JPH05202048A - New indole derivative and its salt - Google Patents

Abstract

PURPOSE:To obtain a new indole derivative extremely useful as an anti-cancer medicine, showing cytodical action on cancerous cells. CONSTITUTION:A compound of formula I [R<1> is H, carboxyl, lower alkyl, alkenyl, cycloalkyl, aryl, acyl or heterocyclmc group; R<2> is H, carbamoyl, lower alkyl, aryl, aralkyl or acyl; R<3> is H, halogen, OH, lower alkyl, alkenyl, cycloalkyl or aryl; Y is direct bond or lower alkylene; Z is halogen, OH, NR<4>R<5> (R<4> and R<5> are H, amino-protecting group, lower alkyl, cycloalkyl, aralkyl, acyl, aryl or are bonded together with N linked to form heterocyclic), trialkylammonio or group of formula II] and a salt thereof such as N-(2- dimethylaminoethyl)3,7-dimethyl-2-phenylindole-4,5-carboximide. The compound of formula I wherein R<2> is H is obtained by reacting a compound of formula III with a compound of the formula H2N-Y-Z.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel indole derivative and its salt that exert a strong cell killing action on cancer cells, and more specifically, it relates to the general formula [1]

[Chemical 4] "In the formula, R ¹ is a hydrogen atom, an optionally protected carboxyl group or an optionally substituted lower alkyl,
One or more groups selected from alkenyl, cycloalkyl, aryl, acyl or heterocyclic groups; R ² represents a hydrogen atom, a carbamoyl group or an optionally substituted lower alkyl, aryl, aralkyl or acyl group; R ³ is one or more groups selected from a hydrogen atom, a halogen atom, an optionally protected hydroxyl group or an optionally substituted lower alkyl, alkenyl, cycloalkyl or aryl group; Y is a bond A hand or a lower alkylene group; Z is a halogen atom, an optionally protected hydroxyl group or a formula

[Chemical 5] (Wherein, R ⁴ and R ⁵ are the same or different, a hydrogen atom, an amino protecting group or substituted optionally may be lower alkyl, cycloalkyl, aralkyl, an acyl or aryl group. Alternatively R ⁴ and R ⁵ may be combined with a nitrogen atom to which they are bonded to form an optionally substituted nitrogen-containing heterocyclic group) or a trialkylammonio group;

[Chemical 6] (In the formula, Y and Z have the same meanings as described above.) The group represented by [4,
It is bonded to the [5] -position or the [5,6] -position. The present invention relates to an indole derivative and a salt thereof.

[0002]

Conventionally, various indole derivatives are known, but the [4,5] -position or [5,5] -position of the indole skeleton is known.
6] position expression

[Chemical 7] (In the formula, each of Y and Z has the same meaning as described above.) A compound to which a group represented by the above is bonded is not known at all.

[0003]

At present, it is desired to develop a carcinostatic agent which exhibits an excellent antitumor effect and has few side effects. Therefore, the object of the present invention is to solve the above problems,
It is to provide a novel compound represented by the general formula [1].

[0004]

Means for Solving the Problems In order to solve the above problems, the present inventors have been searching for various compounds,
It was found that the indole derivative represented by the general formula [1] exerts an excellent antitumor effect and is extremely useful as an anticancer agent,
The present invention has been completed.

The present invention will be described in detail below. In the present specification, unless otherwise specified, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; the lower alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl or n-butyl. , Sec-butyl, te
C _1-5 alkyl group such as rt-butyl or pentyl; lower alkoxy group means lower alkyl-O— group; alkenyl group means, for example, vinyl, allyl, butenyl, decenyl, hexadecenyl, heptadecenyl or octadecenyl. C _2-22 alkenyl group; a lower alkylene group such as methylene, ethylene, propylene,
A C _1-5 alkylene group such as trimethylene, tetramethylene, pentamethylene or 1-methyltrimethylene;
An aryl group is a phenyl, tolyl or naphthyl group; an acyl group is, for example, C _1-6 such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl or hexanoyl.
Alkanoyl group and aroyl group such as benzoyl, toluoyl or naphthoyl;
An acyl-O- group; a cycloalkyl group is, for example,
A C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; an aralkyl group is an aryl-lower alkyl group; a lower alkylsulfonyloxy group is a lower alkyl-SO ₃ —
A group; an arylsulfonyloxy group means aryl-S
An O ₃ -group; a lower alkoxysulfonyloxy group,
A lower alkyl-OSO ₃ -group; a heterocyclic group is, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thienyl, furyl, thiazolyl, pyrrolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyridazinyl or pyrazinyl. 1 selected from oxygen, sulfur and nitrogen atoms as heteroatoms
A 5- or 6-membered heterocyclic group containing one or more heteroatoms; a trialkylammonio group includes, for example, trimethylammonio, triethylammonio, dimethylethylammonio, diethylmethylammonio and trialkylammonio. −n-
By tri-C _1-4 alkylammonio group such as propylammonio or tributylammonio.

Lower alkyl, alkenyl at R ¹
Cycloalkyl, aryl, lower alkyl in the acyl or heterocyclic group and R ^2, aryl, aralkyl or acyl group and a lower alkyl in R ^3, alkenyl, cycloalkyl or aryl group and R,
⁴ and the lower alkyl in R ^5, cycloalkyl, aralkyl, acyl or aryl group, more as a substituent of the nitrogen-containing heterocyclic group which R ⁴ and R ⁵ form together with the nitrogen atom to which they are attached Is a halogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkyl group, an aryl group, an aralkyl group, an optionally protected hydroxy or amino group, or a heterocyclic group. Examples of the nitrogen-containing heterocyclic group for Z include 4-membered, 5-membered or 6-membered nitrogen-containing heterocyclic groups such as azetidinyl, imidazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, triazolyl or tetrazolyl. ..

Also, the formula

[Chemical 8] (In the formula, each of Y and Z has the same meaning as described above.) Is a group represented by [4
It is bonded to the [5] -position or the [5,6] -position, and specifically means the following.

[Chemical 9]

[Chemical 10] “In the formula, R ¹ , R ² , R ³ , Y, and Z each have the same meaning as described above.” In addition, in the description of the production method described later, the group bonded to the indole skeleton (ie,
(Groups forming a pyrrole ring) are described, but it is meant that these groups are bonded to the [4,5] -position or [5,6] -position of the indole skeleton as described above.

Examples of the above-mentioned optionally protected amino, carboxyl and hydroxyl protecting groups include protecting groups usually known in the art, and specifically, Protective Groups in Organic Synthesis [Protective Groups in Organic Syn
thesis: Theodora W. Green (Theodora.
W. Green), (1981), John Willie &
Sands (John Wiley & Sons, Inc.)] and Japanese Patent Sho 60-
Each protecting group described in No. 52755 and the like can be mentioned.

Examples of the salt of the indole derivative represented by the general formula [1] include salts of a commonly known basic group such as amino group or acidic group such as hydroxyl or carboxyl group. Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; and methane. Salts with sulfonic acids such as sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid, and salts with acidic groups include, for example, with alkali metals such as sodium and potassium. Salts; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, Prokai ,
Examples thereof include salts with nitrogen-containing organic bases such as dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine.

Further, when the compound of the general formula [1] has a trialkylammonio group in the molecule, those groups are
A salt may be formed with a halogen anion; a lower alkylsulfonyloxy anion; or an arylsulfonyloxy anion optionally substituted with a lower alkyl group or a halogen atom. In addition, when isomers (for example, optical isomers, geometric isomers, tautomers, etc.) exist in the compound of the general formula [1] and salts thereof, the present invention includes all isomers thereof. ,
It also includes all hydrates, solvates and crystalline forms.

Next, a method for producing the compound of the present invention will be described. The indole derivative of the general formula [1] of the present invention or a salt thereof can be produced by a method known per se or an appropriate combination thereof, for example, according to the following production routes.

[Chemical 11]

[Chemical formula 12]

[Chemical 13]

[Chemical 14]

[Chemical 15]

"Wherein R ¹ , R ² , R ³ , Y and Z are
Each has the same meaning as previously described; R ^1a and R ^1b
Represents a hydrogen atom or an optionally protected carboxyl group similar to R ¹ described above or an optionally substituted lower alkyl, alkenyl, cycloalkyl, aryl or heterocyclic group; R ^1c represents R ¹ described above. ¹ is an optionally protected carboxyl group or an optionally substituted acyl group; R ^2a is the same carbamoyl group as the above R ² or an optionally substituted lower alkyl, aryl or aralkyl; Or an acyl group; R ⁶
Represents a hydrogen atom or an aryl group which may be substituted; R ⁷ represents a hydrogen atom, a lower alkyl group or a hydroxyl group; and D represents a leaving group. "

Examples of the leaving group of D include a halogen atom, an acyloxy group, an arylsulfonyloxy group and a lower alkoxysulfonyloxy group, which are generally known as leaving groups. Examples of the substituent of the optionally substituted aryl group in R ⁶ include a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group and the like. Next, each step of the method for producing the compound of the general formula [1] will be described in more detail according to the above-mentioned production route.

Process 1 The compound of general formula [1a] can be obtained by reacting the compound of general formula [2] with the compound of general formula [3] in the presence or absence of a solvent. This reaction is
It can be carried out according to a method known per se, for example, the method described in Organic Synthesis Col. Vol. 5, pp. 973 to 975 or a method analogous thereto. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction,
For example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, methylene chloride and chloroethane; ethers such as tetrahydrofuran and dioxane; N, N-dimethylformamide and N, N-dimethylacetamide. And amides; phosphoramides such as hexamethylphosphoramide; and solvents such as sulfoxides such as dimethyl sulfoxide, and these solvents may be used alone or in combination of two or more. .. This reaction can also be carried out in the presence of a base when the compound of the general formula [3] is a salt with an inorganic acid or an organic acid. Examples of the base optionally used in this reaction include inorganic bases such as alkali hydrogen carbonate, alkali carbonate or alkali hydroxide; and organic bases such as triethylamine, tripropylamine or tributylamine. General formula [3]
The compound is used in an equimolar amount or more, preferably 1.0 to 6.0 times the molar amount of the compound of the general formula [2]. Also,
The amount of the base used as necessary is determined by the formula [2].
Is equimolar or more to the compound. The reaction temperature and the reaction time are not particularly limited, but are usually 20 to 150 ° C. and 1
It may be carried out for 0 minutes to 10 hours.

Process 2 The compound of general formula [1a '] can be obtained by reacting the compound of general formula [4] with the compound of general formula [3] in the presence or absence of a solvent. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran and dioxane; N,
Amides such as N-dimethylformamide and N, N-dimethylacetamide; phosphoramides such as hexamethylphosphoramide; sulfoxides such as dimethylsulfoxide; and solvents such as pyridine. You may use it individually or in mixture of 2 or more types. Further, in this reaction, the compound of the general formula [3] may be used as a solvent. The amount of the compound of the general formula [3] used is equimolar or more, preferably 1.0 to 20 times the molar amount of the compound of the general formula [4]. The reaction temperature and reaction time are not particularly limited, but are usually 50
It may be carried out at ~ 150 ° C for 10 minutes to 10 hours.

Process 3 The compound of the general formula [1b] is an intermediate of the general formula [5] by reacting the compound of the general formula [5] with the compound of the general formula [6] in the presence or absence of a solvent. It can be obtained via the compound (7a) (hydrazone form).
This reaction is usually called Fischer indole synthesis and is a method known per se, for example, New Experimental Chemistry Course (edited by The Chemical Society of Japan, Maruzen Co., Ltd.), Volume 14 [IV],
It can be carried out according to the method described on pages 1957 to 1960 or a method analogous thereto. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, alcohols such as methanol, ethanol, propanol and butanol; aromatic hydrocarbons such as benzene, toluene and xylene. And; acetic acid and the like, and these solvents may be used alone or in combination of two or more. Moreover, this reaction can also be performed in the presence of an acid. Examples of the acid optionally used in this reaction include:
Inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or polyphosphoric acid;
Lewis acids such as zinc chloride; organic carboxylic acids such as formic acid, acetic acid or trichloroacetic acid; or sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or mesitylenesulfonic acid. The amount of the compound of the general formula [6] used is equimolar or more, preferably 1.0
~ 3.0 times mole. The amount of the acid used as necessary is equimolar or more to the compound of the general formula [5]. Although the reaction temperature and the reaction time are not particularly limited, it is usually 20 ° C. to 200 ° C. and 5 minutes to 48 hours. The intermediate compound of the general formula [7a] can be isolated, but it may be converted to the compound of the general formula [1b] in the same reaction system without isolation.

Production Method 4 The compound of the general formula [1c] is an intermediate compound of the general formula [8] after diazotization of the compound of the general formula [8] to give a diazonium salt. It can be obtained via the compound (7b) (hydrazone form). After converting the compound of the general formula [8] into a diazonium salt, it is reacted with a compound of the general formula [9] to give a compound of the general formula [7]
The reaction for obtaining the compound b] is usually called the Japp-klingemann reaction, and is a method known per se, for example, Organic Reactions (O
rganic Reactions), Volume 10, Chapter 2 or a method analogous thereto. In addition, the compound of the general formula [7b] which is an intermediate is converted to the general formula [1
The reaction for converting to the compound of c] can be carried out according to the same literature as described in Production method 3 or a method analogous thereto. The intermediate compound of the general formula [7b] can be isolated, but it may be converted to the compound of the general formula [1c] in the same reaction system without isolation.

Process 5 The reaction for obtaining the compound of the general formula [1d] is as follows.
It can be obtained by reacting a compound of [1a ′], [1b] or [1c] with a compound of general formula [10] in the presence or absence of a solvent. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include halogenated hydrocarbons such as chloroform, methylene chloride and dichloroethane; ethers such as tetrahydrofuran and dioxane; toluene. And aromatic hydrocarbons such as xylene; nitriles such as acetonitrile and propionitrile; N, N-dimethylformamide and N, N-
Examples include amides such as dimethylacetamide; phosphonylamides such as hexamethylphosphonylamide; and solvents such as sulfoxides such as dimethylsulfoxide, and these solvents may be used alone or in combination of two or more. Good. Moreover, this reaction can also be performed in the presence of a base. Examples of the base optionally used in this reaction include an inorganic base such as alkali hydrogen carbonate or alkali hydroxide; an organic base such as triethylamine, tripropylamine or tributylamine; or sodium hydride. The amount of the compound of the general formula [10] to be used is
It is an equimolar amount or more, preferably 1.0 to 3 times the molar amount of the compound of a], [1a ′], [1b] or [1c].
Further, the amount of the base used as necessary is equimolar or more to the compound of the general formula [1a], [1a ′], [1b] or [1c]. The reaction temperature and reaction time are not particularly limited, but are usually 10 to 140 ° C. and 10 minutes to 4 minutes.
You only have to do this for 8 hours. General formulas [2], [3], [4], [5], [6], [7] in the manufacturing method described above,
[8], [9], [10], [1a], [1a '], [1
In the compounds of b] and [1c], when a salt can be formed, the salt may be used, and examples of the salt include the same salts as those described as the salt of the compound of the general formula [1]. Next, a method for producing the compounds of the general formulas [2], [4], [5] and [8] which are raw materials for producing the compound of the present invention will be described. These compounds can be obtained by known methods or by appropriately combining them, and can be produced, for example, according to the production route shown below.

[0019]

[Chemical 16]

[Chemical 17]

[Chemical 18]

"In the formula, R ¹ , R ^1a , R ^1b , R ^1c , R ³ and R
⁶ , R ⁷ , Y and Z each have the same meaning as described above; R ^2b is a hydrogen atom, a protecting group at the 1-position of the pyrrole ring and the indole ring or a substituent similar to R ² described above. Optionally an lower alkyl, aryl or aralkyl group; R ^3a is a hydrogen atom or an optionally substituted lower alkyl, alkenyl, similar to the above R ³ ;
R ^3b is a hydrogen atom or an optionally protected hydroxyl group similar to R ³ described above or an optionally substituted lower alkyl, alkenyl, cycloalkyl or aryl group; R ⁸ Is a protecting group for a carboxyl group or an optionally substituted lower alkyl, aralkyl or aryl group; G is an oxygen atom or an imino group; and X is a chlorine atom, a bromine atom or an iodine atom. "

Examples of the protecting group at the 1-position of the pyrrole ring and the indole ring of R ^2b, the protecting group of the hydroxyl group of R ^3b and the protecting group of the carboxyl group of R ⁸ include protecting groups known in the art. Specifically, the Protective Groups in
Organic Synthesis [Protecteve Groups in Org
anic Synthesis; Theodora W. Green (The
Odora.W.Green), (1981), John Willy & Sons, Inc.] and Japanese Patent Publication No. 60-52755. .. Examples of the substituent for R ⁸ include the same substituents as described for R ⁶ . Then, the general formula [2],
The production methods of the compounds [4], [5] and [8] will be described in more detail according to the above production route.

Production Method a A method for producing a compound of the general formula [2]. The compound of the general formula [11] is reacted with sodium nitrite in the presence of hydrochloric acid or with amyl nitrite to form a diazonium salt, and then sodium sulfite,
Using a reducing agent such as stannous chloride or zinc dust,
A compound of general formula [12] (hydrazine derivative) can be obtained. This reaction is a method known per se, for example, Organic Synthesis Col. Vol.
1, pages 442 to 445 and the like, or a method analogous thereto. Then, the compound of general formula [12] can be reacted with the compound of general formula [6] to obtain the compound of general formula [13]. This reaction can be carried out according to the same method as the above-mentioned production method 3. Alternatively, the compound of the general formula [11] is diazotized and then reacted with the compound of the general formula [9] to obtain a compound (hydrazone body) of the general formula [14],
Further, it can be converted to the compound of the general formula [13].
These reactions can be carried out according to the same method as the above-mentioned production method 4. Then, the compound of general formula [13] can be obtained by hydrolyzing the compound of general formula [13] and further dehydrating it with acetic anhydride or the like. This reaction is a method known per se, for example, Organic Synthesis, Col. Vol. 2,
It can be carried out according to the methods described on pages 457 to 458 and Col. Vol. 1, pages 410 to 411, or methods analogous thereto.

Production Method b A method for producing the compounds of the general formulas [4a] and [4]. A compound of the general formula [17] can be obtained by reacting a compound of the general formula [15] with a compound of the general formula [16] [Wittig reaction]. This reaction can be carried out according to a method known per se, for example, the method described in Organic Reactions, Volume 14, Chapter 3, or a method analogous thereto. Then, by reacting the compound of the general formula [17] with the compound of the general formula [18], [Diels Alder
(Diels-Alder) reaction], a compound of the general formula [19] can be obtained. This reaction is a method known per se, for example,
Organic Reactions, No.
It can be carried out according to the method described in Volume 4, Chapter 1 and Chapter 2 or a method analogous thereto. Next, the compound of general formula [4a] can be obtained by oxidizing (dehydrogenating) the compound of general formula [19]. This reaction is a method known per se, for example, a new experimental chemistry course,
Volume 15 [I-2], pages 844-860 or 1088-10
It can be carried out according to the method described on page 92 or a method analogous thereto. Alternatively, the compound of the general formula [20] is reacted with the compound of the general formula [21] (Grignard reagent), and then dehydrated to give the compound of the general formula [22]
The compound of general formula [18] is obtained by reacting this compound with the compound of general formula [18] (Diels-Alder reaction), and then oxidizing (dehydrogenating) this compound,
A compound of general formula [4a] can also be obtained.

Then, in the compound of the general formula [4a], when R ^2b is a protecting group for the indole ring, the compound of the general formula [4] is removed by removing the protecting group according to a conventional method. Obtainable. The general formula [4
The compound of a] can also be used as a raw material of the manufacturing method 2. That is, after such a reaction, when R ^2b is a protecting group, it can be eliminated to obtain the compound of the general formula [1a]. When R ^2b is an optionally substituted lower alkyl or aryl group,
It is possible to obtain the compound of the general formula [1a] in which the 1-position of the indole ring is substituted with an optionally substituted lower alkyl or aryl group.

Process c: A process for producing the compounds of the general formulas [5] and [8]. The compound of general formula [25] can be obtained by reacting the compound of general formula [24] with the compound of general formula [3]. This reaction can be carried out according to the same method as the above-mentioned manufacturing method 1 or manufacturing method 2. Then,
The compound of general formula [25] can be obtained by catalytic reduction or reduction with iron-hydrochloric acid or the like to obtain the compound of general formula [8]. Then, the compound of the general formula [8] is diazotized and further reduced to obtain the compound of the general formula [5]. This reaction can be carried out according to the same method as the above-mentioned production method a.

When a salt can be formed in the above-described raw material compounds, that is, the compounds of the general formulas [6], [8], [9], [11] to [21], the salts may be used. Examples of the salt include the same salts as those described for the salt of the compound of the general formula [1]. The compound of the present invention (general formula [1]) and the starting compound thus obtained are subjected to, for example, oxidation, reduction, rearrangement, substitution, alkylation,
Acylation, halogenation, imide exchange, quaternization, deprotection,
Other compounds within the general formula can be derived by subjecting to a reaction known per se such as decarboxylation, dehydration, hydrolysis or introduction of a protecting group, or by appropriately combining them. When the compound of the present invention (general formula [1]) and each starting compound in the above-mentioned production method have isomers (eg optical isomers, geometric isomers, tautomers, etc.), all of them The isomers of can be used, and all solvates, hydrates and crystalline forms can be used. In the compound of the present invention (general formula [1]) and the respective starting compounds in the above-mentioned production method, the compound having an amino group, a hydroxyl group or a carboxyl group is a compound having an amino group, a hydroxyl group or a carboxyl group in advance. Alternatively, after the reaction, these protecting groups can be removed by a method known per se after the reaction. Further, after completion of the reaction, the reaction target product may be directly used in the next reaction without isolation. In addition, the compound of the present invention (general formula [1]) thus obtained and the respective starting compounds are isolated and purified according to a usual method such as extraction, crystallization, distillation, column chromatography and recrystallization. You can When the compound of the general formula [1] of the present invention is used as a medicine, it may be appropriately mixed with itself or an additive such as a pharmaceutically acceptable excipient, carrier and diluent. Can be orally or parenterally administered in the form of tablets, capsules, granules, powders, injections or suppositories. The administration method, dose and frequency of administration can be appropriately selected according to the age, body weight and symptoms of the patient, but usually 1 to 500 mg per day for an adult may be administered in one to several divided doses.

Next, the pharmacological action of typical compounds of the indole derivative of the present invention will be described. Test compound No. 1 ~
The following compounds were used as No. 13. R ^1a , R ^1b , R ^3a , R ^3b and Z in Table 1 and Table 2 are respectively represented by the following formulas.

[Chemical 19] The substituents of the compound represented by are shown below. In addition, No. shows a test compound No. (Below margin)

[0028]

[Table 1]

[0029]

[Table 2]

Antitumor effect HeLa S-3 cell growth inhibition test MEM (Minimum essential medium) containing 10% fetal calf serum
um) A test compound is appropriately diluted with a culture solution, and 0.1 ml of this is dispensed into each well of a 96-well microtiter plate. Next, 0.1 ml of HeLa S-3 cells adjusted to 2 × 10 ⁴ cells / ml with the culture medium is dispensed into each well. Incubate in a carbon dioxide incubator for 4 days at 37 ° C. After culturing, the culture supernatant is removed and fixed with ethanol for 10 minutes.
Fixed cells were stained with Giemsa stain to determine the minimum inhibitory concentration (MIC) for HeLa S-3 cells. The results are shown in Tables 3 and 4.

[0031]

[Table 3]

[0032]

[Table 4]

From the above test results, it can be easily understood that the compound of the general formula [1] of the present invention exhibits an excellent antitumor effect.

[0034]

EFFECTS OF THE INVENTION Therefore, it is clear that the compound of the general formula [1] of the present invention is a very useful compound as an anticancer agent.

[0035]

EXAMPLES Next, the compounds of the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. In addition, silica gel 60 (manufactured by Merck & Co., Inc.) was used for the packing material and the preparative thin-layer chromatography in the column chromatography unless otherwise specified. The mixing ratios of the eluent and the developing solution are all volume ratios. In addition, the parenthesized column in the melting point column indicates the reconstituted solvent. The abbreviations used below have the following meanings. n-PrOH; n-propyl alcohol i-PrOH; isopropyl alcohol EtOH; ethanol Furthermore, the wavenumber of IR shows the absorption of carbonyl.

Reference Example 1 Dimethyl 4-methyl-5- (1-phenylpropylide
Hydrazino) benzene-1,2-dicarboxylate dimethyl = 4-amino-5-methylbenzene-1,2-
3.00 g of dicarboxylate / hydrochloride is suspended in 4.8 ml of 6N hydrochloric acid, and a solution prepared by dissolving 880 mg of sodium nitrite in 3 ml of water is added dropwise thereto over 10 minutes while stirring with ice cooling. Stir at the same temperature for 30 minutes. Then, the obtained yellow reaction mixture was mixed with 5.22 g of stannous chloride dihydrate and 7.7% of 6N hydrochloric acid.
Add all at once to a mixture of ml and 10 g of ice. Further, the mixture is stirred under ice cooling for 30 minutes. The insoluble matter is then filtered and the insoluble matter is washed with 20 ml of 3N hydrochloric acid. The washings are combined with the above filtrate and concentrated to dryness under reduced pressure. 1.70 g of phenyl ethyl ketone, 150 ml of ethanol and 5.67 g of concentrated sulfuric acid were added to the obtained residue.
Is added and the mixture is refluxed for 2 hours. Then, the solvent is distilled off under reduced pressure, 200 ml of ethyl acetate and 100 ml of water are added, and the organic layer is separated. The obtained organic layer is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 40: 1) to give pale yellow crystals of dimethyl = 4-methyl-5- (1 -Phenylpropylidenehydrazino) benzene-1,2-dicarboxylate 66
You get 0 mg. IR (KBr) cm ^-1 ; 1739,1707

Reference Example 2 Dimethyl = 3,7-dimethyl-2-phenylindole
4,5-Dicarboxylate dimethyl = 4-methyl-5- (1-phenylpropylidenehydrazino) benzene-1,2-dicarboxylate
To 620 mg, add 6.2 ml of acetic acid and 250 mg of zinc chloride and reflux for 3 hours. Then, after cooling to room temperature, ethyl acetate
100 ml and 50 ml of water are added and the organic layer is separated. The obtained organic layer is washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluent; toluene:
If purified with ethyl acetate = 40: 1), pale yellow crystalline dimethyl = 3,7-dimethyl-2-phenylindole-4,
340 mg of 5-dicarboxylate are obtained. IR (KBr) cm ^-1 ; 1715

Reference Examples 3 to 11 In the same manner as in Reference Examples 1 and 2, compounds shown in Tables 5 and 6 are obtained. In addition, R ^1a and R in Table 5 and Table 6
^1b is

[Chemical 20] The substituents of the compound represented by are shown below.

[0039]

[Table 5]

[0040]

[Table 6]

Reference Example 12 3,7-Dimethyl-2-phenylindole-4,5-
Dicarboxylic acid anhydride dimethyl = 3,7-dimethyl-2-phenylindole-4,5-dicarboxylate 330 mg, ethanol 6.5
ml and 5N sodium hydroxide aqueous solution 3.9 ml, and reflux for 30 minutes. Then, 3.9 ml of 6N hydrochloric acid was added to the reaction mixture, 50 ml of ethyl acetate was added, and the organic layer was separated.
The separated organic layer is washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, 10 ml of xylene is added thereto, and the mixture is concentrated to dryness under reduced pressure again.
Then, 3.0 ml of acetic anhydride was added to the obtained residue to give 30
Reflux for minutes. Then, it is concentrated to dryness under reduced pressure and xylene
After adding 5 ml and concentrating to dryness again, 3,7-dimethyl-
2-Phenylindole-4,5-dicarboxylic acid anhydride
You get 230 mg. IR (KBr) cm ^-1 ; 1820,1762

Reference Examples 13 to 21 In the same manner as in Reference Example 12, the compounds in Table 7 are obtained. In addition,
R ^1a and R ^{1b in} Table 7 are respectively represented by the following formulas.

[Chemical 21] The substituents of the compound represented by are shown below.

[0043]

[Table 7]

Reference Example 22 Dimethyl = 3,7-dimethyl-2- (1-methyl-4-)
Pyridinio) indole-4,5-dicarboxylate
= Iodidodimethyl = 3,7-dimethyl-2- (4-pyridyl) indole-4,5-dicarboxylate (420 mg) was dissolved in chloroform (50 ml), and methyl iodide (1.55) was added to the solution.
Add ml and stir at room temperature for 24 hours. Then, the precipitated crystals are collected by filtration and dried to give yellow crystals of dimethyl = 3.
7-Dimethyl-2- (1-methyl-4-pyridinio) indole-4,5-dicarboxylate = iodide440 m
get g. IR (KBr) cm ^-1 ; 1712,1641

Reference Example 23 Dimethyl = 3,7-dimethyl-2- (1,2,3,6-
Tetrahydro-1-methylpyridin-4-yl) indo
345 mg of sodium borohydride was suspended in 20 ml of 70% ethanol of 4,5-dicarboxylate , and dimethyl = 3 was added to this suspension under stirring with ice cooling.
7-Dimethyl-2- (1-methyl-4-pyridinio) indole-4,5-dicarboxylate = iodide430 m
A solution prepared by dissolving 30 g of 70% ethanol in 30 ml is added dropwise over 15 minutes. After the dropping is completed, the mixture is stirred under ice cooling for 30 minutes and at room temperature for another 30 minutes. Then 100 ml of ethyl acetate and 5 parts of water
0 ml is added and the organic layer is separated. The separated organic layer is washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent: chloroform: methanol = 50: 1 to 20: 1) to give yellow crystals of dimethyl =
3,7-dimethyl-2- (1,2,3,6-tetrahydro-1-methylpyridin-4-yl) indole-4,
310 mg of 5-dicarbochelate are obtained. IR (KBr) cm ^-1 ; 1718

Reference Example 24 In the same manner as in Reference Example 12, the following compound was obtained. o3,7-dimethyl-2- (1,2,3,6-tetrahydro-1-methylpyridin-4-yl) indole-
4,5-dicarboxylic acid anhydride

Reference Example 25 N- (2-dimethylaminoethyl) -4-amino-5-
Methylbenzene-1,2-dicarboximide 4-methyl-5-nitrobenzene-1,2-dicarboximide 18 g, N, N-dimethylethylenediamine 23.
Add 1 g and stir for 10 minutes. (The reaction mixture is heated to dissolve and then solidify.) Then, after heating under reflux for 10 minutes,
The reaction mixture is concentrated to dryness under reduced pressure, 300 ml of diethyl ether is added to the obtained residue, and the mixture is stirred at room temperature for 10 minutes.
The insoluble matter is collected by filtration and dried to obtain 29.5 g of light brown powder. 100 ml of acetic anhydride is added to 29.5 g of the obtained powder, and the mixture is refluxed for 10 minutes. Then, the mixture is concentrated to dryness under reduced pressure, the obtained residue is dissolved in 200 ml of chloroform, and the mixture is washed twice with 50 ml of water each time. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 23.2 g of a light brown oily substance. IR (neat) cm ^-1 ; 1775,1716 The obtained oily substance (23.2 g) is dissolved in ethanol (300 ml), 5% palladium-carbon (4.60 g) is added to this solution, and catalytic reduction is performed at room temperature and atmospheric pressure with stirring. After completion of the reduction reaction, 200 ml of chloroform is added and the catalyst is filtered off. The filtrate was concentrated to dryness under reduced pressure, and recrystallized from ethanol to give yellow needle crystals of N.
12.0 g of-(2-dimethylaminoethyl) -4-amino-5-methylbenzene-1,2-dicarboximide are obtained. IR (KBr) cm ^-1 ; 1758,1696

Reference Example 26 The following compound was obtained in the same manner as in Reference Example 25 using 4-nitrophthalic anhydride. oN- (2-dimethylaminoethyl) -4-aminobenzene-1,2-dicarboximide IR (KBr) cm ^-1 ; 1755,1690

Reference Example 27 Ethyl = 1-benzyl-4,5-dimethylpyrrole-2
- carboxylate Ethyl 4,5-dimethyl-pyrrole-2-carboxylate 8.57g was dissolved in acetone 120 ml, 98% in the solution
3.22 g of potassium hydroxide and 9.65 g of benzyl bromide are added, and the mixture is stirred at room temperature for 2 hours. Then, after filtering the insoluble matter,
The insoluble matter is washed with 50 ml of acetone. The washing solution is combined with the above filtrate and concentrated to dryness under reduced pressure. The obtained residue is dissolved in 150 ml of ethyl acetate, and washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluent: n-hexane: ethyl acetate = 1: 0 to 30: 1).
If purified with, a colorless oil, ethyl = 1-benzyl-
4,5-Dimethylpyrrole-2-carboxylate 9.61
get g. IR (neat) cm ^-1 ; 1694

Reference Example 28 1-benzyl-2,3-dimethyl-5- (2-pentene
-3-yl) pyrroleethyl = 1-benzyl-4,5-dimethylpyrrole-2
-4.53 g of carboxylate 40 ml of anhydrous diethyl ether
70 ml of a 1M ethylmagnesium bromide-ether solution is added dropwise to the solution under reflux stirring over 20 minutes. After the dropping is completed, the mixture is refluxed for 4 hours. Then, 100 ml of ethyl acetate is added with stirring under ice cooling. In this solution,
50 ml of water is added dropwise over 5 minutes, and 15 ml of 6N hydrochloric acid is added dropwise over 5 minutes. Then, the organic layer is separated, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent: n-hexane: ethyl acetate = 20: 1) to give 1-benzyl-2,3 as a pale yellow oil. -Dimethyl-5- (2-penten-3-yl) pyrrole 4.04 g
To get NMR (CDCl ₃ ) δ (ppm); 0.90 (3H, t, 6Hz), 1.65 (3H, d, 6H
z), 1.95 (3H, s), 2.03 (3H, s), 2.25 (2H, q, 6Hz), 5.02 (2H,
s), 5.35 (1H, q, 6Hz), 5.87 (1H, s), 6.80-7.50 (5H, m)

Reference Example 29 1-Benzyl-4,5-dimethylpyrrole-2-carbo
1.48 g of lithium aluminum hydride was suspended in 150 ml of xylaldehyde anhydrous diethyl ether, and this suspension was stirred under ice-cooling.
Ethyl = 1-benzyl-4,5-dimethylpyrrole-2
− Carboxylate 10.07 g with anhydrous diethyl ether 50 ml
The solution dissolved in is added dropwise over 20 minutes. After the completion of dropping, the mixture is further stirred for 2 hours under ice cooling. Then, 3.0 ml of a saturated sodium sulfate aqueous solution is added dropwise over 2 minutes while stirring with ice cooling. Then 150 ml of ethyl acetate was added to the reaction mixture.
Is added and the insoluble matter is filtered. The insoluble matter is washed with 50 ml of ethyl acetate, the washings are combined with the above filtrate, and concentrated to dryness under reduced pressure. 200 ml of ethyl acetate and 20 g of manganese dioxide are added to the obtained residue, and the mixture is refluxed for 30 minutes with stirring. After cooling to room temperature, the insoluble matter is filtered, the insoluble matter is washed with 100 ml of ethyl acetate, the washing solution is combined with the above filtrate, and concentrated to dryness under reduced pressure. The obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 50: 1) to obtain 3.35 g of 1-benzyl-4,5-dimethylpyrrole-2-carboxaldehyde as pale yellow crystals. obtain. IR (KBr) cm ^-1 ; 1655

Reference Example 30 1-Benzyl-2- (2-methoxyvinyl) -4,5-
Dimethylpyrrole methoxymethyltriphenylphosphonium chloride 4.03
g is suspended in 30 ml of anhydrous tetrahydrofuran, and 7.3 ml of 1.6M n-butyllithium-hexane solution is added dropwise over 5 minutes while stirring with ice cooling. After stirring for 20 minutes under ice cooling, 1-
A solution of 1.79 g of benzyl-4,5-dimethylpyrrole-2-carboxaldehyde in 15 ml of anhydrous tetrahydrofuran is added dropwise over 10 minutes while stirring under ice cooling. After stirring for 10 minutes under ice cooling, 100 ml of ethyl acetate and 50 m of water
l is added and the organic layer is separated. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate,
The solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (eluent: n-hexane: ethyl acetate = 5)
0: 1), colorless crystals of 1-benzyl-2-
(2-Methoxyvinyl) -4,5-dimethylpyrrole 1.
Get 35g. IR (KBr) cm ^-1 ; 1643

Reference Example 31 N-phenyl-1-benzyl-7-ethyl-4,5,5
6,7-Tetrahydro-2,3,6-trimethylindo
4,5-dicarboximido 1-benzyl-2,3-dimethyl-5- (2-penten-3-yl) pyrrole 4.00 g, N-phenylmaleinimide 5.47 g and xylene 50 ml were added to give 3 Reflux for an hour. After cooling to room temperature, the reaction mixture was subjected to column chromatography (eluent; n-hexane: ethyl acetate = 50: 1 to 10 :).
After purification in 1) and recrystallization from isopropanol, colorless crystals of N-phenyl-1-benzyl-7-ethyl-4,5,6,7-tetrahydro-2,3,6-trimethylindole-4, 5-dicarboximide 4.30 g
To get IR (KBr) cm ^-1 ; 1772,1710

Reference Example 32 In the same manner as in Reference Example 31, the following compound is obtained. oN-phenyl-1-benzyl-4,5,6,7-tetrahydro-6-methoxy-2,3-dimethylindole-4,5-dicarboximide IR (KBr) cm ^-1 ; 1775,1707

Reference Example 33 N-phenyl-1-benzyl-7-ethyl-2,3,6
-Trimethylindole- 4,5-dicarboximide N-phenyl-1-benzyl-7-ethyl-4,5,5
3.82 g of 6,7-tetrahydro-2,3,6-trimethylindole-4,5-dicarboximide was dissolved in 100 ml of methylene chloride, and 2,3-dichloro- was added to this solution.
4.06 g of 5,6-dicyano-p-benzoquinone was added, and at room temperature
Stir for 2 hours. The insoluble matter is then filtered and the insoluble matter is washed with 50 ml of chloroform. The washing solution is combined with the above filtrate, washed successively with 10% aqueous potassium carbonate solution and saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent: toluene: ethyl acetate = 50: 1) to give yellow crystals of N-phenyl-1-benzyl-7-ethyl. 1.30 g of 2,3,6-trimethylindole-4,5-dicarboximide are obtained. IR (KBr) cm ^-1 ; 1750,1700

Reference Example 34 N-phenyl-1-benzyl-6-methoxy-2,3-
Dimethylindole-4,5-dicarboximide N-phenyl-1-benzyl-6-methoxy-4,5,
6,7-Tetrahydro-2,3-dimethylindole-
To 950 mg of 4,5-dicarboximide, 10 ml of diphenyl ether and 300 mg of 5% palladium-carbon were added, and the mixture was refluxed for 15 minutes under a nitrogen stream. After cooling to room temperature, 50 ml of ethyl acetate is added and the insoluble matter is filtered off. The filtrate was concentrated under reduced pressure, the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 1: 0 to 30: 1), and recrystallized from n-propanol to give yellow crystals. N-
590 mg of phenyl-1-benzyl-6-methoxy-2,3-dimethylindole-4,5-dicarboximide are obtained. IR (KBr) cm ^-1 ; 1756,1706

Reference Example 35 N-phenyl-7-ethyl-2,3,6-trimethyl group
Ndol-4,5-dicarboximide N-phenyl-1-benzyl-7-ethyl-2,3,6
-Trimethylindole-4,5-dicarboximide
1.16 g, 30 ml of anisole and anhydrous aluminum chloride
Add 3.65 g and stir at room temperature for 2 hours. Then, the solvent is distilled off under reduced pressure, 100 ml of ethyl acetate and 50 ml of water are added to the obtained residue to dissolve it, and the organic layer is separated. The separated organic layer is washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluent; toluene:
Purification with ethyl acetate = 50: 1 to 10: 1) yields yellow crystals of N.
810 mg of -phenyl-7-ethyl-2,3,6-trimethylindole-4,5-dicarboximide are obtained. IR (KBr) cm ^-1 ; 1758,1685

Reference Example 36 In the same manner as in Reference Example 35, the following compound is obtained. oN-phenyl-6-methoxy-2,3-dimethylindole-4,5-dicarboximide IR (KBr) cm ^-1 ; 1758,1704

Example 1 N- (2-dimethylaminoethyl) -3,7-dimethyl
-2-Phenylindole-4,5-dicarboximid
De 3,7-dimethyl-2-phenylindole-4,5-
To 110 mg of dicarboxylic acid anhydride, 0.21 ml of N, N-dimethylethylenediamine and 5 ml of xylene are added, and azeotropic dehydration is carried out for 30 minutes. Cool to room temperature, filter the precipitated crystals,
Once dried, yellow crystals of N- (2-dimethylaminoethyl) -3,7-dimethyl-2-phenylindole-
80 mg of 4,5-dicarboximide are obtained. Melting point; 215-216 ℃ IR (KBr) cm ^-1 ; 1750,1697

Examples 2 to 17 In the same manner as in Example 1, the compounds shown in Tables 8 and 9 are obtained. In addition, R ^1a , R ^1b and Z in Table 8 and Table 9 are
The following formula

[Chemical formula 22] The substituents of the compound represented by are shown below. (Below margin)

[0061]

[Table 8]

[0062]

[Table 9]

Example 18 N- (2-Dimethylaminoethyl) -7-ethyl-2,
3,6-Trimethylindole-4,5-dicarboxy
Imide N- phenyl-7-ethyl-2,3,6-trimethyl-indole-4,5-dicarboximide 400 mg, N,
Add 4.0 ml of N-dimethylethylenediamine and reflux for 2.5 hours. Then, the mixture was concentrated to dryness under reduced pressure, and the obtained residue was recrystallized from isopropanol to give yellow needle crystals of N.
-(2-Dimethylaminoethyl) -7-ethyl-2,
250 mg of 3,6-trimethylindole-4,5-dicarboximide are obtained. Melting point; 231-232 ° C IR (KBr) cm ^-1 ; 1744,1695

Example 19 In the same manner as in Example 18, the following compound is obtained. oN- (2-dimethylaminoethyl) -6-methoxy-
2,3-Dimethylindole-4,5-dicarboximide Melting point: 225 to 227 ° C (i-PrOH) IR (KBr) cm ^-1 ; 1747,1696

Example 20 N- (2-Dimethylaminoethyl) -2,3,7-tri
Methylindole- 4,5-dicarboximide N- (2-dimethylaminoethyl) -4-amino-5-
2 parts of 2.00 g of methylbenzene-1,2-dicarboximide
A solution of 590 mg of sodium nitrite dissolved in 5 ml of water is added dropwise to the solution by dissolving it in 16 ml of N-hydrochloric acid and maintaining the temperature at 5 ° C. over 5 minutes while stirring. After stirring for a further 10 minutes at the same temperature, the reaction mixture obtained is added at once to a mixture of 4.56 g of stannous chloride dihydrate, 5.4 ml of 6N hydrochloric acid and 5 g of ice. Furthermore, the mixture is stirred under ice cooling for 1.5 hours. The insoluble matter is then filtered and the insoluble matter is washed with 20 ml of 2N hydrochloric acid. The filtrate combined with the washing solution is concentrated to dryness under reduced pressure. 20 ml of ethanol is added to the obtained residue and the mixture is concentrated to dryness again. To the obtained residue, 1.16 g of methyl ethyl ketone, 40 ml of acetic acid and 6.0 g of anhydrous zinc chloride are added, and the mixture is refluxed for 2.5 hours. Then, the solvent is distilled off under reduced pressure, 200 ml of chloroform and 100 ml of water are added to the obtained residue to dissolve it, and the pH is adjusted to 6.6 with a saturated aqueous sodium hydrogen carbonate solution. Then, the insoluble matter is filtered and the insoluble matter is washed with 100 ml of chloroform.
The washing solution is combined with the above filtrate, the organic layer is separated, and washed with saturated saline. It was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol to give yellow needle crystals of N- (2-dimethylaminoethyl) -2,3,7-. 690 mg of trimethylindole-4,5-dicarboximide are obtained. The physical properties (melting point and IR) of this compound were the same as those obtained in Example 3.

Example 21 The following compound was obtained in the same manner as in Example 20. oN- (2-Dimethylaminoethyl) -2,3-dimethylindole-4,5-dicarboximide Melting point: 211-212 ° C (n-PrOH) IR (KBr) cm ^-1 ; 1745,1700

Example 22 The following compound was obtained as in Example 20. oN- (2-Dimethylaminoethyl) -2,3-dimethylindole-5,6-dicarboximide Melting point; 198-199 ° C (n-PrOH) IR (KBr) cm ^-1 ; 1750,1695

Example 23 (1) N- (2-dimethylaminoethyl) -4-methyl
Lu-5- [1- (2-methylthiazol-4-yl) e
Tylidene hydrazino] benzene-1,2-dicarboxy
Imide In the same manner as in Example 20, 2.00 g of N- (2-dimethylaminoethyl) -4-amino-5-methylbenzene-1,2-dicarboximide was converted to a diazonium salt and further reduced to obtain a hydrazine derivative. .. To this hydrazine derivative, 1.14 g of 4-acetyl-2-methylthiazole and 50 ml of 3N hydrogen chloride-ethanol solution are added, and the mixture is refluxed for 2 hours. After cooling to room temperature, the insoluble matter is filtered off and washed with 10 ml of ethanol. Chloroform was added to the resulting insoluble matter.
Add 150 ml, 30 ml of methanol and 150 ml of saturated aqueous sodium hydrogen carbonate solution, and stir for 10 minutes. The insoluble matter is then filtered and the insoluble matter is washed with 50 ml of chloroform. The washing solution is combined with the above filtrate, the organic layer is separated, washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluent; chloroform: methanol = 1: 0 to 3).
After purification by 0: 1), yellow crystals of N- (2-dimethylaminoethyl) -4-methyl-5- [1- (2-methylthiazol-4-yl) ethylidenehydrazino] benzene-1,2 are obtained. -2.66 g of dicarboximide are obtained. IR (KBr) cm ^-1 ; 1763,1701

(2) N- (2-dimethylaminoethyl)
-7-methyl-2- (2-methylthiazol-4-i
) Indole-4,5-dicarboximido N- (2-dimethylaminoethyl) -4-methyl-5-
[1- (2-Methylthiazol-4-yl) ethylidenehydrazino] benzene-1,2-dicarboximide 2.
To 66 g, add 19.8 g of polyphosphoric acid and 100 ml of xylene,
Reflux for 1 hour with stirring. After cooling to room temperature, the supernatant is removed by decantation, 250 ml of water and 350 ml of ethyl acetate are added to the resulting residue to dissolve it, and sodium hydrogen carbonate is added to neutralize the residue. The organic layer is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from n-propanol to give yellow needle crystals of N- (2-dimethylaminoethyl) -7-methyl-2-.
(2-methylthiazol-4-yl) indole-4,
890 mg of 5-dicarboximide are obtained. Melting point: 249.5-251 ℃ IR (KBr) cm ^-1 ; 1750,1694

Example 24 The following compound is obtained in the same manner as in Example 23 (1) and (2). o2- (2-aminothiazol-4-yl) -N- (2
-Dimethylaminoethyl) -7-methylindole-
4,5-Dicarboximide Melting point: 243-247 ° C (n-PrOH) IR (KBr) cm ^-1 ; 1747,1690

Example 25 (1) N- (2-dimethylaminoethyl) -4- (1-
Ethoxycarbonyl Pro pyridinium den hydrazino) -5-menu
Cylbenzene-1,2-dicarboximide N- (2-dimethylaminoethyl) -4-amino-5-
Methylbenzene-1,2-dicarboximide 2.90 g 2
A solution prepared by dissolving 1.14 g of sodium nitrite in 6 ml of water is added dropwise to this solution while stirring at 5 ° C. for 5 minutes. After stirring at the same temperature for 10 minutes, this solution was mixed with 2-ethylacetoacetic acid ethyl ester.
2.99g, sodium acetate trihydrate 10.73g, ethanol 3
Add at once to a mixture of 2 ml and 30 g of ice. Further, the mixture is stirred under ice cooling for 2 hours. Then, 100 ml of ethyl acetate is added, the pH is adjusted to 7.0 with a saturated aqueous sodium hydrogen carbonate solution, and the organic layer is separated. The aqueous layer is extracted 3 times with 50 ml of ethyl acetate and combined with the previous organic layer. The combined organic layers are washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluent: chloroform: methanol = 100:
Purification in 1) yields 2.07 g of a yellow oil, N- (2-dimethylaminoethyl) -4- (1-ethoxycarbonylpropylidenehydrazino) -5-methylbenzene-1,2-dicarboximide. .. IR (KBr) cm ^-1 ; 1761,1709

(2) N- (2-dimethylaminoethyl)
-2-Ethoxycarbonyl-3,7-dimethylindole
L-4,5-dicarboximide N- (2-dimethylaminoethyl) -4- (1-ethoxycarbonylpropylidenehydrazino) -5-methylbenzene-1,2-dicarboximide 2.07 g and polyphosphoric acid Recrystallization from ethanol using 8 g and 50 ml of toluene in the same manner as in Example 23 (2) gave yellow crystals of N- (2-dimethylaminoethyl) -2-ethoxycarbonyl-3,7-dimethylindole-. 590 mg of 4,5-dicarboximide are obtained. Melting point: 188.5-189.5 ° C IR (KBr) cm ^-1 ; 1757,1699

Example 26 (1) Using 2-methylacetoacetic acid ethyl ester instead of 2-ethylacetoacetic acid ethyl ester, the following compound was obtained in the same manner as in Example 25 (1). oN
-(2-Dimethylaminoethyl) -4- (1-ethoxycarbonylethylidenehydrazino) -5-methylbenzene-1,2-dicarboximide IR (KBr) cm- ¹ ; 1761,1698 (2) Example 25 The following compound is obtained in the same manner as in (2). oN- (2-dimethylaminoethyl) -2-ethoxycarbonyl-7-methylindole-4,5-dicarboximide IR (KBr) cm ^-1 ; 1760,1706

Example 27 (1) Using sodium 2-ethylacetoacetate, the following compound is obtained in the same manner as in Example 25 (1). o4- (1-acetylpropylidenehydrazino) -N-
(2-Dimethylaminoethyl) -5-methylbenzene-
1,2-Dicarboximide IR (KBr) cm ^-1 ; 1768,1710 (2) In the same manner as in Example 25 (2), the following compound was obtained. o2-Acetyl-N- (2-dimethylaminoethyl)-
3,7-Dimethylindole-4,5-dicarboximide Melting point; 230-231 ° C IR (KBr) cm ^-1 ; 1758,1699,1661

Examples 28,29 N- (2-dimethylaminoethyl) -2-carboxy-
3,7 Jimechirui Ndoru-4,5-Jikarubokishii
Mido and N- (2-dimethylaminoethyl ) -3,7
-Dimethylindole-4,5-dicarboximide N- (2-dimethylaminoethyl) -2-ethoxycarbonyl-3,7-dimethylindole-4,5-dicarboximide To 200 mg, 6N hydrochloric acid 14 ml was added to give 1.5. Reflux for an hour. The reaction mixture is then concentrated to dryness under reduced pressure and the residue obtained is dissolved in 30 ml of water. After adjusting the pH to 5.5 with a saturated aqueous sodium hydrogen carbonate solution, the mixture is concentrated to dryness under reduced pressure again. The obtained residue was purified by column chromatography (eluent: chloroform: methanol = 10: 1 to 3: 1) to give yellow crystals of N- (2-dimethylaminoethyl) -2-carboxy-3,7. -Dimethylindole-
130 mg of 4,5-dicarboximide and N- (2-dimethylaminoethyl) -3,7-dimethylindole-
30 mg of 4,5-dicarboximide are obtained. The physical properties of each compound are shown below. oN- (2-dimethylaminoethyl) -2-carboxy-3,7-dimethylindole-4,5-dicarboximide IR (KBr) cm ^-1 ; 1754,1689,1626 oN- (2-dimethylaminoethyl) -3,7-Dimethylindole-4,5-dicarboximide Melting point; 239-241 ° C (EtOH) IR (KBr) cm ^-1 ; 1747,1693

Example 30 N- (2-Dimethylaminoethyl) -1,2,3,7-
Tetramethylindole-4,5-dicarboximide N- (2-dimethylaminoethyl) -2,3,7-trimethylindole-4,5-dicarboximide 300 mg
Was dissolved in 5 ml of N, N-dimethylformamide, 40 mg of 60% sodium hydride was added to this solution, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was then charged with 140mM of methyl iodide.
A solution of 2 g of N, N-dimethylformamide dissolved therein was added dropwise over 5 minutes. After stirring at room temperature for 20 minutes, the solvent is distilled off under reduced pressure. To the obtained residue are added 10 ml of 2N hydrochloric acid, and then 100 ml of ethyl acetate. The mixture is adjusted to pH 7.5 with saturated aqueous sodium hydrogen carbonate solution, and the organic layer is separated. The obtained organic layer is washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue is recrystallized from isopropanol to obtain 150 mg of yellow needle crystals of N- (2-dimethylaminoethyl) -1,2,3,7-tetramethylindole-4,5-dicarboximide. .. Melting point: 175.5-176.5 ° C (i-PrOH) IR (KBr) cm ^-1 ; 1750,1693

Example 31 In the same manner as in Example 30, the following compound is obtained. oN- (2-dimethylaminoethyl) -1-acetyl-
2,3,7-Trimethylindole-4,5-dicarboximide IR (KBr) cm ^-1 ; 1760,1725,1698

Example 32 N- (2-Dimethylaminoethyl) -2- (4-hydro)
Xyphenyl) -3,7-dimethylindole-4,5
-Dicarboximide anhydrous chloroform 30ml, anhydrous aluminum chloride 273mg
Add 0.31 ml of ethanethiol and stir for 10 minutes at room temperature. To this solution was stirred at room temperature N- (2-dimethylaminoethyl) -2- (4-methoxyphenyl) -3,7.
-Dimethylindole-4,5-dicarboximide 16
A solution prepared by dissolving 0 mg in 20 ml of anhydrous chloroform is added dropwise over 10 minutes. After stirring at room temperature for 4 hours, the solvent is distilled off under reduced pressure. Ethyl acetate was added to the obtained residue.
50 ml and 30 ml of water are added and the pH is adjusted to 7.5 with saturated aqueous sodium hydrogen carbonate solution. The insoluble matter is filtered, the insoluble matter is washed with 30 ml of ethyl acetate, the washing solution is combined with the above filtrate, and the organic layer is separated. The separated organic layer is washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by column chromatography (eluent; chloroform: methanol = 50: 1 to 20: 1), and recrystallized from n-propanol to give yellow crystals. N- (2-Dimethylaminoethyl) -2- (4-hydroxyphenyl) -3,7-dimethylindole-4,5
60 mg of dicarboximide are obtained. Melting point:> 260 ° C (n-PrOH) IR (KBr) cm ^-1 ; 1752,1692

Examples 33 to 35 In the same manner as in Example 32, the compounds in Table 10 are obtained. In addition, R ^1a , R ^1b and Z in Table 10 are represented by the following formulas.

[Chemical formula 23] The substituents are respectively shown.

[0080]

[Table 10]

Example 36 N- (2-Dimethylaminoethyl) -6-hydroxy-
2,3-Dimethylindole-4,5-dicarboxyi
Mido N- (2-dimethylaminoethyl) -6-methoxy-
2,3-Dimethylindole-4,5-dicarboximide (30 mg) was dissolved in anhydrous methylene chloride (2 ml), and this solution was stirred under ice-cooling with a 1 M boron tribromide-methylene chloride solution.
Add 0.5 ml and stir at room temperature for 30 minutes. Then,
50 ml of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution 20
ml is added and the organic layer is separated. The separated organic layer is washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; chloroform: methanol = 20: 1 to 5: 1) to give yellow crystals of N- (2-dimethylaminoethyl). ) -6-Hydroxy-2,3-dimethylindole-4,5-dicarboximide 20 mg are obtained. IR (KBr) cm ^-1 ; 1741,1687

Example 37 N- (2-Dimethylaminoethyl) -3,7-dimethyl
-2-Phenylindole-4,5-dicarboximid
The de hydrochloride N-(2-dimethylaminoethyl) -3,7-dimethyl-2-phenylindole-4,5-dicarboximide 80mg dissolved in chloroform 10 ml, to this solution, with stirring, 2N hydrogen chloride -Add 0.2 ml of ethanol solution. After stirring at room temperature for 10 minutes, the precipitated crystals were collected by filtration and dried to give yellow crystals of N- (2-dimethylaminoethyl)-.
3,7-Dimethyl-2-phenylindole-4,5-
82 mg of dicarboximide hydrochloride is obtained. IR (KBr) cm ^-1 ; 1750,1699

Examples 38 to 69 In the same manner as in Example 37, hydrochlorides of the compounds shown in Tables 11 to 14 are obtained. In addition, R ^1a , R ^1b , and R in Table 11 to Table 14
² , R ^3a , R ^3b and Z are each represented by the following formula

[Chemical formula 24] The substituents of the compound represented by are shown below.

[0084]

[Table 11]

[0085]

[Table 12]

[0086]

[Table 13]

[0087]

[Table 14]

Example 70 The following compound was obtained in the same manner as in Example 37. oN- (2-dimethylaminoethyl) -2,3-dimethylindole-5,6-dicarboximide-hydrochloride IR (KBr) cm ^-1 ; 1755,1690

Front page continuation (72) Inventor Takako Hori 1008 Gofuku-Suehirocho, Toyama City, Toyama Prefecture

Claims (1)

[Claims] 1. A general formula: "In the formula, R ¹ is a hydrogen atom, an optionally protected carboxyl group or an optionally substituted lower alkyl,
One or more groups selected from alkenyl, cycloalkyl, aryl, acyl or heterocyclic groups; R ² represents a hydrogen atom, a carbamoyl group or an optionally substituted lower alkyl, aryl, aralkyl or acyl group; R ³ is one or more groups selected from a hydrogen atom, a halogen atom, an optionally protected hydroxyl group or an optionally substituted lower alkyl, alkenyl, cycloalkyl or aryl group; Y is a bond A hand or a lower alkylene group; Z is a halogen atom, an optionally protected hydroxyl group or a compound of the formula: (Wherein, R ⁴ and R ⁵ are the same or different, a hydrogen atom, an amino protecting group or substituted optionally may be lower alkyl, cycloalkyl, aralkyl, an acyl or aryl group. Alternatively R ⁴ and R ⁵ may form, together with the nitrogen atom to which they are attached, an optionally substituted nitrogen-containing heterocyclic group) or a trialkylammonio group; [Chemical 3] (In the formula, Y and Z have the same meanings as described above.) The group represented by [4,
It is bonded to the [5] -position or the [5,6] -position. And an indole derivative represented by the formula