FR2595700A1 - 5H-pyrido[4,3-b]indole derivatives, process for their preparation and their application as synthetic intermediates - Google Patents

Abstract

New chlorinated derivatives of 5H-pyrido[4,3-b]indole of formula I in which R1 represents hydrogen or a lower alkyl group and R2 represents the hydroxyl group, a lower alkyloxy group or an arylcarbonyloxy group, process for their preparation and their application as synthetic intermediates in the preparation of new compounds which can be used in the pharmaceutical industry.

Description

 The invention relates to chlorinated derivatives of 5-H pyrido-4,3-bindole, to a process for their preparation and to their use as synthetic intermediates in the preparation of compounds useful in the pharmaceutical industry.

dans laquelle R1 représente l'hydrogène ou un groupe alkyle inférieur et
R2 représente un groupe hydroxy, un groupe alkyloxy inférieur ou un groupe arylcarbonyloxy.The new derivatives of the invention correspond to the following formula

wherein R1 represents hydrogen or a lower alkyl group and
R2 represents a hydroxy group, a lower alkyloxy group or an arylcarbonyloxy group.

 The invention also relates tautomeric forms when they exist. By lower alkyl group is meant a linear or branched C1-C4 saturated hydrocarbon chain.

dans laquelle n représente un nombre entier de 2 à 4 ; R1 représente l'hydrogène ou un groupe alkyle inférieur, R2 représente un groupe hydroxy ou un groupe alkyloxy inférieur : R3 et R4 sont chacun indépendamment l'un de l'autre l'hydrogène, un groupe alkyle inférieur ou hydroxyalkyle.These derivatives are intermediates in the preparation of new compounds of formula (A)

wherein n represents an integer of 2 to 4; R 1 is hydrogen or lower alkyl, R 2 is hydroxy or lower alkyloxy; R 3 and R 4 are each independently of one another hydrogen, lower alkyl or hydroxyalkyl.

 These novel compounds (A) which are endowed with interesting antitumor properties have been claimed by the applicants as well as their therapeutic application in a jointly filed application.

Certain 1-chloro-5-H pyrido-4,3-bindole derivatives have been previously described in the literature, in particular by
C. DUCROCQ. A. CIVIER, J. ANDRE-LOUISFERT and E. BISAGNI (J. Heterocycl Chem.

12, 963-967, 19753, CH. S. LEE, T. OHTA, K. SHUDO and T. OKAMOTO tHetérocycles, 16, 1081-1084, 1981). But these derivatives, the synthesis of which is different from the process which is the subject of the invention, contain neither methyl group at the 4-position nor substituent at the 6-position, so that they can not be used as intermediates in the preparation of the new compounds of formula (A).

The invention therefore also relates to a process for the preparation of the compounds of formula (I) above, characterized in that 1) by reaction of 4-hydrazino-5-methyl-2-oxo-1,2-dihydropyridine, prepared according to the method described by E. BISAGNI (French Patent Application No. 08504671 of March 22, 1985), on 3,3-dimethyl-1,5-dioxo-spiro [5,5] undecanone, or any other monoacetal of cyclohexanedione-1, 4 prepared for example according to the method of JM KAMENKA [Bulb. Soc. Chim. France, 3.4 67-88, 1983 2, the hydrazone of formula (II) is obtained.

3 ) La Pyrido-indoledione de formule (III) est deshydrogénée par action du charbon palladié pour former l'hydroxy-6 méthyl-4 2-H Pyrido /4,3-bJ indolone-1 de formule

40) Le dérivé hydroxylé (IV) est estérifié par action dgun anhydride d'acide aromatique pour former une arylcarbonyloxy-8 méthyl-4 2-H 5-H
Pyrido [4,3-b] indolone-1 de formule (V) dans laquelle R2 représente le groupe arylcarbonyloxy.

2) The hydrazone of formula (II) is cyclized according to the reaction of FISHER, and the cyclic derivative obtained hydrolysed to form 4-methyl-tetrahydro6,7,6,9 2-H 5 -H Pyrido [4,3-b ] indoledione-1,8 of formula

3) The pyrido-indoledione of formula (III) is dehydrogenated by the action of palladium on carbon to form 6-hydroxy-methyl-4 2 -H pyrido / 4,3-bj indolone-1 of formula

40) The hydroxyl derivative (IV) is esterified by the action of an aromatic acid anhydride to form an 8-arylcarbonyloxy-methyl-4 2 -H 5 -H
Pyrido [4,3-b] indolone-1 of formula (V) in which R 2 represents the arylcarbonyloxy group.

5) The action of a chlorinating agent on the ester (V) gives an arylcarbonyl-8-oxo-1-chloro-methyl-4,5-H pyrido [4,3-b] indexe of formula (I) in which R1 represents hydrogen and R2 represents an arylcarbonyloxy group.

60) The chlorinated ester of formula (I), wherein R1 and R2 have the above meaning, is hydrolyzed to the corresponding hydroxylated derivative.

It may also be previously alkylated in position-5 by action of an alkyl halide and then hydrolyzed to the corresponding hydroxyl derivative. There is thus obtained a 5-chloro-1-hydroxy-4-methyl-5-pyrido [4,3-b] indole which is optionally alkylated at the 5-position of formula (I) in which R represents hydrogen or an alkyl group and R2 represents the hydroxy group.

7) The action of an alkyl halide on a chlorinated derivative of formula (I), wherein R 1 and R 2 have the above meaning, gives an 8-alkyloxy-1-chloro-methyl-4,5-H pyrido r 4 , 3-b] optionally S-alkylated indole of formula (I) wherein R1 is hydrogen or alkyl and R2 is alkyloxy.

 The formation of the hydrazone of formula III is carried out at the reflux temperature of a polar solvent such as methanol.

 The cyclization of the compound of formula (II) is obtained by heating at temperatures between 2000C and 280 C under reflux of an inert solvent such as diphenyl ether.

 After hydrolysis with a normal aqueous solution of hydrochloric acid brought to reflux, the aromatization of the compound of formula (III), which leads to the compound of formula (IV) is carried out in the same solvent as that used in step previous, at high temperature and in the presence of a catalyst such as palladium on carbon.

 Esterification of the compound of formula (IV) is carried out at the reflux temperature of an aprotic basic solvent such as pyridine.

 The chlorination of the compound of formula (V) which leads to the compound of formula (I) is advantageously carried out at the reflux temperature of phosphorus oxychloride.

 The alkylation of the chlorinated derivative previously obtained is carried out by the action of an alkyl halide R 1 -X tX = I, Br, SO 4) in the presence of a weak base such as potassium carbonate, in a polar solvent. aprotic such as N, N dimethylformamide. It leads to the chlorinated derivative of formula (I) in which R 1 represents an alkyl radical and R 2 represents an aryloxycarbonyl radical.

The hydrolysis of this derivative is carried out by the action of a base such
that sodium hydroxide, potassium hydroxide or ammonia, dissolved in a
polar solvent such as methanol or a hydroalcoholic solvent, at a
temperature between 150C and 450C.

The alkylation in position 6 of the compound of formula (I) in which
R2 represents a hydroxy group, is carried out by the action of a halide
R2-X alkyl in the presence of a strong base (sodium hydroxide or potassium hydroxide)
in a hydroalcoholic environment. In the case of the chlorinated derivative of formula (I)
which R 1 represents hydrogen, it is advantageously carried out in
presence of a weak base such as potassium carbonate in medium
polar aprotic such as dimethylformamide.

The following nonlimiting examples are given by way of illustration
of the present invention.

Example 1 Preparation of 6-benzoyloxy-1-chloro-methyl-4,5-H pyrido
4.3-bJ indole (compound of formula (I) wherein R1 = H, R2 = C6H5-CO-O).

65
A) 3,3-Dimethyl-1,5-dioxa-5-methyl-2-oxo-1,2-dihydro-1H-pyridyl-43
hydrazono] -9 spiro r 5,5 ~ 7 undecane.

 The mixture formed by 4-hydroxy-5-methyl-1H-2-pyridone (16g), ethylene glycol monoethyl ether (400 ml) and hydrazine hydrate (140 ml) is heated at reflux for 4 days and evaporated to dryness under reduced pressure. The solid residue is taken up in 500 ml of boiling absolute ethanol, filtered and the filtrate is concentrated by half.

After one night at room temperature, the crystallized solid is drained and dried. Colorless crystals (13 g) corresponding to the hydrate of the desired compound F - 1351550 are obtained.

Calo. for C6H9N3O, H20 B C, 45.85; H, 7.05; N, 26.74.

 Found: C, 45.29; H, 6.97, N, 26.03.

 The mother liquors, concentrated to 100 ml and left overnight at room temperature, give a new quantity of the compound (2.4 g). The total yield is therefore 15.4 g, or 76%. 100.

The hydrazino-4-methyl-5 1-H pyridone-2 hydrate mixture
(3.56 g) and 3,3-dimethyl-1,5-dioxo spiro [5.5] undecanone-9 (7.92 g)
in absolute ethanol (200 ml) is refluxed for 2 h 15, then
cooled to room temperature. The filtered solid is washed with ethanol
to give 9 g of the pure hydrazone. Evaporation of the mother liquor leaves
a solid residue which is taken up in 100 ml of boiling dioxane, cooled
at room temperature, filtered and recrystallized from ethanol to give 1.2 g of
expected product.

 Yield: 90.3%; F> 2600C.

 Calc. for C17H25N3O3: C, 63.92; H, 7.89: N, 13.16.

 Found: C, 63.64; H, 7.66; N, 12.84.

 Tetrahydro-6,7,8,9-methyl-4H-5-H pyrido [4,3-b] indoledione-1,8.

 The mixture of the above hydrazone (2.3 g) in diphenyl ether (45 ml) was heated under reflux under argon for 40 minutes and allowed to cool to room temperature.

After addition of 150 ml of xylene, the precipitate formed is drained and washed with xylene to give 2 g of the crude intermediate, and then hydrolysed by heating to boiling for 25 minutes in 100 ml of hydrochloric acid.
N, cooled and alkanized by addition of potassium carbonate. The solid obtained is filtered, dried and recrystallized from the minimum amount of ethanol to give 1.1 g of colorless microcrystals corresponding to the hydrate of the expected indoledione.

 Yield: 70.6% JF> 2600C.

 Calo. for C 12 H 12 N 2 O 2 H 2 O: C, 61.53; H, 5.98; N, 11.96.

 Found: C, 61.15; H, 5.87; N, 11.73.

1 H NMR [(CD 3) 2 SO]; #: 2.15 (s, 3H, CH3-4), 2.68 (t, 2H, CH2-7), 3.06
(6H, CH2-6), 3.61 (s, 2H, CH2-9), 6.71 (brs, 1H, H-3), 10.4 (brs),
1H, NH, -5), 11.23 (brs, 1H, NH-2).

C) 8-Hydroxy-4-methyl-2H-5-H pyrido-4,3-b7 indolone-1.

The mixture of the previously obtained ketone (1.37 g) and 10% palladium on carbon (1 g) in diphenyl ether (100 ml) is refluxed,
with stirring, for 30 minutes and cooled to room temperature. 400 ml of ethanol are added, the mixture is filtered and the solid is washed with 200 ml of boiling ethanol and the ethanol is evaporated off under reduced pressure. After adding 150 ml of toluene to the residual diphenyl ether, the precipitate obtained is filtered, dried and taken up in boiling dioxane containing the sufficient amount of ethanol to dissolve it.

The filtered solution is concentrated to remove the ethanol and cooled to provide light beige microcrystals (1.1 g).

Yield: 81% J F> 2600C.

Calc. for C₁₂H₁oN₂O₂: C, 67.28; H, 4.71; N, 13.08.

 Found: C, 66.89; H, 4.74; N, 12.84.

1 H NMR [(CD 3) 2 SO]; #: 2.25 (s, 3H, CH3-4). 6.8 (q, 1H, H-7, J 7-6 = 9 Hz,
J 7-9 - 2.3 Hz), 7.07 (m, 1H, OH-8), 7.32 (d, 1H, H-6), 7.56 (d, 1H, H-9), 8.92
(s, 1H, H-3), 10.09 (brs, 1H, NH-5), 11.4 (brs, 1H, NH-2).

 D) 8-Benzoyloxy-methyl-4H-5-H pyrido [4,3-b] indolone-1.

The preceding pyrido indolone t4 g) is treated with benzoic anhydride
in excess (12.6 g) in pyridine (100 ml) at reflux for 2 h 15 and the
pyridine is evaporated. The residue is taken up in an acidic carbonate solution
excess of sodium and the aqueous phase is decanted after 1 hour with stirring.

To the insoluble fraction, 50 ml of ethanol are added, and the precipitate obtained
is drained, washed with cold ethanol and taken up in boiling ethanol
(100 ml) for 5 minutes.

The cooled mixture provides 4.4 g of light beige microcrystals.

 Yield: 74 ° F:> 2600 ° C.

Calc. for C19H14N2O3: C, 71.69, H, 4.43; N, 8.80.

 Found: C, 71.32; H, 4.39; N, 8.81.

1 H NMR [(CD 3) 2 SO]; #: 2.31 (s, 3H, CH3-4), 7.16 (s, 1H, H-3), 7.24 (q, 1H,
H-7, 37-6 = 8.5 Hz J 7-9 = 1.6 Hz), 7.6 (d, 1H, H-6), 7.73 (m, 3H of C6H5), 7.96 (d, 1H, H-9), 8.23 (m, 2H C6H5), 10.96 (bs, 1H, NH-2), 11.92 (bs, H, NH-5).

 E) 8-Benzoyloxy-1-chloro-methyl-4,5-H pyrido [4,3-b] indole.

The above benzoyloxy-pyrido indolone mixture (3 g) in phosphorus oxychloride (250 ml) is refluxed for 70 h and the excess oxychloride is evaporated under reduced pressure. To the residual oil is added 300 ml of water, heated to boiling with stirring, and then the mixture is neutralized to pH 7-8 by a solution of sodium bicarbonate. The precipitate formed is filtered, dried and chromatographed on a silica column.

 Eluting with pure ethyl acetate, a main fraction is obtained, the evaporation of which gives a solid which recrystallizes in toluene giving 2.4 g of pale yellow flakes, corresponding to the pure chlorinated derivative.

Yield: 75%; Mp = 227-228 ° C.

Calc. for C19H13ClN2O2: C, 67.76, H, 3.89, N, 8.32; Cl, 10.53.

 Found: C, 67.83H, 4.08: N, 7.84; Cl, 11.03.

1H NMR t (CD3) 2SO]; g: 2.48 (s, 3H, CH3-4), 7.47-7.62 (m, 6H, H-6 + H-7 +
H-9 + 3H C6H5), 8.13-8.29 (m, 3H, H-3 + 2H C6H5t, 12.1 (brs, 1H, NH-5).

Example 2
Preparation of 1-chloro-8-hydroxy-methyl-4,5-H pyrido [4,3-b] indole (compound of formula (I) wherein R1 = H and R2 ~ OH).

The mixture of 8-benzoyloxy-1-chloro-methyl-4,5-H pyrido [4,3-b] indole (1.15 g) in methanol saturated with ammonia (100 ml) is stirred at ambient temperature for 18 hours. h and evaporated to dryness. The residue is taken up in water and the precipitate formed is drained, washed with water, dried, chromatographed on a silica column, eluting with pure ethyl acetate.

After evaporation, the expected chlorinated derivative recrystallizes from xylene to give pale yellow microcrystals (750 mg).

Yield: 80.4%: Sublimation at 2650C.

Calc. for C12HgClN2O: C, 61.95; H, 3.90: N, 12.04; Cl, 15.24.

 Found: C, 62.01: H, 3.83: N, 11.97; Cl, 14.97.

1H NMR t (CD3) 2SO]; #: 2.52 (s, 3H, CH 3 - 4), 7.08 (q, 1H, H-7, J 7-6 = 9 Hz, J 7-9 = 2.4 Hz), 7.49 (d, 1H, H). 6), 7.78 (d, 1H.H-9), 8.02 (d, 1H, H-3)
H-3-CH3-4 = 1.2 Hz), 9.26 fs broad, 1H, BH, 11.8 fs broad, 1H, NH-51.

Example 3
Preparation of 1-chloro-4,5-dimethyl-8-hydroxy-5-pyrido [4,3-b] indole (compound of formula (I) in which R 1 and R 5 are CH 3 and R 2 = OH) A) 8-benzoyloxy chloro-1 dimethyl-4,5-pyrido [4,3-b] indole.

 The reaction is carried out starting from the 8-benzoyloxy-1-chloro-methyl-4,5-H pyrido [4,3-b] indole (3 mmol) in 20 ml of N, N-dimethylformamide, adding the sodium carbonate. potassium (2.16 g, 15 mmol) and methyl iodide (0.37 ml, 6 mmol) at 0 ° C. and allowing the reaction mixture to stir at this temperature for one hour and then at room temperature for 12 hours.

 After usual treatment, the expected chlorinated derivative is recrystallized from ethyl acetate.

Yield: 77%; F r 2460C-2480C.

Calc. for: C20H15ClN2O2: C, 68.48; H, 4.31; N, 7.98: Cl, 10.11.

 Found: C, 68.23; H, 4.31; N, 8.08: Cl, 10.25.

B) 1-Chloro-4,5-dimethyl-8-hydroxy-5-H pyrido [4,3-b] indole.

The above compound (108 g, 28 mmol) is treated with a solution of 3.2 g of potassium hydroxide dissolved in 500 ml of methanol at room temperature for five hours.

At first heterogeneous, the medium becomes homogeneous, then a precipitate forms.

The methanol is then evaporated under reduced pressure. The precipitate obtained is taken up in 200 ml of water which is acidified with stirring for 15 minutes with an aqueous solution of N hydrochloric acid. The solution is then basified with ammonia. The precipitate formed is filtered and recrystallized from dioxane.

Yield: 85.7% F => 2600C.

Calc. for: C13H11ClN2O: C, 63.29; H, 4.49; N, 11.35; Cl, 14.37.

Found: C, 63.48; H, 4.52; N, 11.35; Cl, 13.92.

1 H NMR t [CD 3) 2 SO 2 g: 2.76 (d, 3H, CH 3 -4, JCH 3 -H-3 = 1 Hz), 4.10 (s, 3H, N-CH 3)
7.12 tq, 1H, H-7, J 7-6 = 9 Hz, J 7-9 = 2.4 Hz), 7.58 (d, 1H, H-6), 7.84 (d, 1H, H-9) , 7.96 (d, 1H, H-3), 9.34 (s, 1H, OH).

Example 4
Preparation of 1-chloro-4,5-dimethyl-8-methoxy-5H pyrido [4,3-indol (compound of formula (I) wherein R1 = CH3 and R2 = OCH3).

Method A
1-chloro-4,5-dimethyl-8-hydroxy-5-pyrido [4,3-b] indole (0.6 g) in solution in N, N-dimethylformamide is treated with 1.7 g of 12.2 mmol. ) of potassium carbonate and 0.3 ml (2.41 mmol) of methyl iodide for five hours at room temperature. After evaporation of the solvent under reduced pressure, the precipitate is taken up in 50 ml of an aqueous hydrochloric acid solution. Then the medium is basified by ammonia. The precipitate obtained is filtered, dried and recrystallized in cyclohexane.

Yield: 81.6%; Mp 173-1760 ° C.

Method B
1-chloro-4-methyl-6-hydroxy-5-pyrido [4,3-b] indole (0.5 g, 2.15 mmol) is dissolved in anhydrous N, N dimethylformamide (20 ml).

The solution is cooled to -100 ° C. and then potassium carbonate (1.5 g, 10.7 mmol) and methyl iodide (0.32 ml, 2.58 mmol) are introduced in succession. temperature for five hours and then introduced again 1.5 g of potassium carbonate and 0.32 ml of methyl iodide while maintaining the temperature for 3 hours.

After stirring for 15 hours at room temperature, the solvent is evaporated under reduced pressure. The precipitate is taken up in 50 ml of water and then acidified at 0 ° C. with an aqueous solution of hydrochloric acid which is finally neutralized with ammonia. The precipitate obtained is filtered, dried and recrystallized in cyclohexane.

Yield: 57%; Mp 173-1760 ° C.

Calc. for: C14H13ClN2O: C, 64.49; H, 5.03; N, 10.74; Cl, 13.60.

Found: C, 64.45; H, 5.29; N, 10.58; Cl, 13.31.-
1 H NMR t (CD 3) 2 SO 4]: 2.28 td, 3H, CH 3 -4, JCH 3 -H-3 = 1 Hz), 3.91 ts, 3H, OCH 3), 4.14 (s, 3H, NCH 3), 7.29 ( q, 1H, H-7, J 7-6 = 8.9 Hz, J 7-9 = 2.5 Hz), 7.70 (d, 1H, H-6), 7.91 (d, 1H, H-9) , 8 (d, 1H, H-3).

Example 5
Preparation of 1-chloro-8-methoxy-4-methyl-5-pyrido [4,3-b] indole (compound of formula (I) wherein R1 = H and R2 = OCH3.

1-chloro-4-methyl-8-hydroxy-5-pyrido [4,3-b] indole (232 mg, 1 mmol) is dissolved in methanol (20 ml) containing 2.2 ml of 0.5 N solution. potassium hydroxide (1.1 mmol). 600 mg t4.2 mmol) of methyl iodide dissolved in 4 ml of methanol are added.

The medium is stirred at ambient temperature for 72 hours and then the methanol is concentrated under reduced pressure. The product obtained is taken up in an excess 2N sodium hydroxide solution. The residual precipitate is filtered, washed with water, dried and recrystallized from xylene.

Yield: 24% J F = 243-2450C.

Calc. for: C13H11ClN2O: C, 63.29; H, 4.49; N, 11.35 g Cl, 14.37.

 Found: C, 63.48: H, 4.56; N, 11.15; Cl, 14.64.

1 H NMR [(CD 3) 2 SO]:: 2.52 (d, 3H, CH 3 -4, JCH 3 -H-3 = 1 Hz), 3.91 ts, 3H, OCH 3), 7.23 t 1, 1H, H-7, J 7 6 - 9 Hz, J 7-9 = 2.5 Hz), 7.60 (d, 1H, HS), 7.87 (d, 1H, H-9), 8.04 (d, 1H, H-3).

By way of illustration, the preparation of two compounds of formula (A) from a compound of formula (I) is described below.

 1) Preparation of (3-diethylamino-propylamino) -1-methoxy-8-methyl-4,5-pyrido-4,3-bindole and its bimaleate. 0.5 g of 1-chloro-8-methoxy-4-methyl-5-pyrido [4,3-b] indole (compound of Example 5 (I) in which R 1 = H and R 2 = OCH 3) are dissolved in 10 ml of 3-diethylamino propylamine. The reaction mixture is refluxed for 96 hours and the excess amine is distilled under reduced pressure. The residue is taken up in 10 ml of water and then basified with a concentrated aqueous solution of sodium hydroxide and finally extracted with methylene chloride. The organic phase is dried and then concentrated under reduced pressure. The crude product thus obtained is purified by chromatography on an alumina column, eluting firstly with methylene chloride and then with a mixture of methylene chloride and ethanol (98/2 ).

The pure base thus obtained is dissolved in an acetonic solution of maleic acid (at least 2 molar equivalents) which is kept boiling for 2 minutes. After cooling, the bimaleate precipitates.

It is filtered and dried.

Yield: 62%; Mp 176-180 ° C.

Calc. for C28H36N4O9, H2O: C, 56.95, H, 6.44; N, 9.45.

 Found: C, 56.72; H, 6.30; N, 9.61.

 H1 NMR (D2O3; # 1.41 (t, 2x3H, CH3-CH2), 2.22 (m, 2H, CH2-ss), 2.36 ts, 3H, CH3 -4), 3.38 (m, 6H, 2x2H, CH2CH3 + CH2- ), 3.64 (t, 2H, CH2- α), 4.02 (s, 3H, OCH3), 6.16 ts, 4H, CH = CH maleate), 7.17 tq, 1H, H-7, J 7-6 = 9 Hz, J 7-9 = 2.3 Hz), 7.36 (d, 1H, H-6), 7.4 (bs, 1H, H-9t, 7.48 (s, 1H, H-3).

2) Preparation of (3-diethylamino-propylamino) -1-hydroxy-8-methyl-4,5-H pyrido [4,3-b] indole and its bimaleate.

3-Diethylamino-3-prepylamine (15 ml) containing 1-chloro-8-hydroxy-4,5-methyl-5-pyrido [4,3-b] indole (800 mg) compound of Example 2 (I) in which R 1 = H and R2 = OH is heated in an oil bath at 1700C for 18 h and the excess amine is removed under reduced pressure. The residue is taken up in 50 ml of water, extracted with methylene chloride in which the product appears poorly soluble and the new residue obtained after evaporation of the solvent is chromatographed on a column of alumina (35 × 2.2 cm) eluting with pure methylene chloride (300 ml), with the mixture 95-5 v / v methylene chloride-ethanol (400 ml), then finally with the same mixture, in proportion 9/1 v / v (300 ml) .L Evaporation of this last fraction leaves a product which is dissolved in acetone (50 ml) and poured into a solution of maleic acid (1 g) in 50 ml of boiling acetone. The precipitate formed is drained, stirred in suspension in 50 ml of methyl ethyl ketone for 48 h, drained and dried to give 740 mg of yellowish microcrystals corresponding to the bimaleate, hydrated with one molecule of water.

Yield: 41%; F = 2000C with decomposition.

 Calc. for C27H34N409; H2O: C, 56.24, H, 6.29; N, 9.72.

 Found: C, 56.21; H, 6.27; N, 9.74.

Free base: recrystallizes in toluene giving pale yellow microcrystals. F = 1250C.

Calc. for C18H26N4O; 0.5 H2O: C, 68.06; H, 8.06; N, 16.72.

 Found: C, 68.09; H, 8.14; N, 16.55.

RNN H1 [(CD3) 2SO]; #: 1.0 (t, 2x3H, CH3-CH2), 1.80 (m, 2H, CH2-ss), 230 [s, 3H, CH3-4), 2-4-2.69 [m] , 6H, CH2-CH3 + CH tt, 3.55 Eq, 2H, CH2-2
2.35 (q, 2H-CH), 6.22 [t, 1H, NH-1), 6.87 (q, 1H, H-7, J 7-6 = 8/5 Hz, J 7-9 = 2.2 Hz), 7.31 (d, 1H, H-6), 7.52 (d, 1H, H-9), 7.66 (s, 1H, H-3), 8.82 (bs, 1H, OH-8) , 11.05 (s, 1H, NH-5).

Claims (7)

claims 1) Compounds of formula (I)

 wherein R 1 is hydrogen or lower alkyl, st is hydroxy, lower alkyloxy or arylcarbonyloxy, and tautomeric forms thereof when they exist.  2) 8-Benzoyloxy-1-chloro-methyl-4,5-H pyrido [4,3-b] indole. 3) 1-chloro-8-hydroxy-4-methyl-5-pyrido [4,3-b] indole. 4) 1-Chloro-4,5-dimethyl-8-hydroxy-5-H pyrido [4,3-b] indole. 5) 1-Chloro-4,5-dimethyl-8-methoxy-5H pyrido [4,3-b] indole.  6) 1-Chloro-8-methoxy-4,5-methyl-5-pyrido [4,3-b] indole. 7) Process for the preparation of the compounds of formula (I), characterized in that a) 4-hydrazino-5-methyl-2-oxo-1,2-dihydropyridine is reacted with 3,3-dimethyl-1,5-dioxo spiro [5.5] Undecanone or any other monoacetal of cyclohexanedione-1,4 to obtain the hydrazone of formula

  b) The hydrazone of formula (II) is cyclized according to the Fisher reaction and the cyclized derivative obtained is hydrolysed to form 4-methyl-6,7,8,9-tetrahydro-5H pyrido [4,3-b] ] indoledione-1,8 of formula

 e) The pyridoindoledione of formula (III) is hydrogenated to form 8-hydroxy-4-methyl-2-H 5 -H pyrido [4,3-b] indolone-1 of the formula

 d) The indolone of formula (IV) is esterified by the action of an aromatic acid anhydride to form an 8-arylcarbonyloxy-methyl-4H-5H-pyrido [4,3-b] indolone-1 of formula (V). ) in which R2 represents an arylcarbonyloxy group

 e) The ester of formula (V) is chlorinated at position I to obtain the compound of formula (I) in which R1 represents hydrogen and R2 represents an arylcarbonyloxy group. Process according to Claim 7, characterized in that the chlorinated ester of formula (I) is alkylated in the 5-position to obtain the compound of formula CI) in which R 1 represents a lower alkyl group and R 2 represents an arylcarbonyloxy group. Process according to Claim 7, characterized in that the chlorinated ester of formula (I) in which R1 is hydrogen or a lower alkyl group and R2 is an arylcarbonyloxy group is hydrolyzed to give the derivative of formula (I) wherein R 1 is hydrogen or lower alkyl and R 2 is hydroxy. 10) Process according to claim 7, characterized in that the derivative of formula CI) in which R 1 represents hydrogen or lower alkyl radical and R 2 represents a hydroxyl group to give the compound of formula (I) is alkylated in position 8 wherein R1 is hydrogen or an alkyl group and R2 is an alkyloxy group. 11) Process according to claim 7 characterized in that the formation of the compound of formula (1V) is carried out at high'température and in the presence of a catalyst such as palladium on charcoal.