JPS6383073A - Benzo(alpha)phenazine derivative - Google Patents

Abstract

NEW MATERIAL:A benzo[alpha]phenazine derivative expressed by formula I [R1 is H, halogen, methyl, OH or alkoxy; R<2> is -COOR<4> (R<4> is H, alkyl, cycloalkyl, benzyl or phenyl) or formula II (R<5> and R<6> are H, alkyl or mutually links to form a heterocyclic ring together with adjacent N); R<3> is alkyl]. EXAMPLE:Ethyl 10-ethoxy-5-hydroxy-9-methoxycarbonyl-benzo[alpha]phenazine-6- carboxylate. USE:An intermediate for production of benzo[alpha]phenazine-6-carboxamide derivative which is a cancer remedy. PREPARATION:Ethyl 3-hydroxy-1,4-dihydro-1,4-dioxo-2-naphtoate is treated with an acyl chloride or chloroformic acid ester and then condensed with phenylene-diamine to provide a compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to intermediate compounds useful for preparing benzo[alpha-cohuenazine-6-carpoxamide derivatives.

The present inventors have provided a group of benzo[a]phenazine-6-carboxamide derivatives that have antitumor activity and are useful in the treatment of cancer (Japanese Patent Application No. 61-64410). .

SUMMARY OF THE INVENTION The present invention aims to provide intermediate compounds useful for producing the benzo[a]phenazine-6-carboxamide derivatives.

Means for Solving the Problems The present invention provides a method for solving problems based on the formula ■ [wherein R' represents a hydrogen atom, a halogen atom, a methyl group, a hydroxyl group, or an alkoxy group, and R1 represents the formula, 1'C0OR' (wherein R4 represents a hydrogen atom, a straight-chain or branched alkyl group, a cycloalkyl group, a benzyl group, or a phenyl group, or the formula, (wherein R1 and R" are the same or different and represent a hydrogen atom, a lower alkyl group, or a group that is bonded to each other to form a heterocycle together with adjacent nitrogen atoms, and R8 represents a lower alkyl group.

In the present invention, the halogen atom is fluorine, chlorine, bromine or iodine, and the alkoxy group is methoxy group,
It is a lower alkoxy group such as ethoxy group, propoxy group, butoxy group. A straight chain or branched alkyl group is an alkyl group having 1 to 20 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, a neopentyl group,
These include hexyl group, decyl group, eicosyl group, etc. A cycloalkyl group is a cycloalkyl group having 3 to 6 carbon atoms, such as a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, etc. The lower alkyl group represented by RA is a methyl group or an ethyl group, Ethyl group is preferred from the viewpoint of economy and ease of handling. Also,
The lower alkyl group represented by R1 and R'' is an alkyl group such as a methyl group, ethyl group, propyl group, butyl group.

formula! The benzo[α]phenazine derivative represented by
It can be produced from 4-dihydro-1,4-dioxo-2-nathoate according to the following reaction formula (in the formula, R'
, R'', and R' are as described above).

(2) Namely, known ethyl 3-hydroxy-1,4-dihydro-1,4-dioxo-2-naphtonite was dissolved in an organic solvent such as anhydrous tetrahydrofuran, N,N-dimethylformamide, and dioxane. A compound represented by formula I can be obtained by treating with imidazole or an acyl chloride such as acetyl chloride, chloride and baloyl, or a chloroformate such as ethyl chloroformate or benzyl chloroformate, and then condensing phenylene diamines represented by formula (III). can be obtained.

When treating with acyl chloride or chloroformate, it is preferable to use a basic catalyst such as triethylamine or pyridine.

< If The phenylenediamines shown are either known per se or can be obtained from known compounds by known methods.

That is, in the latter case, the following formula ■ or ■' (where R'
and R1 have the same meanings as above). The reduction method may be a known method for reducing a nitro group, for example, catalytic reduction using a catalyst such as palladium-carbon. In this case, the obtained phenylenediamine represented by the formula It is suitable for use in condensation reactions.

The nitro compound of formula (1) or (2) can be produced by a known method. For example, to explain the case where 5-acetylaminosalicylic acid is used as a starting material, first, 5-acetylaminosalicylic acid is reacted with an alkyl halide in the presence of a base, and is esterified and simultaneously alkoxylated. The bases used here are, for example,
Inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. (g) Alkyl rogenide includes methyl iodide, ethyl iodide, propyl iodide, butyl iodide, ethyl bromide, propyl bromide, and the like.

The compound obtained above is then nitrated. The nitration may be carried out by a conventional method, for example, acetic anhydride-fuming nitric acid, sulfuric acid-fuming nitric acid, or the like.

Then, by deacetylation, a nitro compound of formula (1) or (2) can be obtained. Deacetylation easily proceeds, for example, by reaction with concentrated sulfuric acid in an alcoholic solvent. Furthermore, depending on the type of alcohol used here, a transesterified nitro compound of formula (1) or (2) can be obtained.

On the other hand, in order to produce a nitro compound of formula (1) or (2) in which R3 is a carboxamide group, for example, the nitro compound of formula (2) or (2) in which R8 is an alkoxycarbonyl group obtained above is mixed with aqueous ammonia, methylamine, ethylamine, It can be obtained by reaction with amines such as dimethylamine, diethylamine, and piperidine. Alternatively, a nitro compound of the formula ■ or ■゛ in which R8 is an alkoxycarbonyl group is hydrolyzed with an alkali hydroxide to make R8 a carboxyl group, and after activating the carboxyl group with N,N'-carbonyldiimidazole, the above-mentioned By reacting with amines, a nitro compound of formula (1) or (2) in which R8 is a carboxamide group can be obtained.

Furthermore, the nitro compound of the formula (1) or (2) in which R8 is a carboxyl group is converted into the corresponding acid chloride with thionyl chloride, and then reacted with an alcohol to form a nitro compound of the formula (2) or (2) in which R8 is an appropriate carboxy ester. of nitro compounds can be obtained.

A nitro compound of the formula (1) or (2) in which R1 is a hydrogen atom, a halogen atom, or a methyl group can also be obtained by successive esterification, nitration, and deacetylation in the same manner as described above.

Benzo[α]phenazine-6-carboxamide derivatives exhibit a strong survival effect on various cancer-bearing mice.The compounds of the present invention are useful for producing benzo[α]phenazine-6-carboxamide derivatives. .

That is, the compound represented by formula I is prepared by the following formula (where R7
and R1 are the same or different and represent a hydrogen atom or a lower alkyl group, and n represents 2 or 3. , RI, R*, R', R8 and n are as defined above.) A benzo[,ff]phenazine-6-carboxamide derivative is obtained.

This condensation reaction can be carried out using, for example, benzene, toluene, N, N
- The reaction temperature is 10 to 120°C, preferably 15 to 30°C, in an organic solvent such as dimethylformamide, ethanol, dichloromethane, tetrahydrofuran, etc., or without solvent. If the reaction takes a long time, increase the temperature. or the reaction time can be shortened by adding an alkaline catalyst such as sodium alkoxide.The benzo[mycofenazine-6-carboxamide derivatives thus prepared can be converted into R4 by the following method. be able to.

That is, benzo[α] in which %R” is a carboxyl group
The corresponding ester can be obtained by esterifying the phenazine-6-carpoxamide conductor using, for example, diazomethane or diazoethane.

R8 is alkoxycarbonyl [(Z] phenazine-6-carboxamide derivative is transesterified in alcohol under an acid catalyst such as sulfuric acid or para-toluenesulfonic acid to obtain a corresponding ester in which a solvent alkoxy group is introduced. be able to.

In addition, benzo[a
Cofenazine-6-carboxamide derivative, water, alcohol, N. The corresponding carboxylic acid can be obtained by alkaline hydrolysis in a solvent such as N-dimethylformamide or dimethylsulfoxide, or a mixed solvent thereof.

Furthermore, R1 is an alkoxycarbonyl group, benzo[
α-cofenazine-6-carboxamide derivative in an organic solvent such as dioxane or chloroform or without solvent,
The corresponding carboxamide can be obtained by amitrilysis using ammonia and a primary amine under normal pressure or increased pressure.

Actual JE example Next, the present invention will be explained in more detail with reference to Examples.

In addition, a method for producing a nitro compound of formula (1) or (2) and a benzo[a-cofenazine-6-carboxamide derivative] will be shown by way of reference examples.

Example 1 (1) Methyl 5-amino-2-ethoxy-4-nitrobenzoate (m.p. 156-157°C)
873 mg and 50 mg of 10% palladium-carbon were suspended in 50 ml of ethanol, and hydrogenated at room temperature and normal pressure. The catalyst was filtered off, and the filtrate was dried under reduced pressure to obtain crude methyl 4,5-diamino-2-ethoxybenzoate.

(2) Ethyl 3-hydroxy-1,4-dihydro-1
.

895 mg of 4-dioxo-2-naphtonite was added to N. N-
Dissolved in 10 mQ of dimethylformamide, N. Add 620 mg of N'-carbonyldiimidazole and stir at room temperature for 2 hours.
Stir for hours. Add to this the crude methyl obtained in (1) above 4.
10ydN of 5-diamino-2-ethoxybenzoate
．． A solution of N-dimethylformamide was added under water cooling, and the mixture was stirred at room temperature overnight. 200 yd of ethanol was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from chloroform-ethanol to obtain the title compound.

ffi. 1), 270-273°C Yield: 531 mg In the same manner as in Example 1, the compounds of the present invention shown in the table below were obtained.

In addition, the starting materials in the table indicate if the phenylenediamine of formula I is known or isolated and purified, and if the phenylenediamine of formula π is produced from the nitro compound of formula m or ■゛. indicates a nitro compound of formula ■ or ■゛. Furthermore, when the nitro compound of formula (1) or (1) is new, its melting point is recorded and the manufacturing method is described as a reference example.

Example 2 (1) Ethyl 3-hydroxy-1,4-dihydro-1
, 2.48 g of 4-dioxo-2-naphtonite and 1.5 ml of triethylamine were added to 1 ml of anhydrous tetrahydrofuran.
Ethyl chloroformate ITIII was dissolved in 0ml of
The mixture was added dropwise at a temperature below 0.degree. C. and stirred at room temperature for 2 hours. The generated solid was filtered off, and the filtrate was dried under reduced pressure to obtain crude ethyl 3-ethoxycarbonyloxy-1,4-dihydro-1,4-dioxo-2-naphtonite.

(2) 2.16 g of methyl 4.5-diamino-2-methoxybenzoate and 7 m of N,N-dimethylformamide
Add 7 ml of a solution of crude ethyl 3-ethoxycarbonyloxy-1,4-dihydro-1,4-dioxo-2-naphtonite obtained in (1) above in N,N-dimethylformamide to the solution under water cooling, After stirring for 2 hours, 100 mQ of ethanol was added and the precipitated crystals were collected by filtration.
Recrystallization from chloroform-ethanol gave the title compound.

m, p, 202.5-207°C Yield 3.66 g Methyl 4.5-Diamino-2-methoxybenzoate was replaced with the corresponding orthophenylene diamine, and the same procedure as in Example 2 was carried out to obtain the following. The compound was obtained.

Ethyl 9-ethylcarbamoyl-5-hydroxy-10-methoxybenzo[α cofenazine-6-carboxylate m, p, 300°C or higher Ethyl 9-ethylcarbamoyl-5-hydroxy-
10-methoxybenzo[a cohuenazine-6-carboxylate m, p, 190-193°C Example 3 Ethyl 5-hydroxy-10-methoxy-9-dimethylcarbamoylbenzo α 11 N,N-dimethyl of phenazine-6-carboxylate 5-Amino-2-methoxy-4-nitrobenzamide (m, p, 209-211°C) ball 6
2 g and 150 mg of 10% palladium-carbon were suspended in 140 mQ of ethanol and hydrogenated at normal pressure and 70 to 80°C. The catalyst was filtered off, and the filtrate was dried under reduced pressure to obtain crude N,
N-dimethyl 4,5-diamino-2-methoxybenzamide was obtained and dissolved in 30 ml of tetrahydrofuran.

Separately ethyl 3-hydroxy-1,4-dihydro-1,
Example 2: 3.41 g of 4-dioxo-2-naphtonite
In the same manner as in (1), ethyl 3-ethoxycarbonyloxo'<-1,4-dihydro-1,4-dioxo-2
- Naphtonite was obtained, dissolved in 10 ml of tetrahydrofuran, and cooled with water to obtain the previously prepared N,N-dimethyl 4.5-
Add 100 ml of ethanol to a reaction solution that was added to a tetrahydrofuran solution of diamino-2-methoxybenzamide and stirred at room temperature for 2 hours! was added, and the precipitated crystals were collected by filtration and recrystallized from chloroform-ethanol to obtain the title compound.

m, p, 224-227°C Yield 3.70gN, N-
Dimethyl 5-amino-2-methoxy-4-nitrobenzamide was replaced with the corresponding orthonitroaniline and treated in the same manner as in Example 3 to obtain the following compounds.

Ethyl 5-hydroxy-10-methoxy-9-(1-
pyrrolidinocarbonyl)benzo[α]phenazine-6-
Carboxylate m, p, 221-224°C Ethyl 5-hydroxy-10-methoxy-9-neopentyloxycarbonylbenzo[(Z]phenazine-6
-Carboxylate m, p, 153-157°C Reference Example 1 (1) 20 g of 5-acetylaminosalicylic acid, 41 ml of ethyl iodide, and 50.5 g of anhydrous potassium carbonate were added to 300 mQ of acetone and refluxed for 24 hours. After cooling, insoluble materials were filtered off, the filtrate was dried under reduced pressure, and the residue was recrystallized from ether to obtain ethyl 5-acetylamino-2-ethoxybenzoate.

m, p, 78-79°C Yield: 13.68 g (2) 13.06 g of the compound obtained above was suspended in 50 ml of acetic anhydride, and 3 ml of fuming nitric acid was added dropwise under water cooling. After the dropwise addition was completed, the mixture was stirred for 30 minutes under water cooling and for 4 hours at room temperature.

The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain ethyl 5-acetylamino-2-ethoxy-4-nitrobenzoate.

m, p, 118-120°C Yield 6.35 g (3) 1.5 g of the compound obtained above was dissolved in 5% sulfuric acid-meth/-ol (V
/V) 50ml G: Suspend, flow for 4 hours,
After cooling, the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and recrystallized from methanol to obtain the title compound.

m, p, 156-157°C Yield 1. The following compound was obtained by processing in the same manner as in Gig Reference Example 1.

Ethyl 5-amino-2-ethoxy-4-nitrobenzoate +11. p, 140-141°C Butyl 5-amino-2-ethoxy-4-nitrobenzoate m, p, 90-92°C Methyl 5-amino-4-nitro-2-propoxybenzoate m, p, 132-134°C Ethyl 5 -Amino-4-nitro-2-propoxybenzoate m, p, 101-102°C Propyl 5-amino-4-nitro-2-propoxybenzoate m, p, 105-106°C Butyl 5-amino-4-nitro-2 -Propoxybenzoate m, p, 72-75°C Methyl 5-amino-2-butoxy-4-nitrobenshade m, p, 121-122°C Butyl 5-amino-2-butoxy-4-nitrobenzoate m, p, 67-68°C Methyl 4-amino-2-hydroxy-5-nitrobenzoate m, p, 197-199°C Methyl 5-amino-2-chloro-4-nitrobenzoate 111.1), 225-226°C Reference example 2 (1) Methyl 13.57 g of 5-amino-2-methoxy-4-nitrobenzoate was suspended in 250 mQ of dioxane, a solution of 4.36 g of potassium hydroxide and 25 ml of water was added, and the mixture was refluxed for 4 hours. Next, 7 ml of concentrated hydrochloric acid was added to the reaction solution, the solvent was distilled off under reduced pressure, dioxane was added to the residue, and the mixture was refluxed for 1 hour. Insoluble matter was filtered out and 5 was precipitated from the filtrate.
-Amino-2-methoxy-4-nitrobenzoic acid crystals were obtained.

m, p, 252-255℃ Yield 10.99g (2)
4.24 g of the compound obtained above was dissolved in 30 td of N,N-dimethylformamide, and 3.24 g of N,N'-carbonyldiimidazole was added at room temperature. After 30 minutes, 5 mQ of pyrrolidine was added, and stirring was continued for 2 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain the title compound.

m, p, 159-162°C Yield: 4.16 g The following compound was obtained by using dimedelamine or neopentyl alcohol in place of pyrrolidine and treating in the same manner as in Reference Example 2.

N,N-dimethyl 5-amino-2-methoxy-4-nitrobenzamide m, p, 209-211°C Neopentyl 5-amino-2-methoxy-4-nitrobenzoate m, p, 173-177°C Reference example 3 5-Amino-2-methoxy-4- obtained in Reference Example 2 (1)
5.55 g of nitrobenzoic acid was suspended in 40 ml of benzene, 40 ml of thionyl chloride was added, and the mixture was refluxed for 4 hours. Then, excess thionyl chloride and the solvent were distilled off, and the residue was dissolved in 40 ml of benzene, and 12.3 g of phenol and Add 15.3 ml of triethylamine under water cooling,
The mixture was stirred for 30 minutes under water cooling and overnight at room temperature. Water and ethyl acetate were added to the reaction solution, and the organic layer was washed with 10% aqueous sodium hydroxide and then with water, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the benzene eluted fractions were collected and recrystallized from methanol to obtain the title compound.

m, p, 130-132℃ Yield 2.55g Reference Example 4 - (Eng. J2 21" 2 x 1C)"! Dissolve 5.66 g of methyl 5-amino-2-methoxy-4-nitrobenzoate in 200 mQ of dioxane, add 50 mQ of 28% aqueous ammonia, and boil at room temperature for 40 min.
I left it for a while. The solvent was distilled off under reduced pressure, and the residue was recrystallized from dioxane to obtain 5-amino-2-methoxy-4-nitropenzamide.

+11. p, 250-257℃ Yield 4.30g (2
) 3.04 g of the compound obtained above and 110 mg of 10% palladium-carbon were suspended in 300 methanol and hydrogenated at normal pressure and 60°C. Filter off the catalyst, concentrate the filtrate,
Crystals of the title compound were obtained.

m, p, 181-183°C Yield 2.18g Reference Example 4
In the same manner as above, the following compound was obtained.

N-Ethyl 4.5-diamino-2-methoxybenzamide m, p, 65-67°C Reference Example 5 Ethyl 5-hydroxy-10-methoxy-9-methoxycarbonylbenzo[α Cofenazine-6-carboxylate 20.32g was added to benzene Dissolve in 500ml,
Add 11 ml of N,N-dimethylethylenediamine to 2
Refluxed for an hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-ethanol to obtain the title compound.

111, p, 195-196°C Yield: 22.17g Reference Example 6 N-β-dimethylaminoethyl 5-hydroxy-10-methoxy-9-methoxycarbonylbenzo[a]phenazine-6-carboxamide- obtained in Reference Example 5 21,52
g to 400ml of n-butanol to which 8ml of concentrated sulfuric acid was added.
1 and refluxed for 5 hours. n-Butanol was distilled off under reduced pressure, the residue was added to aqueous sodium bicarbonate, and the resulting solid was collected by filtration and recrystallized from chloroform-ethanol to obtain the title compound.

m, p, 116-117"C Yield: 21.41 g Reference Example 7 N-β-dimethylaminoethyl 5-hydroxy-10-methoxy-9-methoxycarbonylbenzo[a]phenazine-6-carboxamide obtained in Reference Example 5 2.24 g was dissolved in 900 ml of dioxane, 100 mQ of 40% methylamine aqueous solution was added, and the reaction solution was left at room temperature for 6 days. The reaction solution was dried under reduced pressure, and the residue was recrystallized from chloroform-ethanol to obtain the title compound. I got it.

m, p, 245-248°C Yield 2.0 Og Reference Example 8 N-β-dimethylaminoethyl 5-hydroxy-10-methoxy-9-methoxycarbonylbenzo[α]phenazine-6-carpoxamide 4 obtained in Reference Example 5, Suspend 48 g in 80 ml of methanol and add 1.1 g of potassium hydroxide.
A solution of 8 g and 80 mQ of water was added and refluxed for 5 hours. water 3
50m1! The crystals precipitated by adding dry ice were collected by filtration, dried, and then recrystallized from N,N-dimethylformamide-ethanol to obtain the title compound.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a hydrogen atom, a halogen atom, a methyl group,
It represents a hydroxyl group or an alkoxy group, and R^2 represents the formula, -COOR^4 (wherein R^4 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, a benzyl group, or a phenyl group. ) or formulas, ▲numeric formulas, chemical formulas, tables, etc.▼ (In the formulas, R^5 and R^6 are the same or different and are hydrogen atoms, lower alkyl groups, or bonded to each other to form a heterocyclic ring together with adjacent nitrogen atoms. ), and R^5 represents a lower alkyl group. ] A benzo[a]phenazine derivative represented by.