HUT64344A - Methods for producing pyrido-benzo-indole derivatives and pharmaceutical preparatives containing them - Google Patents

Description

The present invention relates to pyrido-benzoindole derivatives (I), their hydrates, acid addition salts thereof, and to processes for the preparation thereof and pharmaceutical compositions containing them.

EP-A-239 476 discloses gamma-carboline derivatives of formula (A) wherein R 1 and R 5 are inter alia hydrogen, R 2 is hydrogen, hydroxy or alkyloxy, R 3 and R 4 are alkyl and n is 2-4, the compound has antitumor activity.

· · · · · · · * • «• · · · · · · · · • ·· ·· • · · ····. · ··· · ♦ ·······

- 2 The pyridoindole derivatives which are not substituted at the 4-position are otherwise represented by j. Med. Chem., 1981, 131, 398 (1).

The novel pyrido-benzoindole derivatives of the general formula (I) wherein:

R is hydrogen or C1-C2 alkyl, alk is straight or branched C2-C4 alkylene,

R 1 is hydrogen or C 1 -C 2 alkyl, and

R2 represents a hydroxy group or a methoxy group, and has particularly valuable antitumor activity.

The compounds of formula (I) according to the invention may be prepared by reacting a chlorinated derivative of formula (II) wherein R 1 is as defined above, with an amine of formula (III) wherein alk and R are as defined above. followed by conversion of the resulting methoxylated derivative of formula (Ia), wherein R, R 1 and alk are as defined above, to a 9-hydroxypyrido [4,3-b] benzoyl] indole, if desired.

The amine of formula (III) and the chlorinated derivative of formula (II) are reacted with an excess of amine, preferably in a nitrogen atmosphere, optionally with or without an inert organic solvent, at a boiling point of the reaction mixture to 250 ° C (autoclave).

Demethylation can be accomplished by any known method that does not attack other parts of the molecule.

The chlorinated derivative of formula (II) wherein R 1 is hydrogen may be prepared from a suitable pyridone of formula (IV) by reaction with a chlorinating reagent.

The chlorinating agent used is usually phosphorus trichloride oxide or a halogenated derivative of phosphorus in the presence of a tertiary base (such as diethylaniline, · ·

3 dimethylaniline) in an organic solvent such as nitrile (such as acetonitrile) at a temperature between 75 ° C and 90 ° C (boiling point of the reaction mixture).

The reaction is preferably carried out under a nitrogen atmosphere.

Compounds of formula (II) wherein R 1 is alkyl may be prepared by reacting a compound wherein R 1 is hydrogen with a suitable halogenated derivative in the presence of potassium carbonate.

The compound of formula (IV) may be prepared from the hydrazone derivative of formula (V) by Fisher's thermal reaction as described by Nguyen, C.H. and Bisagni, E., 1986, Tetrahedron Letters, 42 (8): 2203-1.

The compound of formula (V) can be prepared by condensing 4-hydrazino-1H-pyrid-2-one with 6-methoxy-2-tetralone. The reaction is generally carried out in an organic solvent such as an alcohol (such as ethanol) at the reflux temperature of the reaction mixture.

6-Methoxy-tetralone is a. Am. Chern. Soc., 82, 2573 (1960).

4-Hydrazino-1H-pyrid-2-one Nguyen, C.H. and Bisagni, E., 1986, Tetrahedron [42 (8), 2203 (1986)].

The pyrido-benzoindole derivatives of formula (I) may be purified by crystallization or chromatography.

The novel pyridobenzoindole derivatives of the present invention can be converted into an acid addition salt in an acid-bearing solvent. Optionally, the salt precipitates by concentration of the solution and is isolated by filtration or pouring.

Pharmaceutically acceptable salts include the salts formed with mineral acids such as hydrochloride, hydrobromide, sulfate, nitrate, and the like. · ···· ··

4 phosphates or salts with organic acids such as acetate, propionate, succinate, maleate, fumarate, methanesulfonate, para-toluenesulfonate, ethanol sulfonate or salts thereof with substituted derivatives.

The novel pyridobenzoindole derivatives of the invention and their salts may also exist in the form of their hydrates, so that their hydrated forms are the subject of the invention.

When alk in the compound is a branched alkylene group, the pyridobenzoindole derivatives are in the form of their isomers. Isomeric forms are also part of the invention.

The compounds of formula I are particularly valuable as antitumor agents.

The antitumor activity of the compounds was determined in vitro at 15-1.5 micrograms / plate in various cytotoxicity assays according to Corbett, T.I-I. et al. (Investigational new drug, 4, 207-220 (1986)) and in vivo, in mice vaccinated with mice, particularly P388 leukemia, the compounds were effective at 20 mg / kg administered intraperitoneally.

The toxicity of the compounds was investigated in mice with a maximum tolerated dose of 20-40 mg / kg intraperitoneally.

Particularly valuable antitumor activity is provided by the compounds of formula I wherein R is methyl, alk is straight or branched C 2 -C 4 alkylene,

R1 is hydrogen or methyl, and

R2 is hydroxy, and salts and optionally hydrates thereof.

· * «· • 4 · ·« ·· ······· · · · · · · · · · · · · · · · · · · · · ·

The most important of these are 3-climethylaniline-1-amino-9-hydroxy-5H-pyrido [4,3-b] benzo [e] -indole and its salts and hydrates.

The following examples illustrate the invention without limiting it.

Example 1

1.8 g of the appropriate bimaleate are treated with ammonium hydroxide and so on

3-dimethylamino-propyl-l-amino-9-methoxy-5H-pyrido [4,3-b] benzo [e] indole as a free base, this stone \ ^z etően extracted and dried.

The product thus obtained was transferred to a stirred 250 mL flask under argon atmosphere with 66 mL of hydrobromic acid (d = 1.47: 47%). The mixture is refluxed to obtain a homogeneous mixture and then refluxed for 6 hours and concentrated under reduced pressure. The resulting solid residue was dissolved in 200 mL of water and 20 mL of 28% ammonium hydroxide was added dropwise to give a gummy precipitate.

To the resulting mixture was added ethyl acetate (200 mL) and the mixture was stirred for 1 hour. The organic phase was discarded and the sodium chloride-saturated mother liquor was extracted twice with 100 ml of ethyl acetate each time. The organic layer was dried over sodium sulfate, filtered and treated with 5 g of carbon to give a colorless solution, then filtered and concentrated to dryness.

The resulting solid was taken up in ethanol (40 mL) and treated with a solution of maleic acid (2.5 g) in ethanol (20 mL) and refluxed. Thus, 3-dimethylaminopropyl-1-annno-9-hydroxy-5H-pyrido [4,3-b] benzo [e] indole bimaleaph containing 0.25H2O (1.25 g (yield: 70%) as microcrystals, m.p. 195-200 ° C (with decomposition).

3-Dimethylaminopyrid-1-amino-9-ethoxy-5H-pyrido [4,3-b] benzo [eindole bimaleate may also be prepared as follows:

• · »··« ··· «« · • · 9 ·

1.8 g of 1-chloro-9-ethoxy-5H-pyrido [4,3-b] benzo [e] -indole are transferred to a 250 ml flask containing 50 ml of 3-dimethylaminopropylamine ( in a large excess) and heated under reflux (150 ° C) under nitrogen and with stirring for 48 hours (check until the chlorinated derivative is completely gone, check on a silica plate).

The excess diamine was evaporated in a water bath and under reduced pressure, and the resulting residue was taken up in water and made basic with ammonium hydroxide. The resulting solid was filtered, washed with water, taken up in dichloromethane and washed with water (150 mL) and ammonium hydroxide (10 mL).

Purification by alumina chromatography followed by formation of a salt with maleic acid in the usual manner gave 2.56 g (69% yield) of 3-dimethylaminopropyl-1-amino-9-methoxy-5H-pyrido [4,3-b]. ] benzo [e] indole bimaleate, m.p. 204-2 () 6 ° C with decomposition, is obtained.

1-Chloro-9-methoxy-5H-pyrido [4,3-b] benzo [e] -indole can be prepared as follows:

Place in a liter flask with magnetic stirrer, dosing ampoule and refrigeration, under nitrogen, 4 g of 9-methoxy-2H, 5H-pyrido [4,3-b] benzo [e] indol-1-one in boiling, carefully anhydrous ethanol 14.1 g (4 equivalents) of benzyltriethylammonium chloride,

3.6 g (4 equivalents) of acetamide, 40 ml of acetonitrile and 9.12 g (4 equivalents) of freshly distilled diethylaniline.

70 ml of distilled phosphorus trichloride oxide are added slowly from the dispensing ampoule and an exothermic reaction is observed. The mixture is refluxed for 20 hours, first the mixture is homogeneous and a precipitate is formed. It is concentrated to dryness in a water bath at 70 ° C and under reduced pressure (15 mmHg).

To the resulting residue was added 300 ml of ice water and the mixture was stirred vigorously for 2 hours and then heated at 70 ° C for 20 minutes. Then make up to 600 ml with water, boil for 5 minutes and allow to cool to room temperature with stirring. After cooling, a yellow precipitate was obtained, which was filtered cold and then washed with cold water. The precipitate is taken up in 500 ml of distilled water and made alkaline with cold ammonium hydroxide. The mixture was allowed to stand overnight with stirring, and the precipitate was collected and washed with water. We recrystallize it in alcohol and so

2.6 g of yellow needles of 1-chloro-9-methoxy-5H-pyrido [4,3-b] benzo [e] -indole are obtained, m.p. 260 DEG C., 60% yield.

9-Methoxy-2H, 5H-pyrido [4,3-b] benzo [e] indol-1-one can be prepared as follows:

A mixture of 4 g of N-N- (1H-pyrid-2-one-yl) -2-N '- (6-methoxy-1,2,3,4-tetrahydronaphthalenylidene) -hydrazine and 700 ml of diphenyl ether is introduced into a three-liter flask. and refluxing for 30 minutes under vigorous stirring under a nitrogen atmosphere. The mixture becomes homogeneous and colorless. Stop boiling and allow to cool to 200 ° C. Check that the starting material is completely transformed on a Merek silica pad, eluting with dichloromethane: ethanol (8: 2 v / v) (hydrazone Rt = 0.5, intermediate Rf = 0.8). Stirring was continued and a suspension of 4 g of 10% palladium on carbon in 20 ml of diphenyl ether was added slowly, gently (foaming and evolution of hydrogen gas), and the new mixture was refluxed for 30 minutes (intermediate disappearance) (R [= Silicon 0.35 and pure ethyl acetate (expected product R = 0.58). The mixture is taken up in 600 ml of boiling 2-ethoxyethanol and the palladium on carbon is filtered off and then concentrated to dryness. The resulting solid 70 ml · · ···· ·

- 8 anhydrous ethanol was added, stirred for 18 hours, filtered and dried. 11 g (68% yield) of 9-methoxy-2H, 5H-pyrido [4,3-b] benzo [e] indol-1-one are obtained as a yellowish microcrystalline melting point 26 ().

4-N- (1H-Pyrid-2-one-yl) -2-N '- (6-methoxy-1,2,3,4-tetrahydro-naphthalenylidene) -hydrazine can be prepared as follows:

A mixture of 9.8 g of 4-hydrazino-1H-pyrid-2-one in 150 ml of anhydrous ethanol is refluxed. The mixture becomes homogeneous under reflux and 16.6 g of 6-methoxytetral-2-one are added, the mixture becomes rapidly heterogeneous, and then refluxed for 2 hours (until the hydrazine disappears by high pressure liquid chromatography). was checked on Merek silica gel, eluting with a 1: 1 by volume mixture of dichloromethane and ethanol. The resulting precipitate was filtered, taken up in ethanol, which had low solubility in hydrazone, filtered cold to give 19.3 g (83% yield) of 4-N- (1H-pyridon-2-one) - (2-N '). 6-methoxy-1,2,3,4-tetrahydronaphthalenylidene) hydrazine was obtained, m.p. 220-225 ° C with decomposition.

4-Hydrazino-1H-pyrid-2-one was prepared by Bisagni, E. and Nguyen, C.H. (Tetrahedron, 42, 2303 (1986)).

The present invention also provides pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), either alone or in the form of its salts, or in admixture with one or more excipients suitable for use in pharmacy. These compositions are administered parenterally.

The parenteral compositions may be in the form of sterile aqueous or non-aqueous solutions, suspensions or emulsions, the carrier being propylene glycol, polyethylene glycol vegetable oils, in particular olive oil or its organic injectable esters, such as ethyl oleate. These formulations may contain excipients, in particular wetting agents, emulsifying agents or dispersing agents. Sterilization can be accomplished in a variety of ways, for example with a bacteriological parent, by introducing a sterilizing agent into the composition, by irradiation or by heat. Alternatively, solid sterile compositions may be prepared which are dissolved in sterile water or other sterile injectable medium immediately prior to use.

In human therapy, the compositions of the invention are particularly useful in the treatment of gastrointestinal cancer, lung cancer, testicular cancer, ovarian cancer, and in the treatment of cancer of the head and neck.

Generally, the dosage will be determined by the physician according to the age, weight and other factors of the patient.

The pharmaceutical compositions of the invention are preferably administered intravenously. The drug of the invention is generally administered to humans in a dose of 30-200 mg / kg intravenously per treatment.

The following example illustrates the pharmaceutical composition of the invention without limiting it:

Example

8.54 g of [(3-dimethylamino) -pylpiper] -1-amino-9-hydroxy-5H-pyrido [4,3-b] benzo [e] indole bimaleate are dissolved in physiological pyrogen-free in a solvent to give 100 ml of solution.

The resulting solution is aseptically distributed into ampoules so that 2 ml is added to one ampoule. The ampoules are sealed and each ampoule contains 100 mg of [(3-dimethylamino) -propyl] -1-amino-9-hydroxy-5H-pyrido [4,3-b] benzo [e] -indole.

Claims (5)

A novel pyrido-benzoindole derivative of formula (I) wherein: R is hydrogen or C1-C2 alkyl, alk is straight or branched C2-C4 alkylene, R1 is hydrogen or C1-C2 alkyl, and R2 is hydroxy or methoxy, and their acid addition salts, optionally hydrates and isomers, and mixtures thereof. Pyridobenzoindole derivatives according to claim 1, wherein R is methyl, alk is straight or branched C 2 -C 4 alkylene, R1 is hydrogen or methyl, and R2 is hydroxy, and salts and optionally hydrates and isomers thereof, and mixtures thereof. 3. [(3-Dimethylamino) -propyl] -1-amino-9-hydroxy-5H-pyrido [4,3-b] benzo [e] indole, and salts and hydrates thereof. 4. A process for the preparation of pyridobenzoindole derivatives according to claim 1, which comprises reacting an amine of formula III wherein alk and R are as defined in claim 1 with a chlorinated compound of formula II, wherein R 1 is the methoxylated compound according to claim 1, followed by a methoxylated compound of formula (Ia). wherein R 1 is as defined in claim 1, converting it to a 9-hydroxypyrido [4,3-b] benzo [e] indole derivative and optionally converting the resulting product to an acid addition salt. I · · '···· «· ···· ·· • ·. · ··. ···· ·· 5. A pharmaceutical composition comprising the compound of claim 1, alone or in admixture with a pharmaceutically acceptable carrier or excipient, to form a pharmaceutical composition.