FR2661411A1 - New pyridobenzoindole derivatives, their preparation and the compositions which contain them - Google Patents

Abstract

New pyridobenzoindole derivatives of general formula (I), in which R is H, alk is straight or branched (2 to 4 C)alkylene, R1 represents a hydrogen atom or a (1 or 2 C)alkyl radical, R2 represents a hydroxyl or methoxy radical and R3 is (1 or 2 C)alkyl, or else R is (1 or 2 C)alkyl, R1, R2 and alk are defined as above and R3 is ethyl, and their addition salts with acids and, if appropriate, their hydrated forms, useful as anti-tumor agents.

Description

le cas échéant leur hydrates, leurs sels d'addition avec les acides, leur préparation et les compositions pharmaceutiques qui les contiennent.The present invention relates to new pyridobenzoindole derivatives of general formula

where appropriate, their hydrates, their addition salts with acids, their preparation and the pharmaceutical compositions which contain them.

dans laquelle R1 et R5 sont entre autres des atomes d'hydrogène, R2 peut représenter un atome d'hydrogène, un radical hydroxy ou alcoyloxy, R3 et R4 sont notamment des radicaux alcoyle et n égale 2 à 4, qui présentent une activité anti-tumorale.In the European patent application 239,476 have been described derivatives of d-carboline of general formula

in which R1 and R5 are inter alia hydrogen atoms, R2 can represent a hydrogen atom, a hydroxy or alkyloxy radical, R3 and R4 are in particular alkyl radicals and n equal to 2 to 4, which exhibit an anti- tumor.

 Furthermore, other pyridoindole derivatives have been described 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 is mentioned.

The new pyridobenzoindole derivatives of general formula (I) in which - either R represents a hydrogen atom,
alk represents a straight or branched alkylene radical containing 2 to
4 carbon atoms,
R1 represents a hydrogen atom or an alkyl radical containing
1 or 2 carbon atoms,
R2 represents a hydroxy or methoxy radical, and
R3 represents an alkyl radical containing 1 or 2 atoms of
carbon, - either R represents an alkyl radical containing 1 or 2 atoms of
carbon,
alk, R1 and R2 are defined as above and
R3 represents an ethyl radical, have particularly interesting anti-tumor properties.

dans laquelle R1, est défini comme précédemment par action d'une amine de formule générale
H2N - alk - N(R)2 (III) dans laquelle alk et R sont définis comme précédemment, suivie le cas échéant de la transformation du produit méthoxylé ainsi obtenu, de formule générale

dans laquelle R, R1, R3 et alk sont définis comme ci-dessus, en un dérivé hydroxy-9 pyrido [4, 3-b)benzo [e) indole. According to the invention, the products of general formula (I) can be obtained from the chlorinated derivative of general formula

in which R1, is defined as above by the action of an amine of general formula
H2N - alk - N (R) 2 (III) in which alk and R are defined as above, followed where appropriate by the transformation of the methoxylated product thus obtained, of general formula

in which R, R1, R3 and alk are defined as above, into a 9-hydroxy pyrido derivative [4, 3-b) benzo [e) indole.

 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 the reaction mixture, and 250 ° C. (autoclave).

 Demethylation is carried out by any known method which does not alter the rest of the molecule.

dans laquelle R3 est défini comme précédemment, par action d'un agent de chloration. The chlorinated derivative of general formula (II) for which R1 is a hydrogen atom can be prepared from the corresponding pyridone, of general formula

in which R3 is defined as above, by the action of a chlorinating agent.

 It is generally carried out using a chlorinating agent chosen from phosphorus oxychloride or halogenated phosphorus derivatives in the presence of a tertiary base (diethylaniline, dimethylaniline for example) in an organic solvent such as a nitrile (acetonitrile for example), at a temperature between 75 and 900C (reflux temperature of the reaction mixture).

 Preferably, the reaction is carried out under nitrogen.

 The product of general formula (II) for which R1 and an alkyl radical can be obtained by alkylation of the product for which R1 is a hydrogen atom, for example by the action of the suitable halogenated derivative, in the presence of potassium carbonate.

dans laquelle R3 est défini comme précédemment par réaction de
Fisher thermique, par analogie avec la méthode décrite par C.H.The product of formula (IV) can be prepared from the hydrazone of general formula

in which R3 is defined as above by reaction of
Fisher thermal, by analogy with the method described by CH

NGUYEN and E. BISAGNI, Tetrahedron, 42 (8), 2203 (1986).

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

 The 6-methoxy tetralone can be obtained according to the method described in J. Am. Chem. Soc., 82, 2573 (1960).

 Hydrazino-4 methyl-5-1H-pyridone-2 can be prepared according to the method described by C.H. NGUYEN and E. BISAGNI, Tetrahedron, 42 (8), 2203 (1986).

 The pyridobenzoindole derivatives of general formula (I) can be purified by crystallization or by chromatography.

 The new pyridobenzoindole derivatives according to the invention can be converted into addition salts with acids, by the action of an acid in an organic solvent. The salt precipitates, possibly after concentration of its solution, it is separated by filtration or decantation.

 As pharmaceutically acceptable salts, mention may be made of addition salts with mineral acids such as hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, or organic salts such as acetate, propionates, succinates, maleates, fumarates, methanesulfonates, p.toluenesulfonates, isethionates or substitution derivatives of these compounds.

 The pyridobenzoindole derivatives according to the invention and their salts can exist in the form of hydrates, it is understood that these hydrated forms also come within the scope of the present invention.

 Furthermore, when the symbol alk is a branched alkylene radical, the pyridobenzoindole derivatives have isomeric forms. It is understood that these isomeric forms also come within the scope of the invention.

 The derivatives of general formula (I) are particularly advantageous as anti-tumor agents.

 Their anti-tumor properties have in particular been demonstrated at a concentration close to 15 pg / disc in the differential cytotoxicity test, according to the technique described by T.H.

Corbett et al., Investigational new drug, 4, 207-220 (1986), and on mouse grafted tumors, more particularly on P388 leukemia, the products studied have been shown to be active at doses between 5 and 20 mg / kg intraperitoneally.

 Their toxicity in mice expressed by their maximum tolerated dose is between 10 and 20 mg / kg intraperitoneally.

 The following examples, given without limitation, illustrate the present invention.

EXAMPLE 1
((Dimethylamino-2) ethyl amino-1-methoxy-9 methyl-45H-pyrido [4,3-b] benzo [e] indole is placed in a 250 cm3 reaction flask fitted with an agitator and kept under argon, with 80 cm3 of hydrobromic acid (d = 1.47.47%).

 This mixture, which has become homogeneous on boiling, is heated at reflux for 5 hours and concentrated to dryness under reduced pressure. The solid residue is dissolved in water (400 cm3) basified with 28% ammonia (18 cm3) which is added dropwise, to form a gummy precipitate.

 To the resulting mixture, 200 cm 3 of ethyl acetate are added, the whole is stirred overnight and filtered. The organic phase is decanted and the mother liquors are extracted twice with 100 cm3 of ethyl acetate. The organic phase is dried over sodium sulphate, filtered, treated with 4 g of animal charcoal to discolor it, filtered again and concentrated to dryness.

 The solid residue is taken up in 30 cm3 of acetone and 50 cm3 of absolute ethanol, and the homogeneous mixture is filtered hot in a solution of maleic acid (3 equivalents) in 30 cm3 of absolute ethanol to give, after evaporation of the solvent and taking up the residue in acetone, [(dimethylamino-2) ethyl] dimaleate-1-amino-9-hydroxy-methyl-4-5H-pyrido [4,3-b] benzo [e] indole, F = 2100C. The yield for the three stages: substitution, demethylation and salification amounts to 76%.

[(2-Dimethylamino) ethyl) 1-amino-9-methoxy-methyl-45H-pyrido [4,3-b] benzo [e] indole can be prepared as follows
Chloro-1 methoxy-9 methyl-4-5H-pyrido [4,3-b] benzo [e] indole (2 g) is placed in a 50 cm3 flask containing 20 cm3 (large excess) of dimethylamino-2- ethylamine and heated to reflux (1200C) under nitrogen and with stirring, for 16 days (total disappearance of the chlorinated derivative, checked on silica plate).

 The excess diamine is evaporated in a water bath under reduced pressure and the residue is taken up in water and then made alkaline with ammonia. The soldie formed is filtered, washed with water, taken up in methylene chloride and washed with 150 cm3 of water and 10 cm3 of ammonia.

 The organic solution is dried, filtered and concentrated to dryness to give a solid residue corresponding to [(dimethylamino-2) ethyl] maleate-1-amino-9-methoxy-methyl-4-5H-pyrido [4,3-b] benzo [ e] indole; F = 1840C.

1-Chloro-9-methoxy-methyl-4-5H-pyrido [4,3-b] benzo [e] indole can be obtained in the following manner
12.2 g (43 mmol) of 9-methoxy-methyl-4-2H are introduced into a 1 liter flask fitted with a magnetic stirrer, an addition funnel, a condenser and kept under nitrogen. 5H-py rido [4,3-b] benzo [e] indolone-1, 10.4 g (172 mmol) of acetamide 40 g (172 mmol) of benzyl triethylammonium chloride 110 cm3 of acetonitrile and 28 cm3 ( 172 mmol) of freshly rectified diethylaniline.

 200 cm3 of rectified phosphorus oxychloride are gradually added through the bulb, and an exothermic reaction is observed. The mixture is heated at reflux for 10 hours, while after having passed through a homogeneous phase, a precipitate appears.

After the indicated time, it is concentrated to dryness, in a water bath heated to 700C and under reduced pressure (15 mm of mercury).

 To the residue obtained, 300 cm3 of ice water are added and the mixture, well stirred for 2 minutes, is heated to the boil.

A yellow precipitate is formed, which is filtered cold and then washed with cold water. This precipitate is taken up in 300 cm3 of distilled water and the mixture is basified, cold, with ammonia.

The whole is left under stirring for 1 hour and the precipitate is filtered and washed with water. The control in thin layer chromatography shows the presence of the expected compound (rf = 0.5) and the presence of traces of the starting compound (rf = 0.36) (Si02, CH2Cl2
EtOH, 9/1). The expected product crystallizes from alcohol in which it is very slightly soluble (large volumes), giving 12 g (92%) of yellow needles, F> 2700C (rf = 0.58 on silica plate, eluent ethyl acetate pure).

Methoxy-9 methyl-4-2H, 5H-pyrido [4,3-b] benzo [e] indolone-1 can be prepared as follows
In a 4-liter three-necked flask, the N- (methyl-5-1H -pyridone-2 yl) -4 N '- (6-methoxy-1,2,3,4-naphthalenylidene) -2 hydrazine is mixed (31 g, 0.1 mol) and the diphenyl ether (1 liter) then heated to reflux for 40 minutes, keeping the whole under good stirring and under nitrogen. The mixture becomes homogeneous and discolours. The heating is interrupted to allow cooling to 2000C and to control the transformation of the starting compound. Continuing to stir, the 10% palladium-on-carbon (5 g) suspended in diphenyl ether (100 cm 3) is gradually added, with care (foams and evolution of hydrogen), and the new mixture is again heated at reflux for 40 minutes. Hexane (2 liters) is added to the cooled mixture and the precipitate formed is filtered and then washed with hexane. It is then taken up in 1 liter of boiling acetic acid, filtered to remove the palladium-on-charcoal and the latter is washed once with 50 to 100 cm 3 of boiling acetic acid.

The entire filtrate is concentrated to 500 cm3 and the solid obtained after cooling is filtered, washed with boiling acetone and dried to give 22 g (75%) of pale yellow microcrystals, F = 2600C, corresponding to the N- ( 5-methyl-1H-pyridone-2 yl) -4 N '- (6-methoxy-tetrahydro-1,2,3,4-naphthalenylidene) -2 expected hydrazine, slightly hydrated (rf = 0.36 on silica plate, with the mixture
CH2Cl2-EtOH 9/1 as eluent).

N- (methyl-5-1H-pyridone-2 yl) -4 N '- (6-methoxy-1,2,3,4-tetrahydro-naphthalenylidene) -2 hydrazine can be prepared as follows
The mixture of 4-hydrazino-5-1H-pyridone-2 (13.9 g, 0.1 mol) in absolute ethanol (600 cm3) is heated to reflux. To the solution, which has become homogeneous on boiling, 6-methoxy-tetralone-2 (11.3 g, 0.12 mol) is added and the mixture, which has quickly become heterogeneous, is heated at reflux for 4 hours 30 minutes. The precipitate formed is filtered, taken up in 400 cm3 of boiling ethanol in which the hydrazone is very slightly soluble, then filtered cold to give 15.7 g (98%) of colorless microcrystals,
F = 240-2500C, with decomposition.

EXAMPLE 2
[(3-amino) propyl] 1-amino-9-methoxy-methyl-4-5H-pyrido [4,3-b] benzo [e] indole (1.9 g) is placed in a 250 cm3 reaction flask equipped with a stirrer and maintained under argon, with 70 cm3 of hydrobromic acid (d = 1.47; 47%).

 This mixture, which has become homogeneous on boiling, is heated under reflux for 5 hours 30 minutes and concentrated to dryness under reduced pressure. The solid residue is dissolved in water (200 cm3) basified with 28% ammonia (20 cm3) which is added dropwise, to form a gummy precipitate.

 To the resulting mixture, 200 cm3 of ethyl acetate and 50 cm3 of ethanol are added, 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 cm3 of ethyl acetate. The organic phase is dried over sodium sulfate, filtered, treated with 4 g of animal charcoal to discolor it, then filtered and concentrated to dryness.

 The solid residue is taken up in 30 cm3 of acetone, stirred for 15 min. and filtered and then washed twice with 10 cm3 of cold acetone to give 1.5 g (80%) of a solid corresponding to [(amino-3) propyl] amino-1 hydroxy-9-methyl-4- 5H-pyrido [4,3-b] benzo [e] indole, hydrated with 1.3 molecules of water including the bimaleate, recrystallized from an ethanol-acetone mixture, melts at 132-1 360C.

[(3-amino) propyl] 1-amino-9-methoxy-methyl-4-5H-pyrido [4,3-b] benzo (e] indole can be prepared as follows:
The chlorine derivative (2.5 g) is placed in a 250 cm3 flask (large excess) of 3-amino propylamine and heated to 1600C under nitrogen and with stirring for 18 hours (total disappearance of the chlorine derivative, checked on a plate). silica).

 The excess diamine is evaporated in a water bath under reduced pressure and the residue is taken up in water and then made alkaline with ammonia. The solid formed is filtered, washed with water, and dried in a desiccator to give 2.8 g of a solid product corresponding to the expected compound.

 The bimaleate, prepared in absolute ethanol in the presence of an excess of maleic acid and washed with acetone, corresponds to the salt of [(3-amino) propyl] 1-amino-9-methyl-4- methyl 5H-pyrido [4,3-b] benzo [e] indole, monohydrate; F = 1700C.

EXAMPLE 3
[(3-Dimethylamino) propyl] 1-amino-4-ethyl-9-methoxy 5H-pyrido [4,3-b] benzo [e] indole (free base) is placed in a 250 cm3 reaction flask fitted with a agitator under argon, with 66 cm3 of hydrobromic acid (d = 1.47; 47%).

 This mixture, which has become homogeneous on boiling, is heated under reflux for 5 hours and concentrated to dryness under reduced pressure. The solid residue is dissolved in water (200 cm3) basified with 28% ammonia (15 cm3) which is added dropwise, to form a gummy precipitate.

 To the resulting mixture, 200 cm 3 of ethyl acetate are added and the whole is stirred for one hour. The organic phase is decanted and the mother liquors are extracted twice with 100 cm3 of ethyl acetate. The organic phase is dried over sodium sulfate, filtered, treated with 5 g of animal charcoal to discolor it, then filtered and concentrated to dryness.

 The solid residue is taken up in 40 cm3 of acetone, and treated with 2.5 g of maleic acid in solution in 40 cm3 of acetone at the boil. [(Dimethylamino-3) propyl] amino-1-ethyl-4-hydroxy-9 SH-pyrido [4,3-b] benzo [e] indole bimaleate (2.34 g, Yield = 72% for the 3 stages: substition - demethylation - salification) is filtered and dried to give cream microcrystals; F = 1540C.

 [(3-Dimethylamino) propyl] 1-amino-4-ethyl-9-methoxy 5H-pyrido [4,3-b] benzo [e) indole can be obtained in the following manner.

 The chloro-1 ethyl-4-methoxy-9 5H-pyrido [4,3-b] benzo [e] indole (2 g) is placed in a 250 cm3 flask containing 40 cm3 (large excess) of 3-dimethylamino propylamine and heated at reflux, under nitrogen and with stirring, for 72 hours (total disappearance of the chlorinated derivative, checked on silica plate).

 The excess diamine is evaporated in a water bath under reduced pressure and the residue is taken up in water and then made alkaline with ammonia. The solid formed is filtered, washed with water, taken up in methylene chloride and washed with 150 cm3 of water and 10 cm3 of ammonia.

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

 The corresponding bimaleate, formed under the usual conditions, melts at 1540C.

1-Chloro-4-ethyl-9-methoxy 5H-pyrido [4,3-b] benzo [e] indole can be obtained in the following manner
6 g of methoxy-9 ethyl-4-2H, 5H-pyrido are introduced into a 500 cm3 flask fitted with a magnetic stirrer, an addition funnel, a condenser and kept under nitrogen. 3-b] benzo [e) indolone-1 in boiling and dried ethanol, 19.2 g of benzyl triethylammonium chloride, 5.1 g of acetamide, 60 cm3 of acetonitrile and 13.2 g of diethylaniline freshly rectified.

 Through the ampoule, 96 cm3 of rectified phosphorus oxychloride are gradually added, and an exothermic reaction is observed. The mixture is heated at reflux for 6 hours 30 minutes, while after having passed through a homogeneous phase, a precipitate appears. Evaporated to dryness, in a bain-marie heated to 700C and under a vacuum of 15 mm.

 To the residue obtained, 600 cm3 of ice water are added and the mixture, well stirred for 2 hours, is heated to the boil.

After cooling, a yellow precipitate is obtained, which is filtered cold and then washed with cold water. This precipitate is taken up in 500 cm3 of distilled water and the mixture is basified, cold, with ammonia. The whole is left under stirring for 1 hour 30 minutes and the precipitate is filtered and washed with water. It recrystallizes from alcohol to give 4.6 g of yellow needles of 1-chloro-4-ethyl-9-methoxy 5H-pyrido [4,3-b] benzo [e] indole; F = 2600C (yield 62%).

Methoxy-9 ethyl-4-2H, 5H-pyrido [4,3-b] benzo [e] indolone-1 can be obtained in the following way:
In a 1 liter three-necked flask, the N-ethyl-5-1 H-pyridone-2 yl) -4 N'-methoxy tetrahydro-1, 2,3, 4-naphthalenylidene) -2 hydrazine is mixed 5 g) and the diphenyl ether (350 cm3 then heated under reflux for 30 minutes, keeping the whole under good stirring and under nitrogen. The mixture becomes homogeneous and discolours. The heating is stopped to cool to 2000C and check that the starting compound is completely transformed: Merk silica plate, eluent methylene chloride-ethanol 8/2, (rf hydrazone = 0.5, rf intermediate compound = 0.8). Continuing to agitate, the palladium-on-carbon at 10% (2g) suspended in diphenyl ether (20 cm3) is added gradually, with caution (foams and release of hydrogen), and the new mixture is heated at reflux for 30 minutes (disappearance of the intermediate compound) (rf: 0.35 pure silica-ethyl acetate; expected product: rf = 0.58) Hexane (400 cm3) is added to the mixture re cooled and the precipitate formed is filtered and then washed with hexane. It is then taken up in 350 cm3 of boiling acetic acid, filtered to remove the palladium-on-charcoal and the latter washed twice with 30 cm3 of boiling acetic acid. The whole of the filtrate is concentrated to 150 cm3 and the solid obtained after cooling is filtered and dried under vacuum to give 13.7 g (quantitative yield) of pale yellow microcrystals (F> 2600C), corresponding to methoxy-9 ethyl-4-2H, 5H-pyrido [4,3-b] benzo [ e] indolone-1 hydrated.

N-ethyl-5-1H-pyridone-2 yl) -4 N'-methoxy tetrahydro-1,2,3,4-naphthalenylidene) -2 hydrazine can be obtained in the following manner
The mixture of 4-hydrazino-5-1H-pyridone-2 (7 g) in absolute ethanol (250 cm3) is heated to reflux. To the solution, which has become homogeneous on boiling, 6-methoxy-tetralone-2 (9.3 g) is added and the mixture, which has become rapidly heterogeneous, is heated to reflux for 4 hours 30 minutes (disappearance of the controlled hydrazine by TLC on Merk silica plate, eluent methylene chloride-ethanol 7/3 by volume, rf = 0.75). The precipitate formed is filtered, taken up in 100 cm3 of ethanol in which the hydrazone is sparingly soluble and then filtered. when cold to give (12.1 g (85%)) of colorless microcrystals of N-ethyl-5-1H-pyridone-2 yl) -4 N'-methoxy tetrahydro-1,2,3,4-naphthalenylidene) - 2 hydrazine, F = 135 - 1,400C, with decomposition.

Hydrazino-4 ethyl-5-1H-pyridone-2 can be obtained as follows
In a reaction flask placed under nitrogen and fitted with a magnetic stirrer and a condenser, 12 g of 4-hydroxy-ethyl-5-1H-pyridone-2 are mixed, 40 cm3 of monoethyl ether from ethylene glycol and 11 cm3 of hydrazine hydrate.

 The whole is heated at reflux, with stirring, for a total of 4 days.

 After having allowed to stand in the cold overnight, the solid obtained is filtered, washed with 10 cm3 of cold absolute ethanol and dried to give 7.8 g (59%) of 4-hydrazino-5-1H-pyridone -2 monohydrate, F = 130-1320C, with decomposition.

 Hydroxy-4 ethyl-5-1H-pyridone-2 is described by M.

Legraverend, CH Nguyen, A. Zérial and E. Bisagni Nucleosides and
Necleotides 5, 125-134 (1986).

 The present invention also relates to pharmaceutical compositions which contain as active product at least one product of general formula (I) in the pure state (in free form or in salt form) or in combination with one or more pharmaceutically acceptable adjuvants. These compositions can be used parenterally.

 The compositions for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil and injectable organic esters, for example ethyl oleate, can be used. These compositions can also contain adjuvants, in particular wetting agents, emulsifiers or dispersants. Sterilization can be done in several ways, for example using a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which will be dissolved at the time of use in sterile water or any other sterile injectable medium.

 In human therapy, the medicaments according to the present invention are particularly useful in the treatment of digestive cancers, of pulmonary cancers, of cancers of the testes or of the ovaries as well as in the treatments of cancers of the head and of the neck.

 In general, the doctor will determine the dosage he considers most appropriate based on age, weight and all other factors specific to the subject to be treated.

 The preferred mode of administration is the intravenous route. As an indication, the medicaments according to the invention can be administered to humans at a rate of 30 to 200 mg / m 2 per treatment, by intravenous route.

The following example, given without limitation, illustrates a composition according to the present invention
EXAMPLE
A solution containing 6.60 g of [(amino-3) propyl] dimaleate-1-amino-9-hydroxy-4-methyl 5H-pyrido 14.3-b] benzo [e] indole hydrate (1.3 H2O) is prepared. ), by dissolving this product in pyrogen-free physiological solution in sufficient quantity to obtain 100 cm3.

 The solution obtained is aseptically distributed in ampoules, at the rate of 2 cm3 per ampoule. The ampoules are sealed and each contain 100 mg of [(3-amino) propyl] 1-amino-9-hydroxy-4-methyl 5H-pyrido [4,3-b] benzo [e] indole.

Claims (3)

 1 - A new pyridobenzoindole derivative of general formula

 in which - either R represents a hydrogen atom,  alk represents a straight or branched alkylene radical containing 2 to  4 carbon atoms,  R1 represents a hydrogen atom or an alkyl radical containing  1 or 2 carbon atoms,  R2 represents a hydroxy or methoxy radical, and  R3 represents an alkyl radical containing 1 or 2 atoms of  carbon, - either R represents an acyl radical containing 1 or 2 atoms of  carbon,  R1, R2 and alk are defined as above and  R3 represents an ethyl radical, as well as its addition salts with acids, and where appropriate its hydrates and its isomeric forms and their mixtures.  2 - A process for the preparation of a pyridobenzoindole derivative according to claim 1, characterized in that an amine of general formula is made to act  H2N - alk - N (R) 2 in which alk and R are defined as in claim 1, on a chlorinated derivative of formula

 then if necessary converts the methoxylated product obtained into a 9-hydroxy derivative pyrido [4,3-b] benzo [e] indole and optionally converts the product obtained into an addition salt with an acid.  3 - Pharmaceutical composition characterized in that it contains a product according to claim 1 in the pure state or in the form of an association with any compatible and pharmaceutically acceptable diluent or adjuvant.