JPH10152474A - Phenanthridinium derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having an antitumor activity, useful as a carcinostatic. SOLUTION: This compound is shown by formula I [R<1> is a (substituted) lower aliphatic hydrocarbon; R is a (substituted) lower alkyl, lower cycloalkyl or phenyl; T is a lower alkyl; Y and Z are each OH, or methylenedioxy or phenyl when they are bound to each other; and X<-> is an acid or hydroacid residue], e.g. 2,3-(methylenedioxy)-5methyl-6-ethoxy-7-benzyloxy-8methoxy-5,6- dihydrobenzo [c]phenanthridine. The compound shown by formula I is obtained by the following steps; treatment of a compound shown by formula II, after it is N-methylated, with a lower alcohol under a basic condition to produce a compound shown by formula III (L is a lower alkyl), uncleophilic substitution followed by aromatization of the above compound by oxidation to produce a compound shown by formula IV, and then N-lower alkylation followed by deprotection of the above compound. The compound of formula I can also take the structure of a compound shown by formula V, when treated with a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel phenanthridinium derivative represented by the general formula (A) having antitumor activity and expected as a pharmaceutical, and an antitumor agent comprising the derivative as an active ingredient About.

[0002]

2. Description of the Related Art At present, chemotherapy for cancer patients uses alkylating agents, antimetabolites, antibiotics, plant alkaloids and the like. 2,3- (methylenedioxy)
-5-Methyl-7-hydroxy-8-methoxy-benzo [c] phenanthridinium chloride or iodide is described in Chem. Pharm. Bull. , 33,176
No. 3 (JP-A-2-243628, JP-A-3-184916). Also disclosed are benzo [c] phenanthridinium derivatives and their antitumor activity (JP-A-5-208959).

[0003]

The properties of malignant tumors vary widely, and the use of the above-mentioned antitumor agents leads to the emergence of resistance thereto. Therefore, the development of new antitumor agents is desired.

[0004]

Means for Solving the Problems The present inventors have found that a novel phenanthridinium derivative represented by the general formula (A) has antitumor activity. Further, it has been found that the compound of the present invention has resistance to a chemical reduction reaction and a biological metabolic reaction, and is advantageous for use as a pharmaceutical. That is, the present invention relates to the compound represented by formula (A)

[0005]

Embedded image

[Wherein, R ₁ represents a substituted or unsubstituted lower aliphatic hydrocarbon. R represents a substituted or unsubstituted lower alkyl group, lower cycloalkyl group, or phenyl group. T represents a lower alkyl group. Y and Z each are a hydroxyl group or a lower alkoxy group, or both Y and Z are a hydrogen atom or are connected to represent a methylenedioxy group, or Y and Z are connected to form a phenyl ring. And X ^- represents an acid residue or a hydrogen acid residue. And a novel phenanthridinium derivative represented by the formula: Further, the compound of the present invention is excellent in stability against a chemical reduction reaction and a biological metabolic reaction, and is advantageous when used as a pharmaceutical, and relates to these points.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The term "lower aliphatic hydrocarbon" in the present invention means an alkyl group having 1 to 5 carbon atoms or 1 to 5 carbon atoms.
Represents an alkenylmethyl group. Examples of the alkyl group having 1 to 5 carbon atoms include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and the like. Examples of the alkenylmethyl group having 1 to 5 carbon atoms include allyl, 2-butenyl, 3-methyl-2-butenyl and the like. These lower aliphatic hydrocarbons may be substituted, and the substituent may be a hydroxyl group, a C ₁ -C ₅ alkoxy group, a C ₁ -C ₅ alkoxycarbonyl group, acetyl, halogeno, carbamoyl group, or methoxy group. And a phenyl group which may be substituted.

[0008] Specific substituted or unsubstituted lower aliphatic hydrocarbons of the present invention include methyl, ethyl, propyl,
Isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, 2-hydroxypropyl, allyl, 2-butenyl, 3-methyl-2-butenyl, methoxycarbonylmethyl, isopropoxycarbonylmethyl, carbomoylmethyl, benzyl , 4-methoxyphenylmethyl, fluoromethyl, trifluoromethyl and the like. Particularly preferred are methyl, ethyl, allyl, 2-hydroxyethyl, 2-methoxyethyl and trifluoromethyl.

The lower alkyl group in the present invention is a C ₁ -C ₁ -C ₁ -C ₁ -C ₁ -C ₁ -C ₁ -C ₁ -C ₂ alkyl group.
C _{5 represents} a linear or branched alkyl group, and examples include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and pentyl. Preferably,
Methyl, ethyl and propyl are preferred. Further, the lower cycloalkyl indicates a cycloalkyl group of C ₃ -C _8,
For example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group is mentioned. The lower alkyl group, lower cycloalkyl group or phenyl group in the present invention may be substituted, and the substituent may be a hydroxyl group, a C ₁
-C ₅ lower alkyl group, C ₁ -C ₅ lower alkoxy group,
A phenyl group.

Specific examples of the substituted or unsubstituted lower alkyl group, lower cycloalkyl group and phenyl group in the present invention include, for example, methyl group, ethyl group, propyl group, pentyl group, isopropyl group, benzyl group and the like. Substituted or unsubstituted linear or branched alkyl groups, substituted or unsubstituted cyclic alkyl groups such as cyclopropyl group and cyclohexyl group, and substituted or unsubstituted groups such as phenyl group and p-methoxyphenyl group And the like.

The lower alkoxy group in the present invention is, for example, an alkoxy group having 1 to 5 carbon atoms such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy and pentoxy. But preferably methoxy, ethoxy, n-propoxy,
An alkoxy group having 1 to 3 carbon atoms of i-propoxy is preferred.

Further, the acid residue in the present invention is an acid residue that forms a normal salt, for example, X ^- is a halogeno ion such as a chloride ion, a bromide ion, an iodine ion, a fluorine ion, a sulfate ion, a nitrate ion, -Means a toluenesulfonic acid ion, and the like, and a hydroacid residue is an acid residue that forms a hydrogen salt and has one or two hydrogen atoms, for example,
Examples thereof include a hydrogen sulfate ion and a dihydrogen phosphate ion, and a chlorine ion and a hydrogen sulfate ion are particularly preferable.

A preferred compound in the present invention is a compound represented by the above general formula (A), wherein R ₁ is methyl, ethyl, allyl,
- hydroxyethyl, 2-methoxyethyl or indicates trifluoromethyl, lower alkyl group of R is C ₁ -C _5,
Cyclopropyl, cyclohexyl, phenyl or p-
Preferred is a combination wherein methoxyphenyl is indicated, T is methyl, ethyl or propyl, and Y and Z are both connected to form a methylenedioxy group or connected to form a phenyl ring.

The compound represented by the general formula (A) can be obtained by the following production method. Hereinafter, description will be made on two types. 1. Synthesis where R ₁ or a methyl group is shown in the general formula (A); general formula (C)

[0015]

Embedded image [In the formula, Y and Z are each a hydroxyl group or a lower alkoxy group, or both Y and Z are a hydrogen atom or are connected to represent a methylenedioxy group, or Y and Z are connected to form a phenyl ring I do. ]

A 7-benzyloxy-8-methoxy-benzo [c] phenanthridine derivative (JP-A-5-208959) or 8-benzyloxy-9
-Methoxy-naphtho [2,3-c] phenanthlysine as a raw material, N-methylation reaction, and treatment with a lower alcohol under basic conditions to give a compound of the formula (D)

[0017]

Embedded image [Wherein, Y and Z each represent a hydroxyl group or a lower alkoxy group. Alternatively, Y and Z are both hydrogen atoms or are connected to represent a methylenedioxy group, or
Y and Z connect to form a phenyl ring. L represents a lower alkyl group. ]

The compound represented by the formula is obtained. On the other hand, by performing a nucleophilic substitution reaction using an organometallic reagent and the like, and further performing aromatization by oxidation, the compound represented by the general formula (E)

[0019]

Embedded image [In the formula, R represents a substituted or unsubstituted lower alkyl group, lower cycloalkyl group or phenyl group. Y and Z
Represents a hydroxyl group or a lower alkoxy group, respectively.
Alternatively, Y and Z are both hydrogen atoms or connect to represent a methylenedioxy group, or Y and Z connect to form a phenyl ring. And then subjecting to N-lower alkylation and deprotection to give a salt, whereby a compound in which R _{1 in the} general formula (A) represents a methyl group can be obtained. Hereinafter, the above-mentioned manufacturing method will be described in detail.

The compound represented by the general formula (C) and a methylating agent are dissolved without solvent or in a hydrocarbon solvent having 6 to 10 carbon atoms, for example, toluene, benzene, xylene, etc. It is carried out by heating in the presence of a carbonate, preferably a basic salt such as potassium bromide, anhydrous potassium carbonate, anhydrous sodium carbonate and the like. The reaction temperature is usually 5
0-180 ° C, preferably 100-150 ° C, usually 1
The reaction is carried out for up to 36 hours, preferably 2 to 24 hours.

The methylating agent may be any one which is usually used for N-methylation of a pyridine ring. For example, methyl sulfonate or methyl trihalogenomethanesulfonate used for methylation such as substituted methyl benzenesulfonate may be used. desirable. Specific examples include methyl p-toluenesulfonate, methyl 2-nitrobenzenesulfonate, and methyl trifluoromethanesulfonate.

The compound represented by the general formula (D) is obtained by mixing the compound obtained by N-methylation with a lower alcohol such as ethanol, preferably methanol, ethanol or n-propanol, usually at 0 ° C. to room temperature, in the presence of a base. A compound is obtained.

Examples of the base include hydroxides such as sodium hydroxide and potassium hydroxide, basic salts such as anhydrous potassium carbonate and anhydrous sodium carbonate, and organic amino compounds such as triethylamine.

The compound represented by the formula (D) is converted to an aprotic solvent such as a hydrocarbon solvent such as benzene, toluene and xylene, an ether solvent such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane and tetrahydrofuran; Dissolve in a halogen-based solvent such as methylene, 1,2-dichloroethane, etc.
10 equivalents, preferably 1 to 3 equivalents, and in some cases, a reaction accelerator such as trifluoroboron ether complex, tetraisopropoxide titanium, etc.
° C, preferably -20 ° C to room temperature for 5 minutes to 2
Stir for 4 hours, preferably 10 minutes to 10 hours.

The organometallic reagent may be any one used in a usual nucleophilic substitution reaction. Examples thereof include organolithium compounds such as butyllithium and phenyllithium, methylmagnesium bromide, ethylmagnesium bromide, cyclobromide and the like. Propylmagnesium, organomagnesium compounds such as phenylmagnesium bromide, organic zinc compounds such as diethylzinc, organic aluminum compounds such as trimethylaluminum and triisobutylaluminum, and organic copper compounds such as dimethylcopperlithium. Organic magnesium compounds such as magnesium and cyclopropylmagnesium bromide are preferred.

The product of the nucleophilic substitution reaction is oxidatively aromatized with an oxidizing agent to obtain a compound represented by the general formula (E). Various oxidizing agents can be used for this reaction, for example, manganese dioxide, lead tetraacetate, dichlorodicyanobenzoquinone (DDQ), preferably manganese dioxide. The reaction is carried out at 0 to 120 ° C, preferably at room temperature to 100 ° C, for 1 to 120 minutes, preferably for 5 to 60 minutes.

After the N-lower alkylation reaction of the compound represented by the formula (E), the compound is debenzylated and treated with an acid to form a phenanthridinium in which R ₁ is a methyl group in the formula (A). Obtain the derivative. In the N-lower alkylation, the compound represented by the formula (E) and a lower alkylating agent are dissolved in a solvent-free or hydrocarbon solvent having 6 to 10 carbon atoms, for example, toluene, benzene, xylene, etc. Alternatively, the reaction is carried out by heating in the presence of an alkali metal halide or a carbonate, preferably a basic salt such as potassium bromide, anhydrous potassium carbonate, or anhydrous sodium carbonate. The reaction temperature is usually 50 to 1
80 ° C., preferably 100 to 150 ° C., usually 1 to 24
This is performed over a period of time, preferably 2 to 10 hours.

The methylating agent may be any one which is usually used for N-methylation of a pyridine ring. For example, methyl sulfonate or methyl trihalogenomethanesulfonate used for methylation such as substituted methyl benzenesulfonate may be used. desirable. Preferably, more reactive reagents such as methyl 2-nitrobenzenesulfonate and methyl trifluoromethanesulfonate are preferred. Other N-lower alkylations such as ethylation and propylation are also performed using reagents according to the methylating agent.

The debenzylation is carried out at room temperature to under acidic conditions such as concentrated hydrochloric acid.
The treatment is performed at 100 ° C. The reaction time is generally 0.1 to 10 hours, preferably 0.2 to 3 hours.
In the acid treatment, a compound obtained by removing the protecting group is dissolved in a polar solvent such as methanol, and an acid such as hydrochloric acid, p-toluenesulfonic acid or the like is added thereto. The amount of acid is usually
About 1 to 3 mol per mol. When X ^- is a divalent or higher valent acid ion, for example, a sulfate ion, it is necessary to reduce the amount of sulfuric acid to be added. Hydrogen sulfate is produced by sulfuric acid treatment in a 1 to 3 times molar excess, and when a half amount of sulfuric acid is used, normal salt type sulfate is produced. By the above method, a compound in which R ₁ is a methyl group in the general formula (A) is obtained.

Among the compounds of the general formula (c), 8-benzyloxy-9-methoxy-naphtho [2,3-c] phenanthridine can be obtained by the following method. 1-
Aminoanthracene and, for example, reference J. Am. C. S. Pe
rkinI, 1221, (1976) and J.M. Org.
Chem. , 53, 1708, (1988).
The halogenobenzaldehyde is heated in a toluene or benzene at 80 to 110 ° C. for 1 to 3 hours and then concentrated, and water to be replicated is removed from the system by azeotropic distillation with the toluene or benzene. Desirably, toluene or benzene is newly added to the concentrated residue, and the above operation of heating and concentration is repeated 2 to 4 times to obtain a dehydration-condensation product (Schiff base) almost quantitatively. By reducing the condensation site of the dehydration condensation product, the compound represented by the general formula (F ′)

[0031]

Embedded image [Wherein, W represents a halogeno group. ]

The compound represented by the formula is obtained. The reducing agent is carbon-
Any method capable of reducing the nitrogen double bond may be used. In particular, it is preferable to use sodium cyanoborohydride or dimethylaminoboron at a reaction temperature of -10 to 40C.

An organic tin hydride compound, preferably a trihydrocarbon (1-8 carbon) tin hydride compound, for example, tributyltin hydride, trioctyl hydride Ring closure (condensation reaction by elimination reaction of hydrogen halide) is performed using tin or a dihydrocarbon (C1 to C8) tin hydride compound, for example, diphenyltin hydride. Among these, a preferred organic tin hydride compound usually used is tributyltin hydride. In order to carry out this reaction, a compound represented by the general formula (F ′) and 1 to 6 equivalents, preferably 2 to 3 equivalents, of an organic tin hydride compound are mixed with an organic solvent, preferably a C 6 to C 10 carbonized compound. It is dissolved in a hydrogen solvent such as toluene, xylene, benzene, etc., and is preferably a radical reaction initiator such as 2,2.
Add 2'-azobis (isobutyronitrile), 2,2'-azobis (2-methylbutyronitrile), benzoyl peroxide or the like, and add 60 to 150 ° C, preferably 80 ° C.
Heating is carried out at ~ 130 ° C for 2 minutes to 4 hours, preferably 5 minutes to 1 hour to complete ring closure.

Thereafter, the oxidative aromatization of the ring closure by the oxidizing agent is preferably carried out at 0 to 120 ° C., preferably at room temperature to 100 ° C. for 1 to 120 minutes, preferably without separating the condensed substance from the reaction mixture. Is carried out for 5 to 60 minutes to obtain 8-benzylnoxy-9-methoxy-naphtho [2,3-c] phenanthridine. Various oxidizing agents can be used for this reaction, for example, manganese dioxide, lead tetraacetate, dichlorodicyanobenzoquinone (DDQ), preferably manganese dioxide. 2. Synthesis in the case where R ₁ represents a substituted or unsubstituted lower aliphatic hydrocarbon other than a methyl group in the general formula (A);
General formula (1)

[0035]

Embedded image [Wherein, R ₂ represents a substituted or unsubstituted lower aliphatic hydrocarbon other than a methyl group. Y and Z each are a hydroxyl group or a lower alkoxy group, or both Y and Z are a hydrogen atom or are connected to represent a methylenedioxy group, or Y and Z are connected to form a phenyl ring. ]

Using a compound represented by the following formula as a raw material, a 7-benzyloxy-8-methoxy-benzo [c] phenanthridine derivative represented by the general formula (c) (Japanese Patent Application Laid-Open No.
08959) can be synthesized by a method similar to the method for producing the compound represented by the case where R _{1 in the} general formula (A) is a methyl group. However, when R ₁ in the general formula (A) is a compound represented by a substituted or unsubstituted lower aliphatic hydrocarbon other than a methyl group and has a hydroxyl group on the substituent R ₁ , the compound represented by the general formula (1) substituents R ₂ in the substituted methyl group protected by a protecting group, the protecting groups are those that can be easily deprotected in the manufacturing process. Among the compounds represented by the general formula (1), when Y and Z each represent a hydroxyl group or a lower alkoxy group, or when Y and Z both represent a hydrogen atom or a connected methylenedioxy group, Equation (2)

[0037]

Embedded image [Wherein, R ₂ represents a substituted or unsubstituted lower aliphatic hydrocarbon other than a methyl group. ]

Using the compound represented by the formula as a starting material, 7-benzyloxy-8-methoxy- represented by the general formula (c)
It can be obtained by a method similar to the method for producing a benzo [c] phenanthridine derivative (JP-A-5-208959).

That is, for example, reference C. S. Pr
ekinI, 1221, (1976) and J.I. Org.
Chem. , 53 , 1708, (1988), after brominating 2-benzyloxy-3-hydroxybenzaldehyde, the compound of the general formula (3)

[0040]

Embedded image R ₂ —A ₁ (3) wherein R ₂ represents a group as described above. A ₁ represents a leaving group such as a halogeno group or an alkylsulfonyl group. ]

Can be obtained by reacting the compound represented by the formula (I) with an organic solvent in the presence or absence of a base. Among the compounds represented by the general formula (1), when Y and Z are connected to form a phenyl ring, the compound represented by the general formula (2) is used as a starting material, −
9-methoxy-naphtho [2,3-c] phenanthridine. The compound of the present invention,
The phenanthridinidine derivative represented by the general formula (A) easily releases one equivalent of an acid from the molecule by a base treatment, and the following general formula (B)

[0042]

Embedded image [Wherein, R ₁ represents a substituted or unsubstituted lower aliphatic hydrocarbon. R represents a substituted or unsubstituted lower alkyl group, lower cycloalkyl group or phenyl group. T represents a lower alkyl group. Y and Z each represent a hydroxyl group or a lower alkoxy group, or both Y and Z are a hydrogen atom or are connected to each other to represent a methylenedioxy group;
And Z are connected to form a phenyl ring. It is possible to take the structure of a novel phenanthridinium derivative represented by

Alternatively, conversely, a compound of the general formula (A) can be easily obtained by treating the compound of the general formula (B) with an acid. Although the compound of the general formula (B) is more liposoluble than the compound of the general formula (A), it is considered that the compound of the general formula (A) is expressed in vivo as a compound of the general formula (B). Has antitumor activity.
Further, the compound of the general formula (B) also serves as an intermediate in synthesizing the general formula (A).

The compounds of the present invention have the following chemical and biological characteristics. The phenanthridinium derivative represented by the general formula (A) has an alkyl group or an acyl group represented by R, and thus has a known phenanthridinium derivative, for example, 2,3- (methylenedioxy) -5.
-Methyl-7-hydroxy-8-methoxy-benzo [c] phenanthridinium hydrosulfate
08959), the site that is expected to be chemically and biologically highly reactive is sterically protected, which leads to an improvement in stability against chemical reduction reactions and biological metabolic reactions. I found something to contribute.

For example, the known compound 2,3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxy-benzo [c] phenanthridinium hydrogensulfate is dissolved in an aqueous solution at room temperature. In the presence of the reducing agent, sodium cyanoborohydride, it is rapidly reduced and disappears in a few minutes. Also, in the document Arch. Biochem. B
iophys. 282, 183 (1990), an in vitro metabolism test using a liver homogenate (S9) prepared from human liver showed formation of metabolites. . This product corresponds to the reduced product generated by the above-described chemical reduction reaction.

The [0046] present invention compounds, 8-2,3 (methylenedioxy) -5,6-dimethyl-7-hydroxy-methoxy - benzo [c] phenanthridinium chloride (Compound A-1) (X ^- = Cl ^-) the aqueous solution, when treated with sodium cyanoborohydride at room temperature, the above-described 2,3 (methylenedioxy) -5-methyl-7-hydroxy-8-methoxy - benzo [c] Fe Its disappearance is apparently slower than that of nonthridinium hydrogensulfate.
Furthermore, in an in vitro metabolism test using a liver homogenate (S9) prepared from a human liver, no metabolite was produced, and it was confirmed that the liver had resistance to a reductive metabolic reaction. Therefore, the compounds of the present invention are highly useful as pharmaceuticals due to improved stability.

Next, Tables 1 and 2 show typical compounds of the phenanthridinium derivative represented by the general formula (A), but the present invention is not limited thereto.

[0048]

[Table 1] Table 1 ──────────────────────────────────── Compound number Compound name ──── ──────────────────────────────── A-1 2,3- (methylenedioxy) -5,6-dimethyl -7-Hydroxy-8-methoxy-benzo [c] phenanthridinium salt A-2 2,3- (methylenedioxy) -5-methyl-6-ethyl-7-hydroxy-8-methoxy-benzo [C] Phenanthridinium salt A-3 2,3- (Methylenedioxy) -5-methyl-6-propyl-7-hydroxy-8-methoxy-benzo [c] phenanthridinium salt A -4 2,3- (methylenedioxy) -5-methyl-6-cyclopropyl-7-hydroxy-8-methoxy-benzo [ c] Phenanthridinium salt A-5 2,3- (methylenedioxy) -5-methyl-6-pentyl-7-hydroxy-8-methoxy-benzo [c] phenanthridinium salt A-6 2 , 3- (Methylenedioxy) -5-methyl-6-phenyl-7-hydroxy-8-methoxy-benzo [c] phenanthridinium salt A-7 2,3- (methylenedioxy) -5 -Methyl-6- (p-methoxyphenyl) -7-hydroxy-8-methoxy-benzo [c] phenanthridinium salt A-8 2,8-Dimethoxy-3,7-dihydroxy-5,6- Dimethyl-benzo [c] phenanthridinium salt A-9 2,7-dihydroxy-3,8-dimethoxy-5,6-dimethyl-benzo [c] phenanthridinium salt A-10 5,6- Jime Salt of ru-7-hydroxy-8-methoxy-benzo [c] phenanthridinium ──────

[0049]

[Table 2] Table 2 ──────────────────────────────────── Compound number Compound name ──── Ａ A-11 6,7-dimethyl-8-hydroxy-9-methoxy-naphtho Salt of [2,3-c] phenanthridinium A-12 6-Methyl-7-ethyl-8-hydroxy-9-methoxy-naphtho [2,3-c] phenanthridinium salt A-13 Salt of 6-methyl-7-phenyl-8-hydroxy-9-methoxy-naphtho [2,3-c] phenanthridinium ─────────────────

[0050]

The following are test examples of the antitumor activity of the compounds of the present invention. The phenanthridinium derivative represented by the general formula (A) exhibits a growth inhibitory effect on tumor cells as described below. 1. Proliferation inhibitory activity against cancer cells Tumor cells HeLa S3 derived from human uterine cancer were transformed for 24 hours.
After culturing at 37 ° C under 5% carbon dioxide, the test drug is allowed to act for 72 hours. Thereafter, the cells were stained with 0.05% methylene blue, and a dye was extracted from the stained cells.
The degree of cell growth inhibition is determined from the nm absorbance, and the 50% growth inhibition concentration (IC ₅₀ value) is calculated. Table 3 shows the results.

[0051]

Table 3 化合物 Compound No. 50% growth inhibitory concentration ( The IC ₅₀ values) (μM) ──────────────────────────────────── A-1 (X - = ^{Cl -) 2.9 A-3 (} X - = Cl -) 2.9 A-4 (X - = Cl -) 6.5 A-11 (X - = Cl -) 0.84 ───── ───────────────────────────────

2. Acute toxicity test The compound of the present invention, 2,3- (methylenedioxy) -5,
6-dimethyl-7-hydroxy-8-methoxy-benzo [c] phenanthridinium chloride (compound A-
1) (X ⁻ ＣｌCl ⁻ ) and 6,7-dimethyl-8-hydroxy-9-methoxy-naphtho [2,3-c] phenanthridinium chloride (compound A-11) (X ⁻ ＣC
l ^-) of the were subjected to acute toxicity tests by intravenous injection into 6 weeks old female CDF1 mice, respectively, 50 mg / kg
All mice survived the administration without lethal toxicity.

In the case of using the phenanthridinium derivative represented by the general formula (A) of the present invention as a pharmaceutical, various methods known in the art can be applied to the preparation and administration. That is, the administration method can be injection, oral, rectal administration and the like. The preparation may take the form of injections, powders, granules, tablets, suppositories and the like. Various auxiliaries used in pharmaceuticals, that is, carriers and other auxiliaries, such as stabilizers, preservatives, soothing agents, emulsifiers, etc. are used as needed, as long as they do not adversely affect the main drug during formulation. Can be done.

The content of the phenanthridinium derivative represented by the general formula (A) in the preparation can be varied in a wide range depending on the form of the preparation.
It contains 0% (by weight), preferably 0.1 to 50% (by weight), with the balance consisting of carriers and other auxiliaries commonly used for pharmaceuticals. The dosage of the phenanthridinium derivative represented by the general formula (A) varies depending on symptoms and the like, but is about 50 to 500 mg per adult per day.

[0055]

From the above results, the general formula (A) of the present invention can be obtained.
The phenanthridinium derivative represented by has antitumor activity and is expected as a therapeutic agent for cancer.

[0056]

EXAMPLES Next, the production of the phenanthridinium derivative represented by the general formula (A) will be specifically described with reference to examples. However, the compounds of the present invention are not limited to only these examples. Absent. Example 1 Synthesis of 2,3- (methylenedioxy) -5-methyl-6-ethoxy-7-benzyloxy-8-methoxy-5,6-dihydrobenzo [c] phenanthridine Dioxy) -7-benzyloxy-
8-methoxy-benzo [c] phenanthridine (4.4
87 g, 10.96 mmol) and methyl 2-nitrobenzenesulfonate (4.30 g, 19.79 mmol)
1) was dissolved in toluene (90 mL),
The mixture was heated and stirred for 4 hours. After cooling to room temperature, the precipitated crystals were collected by filtration and further washed with toluene. This crystal is N,
The suspension was suspended in N-dimethylformamide (62 mL), pyridine (0.62 mL) was added, and the mixture was stirred at 60 ° C for 2 hours. After allowing to cool to room temperature, the crystals were collected by filtration and washed with toluene and hexane in that order. The resulting yellowish crystals were suspended in ethanol (124 mL), a 0.1N aqueous sodium hydroxide solution (93 mL) was added, and the mixture was stirred until the yellowish color completely disappeared. The light brown crystals were collected by filtration, washed with 50% ethanol water, and treated with 2,3- (methylenedioxy) -5.
-Methyl-6-ethoxy-7-benzyloxy-8-methoxy-5,6-dihydrobenzo [c] phenanthridine (3.016 g, 59% yield) was obtained as a light brown powder.

FAB-MS (positive mode) m / z: 424 ([M-CH3CH2
O] ⁺ ); ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.78 (1 H, d, J = 8.6 Hz), 7.64 (1 H,
d, J = 8.6Hz), 7.63 (1H, s), 7.46 (1H, d, J = 8.6Hz), 7.58 ~ 7.33 (5H, m), 7.11 (1H, s), 7.0
6 (1H, d, J = 8.6Hz), 6.04 (2H, s), 5.64 (1H, s), 5.21 (1H, d, J =
10.9Hz), 5.09 (1H, d, J = 10.9Hz), 3.94 (3H, s), 3.90 (1H, dq,
J = 9.6 & 7.1Hz), 3.60 (1H, dq, J = 9.6 & 7.1Hz), 2.61 (3H, s), 1.
05 (3H, t, J = 7.1Hz).

Example 2 Synthesis of 2,3- (methylenedioxy) -6-methyl-7-benzyloxy-8-methoxy-benzo [c] phenanthridine 2,3- (methylenedioxy) -5 Methyl-6-ethoxy-7-benzyloxy-8-methoxy-5,6-dihydrobenzo [c] phenanthridine (1.878 g,
4.00 mmol) in tetrahydrofuran (12 mL)
And added with methylmagnesium bromide (0.92 M solution in tetrahydrofuran, 13.0 mL, 12 mmol) and stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was extracted with toluene (100 mL). The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was distilled off under reduced pressure to give 2,3-
(Methylenedioxy) -5,6-dimethyl-7-benzyloxy-8-methoxy-5,6-dihydrobenzo [c] phenanthridine (1.746 g, 99% yield)
Was obtained as a light brown powder. This dihydro form (0.924
g, 2.10 mmol) was dissolved in toluene (30 mL), activated manganese dioxide (9.24 g) was added, and the mixture was heated under reflux for 50 minutes. After filtering off the manganese dioxide, it was concentrated under reduced pressure. The residue was crystallized from a mixed solvent of hexane and methylene chloride to give 2,3- (methylenedioxy) -6-methyl-7-benzyloxy-8-methoxy-benzo [c].
Phenanthridine (0.439 g, 49% yield) was obtained as pale orange needles.

FAB-MS (positive mode) m / z: 424 ([M + H] ⁺ ); ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 8.73 (1 H, s), 8.39 (1 H, d, J = 9.2H
z), 8.27 (1H, d, J = 8.9Hz), 7.75 (1H, d, J = 9.1Hz), 7.62-7.5
4 (2H, m), 7.55 (1H, d, J = 9.0Hz), 7.48 ~ 7.36 (3H, m), 7.22 (1
(H, s), 6.10 (2H, s), 5.16 (2H, s), 4.03 (3H, s), 3.26 (3H, s).

[0060] Example 3 Compound ^{(A-1) (X -} = Cl -), 2,3- ( methylenedioxy) -5,6-dimethyl-7-hydroxy -8
Synthesis of -methoxy-benzo [c] phenanthridinium chloride 2,3- (methylenedioxy) -6-methyl-7-benzyloxy-8-methoxy-benzo [c] phenanthridine (2.52 g, 5 .95 mmol) with toluene (1
20 mL), and methyl trifluoromethanesulfonate (6.73 mL, 59.5 mmol) was added thereto.
For 3 hours. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with toluene, compound (A-1) (X ^-
= CF ₃ SO ₃ ⁻ ) (2.68 g, yield 91%) as yellow crystals. The crystals were dissolved in 80% acetonitrile water (200 mL) and ion-exchange resin Dowex-
It was converted to the hydrochloride salt through ^- (type Cl) 1. After concentrating the fraction, the obtained powder was recrystallized from methanol to give compound (A-1) (X ⁻ = Cl ⁻ ) (137 mg).
Was obtained as a light brown powder.

FAB-MS (positive mode) m / z: 348 (M ⁺ ); UVλ _max (in 1M HCl) nm: 443,342,322,272; ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 8.62 (1H, d, J = 9.1Hz), 8.43 (1
H, d, J = 9.2Hz), 8.15 (1H, d, J = 8.8Hz) 8.03 (1H, d, J = 9.0Hz),
7.95 (1H, s), 7.68 (1H, s), 6.32 (2H, s), 4.50 (3H, s), 4.07 (3
H, s), 3.55 (3H, s).

Example 4 Synthesis of 2,3- (methylenedioxy) -6-ethyl-7-benzyloxy-8-methoxy-benzo [c] phenanthridine In Example 2, instead of methylmagnesium bromide Except that ethyl magnesium bromide was used, 2,3- (methylenedioxy) -6-ethyl-7-benzyloxy-8-methoxy-benzo [c] was obtained in the same manner as in Example 2. Phenanthridine (47% yield) was obtained as a light brown powder.

FAB-MS (positive mode) m / z: 438 ([M + H] ⁺ ); ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 8.78 (1 H, s), 8.45 (1 H, d, J = 9.3H
z), 8.31 (1H, d, J = 9.0Hz), 7.78 (1H, d, J = 8.8Hz), 7.61-7.5
6 (2H, m), 7.59 (1H, d, J = 9.1Hz), 7.49 ~ 7.37 (3H, m), 7.24 (1H
H, s), 6.12 (2H, s), 5.18 (2H, s), 4.05 (3H, s), 3.68 (2H, q, J =
(7.3Hz), 1.50 (3H, t, J = 7.3Hz).

[0064] Example 5 Compound ^{(A-2) (X -} = Cl -), 2,3- ( methylenedioxy) -5-methyl-6-ethyl-7-hydroxy-8-methoxy - benzo [c] Synthesis of phenanthridinium chloride 2,3- (methylenedioxy) -6-ethyl-7-benzyloxy-8-methoxy-benzo [c] phenanthridine (100 mg, 0.23 mmol) was added to toluene (4
mL), methyl trifluoromethanesulfonate (0.26 mL, 2.30 mmol) was added, and the mixture was added at 100 ° C.
For 5 hours. After allowing to cool to room temperature, the precipitated yellowish crystals were collected by filtration. Add acetic acid (2
mL) and concentrated hydrochloric acid (1 mL).
Stirred for minutes. After concentration under reduced pressure, the mixture was diluted with methylene chloride, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by shaking until the orange color became completely reddish purple. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and a 4M hydrochloric acid-dioxane solution was added thereto until the solution became completely orange. The solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with 8% methanol-methylene chloride) to give compound (A-2) (X ⁻ = Cl ⁻ ).
(32 mg, 35% yield) was obtained as an orange powder.

FAB-MS (positive mode) m / z: 362 (M ⁺ ); UVλ _max (in ¹ M HCl) nm: 451, 345, 326, 274; ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 11.40 (1 H, brs) , 8.64 (1H, d, J
= 9.1Hz), 8.47 (1H, d, J = 9.2Hz), 8.17 (1H, d, J = 8.9Hz), 8.06
(1H, d, J = 9.1Hz), 8.04 (1H, s), 7.69 (1H, s), 6.31 (2H, s), 4.
57 (3H, s), 4.07 (3H, s), 3.97 (2H, q, J = 7.4Hz), 1.51 (3H, t, J
= 7.4Hz).

Example 6 Synthesis of 2,3- (methylenedioxy) -6-propyl-7-benzyloxy-8-methoxy-benzo [c] phenanthridine In Example 2, instead of methylmagnesium bromide Except for using propylmagnesium bromide, 2,3- (methylenedioxy) -6-propyl-7-benzyloxy-8-methoxy-benzo [c] was obtained in the same manner as described in Example 2. Phenanthridine (59% yield)
Was obtained as a light brown powder.

FAB-MS (positive mode) m / z: 452 ([M + H] ⁺ ); ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 8.67 (1 H, d, J = 9.3 Hz), 8.53 (1
H, d, J = 9.6Hz), 8.41 (1H, s), 7.91 (1H, d, J = 8.9Hz), 7.85 (1
(H, d, J = 9.2Hz), 7.61 (1H, m), 7.57 (1H, m), 7.49 (1H, s), 7.50
~ 7.37 (3H, m), 6.20 (2H, s), 5.17 (2H, s), 4.05 (3H, s), 3.55
~ 3.47 (2H, m), 1.94 ~ 1.80 (2H, m) 0.87 (3H, t, J = 7.4Hz).

[0068] EXAMPLE 7 Compound ^{(A-3) (X -} = Cl -), 2,3- ( methylenedioxy) -5-methyl-6-propyl-7-hydroxy-8-methoxy - benzo [c] Synthesis of phenanthridinium chloride In Example 5, 2,3- (methylenedioxy) -6
2,3- (methylenedioxy) -6-propyl-7-benzyloxy-8- instead of -methyl-7-benzyloxy-8-methoxy-benzo [c] phenanthridine
Compound (A-3) (X ⁻ = Cl ⁻ ) (yield 28%) was converted to vermilion powder by a method similar to that described in Example 5 except that methoxy-benzo [c] phenanthridine was used. As obtained.

FAB-MS (positive mode) m / z: 376 (M ⁺ ), 751
([2M-H] ⁺ ); ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 11.40 (1 H, brs), 8.63 (1 H, d, J
= 9.1Hz), 8.46 (1H, d, J = 9.2Hz), 8.16 (1H, d, J = 8.9Hz), 8.05
(1H, d, J = 9.0Hz), 8.02 (1H, s), 7.68 (1H, s), 6.31 (2H, s), 4.
57 (3H, s), 4.07 (3H, s), 3.96 to 3.80 (2H, m), 2.02 to 1.80 (2
H, m), 1.19 (3H, t, J = 7.1Hz).

Example 8 2,3- (Methylenedioxy) -6-cyclopropyl-
Synthesis of 7-benzyloxy-8-methoxy-benzo [c] phenanthridine Same as the method described in Example 2 except that cyclopropylmagnesium bromide was used instead of methylmagnesium bromide in Example 2. By a suitable method, 2,3- (methylenedioxy) -6-cyclopropyl-7-benzyloxy-8-methoxy-benzo [c] phenanthridine (65% yield) was obtained as a colorless powder.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 8.60 (1 H, s), 8.43
(1H, d, J = 9.3Hz), 8.28 (1H, d, J = 9.2Hz), 7.70 (1H, d, J = 8.9H
z), 7.57 (1H, d, J = 9.2Hz), 7.60 ~ 7.52 (2H, m), 7.46 ~ 7.33
(3H, m), 7.22 (1H, s), 6.11 (2H, s), 5.17 (2H, s), 4.04 (3H,
s), 3.82-3.67 (1H, m), 1.58-1.48 (2H, m), 1.06-0.95 (2
H, m).

[0072] Example 9 Compound ^{(A-4) (X -} = Cl -), 2,3- ( methylenedioxy) -5-methyl-6-cyclopropyl-7
Synthesis of hydroxy-8-methoxy-benzo [c] phenanthridinium chloride In Example 5, 2,3- (methylenedioxy) -6
2,3- (Methylenedioxy) -6-cyclopropyl-7-benzyloxy-8-methoxy-benzo [c] instead of -methyl-7-benzyloxy-8-methoxy-benzo [c] phenanthridine Except for using phenanthridine, a method similar to that described in Example 5 was used.
Compound ^{(A-4) (X -} = Cl -) (5% yield) as a vermilion powder.

FAB-MS (positive mode) m / z: 374 (M ⁺ ); ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 11.10 (1 H, brs), 8.64 (1 H, d, J
= 9.1Hz), 8.42 (1H, d, J = 9.2Hz), 8.16 (1H, d, J = 9.2Hz), 8.12
(1H, s), 8.03 (1H, d, J = 9.0Hz), 7.68 (1H, s), 6.32 (2H, s), 4.
65 (3H, s), 4.06 (3H, s), 2.92 (1H, m), 1.68 to 1.56 (2H, m), 1.
34 ~ 1.22 (2H, m).

[0074] Example 10 Compound ^{(A-6) (X -} = Cl -), 2,3- ( methylenedioxy) -5-methyl-6-phenyl-7-hydroxy-8-methoxy - benzo [c] Synthesis of phenanthridinium chloride 2,3- (methylenedioxy) -5-methyl-6-ethoxy-7-benzyloxy-8-methoxy-5,6-dihydrobenzo [c] phenanthridine (536 mg,
1.14 mmol) was dissolved in tetrahydrofuran (5 mL), and phenylmagnesium bromide (1M solution in tetrahydrofuran, 3.42 mL) was added thereto under ice-cooling.
And then at room temperature for 90 minutes. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluted with 30 to 50% methylene chloride-hexane) to give 2,3- (methylene chloride). Dioxy) -5-methyl-6-phenyl-7-benzyloxy-8-methoxy-5,6-dihydrobenzo [c]
Phenanthridine (571 mg, 96% yield) was obtained as a colorless powder.

This compound (235 mg, 0.476 mm
ol) in toluene (5 mL) and 2,3-dichloro-5,6-dicyanobenzoquinone (177 mg, 0.1 mL).
714 mmol) and stirred at room temperature for 1 hour. After adding saturated sodium hydrogen sulfite, the mixture was extracted with ethyl acetate. The organic layer was washed with a 1M aqueous sodium hydroxide solution and then with a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with 0 to 1% triethylamine-toluene) to give 2,3- (methylenedioxy) -5-methyl-6-phenyl -7-Benzyloxy-8-methoxy-benzo [c] phenanthridinium hydroxide (225 mg, 91% yield) was obtained as a colorless powder.

This compound (56 mg, 0.11 mmol)
l) was dissolved in acetic acid (1 mL) and concentrated hydrochloric acid (0.5 mL), and the mixture was stirred at 50 ° C for 2 hours. After neutralizing with sodium hydrogen carbonate under ice-cooling, the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was treated with 1,4-dioxane (5 m
L), and 4M hydrochloric acid-dioxane solution (70 μL)
Was added and stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, and Compound (A-6) (X ⁻ = Cl ⁻ ) (36 mg,
(75% yield) as a vermilion powder.

FAB-MS (positive mode) m / z: 410 (M ⁺ ); UVλ _max (in 0.1 M HCl) nm: 465,330,276; ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 10.60 (1H, brs), 8.76 (1H, d, J
= 9.2Hz), 8.55 (1H, d, J = 9.2Hz), 8.26 (1H, d, J = 9.2Hz), 8.17
(1H, s), 8.09 (1H, d, J = 9.0Hz), 7.82 ~ 7.75 (2H, m), 7.72 ~
7.65 (3H, m), 7.73 (1H, s), 6.32 (2H, s), 4.12 (3H, s), 3.97 (3
H, s); ¹³ C-NMR (25 MHz, DMSO-d ₆ ) δ: 162.9 (s), 148.5 (s), 148.2
(s), 148.0 (s), 147.1 (s), 134.6 (s), 132.6 (s), 131.4 (s), 1
30.6 (d), 130.3 (d), 128.6 (d), 128.1 (s), 124.9 (s), 123.0
(d), 120.7 (s), 117.8 (d), 114.7 (s), 113.1 (d), 105.2 (d), 1
04.2 (d), 102.4 (t), 56.7 (q), 51.4 (q).

Example 11 N-((2'-benzyloxy) -3'-methoxy-
Synthesis of 6'-bromobenzyl) -1-anthrylamine 2-benzyloxy-3-methoxy-6-bromobenzaldehyde (8.32 g, 23.2 mmol) and 1-
Aminoanthracene (ALDRICH, 90%, 5.0
0 g, 23.3 mmol) was dissolved in toluene (230 mL). The mixture was heated and refluxed at 120 ° C. for 2 hours with vigorous stirring. While heating at 120 ° C., toluene (1
80 mL) was gradually added over 3 hours, and the solvent was distilled off at the same time. After cooling to room temperature, toluene (70 mL) was added. Under water cooling, dimethylamine-borane complex (1.03
g, 17.5 mmol) and acetic acid (30 mL) were sequentially added. After stirring at room temperature for 75 minutes, a 1 M aqueous hydrochloric acid solution (130 mL) was added under water cooling. The reaction solution was filtered, and the filtrate was separated into an organic layer and an aqueous layer. The aqueous layer was washed with toluene (200m
L × 2) and combined with the previously obtained organic layer,
It was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with 10% ethyl acetate-hexane) to give N-((2′-benzyloxy) -3′-methoxy-6). '-Bromobenzyl) -1-anthrylamine (1
2.77 g, quantitative yield) as a yellow powder.

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 8.86 (1 H, s), 8.
38 (1H, s), 7.98 (2H, m), 7.50 ~ 7.07 (10H, m), 6.57 (1H, m),
6.20 (1H, t, J = 4.5Hz), 5.05 (2H, s), 4.47 (1H, s), 4.44 (1H,
s), 3.90 (3H, s).

Example 12 8-benzyloxy-9-methoxy-naphtho [2,3-
c] Synthesis of phenanthridine N-((2′-benzyloxy) -3′-methoxy-
6'-bromobenzyl) -1-anthrylamine (1
0.81 g, 21.70 mmol) in toluene (1 L)
And then dissolved in trioctyltin hydride (19.95
g, 43.43 mmol) and the temperature was raised to 105 ° C. Subsequently, 2,2′-azobis (2-methylbutyronitrile) (8.36 g, 43.46 mmol) was added, and 1
The mixture was refluxed under heating at 20 ° C. for 2 hours. After cooling to room temperature, activated manganese dioxide (10.81 g) was added and stirred for 30 minutes. Ethanol (200 mL) was added, and the reaction solution was filtered to remove manganese dioxide. The filtrate was evaporated under reduced pressure, and the obtained residue was crystallized from a mixed solvent of hexane and methylene chloride to give 8-benzyloxy-9-methoxy-naphtho [2,3-c] phenanthridine (4.04 g, yield). Rate 4
5%) as a pale yellow powder.

FAB-MS (positive mode) m / z: 416 ([M + H] ⁺ ); ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 9.82 (1 H, s), 9.65 (1 H, s) ), 8.6
7 (3H, m), 8.37 ~ 8.15 (3H, m), 7.94 (1H, d, J = 9.3Hz), 7.60 (4
H, m), 7.40 (3H, m), 5.35 (2H, s), 4.10 (3H, s).

Example 13 Synthesis of 6-methyl-7,9-dimethoxy-8-benzyloxy-6,7-dihydronaphtho [2,3-c] phenanthridine 8-benzyloxy-9-methoxy-naphtho [ 2,3-
c] phenanthridine (129 mg, 0.31 mmol
l) and methyl 2-nitrobenzenesulfonate (142
mg, 0.65 mmol) was dissolved in toluene (3.7 mL) and heated at 120 ° C. for 18 hours under reflux. After cooling to room temperature, the precipitated crystals were collected by filtration and further washed with toluene. This was suspended in ethanol (30 mL), and a 0.1 M aqueous sodium hydroxide solution (20 mL) was further added and shaken. After the solid in the suspension was thoroughly ground, the precipitate was collected by filtration, dried under reduced pressure, and treated with 6-methyl-7,9-
Dimethoxy-8-benzyloxy-6,7-dihydronaphtho [2,3-c] phenanthridine (113 mg, 7
6%) as a yellow powder.

FAB-MS (positive mode) m / z: 430 ([M-CH3CH
2O] ⁺ ); ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 8.85 (1 H, s), 8.40 (1 H, s), 8.10
~ 7.10 (13H, m), 5.78 (1H, s), 5.25 (1H, d, J = 10.9Hz), 5.13
(1H, d, J = 10.9Hz), 3.97 (3H, s), 3.70 (2H, m), 2.80 (3H, s),
1.05 (3H, t, J = 7.0Hz).

Example 14 6-Methyl-7-ethoxy-8-benzyloxy-9-
Synthesis of methoxy-6,7-dihydronaphtho [2,3-c] phenanthridine Lysine was prepared in the same manner as in Example 13 except that methanol was used instead of ethanol. -Methyl-7-ethoxy-8-benzyloxy-9-methoxy-6,7-dihydronaphtho [2,3-
c] Phenanthridine was obtained as a yellow powder.

FAB-MS (positive mode) m / z: 430 ([M-CH3O]
⁺ ); ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 8.87 (1 H, s), 8.40 (1 H, s), 8.10
~ 7.30 (12H, m), 7.12 (1H, d, J = 8.7Hz), 5.61 (1H, s), 5.22 (1
H, d, J = 10.9Hz), 5.10 (1H, d, J = 10.9Hz), 3.97 (3H, s), 3.45
(3H, s), 2.80 (3H, s).

Example 15 Synthesis of 6,7-dimethyl-8-benzyloxy-9-methoxy-6,7-dihydronaphtho [2,3-c] phenanthridine 6-methyl-7-ethoxy-8-benzyl Oxy-9-
Methoxy-6,7-dihydronaphtho [2,3-c] phenanthridine (1.52 g, 3.19 mmol) was dissolved in tetrahydrofuran (67.5 mL) and cooled to 0 ° C. Subsequently, methylmagnesium bromide (0.93 M solution in tetrahydrofuran, 10.3 mL, 9.58 mmol)
l) was added. After the temperature was raised to room temperature, the mixture was stirred overnight. 0 ° C
And a saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The oily substance obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluted with methylene chloride) to give 6,7-dimethyl-8-benzyloxy-9-methoxy-6,7-dihydro. Naphtho [2,3-c] phenanthridine (1.33
g, yield 93%) as a pale yellow powder.

FAB-MS (positive mode) m / z: 450 (M ⁺ ); ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 8.87 (1 H, s), 8.37 (1 H, s), 8.06
(1H, m), 7.97 (1H, m), 7.88 (1H, d, J = 9.1Hz), 7.80 (1H, d, J =
9.2Hz), 7.60 (1H, d, J = 8.5Hz), 7.56 (1H, m), 7.52 (1H, m), 7.
50〜7.33 (5H, m), 7.00 (1H, d, J = 8.6Hz), 5.30 (2H, s), 4.60
(1H, q, J = 6.9Hz), 3.99 (3H, s), 2.55 (3H, s), 1.13 (3H, d, J =
6.9Hz).

Example 16 Synthesis of 7-methyl-8-benzyloxy-9-methoxy-naphtho [2,3-c] phenanthridine Lysine 6,7-dimethyl-8-benzyloxy-9-methoxy-6,7 -Dihydronaphtho [2,3-c] phenanthridine (1.33 g, 2.98 mmol) was added to toluene (1
43 mL). Activated manganese dioxide (13.3
The mixture was heated and refluxed at 120 ° C. for 8 hours for 8 hours while gradually adding g). After cooling to room temperature, manganese dioxide was removed by filtration. The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography (eluted with methylene chloride), crystallized from a methylene chloride-methanol mixed solvent to give 7-
Methyl-8-benzyloxy-9-methoxy-naphtho [2,3-c] phenanthridine (407 mg, yield 3
2%) as a pale yellow powder.

FAB-MS (positive mode) m / z: 430 ([M + H] ⁺ ); ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 9.92 (1 H, s), 8.45 (1 H, s), 8.45
(1H, d, J = 9.4Hz), 8.38 (1H, d, J = 9.3Hz), 8.30-8.20 (2H,
m), 8.05 (1H, m), 7.63 (1H, d, J = 9.2Hz), 7.55 (1H, d, J = 9.7H
z), 7.64 to 7.35 (6H, m), 5.20 (2H, s), 4.06 (3H, s), 3.38 (3H,
s).

Example 17 Compound (A-11) (X ⁻ ＣｌCl ⁻ ), 6,7-dimethyl-8-hydroxy-9-methoxy-naphtho [2,3-
c] Synthesis of phenanthridinium chloride 7-methyl-8-benzyloxy-9-methoxy-naphtho [2,3-c] phenanthridine (400 mg, 0.1 mg).
93 mmol) in toluene (16 mL) and methyl trifluoromethanesulfonate (1.06 mL, 9.
33 mmol), and the mixture was heated under reflux at 120 ° C. overnight. After cooling to room temperature, the deposited orange precipitate was collected by filtration.
To this was added methylene chloride and a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was shaken until the orange color became completely purple. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 6% methanol-methylene chloride) to obtain a dark purple solid (257 mg). After dissolving this in methylene chloride, a 4 M hydrochloric acid-dioxane solution was added until the solution became completely orange. The precipitated crystals were collected by filtration to give compound (A-11) (X ⁻ = C
l ^-) (yield 147 mg, 41% yield) as an orange powder.

FAB-MS (positive mode) m / z: 354 (M ⁺ ); UVλ _max (in 0.1 M HCl) nm: 463,360,296,283; ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 9.20 (1H, s), 8.80 (1H, s), 8.6
5 (1H, d, J = 9.3Hz), 8.41 (1H, d, J = 9.1Hz), 8.37 (1H, d, J = 9.2Hz)
Hz), 8.30 (1H, m), 8.22 (1H, m), 8.02 (1H, d, J = 8.9Hz), 7.78
~ 7.68 (2H, m), 4.67 (3H, s), 4.05 (3H, s), 3.60 (3H, s).

[0092] Example 18 (Formulation example) Compound ^{(A-1) (X -} = Cl -), 2,3- ( methylenedioxy) -5,6-dimethyl-7-hydroxy-8
After weighing 1 g of methoxy-benzo [c] phenanthridinium chloride, 1 g of polysorbate, and 1 g of Macrogol 400, each was dispersed and dissolved in 100 g of distilled water for injection, and filtered with a membrane filter. Dispense into ampoules and freeze-dry in a conventional manner to give 50 per ampoule.
An injectable preparation containing mg of the compound (A-1) (X ⁻ = Cl ⁻ ) was obtained.

[0093] Example 19 (Formulation example) Compound ^{(A-11) (X -} = Cl -), 6,7- dimethyl-8-hydroxy-9-methoxy - naphtho [2,3
c] 1 g of phenanthridinium chloride, 1 g of polysorbate, and 1 g of Macrogol 400 were weighed, respectively, then dispersed and dissolved in 100 g of distilled water for injection, and filtered with a membrane filter. Dispense into ampoules, freeze-dry in a conventional manner, and add 50 mg of compound (A) per ampoule.
^{-11) (X - = Cl -} ) was obtained injectable formulation containing.

Claims (6)

[Claims] 1. A compound of the general formula (A) [Wherein, R ₁ represents a substituted or unsubstituted lower aliphatic hydrocarbon. R represents a substituted or unsubstituted lower alkyl group, lower cycloalkyl group, or phenyl group. T represents a lower alkyl group. Y and Z each represent a hydroxyl group or a lower alkoxy group, or both Y and Z are a hydrogen atom or are connected to represent a methylenedioxy group, or Y and Z are connected to form a phenyl ring. And X ^- represents an acid residue or a hydrogen acid residue. ] The novel phenanthridinium derivative represented by these. 2. A compound of the general formula (B) [Wherein, R ₁ represents a substituted or unsubstituted lower aliphatic hydrocarbon. R represents a substituted or unsubstituted lower alkyl group, lower cycloalkyl group, or phenyl group. T represents a lower alkyl group. Y and Z each are a hydroxyl group or a lower alkoxy group, or both Y and Z are a hydrogen atom or are connected to represent a methylenedioxy group, or Y and Z are connected to form a phenyl ring. ] The novel phenanthridinium derivative represented by these. (3) R ₁ is methyl, ethyl, allyl, 2-hydroxyethyl, 2-methoxyethyl or trifluoromethyl, and R is a C ₁ -C ₅ lower alkyl group, cyclopropyl, cyclohexyl, phenyl or p- 2. The compound according to claim 1, wherein T represents methyl, ethyl or propyl, and Y and Z both represent a methylenedioxy group, or represent a phenyl ring. Compound. (4) 6,7-dimethyl-8-hydroxy-9-
Methoxy-naphtho [2,3-c] phenanthridinium salt. 5. An antitumor agent comprising the phenanthridinium derivative represented by the general formula (A) or (B) according to claim 1 or 2 as an active ingredient. 6. A medicament comprising a phenanthridinium derivative represented by the general formula (A) or (B) according to claim 1 or 2 as an active ingredient.