WO1997025329A1

WO1997025329A1 - 5H,10H-IMIDAZO[1,2-a]INDOLO[3,2-e]PYRAZINE-4-ONE DERIVATIVES, PREPARATION THEREOF AND DRUGS CONTAINING SAME

Info

Publication number: WO1997025329A1
Application number: PCT/FR1997/000016
Authority: WO
Inventors: Jean-Claude Hardy; Franco Manfre; Serge Mignani
Original assignee: Rhone-Poulenc Rorer S.A.
Priority date: 1996-01-10
Filing date: 1997-01-06
Publication date: 1997-07-17
Also published as: AU1382797A; FR2743365A1

Abstract

Compounds of formula (I), wherein R is a hydrogen atom or an -alk-COOH radical, racemic mixtures, enantiomers and diastereoisomers thereof, salts thereof, the preparation thereof and drugs containing said compounds, are disclosed. The compounds of formula (I) have valuable pharmacological properties and are antagonists of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor also known as the quisqualate receptor. Furthermore, the compounds of formula (I) are non-competitive antagonists of the N-methyl-D-aspartate (NMDA) receptor, and specifically ligands for NMDA receptor glycine modulator sites.

Description

DERIVATIVES FROM 5H.10H-IMIDAZOM .2-a1INDOLθr3.2-e1PYRAZINE-4-ONE. THEIR PREPARATION AND THE MEDICINES CONTAINING THEM

The present invention relates to compounds of formula:

their racemates, enantiomers and diastereoisomers, their salts, their preparation and the drugs containing them.

In formula (I), R represents a hydrogen atom or an -alk-COOH radical and alk represents an alkyl radical.

Unless otherwise stated, in the definitions above and those which follow, the alkyl and alkoxy radicals contain 1 to 6 carbon atoms in a straight or branched chain.

The compounds of formula (I) for which R represents an -alk-COOH radical have enantiomeric and diastereoisomeric forms. These are part of the invention.

The compound of formula (I) for which R represents a hydrogen atom can be prepared by cyclization in the presence of ammonium acetate of a derivative of formula:

in which Ra represents an acetyl radical and alk represents an alkyl radical, followed by hydrolysis of the ester function.

This cyclization is preferably carried out within acetic acid, at the boiling temperature of the reaction medium. The hydrolysis is generally carried out by means of an inorganic base such as sodium hydroxide, in an inert solvent such as a water-dioxane mixture, at a temperature in the region of 20 ° C. and then by treatment with a mineral acid such as hydrochloric acid in solution in water, at a temperature close to 20 ° C.

The derivatives of formula (II) can be obtained by the action of a derivative of formula:

in which Ra represents an acetyl radical on an alkyl imidazole-2,4-dicarboxylate.

This reaction is generally carried out in an inert solvent such as acetone, with an inorganic base such as an alkali metal carbonate (potassium carbonate for example), at the boiling temperature of the medium. reactional.

The derivative of formula (III) can be prepared by application or adaptation of the method described by V.S. VELEZHEVA et al., Khim. Farm. Zh., 24 (12), 46 (1990).

The alkyl imidazole-2,4-dicarboxylate can be obtained by application or adaptation of the method described by P.S. BRANCO et al., Tetrahedron, 48 (30), 6335 (1992).

The compounds of formula (I) for which R represents an -alk-COOH radical can be prepared by the action of a derivative of formula:

for which alk represents an alkyl radical on a derivative Hal-alk-COOalk 'for which Hal represents a halogen atom (preferably chlorine or bromine), alk and alk' represent an alkyl radical, followed by hydrolysis.

This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloroethane for example), in the presence of a base such as an alkali metal hydroxide (soda for example) and n hydrogen sulphate -tetrabutylammonium, at a temperature close to 20 ° C. The hydrolysis is generally carried out by means of an inorganic base such as sodium hydroxide, in an inert solvent such as a water-dioxane mixture, at a temperature in the region of 20 ° C. and then by treatment with a mineral acid such as hydrochloric acid in solution in water, at a temperature close to 20 ° C.

The derivatives of formula (IV) are obtained by the process described above for obtaining the compound of formula (I) for which R represents a hydrogen atom before hydrolysis.

The compounds of formula (I) can be purified by the usual known methods, for example by crystallization, chromatography or extraction.

The enantiomers of the compounds of formula (I) can be obtained by duplication of the racemates, for example by chromatography on a chiral column according to W.H. PIRCKLE et al., Asymmetry synthesis, vol. 1, Académie Press (1983) or by synthesis from chiral precursors.

The diastereoisomers of the compounds of formula (I) can be separated by the usual known methods, for example by crystallization or chromatography. The compounds of formula (I) can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid within an organic solvent such as an alcohol, a ketone, an ether or a solvent chlorine.

The compounds of formula (I) can optionally be converted into metal salts or into addition salts with nitrogenous bases according to methods known per se. These salts can be obtained by the action of a metal base (alkaline or alkaline earth, for example), ammonia, an amine or a salt of an amine on a compound of formula (I), in a solvent . The salt formed is separated by the usual methods.

These salts are also part of the invention.

As examples of pharmaceutically acceptable salts, there may be mentioned addition salts with mineral or organic acids (such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophyllinacetate, salicylate, methylene- bis-β- oxynaphthoate, hydrochloride, sulphate, nitrate and phosphate), salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (calcium, magnesium), ammonium salt, salts of nitrogen bases (ethanolamine, trimethylamine, methylamine, benzylamine, N-benzyl-β-phenethylamine, choline, arginine, leucine, lysine, N-methyl glucamine).

The compounds of formula (I) have interesting pharmacological properties. These compounds are antagonists of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, also known as the quisqualate receptor.

Furthermore, the compounds of formula (I) are non-competitive antagonists of the N-methyl-D-aspartate receptor (NMDA) and, more particularly, they are ligands for the glycine modulating sites of the NMDA receptor.

These compounds are therefore useful for treating or preventing all ischemias (such as focal or global ischemia) consecutive to cerebrovascular accidents such as thromboembolic and hemorrhagic stroke, arrest heart, low blood pressure, cardiac, vascular, or pulmonary surgery or severe hypoglycemia. They are also useful in the treatment of the effects due to anoxia, whether it is perinatal or following drowning, high pressure or cerebro-spinal lesions. These compounds can also be used to treat or prevent the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease and other dementias, amyotrophic lateral sclerosis or other motor neuron diseases, olivo-pontocerebellar atrophy and PARKINSON's disease. These compounds can also be used with respect to epileptogenic and / or convulsive manifestations, for the treatment of cerebral or spinal traumas, traumas linked to the degeneration of the inner ear (R. PUJOL et al., Neuroreport, 3 , 299-302 (1992) or retina (JL MONSINGER et al., Exp. Neurol., 113, 10-17 (1991), tinnitus, anxiety (KEHNE et al., Eur. J. PharmacoL , 193, 283 (1991)), depression (TRULLAS et al. Eur. J. PharmacoL, 185, 1 (1990)), schizophrenia (REYNOLDS, TIPS, 13, 116 (1992)), TOURETTE, hepatic encephalopathies, sleep disturbances, attention deficit disorders, disorders of hormonal conditions (excess of HG or HL secretion, corticosterone secretion), as analgesics (DICKENSON et al., Neurosc. Letters, 121, 263 (1991)), anti-inflammatory drugs (SLUTA et al., Neurosci. Letters, 149, 99-102 (1993)) anti-inflammatory drugs (SORRELS et al., Br ain Res., 572, 265 (1992)), antimigraine, antiemetics and to treat poisoning by neurotoxins or other substances agonists of the NMDA or AMPA receptor, as well as neurological disorders associated with viral diseases such as meningitis and encephalitis viral, AIDS (LIPTON et al., Neuron, 7, 111 (1991)), rabies, measles and tetanus (BAGETTA et al., Br. J. PharmacoL, 101, 776 (1990)). These compounds are also useful for the prevention, tolerance and dependence of symptoms of abstinence from drugs, alcohol and the inhibition of addiction and dependence on opiates, barbiturates, amphetamine and benzodiazepines. They can also be used in the treatment of deficits linked to mitochondrial anomalies such as mitochondrial myopathy, LEBER syndrome, WERNICKE encephalopathy, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutiric-amino aciduria, saturnine encephalopathy (chronic lead poisoning) and sulfite oxidase deficiency.

The affinity of the compounds of formula (I) with respect to the AMPA receptor was determined by studying the antagonism of the specific binding of [^ HJ-AMPA on membranes of rat cerebral cortex (HONORE et al., Neuroscience letters, 54, 27 (1985)). The [ ³ H] -AMPA is incubated in the presence of 0.2 mg of protein at 4 ° C for 30 minutes in 10mM KH2PO4 buffer, 100mM KSCN, pH7.5. The non-specific binding is determined in the presence of 1 mM L-glutamate. The bound radioactivity is separated by filtration on PHARMACIA filters (Printed Filtermate A). The inhibitory activity of these products is less than or equal to 100 μM.

The affinity of the compounds of formula (I) for the glycine site linked to the NMDA receptor was determined by studying the antagonism of the specific binding of [3H] -DCKA on membranes of rat cerebral cortex according to the method described. by T. CANTON et al., J. Pharm. PharmacoL, 44, 812 (1992). The [3H] -DCKA (20nM) is incubated in the presence of 0.1 mg of proteins at 4 ° C. for 30 minutes in 50 mM HEPES buffer, pH 7.5. The non-specific fixation is determined in the presence of 1 mM glycine. The bound radioactivity is separated by filtration on Whatman GF / B filters. The inhibitory activity of these products is less than or equal to 100 μM.

The compounds of formula (I) have a low toxicity. Their LD50 is greater than 50 mg / kg by the IP route in mice.

The following examples illustrate the invention.

EXAMPLE 1

A mixture of 750 mg of diethyl 1- (1-acetyl-2,3-dihydro-3-oxo-indole-2-yl) imidazole-2,4-dicarboxylate, 7.5 g, is refluxed for 3 hours. ammonium acetate and 40 ml of acetic acid. The reaction mixture is concentrated on a rotary evaporator until a thick suspension is obtained, then 100 ml of distilled water are added. After filtration and drying in an oven, 480 mg of 4,5-dihydro-4-oxo-imidazo [1, 2-a] indolo [3,2-e] pyrazine-2- are obtained. ethyl carboxylate in the form of a purple solid [NMR Spectrum ^" Η in DMSO-d6, T = 300K, δ in ppm (300 Mhz): 1.40 (3H, t, J = 6Hz, CH3), 1.95 ( 3H, s, CH3CO2H), 4.40 (2H, q, J = 6Hz, OCH ₂ ), 7.20 (1H, t, J = 8Hz, CH arom.), 7.32 (1H, t, J≈δHz, CH arom.), 7.60 (1 H, d, J = 8Hz, CH arom.), 7.98 (1 H, d, J = 8Hz, CH arom.), 8.70 (1 H, s, H imidazole), 12 and 12.5 (1 H each, s, NH2 ⁺ ), 12.2 (1 H, s, NHCO)].

Under a cover of argon, a mixture of 476 mg of 4,5-dihydro-4-oxo-imidazo [1, 2- a] indolo [3,2-e] is stirred for 24 hours at a temperature in the region of 20 ° C. ethyl pyrazine-2-carboxylate, 10 ml of dioxane, 10 ml of water and 24 ml of 1N sodium hydroxide The reaction mixture is cooled to a temperature between 0 and 5 ° C and added with 24 ml of acid hydrochloric 1 N. The precipitate obtained is washed with distilled water, triturated in a mixture of 0.1 N sodium hydroxide and water, then filtered. The filtrate is acidified with 0.1 N hydrochloric acid and the precipitate formed is filtered, washed with distilled water and dried in an oven. 155 mg of 4,5-dihydro-4-oxo-imidazo [1,2-a] indolo [3,2- e] pyrazine-2-carboxylic acid are obtained in the form of a purplish brown solid melting above 300 ° C [Analysis Cι ₃ H ₈ N ₄ θ ₃ % calculated C: 58.21, H: 3.01, N: 20.89, O: 17.89,% found C: 58.6, H: 3, 0, O: 18.0].

Diethyl 1 - (1-acetyl-2,3-dihydro-3-oxo-indole-2-yl) imidazole-2,4-dicarboxylate can be prepared as follows: a mixture is heated at reflux for 2 hours 1.9 g of diethyl imidazole-2,4-dicarboxylate, 200 ml of acetone and 5.5 g of potassium carbonate. A solution of 2.75 g of 1-acetyl-2-bromo-1, 2-dihydro-3H-indole-3-one in 50 ml of acetone is then added dropwise, and the reflux is continued for 3 hours. The reaction mixture is filtered and the filtrate is evaporated on a rotary evaporator. The evaporation residue (4.8 g) is chromatographed on a silica column, eluting with a mixture of dichloromethane and ethyl acetate (75-25 by volume). The purple oil obtained (1.4 g) is added with 50 ml of a mixture of dichloromethane and isopropyl ether (50-50 by volume) and evaporated again. 1.3 g are obtained 1- (1-acetyl-2,3-dihydro-3-oxo-indole-2-yl) diethyl imidazole-2,4-dicarboxylate in the form of a purple meringue used as it is in subsequent syntheses [NMR Spectrum ^" Η in DMSO-d6 + CD3CO2D, T = 393K, δ in ppm (250 Mhz): 1.32 (3H, t, J = 6Hz, CH3), 1.35 (3H, t, J = 6Hz , CH3), 2.20 (3H, s, CH3CO), 4.30 (2H, q, J = 6Hz, OCH ₂ ), 4.39 (2H, q, J = 6Hz, OCH ₂ ), 7.40 (1H, t, J = 8Hz, CH arom.), Between 7.70 and 8.00 (3H, m , CH arom. And imidazole), 7.72 (1 H, d, J≈δHz, CH arom.), 8.34 (1 H, d, J = 8Hz, CH arom.)].

Diethyl imidazole-2,4-dicarboxylate can be synthesized as described by P.S. BR ANCO et al., Tetrahedron, 48 (30), 6335 (1992).

1-acetyl-2-bromo-1, 2-dihydro-3H-indole-3-one can be synthesized as described by V.S. VELEZHEVA et al., Khim.-Farm. Zh., 24 (12), 46 (1990).

EXAMPLE 2

Under a cover of argon, to a mixture stirred at a temperature in the region of 20 ° C of 5.4 g of 4,5-dihydro-4-oxo-imidazo [1, 2-a] indolo [3,2-e] ethyl pyrazine-2-carboxylate, 100 ml of 1, 2-dichloroethane, 1 g of tetrabutylammonium hydrogen sulphate and 1.5 g of sodium hydroxide powder are added dropwise 1.68 ml of ethyl bromoacetate and keeps the agitation going all night. The reaction mixture is filtered and the brown solid obtained is purified by chromatography on a silica column, first eluting with dichloromethane, then a mixture of dichloromethane and methanol (95-5 by volume) and finally a mixture of dichloromethane and methanol (90-10 by volume). 576 mg of 2-ethoxycarbonyl-4,5-dihydro-4-oxo-imidazo [1,2-a] indolo [3,2-e] pyrazine-10-ethyl acetate are obtained in the form of a brown solid [NMR ¹ H spectrum in DMSO-d6, T = 300K, δ in ppm (300 MHz): 1.18 (3H, t, J = 6Hz, CH ₃ ), 1.37 (3H, t, J = 6Hz, CH ₃ ), 4.18 (2H, q, J = 6Hz, OCH ₂ ), 4.38 (2H, q, J = 6Hz, OCH ₂ ), 5.75 (2H, s, NCH ₂ ), 7.26 ( 1 H, t, J = 8Hz, CH arom.), 7.37 (1 H, t, J≈δHz, CH arom.), 7.72 (1 H, d, J = 8Hz, CH arom.), δ, 00 (1 H, d, J = 8 Hz, CH arom.), 6.71 (1 H, s, H imidazole)].

The hydrolysis is carried out as in Example 1 but from 576 mg of 2-ethoxycarbonyl-4,5-dihydro-4-oxo-imidazo [1, 2-a] indolo [3,2-e] pyrazine -10- ethyl acetate, 10 ml of dioxane, 10 ml of water and 7.5 ml of 1N sodium hydroxide. 450 mg of 2-carboxy-4,5-dihydro-4-oxo-imidazo acid are obtained. [1, 2-a] indolo [3,2- e] pyrazine-10-acetic in the form of a beige solid melting above 300 ° C [Analysis C ^ H ^ Os% calculated C: 55.22, H: 3.09, N: 17.17, O: 24.52,% found C: 55.0, H: 2.8, N: 16.7, O: 24.2]. The medicaments according to the invention consist of a compound of formula (I) or a salt of such a compound, in the pure state or in the form of a composition in which it is associated with any other product. pharmaceutically compatible, which may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sac charose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

As liquid compositions for oral administration, it is possible to use solutions, suspensions, emulsions, syrups and pharmaceutically acceptable elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or 'paraffin oil. These compositions can include substances other than diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers.

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

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

In human therapy, the compounds according to the invention are particularly useful for the treatment and / or prevention of conditions which require the administration of an AMPA receptor antagonist or an NMDA receptor antagonist. These compounds are particularly useful for treating or preventing all ischemia and in particular cerebral ischemia, the effects due to anoxia, the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease and other dementias. , amyotrophic lateral sclerosis or other motor neuron diseases, olivo-pontocerebellar atrophy, PARKINSON disease, with regard to epileptogenic and / or convulsive manifestations, cerebral or spinal trauma, related trauma degeneration of the inner ear or retina, tinnitus, anxiety, depression, schizophrenia, TOURETTE syndrome, hepatic encephalopathies, sleep disorders, attention deficit disorders, disorders of hormonal conditions (excess of HG or HL secretion, corticosterone secretion), as analgesics, anti-inflammatories, antianorexics, antimigraine antiemetic and to treat poisoning by neurotoxins or other substances agonists of the NMDA or AMPA receptor, as well as the neurological disorders associated with viral diseases such as meningitis and viral encephalitis, AIDS, rabies, measles and tetanus, for the prevention, tolerance and dependence of symptoms of abstinence from drugs, alcohol and the inhibition of addiction and dependence on opiates, barbiturates, amphetamine and benzodiazepines, in the treatment of deficits related to mitochondrial abnormalities such as myopathy mitochondrial, LEBER syndrome, WERNICKE encephalopathy, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutiricaminoaciduria, saturnine encephalopathy (chronic lead poisoning) and sulfite oxidase deficiency.

The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 10 mg and 100 mg per day orally for an adult with unit doses ranging from 5 mg to 50 mg of active substance.

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

The following examples illustrate compositions according to the invention:

EXAMPLE A

Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared:

- Compound of formula (I) 50 mg

- Cellulose 18 mg

- Lactose 55 mg

- Colloidal silica 1 mg - Carboxymethyl starch sodium 10 mg

- Talc 10 mg

- Magnesium stearate 1 mg

EXAMPLE B

Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique:

- Compound of formula (I) 50 mg

- Lactose 104 mg

- Cellulose 40 mg

- Polyvidone 10 mg - Carboxymethyl starch sodium 22 mg

- Talc 10 mg

- Magnesium stearate 2 mg

- Colloidal silica 2 mg - Mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3,5-24,5) q.s.p. 1 film-coated tablet finished at 245 mg

EXAMPLE C

A solution for injection containing 10 mg of active product having the following composition is prepared: - Compound of formula (I) 10 mg

- Benzoic acid 80 mg

- Benzyl alcohol 0.06 ml

- Sodium benzoate 80 mg

- 95% ethanol 0.4 ml - Sodium hydroxide 24 mg

- Propylene glycol 1, 6 ml

- Water q.s.p. 4 ml

Claims

1 - Compounds of formula:

in which R represents a hydrogen atom or an -alk-COOH radical and alk represents an alkyl radical, it being understood that the alkyl radicals contain 1 to 6 carbon atoms in a straight or branched chain, their racemates, enantiomers, diastereoisomers and their salts.

2 - Process for the preparation of the compound of formula (I) according to claim 1 for which R represents a hydrogen atom characterized in that one cyclizes, in the presence of ammonium acetate a derivative of formula:

in which Ra represents an acetyl radical and alk represents an alkyl radical, then hydrolyzes the ester function, isolates the product and optionally transforms it into salt.

3 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical -alk-COOH characterized in that a compound of formula is reacted:

for which alk represents an alkyl radical on a derivative Hal-alk-COOalk 'for which Hal represents a halogen atom alk and alk' represent an alkyl radical, then hydrolysis, isolates the product and optionally transforms it into salt.

4 - Medicines containing as active ingredient at least one compound of formula (I) according to claim 1 or a salt of such a compound.