J = 6.8Hz, 3H), 1.22-
1.40 (m, 8H), 1.59-1.70 (m, 2H), 2.38 (t, J = 7.3Hz, 2H), 2.89
-2.96 (m, 6H), 3.50 (t, J = 6.0Hz, 2H), 4.40 (t, J = 6.0Hz, 2H),
7.68 (t, J = 7.6Hz, 1H), 7.75 (dd, J = 2.0,8.8Hz, 1H), 8.10 (d,
J = 7.6Hz, 1H), 8.30 (d, J = 8.8Hz, 1H), 8.53 (d, J = 7.6Hz, 1H),
8.66 (d, J = 2.0Hz, 1H), 9.31 (br-s, 1H), 10.25 (s, 1H)

Example 22 2- [2- (Dimethylamino) ethyl] -8- (1-pyrrolyl) -1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

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96 mg of the free base of the compound of Example 4 (0.3 mmo
l) was dissolved in acetic acid (10 ml), 39 μl of 2,5-dimethoxytetrahydrofuran (0.3 ml) was added, and the mixture was heated under reflux for 30 minutes. After allowing to cool, the solvent was evaporated, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated, and hexane + ethanol was added to the residue for crystallization to give 85 mg (75%) of the free base of the title compound. This was suspended in ethanol and 1N hydrochloric acid was added to give 80 mg (65%) of the title compound as a hydrochloride salt. (Free base) ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.23 (s, 6H), 2.5
6 (t, J = 6.9Hz, 2H), 4.16 (t, J = 6.9Hz, 2H), 6.35 (t, J = 2.2Hz,
2H), 7.52 (t, J = 2.2Hz, 2H), 7.69 (t, J = 7.7Hz, 1H), 7.89 (dd,
J = 2.2,8.8Hz, 1H), 8.10 (dd, J = 0.9,7.7Hz, 1H), 8.39 (d, J =
8.8Hz, 1H), 8.56 (dd, J = 0.9,7.7Hz, 1H), 8.60 (d, J = 2.2Hz, 1
H)

Example 23 8-Dimethylamino-2- [2- (dimethylamino) ethyl] -1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione dihydrochloride

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36 mg (1 mmol) of the free base of Example 4 was suspended in ethanol and formaldehyde aqueous solution (37%) 1 m
1, 1N hydrochloric acid (1 ml) and 10% palladium on carbon (5 mg) were added, and reductive alkylation was carried out under zero hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated, aqueous sodium hydrogen carbonate was added for neutralization, and the mixture was extracted with ethyl acetate. After washing with water and concentration, ethanol and 1N hydrochloric acid were added to the residue to give the title compound (20 mg, 51%). ¹ HNMR (DMSO-d ₆ + D ₂ O) δ (ppm); 2.93 (br-s, 6H), 3.14 (b
rs, 6H), 3.46-3.54 (m, 2H), 4.37-4.45 (m, 2H), 7.34-7.48
(m, 1H), 7.70 (t, J = 7.6HZ, 1H), 7.96-8.07 (m, 1H), 8.11 (d, J
= 7.6Hz, 1H), 8.24-8.32 (m, 1H), 8.55 (d, J = 7.6Hz, 1H)

Example 24 8-Butyryl-2- [2- (dimethylamino) ethyl]
-1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

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The title compound was obtained in the same manner as in Production Example 2 and Example 2. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 1.00 (t, J = 7.4Hz, 3H), 1.67-
1.78 (m, 2H), 2.89 (br-s, 6H), 3.18 (t, J = 7.1Hz, 2H), 3.38-
3.55 (m, 2H), 4.41 (t, J = 5.7Hz, 2H), 7.75 (t, J = 7.7Hz, 1H),
8.15 (dd, J = 0.5,7.7Hz, 1H), 8.31 (dd, J = 1.6,8.6Hz, 1H), 8.
48 (d, J = 8.6Hz, 1H), 8.73 (dd, J = 0.5,7.7Hz, 1H), 9.04 (d, J =
1.6Hz, 1H), 9.54 (br-s, 1H)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/55 A61K 31/55 C07D 498/04 C07D 498/14 498/14 513/04 381 513 / 04 381 498/04 112T (72) Inventor Junichi Kamada 2-23-5 Amakubo, Tsukuba City, Ibaraki Prefecture, Maison Gakuen 306 (72) Inventor Kentaro Yoshimatsu 2-9-44 Otodo Minami, Tsuchiura City, Ibaraki Prefecture (72) Invention Takeshi Nagasu 852-13 Nagakuni, Tsuchiura City, Ibaraki Prefecture 852-13 (72) Katsuji Nakamura 1-14-10 Matsushiro, Tsukuba City, Ibaraki Prefecture, A-202 Crest Matsushiro A-202 (72) Toshimitsu Kaminaka 2-Sakaecho, Ushiku City, Ibaraki Prefecture 7-1-203 (72) Inventor Atsumi Iijima 34-4 Hongo, Shinji-mura, Shinji-gun, Ibaraki Prefecture (72) Inventor Hiroshi Yoshino 2-4-7 Tsukushino, Abiko-shi, Chiba Inventor Nozomu Koyanagi Tsukuba, Ibaraki Prefecture City toko 1-10-5 (72) Inventor Kyosuke Kito 1-10-8 Tokodai, Tsukuba, Ibaraki

Claims (4)

[Claims] 1. A compound of the general formula (I) [In the formula, A ring and B ring are the same or different and mean a monocyclic aromatic ring which may have a substituent. X means a bond, an oxygen atom, a sulfur atom or -CH = CH-. Y is of the formula ef (wherein e is a lower alkylene group, f
Means an amino group which may be substituted with a lower alkyl group), or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein X is a bond, or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, wherein ring A and ring B are benzene which may have the same or different substituents, or a pharmaceutically acceptable salt thereof. 4. An antitumor agent comprising the fused tetracyclic heterocyclic derivative according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof as an active ingredient.