DD296926A5 - NEW PYRIDOBENZOINDOL DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

New pyridobenzoindole derivatives of the general formula I (see formula sheet) in which R is H or alkyl (1 or 2 C), alk is straight or branched alkylene (2 to 4 C), R 1 is a hydrogen atom or an alkyl radical (1 or 2C), R2 is a hydroxy radical or a methoxy radical and R3 is methyl or ethyl, and their acid addition salts, processes for their preparation and pharmaceutical compositions containing them as anti-tumor agents.

Description

For this 2 pages formulas

The present invention relates to novel pyridobenzoindole derivatives of the general formula (I) (see formula sheet), optionally their hydrates, their acid addition salts, their preparation and the pharmaceutical compositions containing them.

European Patent Application 239476 has described ct-carboline derivatives of the general formula (A) (see formula sheet) in which R and R _{6 are,} inter alia, hydrogen atoms, R _{2 represents} a hydrogen atom, a hydroxy radical or an alkyloxy radical R ₃ and R _{4 may} in particular denote alkyl radicals and η is 2 to 4 which have an anti-tumor effect.

In addition, other pyridoindole derivatives have been reported in the literature by C. DUCROCQ et al., J. Het. Chem., 12 (5), 963 (1975) or by Ch. S. LEE et al. Heterocycles, 16 (7), 1081 (1981), but no therapeutic activity was mentioned.

The novel pyridobenzoindole derivatives of the general formula (I) (see formula sheet) in which R represents a hydrogen atom or an alkyl radical having 1 or 2 carbon atoms, alk represents a straight or branched alkylene radical having 2 to 4 carbon atoms, R ₁ is a hydrogen atom or an alkyl radical having 1 or 2 carbon atoms, R _{2 represents} a hydroxy radical or a methoxy radical, and

R _{3 is} an alkyl radical having 1 or 2 carbon atoms, have particularly interesting antitumor properties.

According to the invention, the products of general formula (I) (see formula sheet) can be prepared starting from a chlorinated derivative of general formula (II) (see formula sheet) in which R _{1 is} as defined above, by reaction with an amine of general formula (III) (see formula sheet) in which alk and R are as defined above, optionally followed by the conversion of the thus obtained methoxylated product of general formula (Ia) (see formula sheet) in which R, R ₁ , R ₃ and alk as defined above, into a 9-hydroxy-pyrido [4,3-b] benzo [e] indole derivative.

The reaction of the amine of general formula (III) with the chlorinated derivative of general formula (II) is carried out in the presence of an excess of the amine, preferably under nitrogen, optionally in an inert organic solvent or without solvent, at a temperature between the reflux temperature of Reaction mixture and 250 ⁰ C (autoclave).

Demethylation is by any known method that does not affect the rest of the molecule. The chlorinated derivative of the general formula (II) (see formula sheet) in which R 1 is a hydrogen atom can be prepared from the corresponding pyridone of the general formula (IV) (see formula sheet) in which R _{3 is} as defined above, by the action of a Chlorinating agent are prepared.

It is generally carried out with a chlorinating agent selected from phosphorus oxychloride or the halogenated derivatives of phosphorus in the presence of a tertiary base (eg diethylaniline or dimethylaniline) in an organic solvent such as a nitrite (for example acetonitrile) and at a temperature between 75 ° C and 90 ° C (reflux temperature of the reaction mixture)

 Preferably, the reaction is carried out under nitrogen.

The product of general formula (II) wherein R _{1 is} an alkyl radical can be obtained by alkylating the product in which R _{1 is} a hydrogen atom, for example by the action of the appropriate halogen derivative in the presence of potassium carbonate.

The product of the general formula (IV) (see formula sheet) can be prepared starting from a hydrazone of the general formula (V) (see formula sheet) in which R _{3 is} as defined above, by thermal Fischer reaction, in analogy to that of CH NGUYEN and E. BISAGNI, Tetrahedron, 42 (8), 2203 (1986).

The hydrazone of general formula (V) is prepared by condensation of 4-hydrazino-5-methyl (or ethyl) -1H-pyrid-2-one with 6-methoxy-2-tetralone. The reaction is generally carried out in an organic solvent such as an alcohol (e.g., ethanol) at the reflux temperature of the reaction mixture.

The 6-methoxy-tetralone can be prepared according to the method described in J. Am. Chem. Soc., 82, 2573, (1960). The 4-hydrazino-5-methyl-1H-pyrid-2-one can be prepared by the method described by C.H. NGUYEN and E. BISAGNI, Tetrahedron, 42 (8), 2203 (1986).

The pyridobenzoindole derivatives of the general formula (I) can be purified by crystallization or chromatography. The novel pyridobenzoindole derivatives of the present invention can be converted into addition salts with acids by the action of an acid in an organic solvent. The salt which optionally precipitates after concentrating its solution is separated by filtration or decantation.

As pharmaceutically acceptable salts may be mentioned the addition salts with mineral acids, such as the hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, or with organic acids such as acetates, propionates, succinates, maleates, pumarates, methanesulfonates, para-toluenesulfonates, isethionates, or the substitution derivatives of these compounds. The pyridobenzoindole derivatives of the present invention and their salts may exist in the form of hydrates, and it is to be understood that these hydrate forms are also within the scope of the present invention. When the symbol alk is also a branched alkylene radical, the pyridobenzoindole derivatives have isomeric forms. It is also to be understood that these isomeric forms are also within the scope of the present invention. The derivatives of the general formula (I) are particularly interesting as antitumor agents.

Their anti-tumor properties are particularly evident in concentrations of about 15 μg / disc in the differential cytotoxicity test, according to the technique described by TH Corbett et al., Investigational new drug, 4, 207-220 (1986) and those transplanted by the mouse Tumors, in particular leukemia P388, the products tested prove effective at doses between 5 and 20mg / kg by intraperitoneal route.

Their toxicity to mice, expressed in their maximum tolerated dose, is between 10 and 20 mg / kg by intraperitoneal route.

Of particular interest with regard to their antitumor effect are mainly the pyridobenzoindole derivatives of the general formula (I) in which

R represents a hydrogen atom or a methyl radical, alk represents a straight or branched alkylene radical having 2 to 4 carbon atoms, R _{1 represents} a hydrogen atom or a methyl radical, R _{2 represents} a hydroxy radical and R _{3 represents} a methyl or methyl radical Ethyl radical, as well as their salts and optionally their hydrates. Of particular interest among these products are the pyridobenzoindole derivatives in which R is methyl radical, alk is straight or branched alkylene radical of 2 to 4 carbon atoms, Ri is hydrogen or methyl radical, R _{2 is} hydroxy radical and R _{3 is} a methyl radical, and their salts and optionally their hydrates

 In particular

1-amino - [(3-dimethylamino) -propyl] -9-hydroxy-4-methyl-5H-pyrido [4,3-b] benzo [e] -indole and its salts and hydrating forms,

- 1-amino - [(3-dimethylamino-2-methyl) propyl] -9-hydroxy-4-methyl-5H-pyrido [4,3-b] benzo [e] indole, and its salts and its hydrated To form.

The following nonlimiting examples illustrate the invention.

example 1

The 1-amino - [(3-dimethylamino) -propyl] -9-methoxy-4-methyl-5 H -pyrido [4,3-b] benzo [e] -indole (8.7 g) is added together with 220 cm ³ Hydrobromic acid (d = 1.47.47%) in a equipped with a stirrer equipped reaction flask of 500cm ³ and kept under argon.

This mixture, which became homogeneous on boiling, is refluxed for 4 hours and then concentrated to dryness under reduced pressure. The solid residue is dissolved in water (800cm ³ ) and alkalized by dropwise addition of 28% ammonium hydroxide (85cm ³ ) to form a gummy precipitate.

To the resulting mixture is then added 800cm ^{3 of} ethyl acetate. The whole is stirred for 1 hour and filtered to a

small insoluble matter to remove. The organic phase is decanted and the mother liquors are extracted twice with 400 cm ^{3 of} ethyl acetate. The organic phase is dried over sodium sulfate, filtered, treated for decolorization with 16 to 20 g of charcoal and filtered again and concentrated to dryness.

The solid residue is taken up in 80 cm ^{3 of} acetone, stirred for 1 hour, filtered and then washed twice with 15 cm ^{3 of} cold acetone. The treatment with acetone is repeated once to yield 6.3 g of a yellow-beige crystalline powder, mp = 216-218 ° C, corresponding to 1-amino - [(3-dimethylamino) -propyl] -9-hydroxy-4-methyl 5H-pyrido [4,3-b] benzo [e] indole.

The 1-amino - [(3-dimethylamino) -propyl] -9-hydroxy-4-methyl-5H-pyrido [4,3-b] benzo [e] indole (7.5 g) is dissolved in boiling methyl ethyl ketone (650 cm ³ ), added to a solution of methanesulfonic acid (6.4 g, 3 equivalents) in 300 cm ^{3 of} boiling methyl ethyl ketone and the mixture refluxed for 5 minutes. It forms an insoluble rubbery mass, which decays within 18 hours with stirring gradually to a gray powder. The solid is filtered, washed with methyl ethyl ketone and quickly placed in a desiccator containing phosphoric anhydride. After 18 hours under reduced pressure (15 mm Hg), 11.7 g (97%) of 1-amino - [(3-dimethylamino) -propyl] -9-hydroxy-4-methyl-5H-pyrido [4,3-b ] -benzo [e] -indole-dimethanesulfonate, mp = 245-255 ° C.

A solution of 1-amino-t (3-dimethylamino) -propyl] -9-hydroxy-4-methyl-5H-pyrido [4,3-b] benzo [e] indole (670 mg) in boiling methanol (150 cm ³ ) is poured into 100 cm ^{3 of} methanol, which is saturated with hydrochloric acid. The solution is then concentrated to 30cm ³ and added to 60cm ³ of acetone. The precipitate is filtered after 15 minutes of standing in the cold, washed with acetone and quickly placed in a desiccator under vacuum. This gives 620 mg (72%) of microcrystals of 1-amino - [(3-dimethylamino) -propyl] -9-hydroxy-4-methyl-5H-pyrido [4,3-b] -benzo [e] indole dihydrochloride hydrate (1.5H ₂ O), mp 250-260 ⁰ C with decomposition.

The 1-amino - [(3-dimethylamino) -propyl] -9-hydroxy-4-methyl-5H-pyrido [4,3-b] benzo [e] indole (350 mg) in boiling acetone (100 cm ³ ) is poured into a solution of maleic acid (350mg, 3 equivalents) in refluxing acetone (30cm ³⁾ and the mixture in a sealed flask left overnight at ambient temperature. The resulting solid is filtered, washed with acetone and left under vacuum for 18 hours to give beige microcrystals of 1-amino - [(3-dimethylamino) -propyl] -9-hydroxy-4-methyl-5H-pyrido [4,3 -b] -benzo [e] to obtain indole dimaleate, mp = 204-206 ⁰ C.

The 1-amino - [(3-dimethylamino) -propyl] -9-methoxy-4-methyl-5H-pyrido [4,3-b] benzo [e] indole can be prepared in the following manner:

The 1-chloro-9-methoxy-4-methyl-5H-pyrido [4,3-b] benzo [e] -indole (7.2 g, 24 mmol) is placed in a flask of 800 cm ³ containing 120 cm ³ (large excess) contains 3-dimethylamino-propylamine. The mixture is then heated for 72 hours under nitrogen and stirring at reflux (complete disappearance of the chlorinated derivative, control on the silica plate). The excess of diamine is evaporated on the water bath under reduced pressure and the residue taken up in water and then alkalized with ammonia. The solid formed is filtered, washed with water, taken up in methylene chloride and washed with 150 cm ^{3 of} water to which 10 cm ³ ammonia were added. The organic solution is dried, filtered and evaporated to give a solid residue which is added to the 1-amino - [(3-dimethylamino) -propyl] -9-methoxy-4-methyl-5H-pyrido [4,3-b ] benzo [e] indole, pure in thin layer chromatography (8.7 g).

The 1-chloro-9-methoxy-4-methyl-5H-pyrido [4,3-b] benzo [e] indole can be obtained in the following manner: In a 1 liter flask equipped with a magnetic Stirrer, a dropping funnel, a condenser and kept under nitrogen, carried 12.2 g (43 mmol) of 9-methoxy-4-methyl-2H, 5H-pyrido [4,3-b] benzo [e] indole-1 -one, 10.4 g (172 mmol) of acetamide, 40 g (172mMol) of benzyl-triethylammonium chloride, 110cm ³ of acetonitrile and 28 cm ³ (172 mmol) of freshly rectified diethylaniline a. About the dropping funnel is added gradually 200 cm ^{3 of} rectified phosphorus oxychloride and observed an exothermic reaction. The mixture is refluxed for 10 hours, and after passing through a homogeneous phase, a precipitate appears. After this time, concentrated on the heated to a temperature of 70 ⁰ C water bath under reduced pressure (15 mm Hg) to dryness.

To the residue obtained are added 300 cm ³ of ice water and heated for two minutes the well stirred mixture to boiling. It forms a yellow precipitate, which is filtered cold and then washed with cold water. This precipitate is taken up in 300 cm ^{3 of} distilled water and the mixture is alkalized in the cold by ammonia. The whole is stirred for one hour and the precipitate is filtered and washed with water. The control by thin layer chromatography shows the presence of the expected compound (Rf = 0.5) and that of traces of the starting compound (Rf = 0.36) (silica, methylene chloride / ethanol, 9/1). The expected product crystallises in alcohol, in the essehr is slightly soluble (large volume), and produces 12 g (92%) of yellow needles, mp higher than 270 ⁰ C (Rf = 0.58 on silica plate, eluent pure ethyl acetate).

The 9-methoxy-4-methyl-2H, 5H-pyrido [4,3-b] benzo [e] -indol-1-one can be prepared in the following manner: In a 3-necked flask of 4 liters, mix N- 4- (5-methyl-1H-pyridone-2-yl) -N'-2- (6-methoxy-1,2,3,4-tetrahydronaphthalenylidene) -hydrazine (31 g, 0.1 mol) and diphenyl ether ( 1 liter) and then heated for 40 minutes under reflux, while stirring well under nitrogen. The mixture becomes homogeneous and decolorizes. Then the heating is interrupted to allow to cool to a temperature of 200 ⁰ C and to control the reaction of the starting material. Then, stirring is continued, and gradually added with care (foaming and evolution of hydrogen) palladium-carbon (10%, 5g) in suspension of diphenyl ether (100cm ³ ), and the new mixture is heated again for 40 minutes under reflux. Hexane (2 liters) is added to the cooled mixture, and the precipitate formed is filtered and then washed with hexane. Then it is taken up in 1 liter of boiling acetic acid and filtered to remove the palladium-carbon, which in turn is washed once with 50 to 100 cm ^{3 of} boiling acetic acid. Concentrate the entire filtrate to 500 cm ³ and filter the resulting solid after cooling, wash with boiling acetone and dry to give 22 g (75%) of pale yellow microcrystals, mp = 260 ° C, corresponding to the expected 9-methoxy-4-. methyl-2H, 5H-pyrido [4,3-b] benzo [e] -indol-1-one, low hydration (Rf = 0.36 on the silica plate, with the methylene chloride-ethanol mixture, 9 / 1 as eluent).

The N, 4- (5-methyl-1H-pyridone-2-yl) -N'-2- (6-methoxy-1,2,3,4-tetrahydro-naphthalenylidene) -hydrazine may be prepared in the following manner getting produced:

The mixture of 4-hydrazino-5-methyl-1 H-pyridone-2 (13.9 g, 0.1 mol) in absolute ethanol (600cm ³⁾ was heated under reflux. 6-Methoxy-2-tetralone (11.3 g, 0.12 mol) is then added to the mixture, which has become homogeneous while boiling, and the mixture, which has become rapidly heterogeneous, is refluxed for 4 hours for 30 minutes. The precipitate formed is filtered, taken up in 400 cm ³ of boiling ethanol, in which the hydrazone is very slightly soluble, and then filtered cold to give (98%) to give 15,7g colorless microcrystals, mp = 240-250 ⁰ C (decomposition) ,

Example 2

The (R.Sl-i-amino-fS-dimethylamino) -methyl-propyl-S-methoxy-methyl-SH-pyridoKS-bl-benzoil-indole dimaleate (3 g) is dissolved in water and added to ammonia Extraction with 100 cm ^{3 of} methylene chloride, drying and concentration to dryness gives the corresponding free base, which is used as it is in the further synthesis.

The (R, S) -1-amino- (3-dimethylamino-2-methyl-propyl) -9-methoxy-4-methyl-5 H -pyrido [4,3-b] benzo [e] -indole is described in U.S. Pat 120 cm ³ hydrobromic acid (d = 1.47.47%) was added, working in an analogous manner as in Example 1.

After four hours of heating under reflux and cooling, a precipitate appears. The reaction mixture is concentrated to dryness under reduced pressure, then the residue is added to 200 cm ^{3 of} water and the resulting solution is filtered to remove a small insoluble portion. The filtrate is 20cm ^{3 of} triethylamine and 30cm ³ conc. Added ammonia and then 200cm ^{3 of} methylene chloride. After stirring for one hour at ambient temperature, the mixture is extracted four times with 100 cm ^{3 of} methylene chloride, dried and concentrated to dryness.

The solid residue is chromatographed on alumina, eluting sequentially with 500 cm ^{3 of} methylene chloride, 1 liter of a mixture of methylene chloride and ethanol (97/3) and 1 liter of a mixture of methylene chloride and ethanol (80/20). The fractions corresponding to the last liter of eluent are combined and concentrated to dryness. This gives 2.1 g of crude (R, S) -1-amino- (3-dimethylamino-2-methyl-propyl) -9-hydroxy-4-methyl-5H-pyrido [4,3-b] - benzo [e] indole.

The product obtained is dissolved in 200 cm ^{3 of} acetone, brought to boiling and then maleic acid (2.1 g, 3 equivalents) is added in solution of 50 cm ^{3 of} boiling acetone. Then the mixture is concentrated to half its volume and allowed to cool. This gives 2.25 g of (R, S) -1-amino- (3-dimethylamino-2-methyl-propyl) -9-hydroxy-4-methyl-5H-pyrido [4,3-b] -benzo [e] -indole dimaleate of melting point 215-22O ⁰ C.

The (R, S) -1 -amino-fS-dimethylamino-methyl-propyl-D-methoxy-methyl-SH-pyrido-S-bl-benzotelindole dimaleate can be obtained in the following manner:

The 1-chloro-9-methoxy-4-methyl-5H-pyrido [4,3-b] benzo [e] indole (2.1 g) is autoclaved together with 3-dimethylamino-2-methylpropylamine for 16 hours heated to a temperature of 180 ⁰ C long. The reaction is carried out under the conditions described in Example 1, alkalized with ammonia, taken up in methylene chloride and chromatographed on alumina eluting with 1.5 liters of methylene chloride. After concentration to dryness, the residue obtained is dissolved in 60 cm ^{3 of} acetone and heated for 2 minutes with maleic acid (2.5 g, 3 equivalents) dissolved in 50 cm ^{3 of} acetone. After cooling and precipitation, 3.2 g of (R, S) -1-amino- (3-dimethylamino-2-methyl-propyl) -9-methoxy-4-methyl-5H-pyrido [4,3-b] - benzo [e] indole dimaleate of melting point 180 ° C.

Example 3

The procedure is analogous to Example 2, but starting from 1-amino - [(3-dimethylamino) -propyl] -9-methoxy-4,5-dimethy! -Pyrido [4,5-b] benzo [e ] indole-tri-methanesulfonate hydrate (2H ₂ O) to give the 1-amino - [(3-dimethylamino) -propyl] -9-hydroxy-4,5-dimethyl-pyrido [4,3-b] -benzo [e] indole-di-methanesulfonate hydrate (1.5 _H2 O) mp = 135-150 ⁰ C, with a yield

The 1-amino - [(3-dimethylamino) -propyl] -9-methoxy-4,5-dimethyl-pyrido [4,3-b] benzo [e] -indole-tri-methanesulfonate hydrate (2 H ₂ O ) can be obtained as described in Example 2, but starting from 1-chloro-9-methoxy-4,5-dimethyl-pyrido [4,3-b] benzo [e] indole. The product is obtained with a yield of 86%, mp = 115 to 125 ° C.

The 1-chloro-9-methoxy-4,5-dimethyl-pyrido [4,3-b] benzo [e] indole can be obtained in the following manner:

The 1-chloro-9-methoxy-4-methyl-5H-pyrido [4,3-b] -benzo [e] indole (15 mmol) is dissolved in 100 cm ³ of dimethylformamide and stirring for 15 hours at ambient temperature with 1 , 15 cm ³ (18 mmol) of methyl iodide in the presence of 16.6 g (120 mmol) of potassium carbonate. Then the reaction mixture is concentrated to dryness under reduced pressure.

The residue is taken up in water and extracted with methylene chloride. The solution is dried over magnesium sulfate and concentrated to dryness. Then, the solid residue is recrystallized in ethanol to obtain 1-chloro-g-methoxy-1-dimethylpyrido [4,3-b] benzo [e] indole as white needles in a yield of 86%, m.p. = 185 to 187 ^° C.

Example 4

The 1-amino - [(2-dimethylamino) ethyl] -9-methoxy-4-methyl-5H-pyrido [4,3-b] benzo [e] indole is added along with 80 cm ³ hydrobromic acid (d = 1 , 47.47%) in a reaction flask of 250 cm ³ , which is equipped with a stirrer and is kept under argon.

This mixture, which has become homogeneous during boiling, is refluxed for 5 hours and then concentrated to dryness under reduced pressure. The solid residue is dissolved in water (400cm ³⁾ and washed with 28% ammonium hydroxide (18cm ³⁾ is alkalized, the dropwise adding, to form a gummy precipitate. Are added to the resulting mixture 200cm ³ of ethyl acetate, the whole is stirred overnight and filtered. The organic phase is decanted and the mother liquors are extracted twice with 100 cm ^{3 of} ethyl acetate. The organic phase is then dried over sodium sulfate, filtered, treated with 4 g of charcoal for decolorizing, filtered again and concentrated to dryness. The solid residue is taken up in 30 cm ^{3 of} acetone and 50 cm ^{3 of} absolute ethanol, and the homogeneous mixture is heat-filtered into a solution of maleic acid (3 equivalents) in 30 cm ^{3 of} absolute ethanol, after evaporating the solvent and taking up the residue in acetone of the 1 -Amino - [(2-dimethylamino) ethyl] -9-hydroxy-4-methyl-5H-pyrido {4,3-b] benzo [e] indole dimaleate to give (mp = 210 ⁰ C). The yield for the three stages of substitution, demethylation and salt formation is 76%.

The 1-amino - [(2-dimethylamino) ethyl] -9-methoxy-4-methyl-5H-pyrido [4,3-b] benzo [e] indole can be prepared in the following manner:

The i-chloro-S-methoxy-methyl-SH-pyridoKS-bl-benzotel-indole (2g) is placed in a 50cm ³ flask containing 20cm ³

(large excess) 2-dimethylamino-ethylamine and heated under reflux (120 ⁰ C), under nitrogen and with stirring for 16 days (complete disappearance of the chlorinated derivative, control on the Kieseideplatte).

The diamine excess is evaporated on a water bath under reduced pressure and the residue taken up in water and alkalized with ammonia. The solid formed is filtered off, washed with water, taken up in methylene chloride and washed with 150 cm ^{3 of} water and 10 cm ^{3 of} ammonia.

The organic solution is dried, filtered and concentrated to dryness to give a solid residue which is added to the 1-amino - [(2-dimethylamino) -ethyl] -9-methoxy-4-methyl-5H-pyrido [4 , 3-b] benzo [e] indole, mp = 184 ° C.

Example 5

The 1-amino - [(3-amino) -propyl] -9-methoxy-4-methyl-5H-pyrido [4,3-b] benzo [e] -indole (1.9g) is added along with 70cm ³ hydrobromic acid (d = 1.47.47%) in a reaction flask of 250cm ³ , which is equipped with a stirrer and is kept under argon.

This mixture, which has become homogeneous on boiling, is refluxed for 5 hours 30 minutes and then concentrated to dryness under reduced pressure. The solid residue is dissolved in water (200cm ³ ) and alkalized with 28% ammonium hydroxide (20cm ³ ), which is added dropwise to form a gummy precipitate.

Are added to the resulting mixture 200cm ³ of ethyl acetate and 50 cm ³ of ethanol, the whole is stirred for 1 hour and filtered to remove a small insoluble fraction. The organic phase is decanted and the mother liquors are extracted twice with 100 cm ^{3 of} ethyl acetate. The organic phase is then dried over sodium sulfate, filtered, treated with 4 g of charcoal for decolorization, filtered again and concentrated to dryness.

The solid residue is taken up in 30 cm ^{3 of} acetone, stirred for 15 minutes, filtered and then washed twice with 10 cm ^{3 of} cold acetone to give 1.5 g (80%) of a solid which is added to the 1-amino - [(3-amino ) -propyl] -9-hydroxy-4-methyl-5H-pyrido [4,3-b] benzo [e] -indole, hydrated with 1.3 molecules of water, corresponding to that in an ethanol-acetone mixture recrystallized bimaleate at 132-136 ⁰ C melts.

The 1-amino - [(3-amino) -propyl] -9-rethoxy-4-methyl-5H-pyrido [4,3-b] benzo [e] -indole can be prepared in the following manner :

The chlorinated derivative (2.5 g) is placed in a flask of 250 cm ³ containing a large excess of 3-amino-propylamine and heated under nitrogen atmosphere and stirring for 18 hours at a temperature of 160 ⁰ C (complete disappearance of the chlorinated derivative , Control on the silica plate).

The diamine excess is evaporated on a water bath under reduced pressure, the residue taken up in water and then alkalized with ammonia. The resulting solid is filtered off, washed with water and dried in a desiccator to give 2.8 g of a solid product corresponding to the compound sought.

The bimaleate, prepared in absolute ethanol in the presence of an excess of maleic acid and washed with acetone, corresponds to the salt of 1-amino - [(3-amino) -propyl] -9-methoxy-4-methyl-5H-pyrido [4, 3-b] -benzo [e] -indols, monohydrate, m.p. = 170 ⁰ C.

Example 6

The 1-amino - [(3-dimethylamino) -propyl] -9-methoxy-4-ethyl-5 H -pyrido [4,3-b] benzo [e] -indole (free base) is added along with 66 cm ^{3 of} hydrobromic acid (d = 1.47.47%) in a reaction flask of 250cm ³ , which is equipped with a stirrer and is kept under argon.

This mixture, which has become homogeneous during boiling, is refluxed for 5 hours and then concentrated to dryness under reduced pressure. The solid residue is dissolved in water (200cm ³ ) and basified with 28% ammonium hydroxide (15cm ³ ), which is added dropwise to form a gummy precipitate.

To the resulting mixture add 200 cm ^{3 of} ethyl acetate and stir for one hour. The organic phase is decanted and the mother liquors are extracted twice with 100 cm ^{3 of} ethyl acetate. The organic phase is then dried over sodium sulfate, filtered, treated with 5 g of charcoal for decolorizing, filtered again and concentrated to dryness.

The solid residue is taken up in 40 cm ³ of acetone and treated with 2.5 g of maleic acid in solution of 40 cm ³ of acetone under boiling. The bimaleate of 1-amino - [(3-dimethylamino) -propyl] -9-hydroxy-4-ethyl-5H-pyrido [4,3-b] benzo [e] -indole (2.34g, yield 72%) for the three stages of substitution, demethylation and salt formation) is filtered and dried to give cream-colored microcrystals, mp = 154 ° C.

The 1-amino - [(3-dimethylamino) -propyl] -9-hydroxy-4-ethyl-5H-pyrido [4,3-b] benzo [e] -indole can be obtained in the following manner:

The 1-chloro-9-methoxy-4-ethyl-5H-pyrido [4,3-b] -benzo [e] indole (2 g) is placed in a flask of 250cm ^3, which 40cm ³ (large excess) 3 Dimethylamino-propylamine and heated under reflux, under nitrogen and with stirring for 72 hours (complete disappearance of the chlorinated derivative, control on the silica plate).

The diamine excess is evaporated on a water bath under reduced pressure and the residue taken up in water and alkalized with ammonia. The solid formed is filtered off, washed with water, taken up in methylene chloride and washed with 150 cm ^{3 of} water and 10 cm ^{3 of} ammonia.

The organic solution is dried, filtered and evaporated to give a solid residue which is similar to the expected 1-amino - [(3-dimethylamino) -propyl] -9-methoxy-4-ethyl-5H-pyrido [4.3- b] benzo [e] indole corresponds.

The Bimaleat formed under conventional conditions, appropriate melting at 154 ^C C.

The 1-chloro-9-methoxy-4-ethyl-5H-pyrido [4,3-b] benzo [e] indole can be obtained in the following manner:

A flask of 500 cm ³ , equipped with a magnetic stirrer, a dropping funnel, a condenser and kept under nitrogen, carries 6 g of 9-methoxy-4-ethyl-2H, 5H-pyrido [4,3-b] benzoate]. indol-1-one in boiling ethanol and dried, 19,2g benzyl-triethylammonium chloride, 5.1 g of acetamide, 60 cm ³ of acetonitrile and 13.2 g freshly rectified Diethylanilinein.

96 cm ^{3 of} rectified phosphorus oxychloride are gradually added via the dropping funnel and an exothermic reaction is observed. The mixture is refluxed for 6 hours for 30 minutes, and after passing through a homogeneous phase, a precipitate appears. Then dewatered on the heated to a temperature of 70 ⁰ C water bath under reduced pressure (15 mm Hg) to dryness.

To the residue obtained are added 600 cm ³ of ice water and heated the mixture stirred for two hours well to boiling. After cooling, a yellow precipitate forms, which is filtered cold and then washed with cold water. This precipitate is taken up in 500 cm ^{3 of} distilled water and the mixture is alkalized in the cold by ammonia. The whole is stirred for one hour for 30 minutes and the precipitate is filtered and washed with water. It recrystallizes in alcohol to give 4.6 g of yellow needles of i-chloro-S-methoxy-ethyl-δ-pyridyl-β-benzotel-indole, mp = 260 ° C (Yield

The 9-methoxy-4-ethyl-2H, 5H-pyrido [4,3-b] benzo [e] indole-1-one can be obtained in the following manner:

In a 1 liter three-necked flask, 4-N- (5-ethyl-1H-pyridone-2-yl) -N'-2- (methoxy-1,2,3,4-tetrahydronaphthalenylidene-1-hydrazine (14.5 g) is mixed. and diphenyl ether (350 cm ³ ) and then heated under reflux for 30 minutes, while stirring well under nitrogen, the mixture becomes homogeneous and decolorizes itself, then the heating is interrupted to allow to cool to a temperature of 200 ° C and to check that the starting compound is completely reacted: Silica plate Merck, eluent methylene chloride / methanol (8/2, vol.) Rf hydrazone = 0.5, Rf intermediate = 0.8.

Then, stirring is continued, and gradually added with care (foaming and evolution of hydrogen) palladium-carbon (10%, 2g) in suspension of diphenyl ether (20cm ³ ), and the new mixture is again heated under reflux for 30 minutes ( Disappearance of the intermediate, R f = 0.35 silica, pure ethyl acetate; expected product: R f = 0.58). Hexane (400 cm ³ ) is then added to the cooled mixture, and the precipitate formed is filtered and then washed with hexane. Then it is taken up in 350 cm ³ of boiling acetic acid and filtered to remove the palladium-carbon, which in turn is washed twice with 30 cm ³ of boiling acetic acid. The entire filtrate is concentrated to 150cm ³ and the resulting solid filtered after cooling and dried under vacuum to give 13.7g (yield quantitative) pale yellow microcrystals, mp greater than 260 ° C, corresponding to the expected 9-methoxy-4-ethyl 2H, 5H-pyrido [4,3-b] benzo [e] -indol-1-one which is hydrated.

The N-4- (5-ethyl-1H-pyridone-2-yl) -N'-2- (methoxy-1,2,3,4-tetrahydro-naphthalenylidene) -hydrazine can be obtained in the following manner :

The mixture of 4-hydrazino-5-ethyl-1H-pyridone-2 (7g) in absolute ethanol (250cm ³ ) is heated to reflux. 6-Methoxy-2-tetralone (9.3 g) is then added to the mixture, which has become homogeneous, and the mixture, which has become rapidly heterogeneous, is refluxed for 4 hours 30 minutes (disappearance of hydrazine, monitored by thin-layer chromatography on silica Plate Merck, eluent methylene chloride / ethanol, 7/3, vol., Rf = 0.75). The precipitate formed is filtered, taken up in 100 cm ³ of ethanol, in which the hydrazone is not very soluble, and then filtered cold to 12.1 g (85%) of colorless microcrystals of N-4- (5-ethyl-1H-pyridone-2 to give yl) -N-2- (methoxy-1,2,3,4-tetrahydronaphthalenyliden) -hydrazine, = 135-140 ⁰ C mp (decomposition).

The 4-hydrazino-5-ethyl-1H-pyridone-2 can be obtained in the following manner:

Provided in a reaction flask, placed under nitrogen and with a magnetic stirrer and a condenser, 12 g of 4-hydroxy-5-ethyl-1 ^H-pyridone-3 2,40cm ethylene glycol monoethyl ether and 11 cm ³ of hydrazine hydrate mixed. The whole is heated for a total of 4 days while stirring and under reflux.

After allowing to cool overnight, the resulting solid is filtered, washed with 10 cm ^{3 of} cold absolute ethanol and dried to give 7.8 g (59%) of 4-hydrazino-5-ethyl-1H-pyridone-2 monohydrated, mp = 130 -132 ⁰ C (decomposition), to give.

The 4-hydroxy-5-ethyl-1H-pyridone-2 is described by M. Legraverend, C.H. Nguyen, A.Zerial and E. Bisagni, Nucleosides and Necleotides 5, 125-134 (1986).

The present invention also relates to the pharmaceutical compositions containing as active ingredient at least one product of general formula (I) (see formula sheet) in the pure state (in free form or in the form of salt) or in combination with one or more pharmaceutically acceptable additives. These compositions can be applied parenterally.

The compositions for parenteral administration may preferably be sterile aqueous or nonaqueous solutions, suspensions or emulsions. As a solvent or as a filler, there may be used propylene glycol, a polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, for example, ethyl oleate.

These compositions may also contain additives, in particular wetting agents, emulsifiers or dispersants. The sterilization can be carried out in several ways, for example by means of a bacteriological filter, incorporation of sterilizing agents in the composition, by irradiation or heating. They may also be prepared in the form of solid sterile compositions, which are then dissolved at the moment of use in sterile water or other injectable sterile medium.

In human therapeutics, the medicaments of the invention are particularly useful in the treatment of carcinogenic manifestations of the digestive tract, the lung, the testes or ovaries, and the head or neck.

In general, the doctor will determine the dosage that he considers the most appropriate, depending on the age, weight and other factors of the person being treated.

The preferred mode of administration is the intravenous route. For information, it should be stated that the medicaments according to the invention can be administered to humans in a ratio of 30 to 200 mg / m ² per treatment by intravenous route.

The following non-limiting example illustrates a composition of the invention:

example 1

A solution was prepared containing 6.44 g of i-amino-IO-dimethylamino-1-propyl-S-hydroxy-1-methyl-SH-pyrido-1-S-B-benzoil-indole dihydrochloride hydrate (1.5H ₂ O). contains by dissolving this product in a pyrogen-free physiological solution, the amount of which is such that 100cm ³ are obtained.

The solution obtained is then divided aseptically into ampoules, namely ² cm ³ per ampoule. The ampoules are fused and each contain 100 mg of 1-amino - [(3-dimethylamino) -propyl] -9-hydroxy-4-methyl-5H-pyrido [4,3-b] benzo [e] -indole.

2 ν ο 9 2

- alk - N (R) 2

HN (CHR ₅ J _n NT

R ₄

(A)

H 3 Co

HN - alk - N (R) 2

2> 6 9 2 6

H ₂ N - alk. - N (R) ₂ (III)

H 3 Co

(IV)

(V)

Claims (7)

1. A novel pyridobenzoindole derivative of the general formula (I) (see formula sheet) in which R represents a hydrogen atom or an alkyl radical having 1 or 2 carbon atoms, alk represents a straight or branched alkylene radical having 2 to 4 carbon atoms, R _{1 is} a hydrogen atom or an alkyl radical having 1 or 2 carbon atoms, R _{2 is} a hydroxy radical or a methoxy radical, and R _{3 is} an alkyl radical having 1 or 2 carbon atoms, and its addition salts with acids and optionally its Hydrates, its isomeric forms and mixtures thereof. The novel pyridobenzoindole derivative according to claim 1, wherein R represents a hydrogen atom or a methyl radical, alk represents a straight or branched alkylene radical having 2 to 4 carbon atoms, R _{1 represents} a hydrogen atom or a methyl radical, R ₂ Hydroxy radical and R _{3 represents} a methyl or ethyl radical, and its salts and optionally its hydrates, its isomeric forms and mixtures thereof. 3. A novel pyridobenzoindole derivative according to claim 1, wherein R is a methyl radical, alk is a straight or branched alkylene radical having 2 to 4 carbon atoms, R _{1 is} a hydrogen atom or a methyl radical, R _{2 is} a hydroxy radical and R _{3 represents} a methyl radical, and its salts and optionally its hydrates, its isomeric forms and mixtures thereof. 4. 1-Amino - [(3-dimethylamino) -propyl] -9-hydroxy-4-methyl-5H-pyrido [4,3b] benzo [e] -indole and its salts and its hydrated forms. 5. 1-Amino - [(3-dimethylamino-2-methyl) -propyl] -9-hydroxy-4-methyl-5H-pyrido [4,3-b] benzo [e] -indole and its salts, its hydrated Forms, its isomeric forms and their mixtures. 6. A process for the preparation of a pyridobenzoindole derivative according to claim 1, characterized in that an amine of the general formula (III) (see formula sheet), in which alk and R are as defined in claim 1, with a chlorinated derivative of the general formula (II) (see formula sheet), in which R ₁ and R _{2 are} as defined in claim 1, brings to reaction and then optionally the resulting methoxy product of the general formula (I a) (see formula sheet), in which R ₁ and R _{3 are as} defined in claim 1, converted into a 9-hydroxy-pyrido [4,3b] benzo [e] -indole derivative and further optionally converting the resulting product with an acid in an acid addition salt. Pharmaceutical composition, characterized in that it contains a product according to claim 1 as such or in association with one or more pharmaceutically acceptable additives.