WO1995012594A1

WO1995012594A1 - 7H-IMIDAZO(1,2-a)PYRAZINE-8-ONE NMDA RECEPTOR ANTAGONISTS

Info

Publication number: WO1995012594A1
Application number: PCT/FR1994/001268
Authority: WO
Inventors: Jean-Claude Aloup; François Audiau; Dominique Damour; Arielle Genevois-Borella; Patrick Jimonet; Serge Mignani
Original assignee: Rhone-Poulenc Rorer S.A.
Priority date: 1993-11-05
Filing date: 1994-11-02
Publication date: 1995-05-11
Also published as: FR2711993B1; EP0726900A1; FR2711993A1; JPH09504539A; IL111526A0; ZA948592B; AU8109794A

Abstract

Drugs containing as the active ingredient at least one compound of formula (I), wherein R1 represents a hydrogen atom or an alkyl or phenyl radical, R2 represents (a) a phenyl radical, (b) a phenyl radical substituted by one or more substituents selected from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals, (c) a naphthyl radical, (d) a naphthyl radical substituted by one or more substituents selected from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals, (e) a 2-,3- or 4-pyridyl radical, (f) a 2-, 3- or 4-pyridiyl radical substituted by one or more substituents selected from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals, (g) a 2- or 3-furyl radical, (h) a 2- or 3-furyl radical substituted by one or several substituents selected from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals or a salt of such a compound. The invention concerns the novel compounds of formula (I) and their preparation.

Description

7H-IMIDAZ0 (1.2-a) PYRAZINE-8-0NE NMDA RECEPTOR ANTAGON1STS

The present invention relates to medicaments containing as active principle at least one compound of formula:

or a salt of such a compound, the new compounds of formula (I) and their preparation.

6-phenyl-7H-imidazo [1,2-a] pyrazine-8-one has been described by DD DAVEY (J. Org. Chem., 52, 4379 (1987)) but no pharmacological property is mentioned for this compound.

In formula (I),

R-j represents a hydrogen atom or an alkyl or phenyl radical and

R2 represents (a) a phenyl radical, (b) a phenyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals, (c) a radical naphthyl, (d) a naphthyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals, (e) a 2-, 3- or 4 radical -pyridyle, (f) a 2-, 3- or 4-pyridyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals, (g) a 2- or 3-furyl radical, (h) a 2- or 3-furyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals.

Unless otherwise stated, in the definitions above and those which follow, the alkyl and alkoxy radicals and portions contain 1 to 4 atoms carbon in a straight or branched chain and the halogen atoms are fluorine, chlorine, bromine and iodine.

The compounds of formula (I) with the exception of 6-phenyl-7H-imidazo [1, 2-a] pyrazine-8-one are new and as such are part of the invention.

The new compounds of formula (I) can be prepared by dealkylation and dealkification of the derivatives of formula:

in which R-] and R2 have the same meanings as in formula (I), alk represents an alkyl radical and Hal represents a halogen atom and, preferably, a bromine atom.

This reaction is preferably carried out in the presence of imidazole, at a temperature between 100 and 200 ° C.

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

R ₁ -CO-CH (R) -Hai (III)

in which R- | and R ₂ have the same meanings as in formula (I) and Hal represents a halogen atom, on a 1-alkylimidazole-2-carboxamide.

This reaction is generally carried out in an inert solvent such as dimethylformamide and acetonitrile, at a temperature between 50 and 150 ° C.

The 1-alkylimidazole-2-carboxamides can be obtained by adaptation or application of the method described by DD DAVEY, J. Org. Chem., 52, 4379 (1987). The derivatives of formula (III) are marketed or can be obtained by application or adaptation of the methods described by K. SCHANK, Chem. Ber., 102, 385 (1969); A. ARCORIA, J. Het. Chem., 12, 385 (1975), RM LAIRD and RE PARKER, J. Am. Chem. Soc., 83, 4277 (1961), JN CHATTERJEA, J. Indian Chem. Soc, 32, 265 (1955) and J. Indian Chem. Soc, 34, 347 (1957), K. YAMAGUCHI. and H. SHOJI., J. Pharm. Soc. Japan, 74, 20 (1954), MI SHEVCHUK and AV DOMBROVSKII, Zh. Obshch. Khim., 33, 1135 (1963), WT CALDWELL and GC SCHWEIKER, J. Am. Chem. Soc, 75, 5884 (1953), R. FUCHS, J. Am. Chem. Soc, 78, 5612 (1956), in patent WO 91/09857 and in the examples.

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

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.

These salts are also part of the invention.

As examples of pharmaceutically acceptable salts, mention may be made of addition salts with mineral or organic acids such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophyllinacetate, salicylate, methylene-bis - β-oxynaphtoate, hydrochloride, sulfate, nitrate and phosphate.

The compounds of formula (I) have interesting pharmacological properties. They are non-competitive antagonists of the N-methyl-D-aspartate receptor (NMDA) and, more particularly, they are ligands for the glycine modulator sites of the NMDA receptor.

Furthermore, certain compounds of formula (I) and, in particular, those for which R- | represents a hydrogen atom or a phenyl radical and R ₂ represents a phenyl, 4-chlorophenyl, 4-phenylphenyl radical,

3,4-dichlorophenyl, 2-, 3- or 4-pyridyl or 2- or 3-furyl are also α-amino-3-hydroxy-5-methyl-8-isoxazolepropionic acid receptor antagonists (AMPA), also known as the quisqualate receptor.

These compounds are therefore useful for treating or preventing all ischemias (such as focal or global ischemia) consecutive to cerebrovascular accidents, cardiac arrest, hypotension, cerebral palsy, cardiac or pulmonary surgery or severe hypoglycemia. They are also useful in the treatment of effects due to anoxia, whether perinatal or consecutive to drowning, suffocation, CO poisoning or cerebro-spinal lesions. These compounds can also be used to treat or prevent the development of neurodegenerative diseases, HUNTINGTON's chorea, ALZHEIMER's disease, senile dementia, amyotrophic lateral sclerosis, atrophy olivo-pontocérébelleuse 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 trauma, to combat poisoning due to toxins agonists of glutamatergic receptors, of 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), as analgesics (DICKENSON et al., Neurosc. Letters, 121, 263 (1991), antianorexics (SORRELS et al., Brain Res., 572, 265 (1992), antimigraine, antiemetics and to treat poisoning by neurotoxins or other NMDA receptor agonist substances, as well as neurological disorders associated with viral diseases such as 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 s for the prevention of symptoms of abstinence from drugs and alcohol and the inhibition of addiction and dependence on opioids.

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 [ ³ H] -DCKA (20 nM) 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. Nonspecific binding 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 generally less than or equal to 100 μM.

The affinity of the compounds of formula (I) vis-à-vis the AMPA receptor was determined by studying the antagonism of the specific binding of [ ³ H] - AMPA on membranes of rat cerebral cortex (HONORE et al. , Neu¬ roscience 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 KH P04 10mM buffer, KSCN 100ιτιM, 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 generally less than 100 μM.

The compounds of formula (I) have a low toxicity. Their

LD50 is greater than 50 mg / kg via the IP route in mice.

The preferred compounds of formula (I) are the following:

- 6-phenyl-7H-imidazo [1, 2-a] pyrazine-8-one,

- 6- (4-chlorophenyl) -7H-imidazo [1, 2-a] pyrazine-8-one, - 6- (2-pyridyl) -7H-imidazo [1, 2-a] pyrazine-8-one,

- 6- (2-furyl) -7H-imidazo [1, 2-a] pyrazine-8-one,

- 5-methyl-6-phenyl-7H-imidazo [1, 2-a] pyrazine-8-one

- 6- (3,4-dichlorophenyl) -7H-imidazo [1, 2-a] pyrazine-8-one,

- 5,6-diphenyl-7H-imidazo [1, 2-a] pyrazine-8-one.

The following examples illustrate the invention.

EXAMPLE 1

A solution stirred and maintained under a nitrogen atmosphere of 4.5 g of 1-methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo bro¬ mure [1, 2-a] pyrazinium in 24 g imidazole is heated for 20 hours at 175 ° C, cooled to 100 ° C and then poured onto 180 g of a mixture of water and ice (50-50 by weight). The solid is separated by filtration, washed twice with 60 cm ³ in total of distilled water and dried under reduced pressure. The product obtained (2.8 g) is dissolved in 150 cm ³ of boiling ethanol and the solution, supplemented with bleaching black, is filtered hot, cooled and stored for 1 hour at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed with 10 cm ³ of ice-cold ethanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 50 ° C. 1.6 g of 6-phenyl-7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 264 ° C. NMR spectrum: [300 MHz; (CD ₃ ) ₂ SO d6; δ in ppm]: 7.52 (mt, 3H: -H in 3, -H in 4 and -H in 5 of phenyl); 7.54 and 7.86 (2s wide, 1 H each: -H _. Of imidazole); 7.71 (broad d, J = 8 Hz, 2H: - in 2 and -JH in 6 of phenyl); 7.92 (s, 1H: = CH-N); 11.53 (mf, 1H: -CONH-).

1-Methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide can be prepared as follows: a stirred solution of 3.9 g of 2 -bromoacetophenone and 2 g of 1-methylimidazole-2-carboxamide in 60 cm ³ of acetonitrile is kept boiling for 20 hours and cooled to 15 ° C. The crystals are separated by filtration, washed with ethyl ether and dried under reduced pressure. 4.5 g of 1-methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1,2-a] pyrazinium are thus obtained.

1-methylimidazole-2-carboxamide can be prepared as described by D. D. DAVEY, J. Org. Chem., 52, 4379 (1987).

EXAMPLE 2

The procedure is as in Example 1 but using 4.5 g of 6- (3-chlorophenyl) -1-methyl-8-oxo-7,8-dihydro-imidazo [1,2-a] pyrazinium bromide and 20 g of imidazole. The crude product (2.8 g) is dissolved in 350 cm ³ of boiling methanol and the solution, supplemented with bleaching black, is filtered hot. The filter is washed twice with 150 cm ³ in total of boiling methanol, then the filtrate and the washing are combined, concentrated under reduced pressure (15 mm Hg; 2 kPa) at 40 ° C so as to reduce their volume to 50 cm. ³ and kept for 16 hours at a temperature close to 5 ° C. The crystals are separated by filtration, washed twice with 20 cm ³ in total of ice-cold methanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60 ° C. 1.8 g of 6- (3-chlorophenyl) -7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 292 ° C. (decomposition). NMR spectrum: [300 MHz; (CD ₃ ) ₂ SO d6; δ in ppm]: 7.52 (mt, 2H: -H in 4 and -H in 5 of phenyl); 7.54 and 7.85 (2s large, 1 hour each: -M imidazole); 7.68 (broad d, J = 8 Hz, 1 H: -d 6 in phenyl); 7.82 (broad s, 1 H: -H in 2 of phenyl); 8.01 (s, 1H: = CH-N); 11.60 (mf, 1 H: -CONJd-).

6- (3-chlorophenyl) -1-methyl-8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide can be prepared as in Example 1 for the preparation of bromide of 1-methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium but from 5.2 g of 2-bromo-3'-chloroaceto-phenone to 85% and 2 g of 1-methylimidazole-2-carboxamide in 60 cm ³ of acetonitrile. 4.5 g of 6- (3-chlorophenyl) -1-methyl-8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium are thus obtained.

2-Bromo-3'-chloroacetophenone can be prepared as described by R. M. LAIRD and R. E. PARKER, J. Am. Chem. Soc., 83, 4277 (1961).

EXAMPLE 3

The procedure is as in Example 1 but using 5 g of 6- (4-chlorophenyl) -1-methyl-8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide and 24 g imidazole. The crude product (4.4 g) is recrystallized from 500 cm ³ of methanol and thus 1.7 g of 6- (4-chlorophenyl) -7H-imidazo [1, 2-a] pyrazine-8- are obtained. one melting at 300 ° C (decomposition). NMR spectrum: (200 MHz; (CD ₃ ) ₂ SO d6; δ in ppm): 7.53 and 7.83 (2d, J = 1 Hz, 1 H each: -H of imidazole); 7.60 (d, J = 8 Hz, 2H: -H in 3 and -H in 5 of phenyl); 7.75 (d, J = 8 Hz, 2H: -H in 2 and -H in 6 of phenyl); 7.97 (s, 1H: = CH-N); 11.60 (mf, 1H: -CONH-).

6- (4-chlorophenyl) -1-methyl-8-oxo-7,8-dihydro-imidazo [1,2-a] pyrazinium bromide can be prepared as in Example 1 for the preparation of bromide of 1-methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium but from 4.5 g of 2-bromo-4'-chloroacetophenone and 2 g of 1-methylimidazole-2-carboxamide in 60 cm ³ of acetonitrile. This gives 4.6 g of 6- (4-chlorophenyl) -1-methyl-8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide.

EXAMPLE 4 The procedure is as in Example 1 but starting with 3.3 g of 1-methyl-6- (2-methylphenyl) -8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide and 16 g of imidazole. The crude product (3.2 g) is recrystallized from 25 cm ³ of methanol and 1.15 g of 6- (2-methylphenyl) -7H- imidazo [1, 2-a] pyrazine-8-one are thus obtained. at 250 ° C. NMR spectrum: (200 MHz; (CD ₃ ) ₂ SO d6; δ in ppm): 2.33 (s, 3H: -CH ₃ ); from 7.25 to 7.45 (mt, 4H: -Jd aromatics); 7.50 (s, 1H: = CH-N); 7.52 and 7.82 (2d, J = 1 Hz, 1 H each: -H of imidazole); 11.39 (mf, 1H: -CONH-).

1-methyl-6- (2-methylphenyl) -8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide can be prepared as in Example 1 for the preparation of bromide of 1-methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium but from 4.5 g of 2-bromo-2'-methylaceto-phenone and 2 g of 1-methylimidazole-2-carboxamide in 60 cm ³ of acetonitrile. 1.5 g of 1-methyl-6- (2-methylphenyl) -8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium are thus obtained.

2-Bromo-2'-methylacetophenone can be prepared as described by J.N. CHATTERJEA, J. Indian Chem. Soc, 32, 265 (1955).

EXAMPLE 5

The procedure is as in Example 1 but starting with 3.3 g of 1-methyl-6- (3-methylphenyl) -8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide and 15 g of imidazole. The crude product (2.1 g) is recrystallized from 135 cm ³ of methanol and 1.2 g of 6- (3-methylphenyl) -7H- imidazo [1, 2-a] pyrazine-8-one are thus obtained. at 287 ° C (decomposition). NMR spectrum: (300 MHz; (CD ^ SO d6; δ in ppm): 2.36 (s, 3H: -CHg); 7.27 (d, J = 8 Hz, 1 H: -Jd in 4 of phenyl); 7.36 (t, J = 8 Hz, 1 H: -H in 5 of phenyl); 7.50 (d, J = 8 Hz, 1 H: -JH in 6 of phenyl); 7.53 and 7.78 (2s wide, 1 H each: - imidazole); 7.55 (s broad, 1 H: -H in 2 of phenyl); 7.90 (s, 1 H: = CJH-N ); 11, 60 (mf, 1H: -CONH-).

1-methyl-6- (3-methylphenyl) -8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide can be prepared as in Example 1 for the preparation of bromide of 1-methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium but from 4.3 g of 2-bromo-3'-methylaceto- phenone and 2 g of 1-methylimidazole-2-carboxamide in 60 cm ³ of acetonitrile. 4.3 g of 1-methyl-6- (3-methylphenyl) -8-oxo-7,8-dihydro-imidazo [1,2-a] pyrazinium bromide are thus obtained.

2-Bromo-3'-methylacetophenone can be prepared as described by J. N. CHATTERJEA, J. Indian Chem. Soc, 34, 347 (1957).

EXAMPLE 6

The procedure is as in Example 1 but starting with 3.9 g of 1-methyl-6- (4-methylphenyl) -8-oxo-7,8-dihydro-imidazo [1,2-a] pyrazinium bromide and 18 g of imidazole. The crude product (3 g) is dissolved in 700 cm ³ of boiling methanol and the solution, added with bleaching black, is filtered hot. The filter is washed with 50 cm ³ of boiling methanol, then the filtrate and the washing are combined, concentrated under reduced pressure (15 mm Hg; 2 kPa) at 40 ° C so as to reduce their volume to 50 cm ³ and kept for 60 hours at a temperature close to 5 ° C. The crystals are separated by filtration, washed with 5 cm ³ of ice-cold methanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60 ° C. 1.75 g of 6- (4-methylphenyl) -7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 330 ° C. (sublimation). NMR spectrum: (300 MHz; (CD ₃ ) ₂ SO d6; δ in ppm): 2.36 (s, 3H: -CJd ₃ ); 7.34 (d, J = 8 Hz, 2H: -H in 3 and -Jd in 5 of phenyl); 7.54 and 7.85 (2d, J = 1 Hz, 1 H each: -JH of imidazole); 7.62 (d, J = 8 Hz, 2H: -H in 2 and -JH in 6 of phenyl); 7.88 (s, 1H: = CH-N); 11.50 (mf, 1H: -CONH-).

1-methyl-6- (4-methylphenyl) -8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide can be prepared as in Example 1 for the preparation of bromide of 1-methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium but from 4.1 g of 2-bromo-4'-methylaceto-phenone and 2 g of 1-methylimidazole-2-carboxamide in 60 cm ³ of acetonitrile. 3.9 g of 1-methyl-6- (4-methylphenyl) -8-oxo-7,8-dihydro-imidazo [1,2-a] pyrazinium are thus obtained.

2-bromo-4'-methylacetophenone can be prepared as described by K. YAMAGUCHI. and H. SHOJI., J. Pharm. Soc. Japan, 74, 20 (1954).

EXAMPLE 7 The procedure is as in Example 1 but starting with 5.1 g of 1-methyl-6- (3-nitrophenyl) -8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide and 24 g of imidazole. 1.4 g of crude product (out of the 3.2 g obtained in total) is chromatographed on 84 g of neutral silica gel (0.020-0.045 mm) contained in a column 3.1 cm in diameter, eluting under pressure with a mixture of ethyl acetate and methanol (90-10 by volume) and collecting 20 cm ³ fractions. Fractions 35 to 85 are concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 50 ° C. The product obtained (0.6 g) is dissolved in 5 cm ³ of boiling dimethylformamide and the solution, supplemented with bleaching black, is filtered hot, cooled and stored for 16 hours at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed with ice-cold dimethylformamide and with ice-cold ethanol and then dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60 ° C. 0.15 g of 6- (3-nitrophenyl) -7H-imidazo [1, 2-a] pyrazine-8-one is thus obtained, melting at 350 ° C. (sublimation). NMR spectrum: (300 MHz; (CD ₃ ) ₂ SO d6; δ in ppm): 7.57 and 7.89 (2s wide, 1 H each: -JH of imidazole); 7.85 (t, J≈8.5 Hz, 1H: -JH in 5 of phenyl); 8.13 (s, 1H: = CH-N); 8.17 (broad d, J = 8.5 Hz, 1 H: -JH in 6 of phenyl); 8.34 (broad d, J = 8.5 Hz, 1 H: -Jd in 4 of phenyl); 8.60 (broad s, 1 H: -d 2 in phenyl); 11.80 (mf, 1H: -CONJH-).

1-methyl-6- (3-nitrophenyl) -8-oxo-7,8-dihydro-imidazo [1,2-a] pyrazinium bromide can be prepared as in Example 1 for the preparation of bromide of 1-methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium but from 4.5 g of 2-bromo-3'-nitroaceto-phenone and 2 g of 1-methylimidazole-2-carboxamide in 60 cm ³ of acetonitrile. 5.1 g of 1-methyl-6- (3-nitrophenyl) -8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium are thus obtained.

2-bromo-3'-nitroacetophenone can be prepared as described by M. I. SHEVCHUK and A. V. DOMBROVSKII, Zh. Obshch. Khim., 33, 1135 (1963).

EXAMPLE 8

The procedure is as in Example 1 but starting with 6 g of 1-methyl- 6- (4-nitrophenyl) -8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide and 24 g imidazole. The crude product (4.5 g) is recrystallized from 50 cm ³ of dimethylformamide and 0.96 g of 6- (4-nitrophenyl) -7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 400 ° C. (decomposition). NMR spectrum: (300 MHz; (CDg) ₂ SO d6; δ in ppm): 7.58 and 7.90 (2s wide, 1 H each: -H of imidazole); 8.02 (d, J = 8.5 Hz, 2H: -Jd in 2 and -JH in 6 of phenyl); 8.15 (s, 1H: = CH-N); 8.38 (d, J = 8.5 Hz, 2H: -H in 3 and -H in 5 of phenyl); 11, 80 (mf, 1 H: -CONJd-).

1-methyl-6- (4-nitrophenyl) -8-oxo-7,8-dihydro-imida- zo [1,2-a] pyrazinium bromide can be prepared as in Example 1 for the preparation 1-methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide but from 4.6 g of 2-bromo-4'-nitroacetophenone and 2 g of 1-methylimidazoie-2-carboxamide in 60 cm ³ of acetonitrile. 6 g of 1-methyl-6- (4-nitrophenyl) -8-oxo-7,8-dihydro-imidazo [1,2-a] pyrazinium bromide are thus obtained.

2-Bromo-4'-nitroacetophenone can be prepared as described by M. I. SHEVCHUK and A. V. DOMBROVSKII, Zh. Obshch. Khim., 33, 1135 (1963).

EXAMPLE 9

2.6 g of bromine are added dropwise over 5 minutes at a temperature in the region of 25 ° C to a solution of 2.3 g of 3'-cyanoacetophenone in 40 cm ³ of chloroform. The mixture is stirred for 20 minutes at the same temperature and then concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 40 ° C. The product obtained (5.6 g) is supplemented with 75 cm ³ of acetonitrile and 2 g of 1-methylimidazole-2-carboxamide then the mixture is stirred at the boil for 24 hours. After cooling to 20 ° C, the crystals are separated by filtration, washed successively with 15 cm ³ of acetonitrile, 15 cm ³ of ethyl ether and dried under reduced pressure (15 mm Hg; 2 kPa) at 60 ° C. The product obtained (3.9 g) is heated for 24 hours at 175 ° C in 24 g of imidazole and the mixture, cooled to 100 ° C, is poured onto a mixture of 75 g of ice and 75 g distilled water. The insoluble material is separated by filtration, washed with 50 cm ³ of distilled water and dried under reduced pressure. The product obtained (1.65 g) is chromatographed on 96 g of neutral silica gel (0.020-0.045 mm) contained in a column 3.3 cm in diameter, eluting under pressure with a mixture of dichloromethane and methanol (93 -7 by volume) and collecting 3 successive fractions of 100 cm ³ > 150 cm ³ and 1850 cm ³ . The last fraction is concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 50 ° C. The product obtained (0.9 g) is dissolved in 30 cm ³ of boiling dimethylformamide and the solution, supplemented with bleaching black, is filtered hot, cooled and stored for 16 hours at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed successively with 5 cm ³ of ice-cold dimethylformamide, twice with 20 cm ³ in total of distilled water and with 10 cm ³ of ethanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60 ° C. 0.65 g of 6- (3-cyanophenyl) -7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 335 ° C (decomposition). NMR spectrum: (200 MHz; (CD ₃ ) ₂ SO d6; d in ppm): 7.54 and 7.83 (2s wide, 1 H each: -H of imidazole); 7.72 (t, J = 8 Hz, 1 H: -H at 5 of phenyl); 7.94 and 8.03 (2d wide, J = 8.5 Hz, 1 H each: -JH in 4 and -H in 6 of phenyl); 8.05 (s, 1H: = CH-N); 8.23 (broad s, 1H: -H in 2 of phenyl); 11.60 (mf, 1 H: -CONH-),

EXAMPLE 10

A stirred solution of 4.3 g of 2-bromo-4'-cyanoacetophenone and 2 g of 1-methylimidazole-2-carboxamide in 60 cm ³ of acetonitrile is kept boiling for 6 hours and cooled to 15 °. vs. The crystals are separated by filtration, washed with 15 cm ³ of acetonitrile and dried under reduced pressure. The product obtained (4.9 g) is heated for 20 hours at 175 ° C in 25 g of imidazole and the mixture cooled to 100 ° C is poured onto 150 g of a mixture of water and ice (50- 50 by weight). The solid is separated by filtration, washed with 15 cm ³ of distilled water and dried under reduced pressure. The product obtained (4.2 g) is dissolved in 60 cm ³ of boiling dimethylformamide and the solution, supplemented with bleaching black, is filtered hot, cooled and stored for 16 hours at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed successively with 10 cm ³ of ice-cold dimethylformamide, twice with 20 cm ³ in total of distilled water and then with 10 cm ³ of ice-cold ethanol and dried under reduced pressure (1 mm Hg; 0, 13 kPa) at 80 ° C. 1.45 g of 6- (4-cyanophenyl) -7H-imidazo [1, 2- a] pyrazine-8-one are thus obtained, melting at 356 ° C (decomposition). NMR spectrum: (200 MHz; (CD ₃ ) ₂ SO d6; δ in ppm): 7.54 and 7.84 (2d, J = 1 Hz, 1 H each: -JH of imidazole); 7.90 and 8.00 (2d, J = 8.5 Hz, 2H each: -H aromatic); 8.08 (s, 1H: = CH-N); 11.67 (mf, 1H: -CONH-). EXAMPLE 11

The procedure is as in Example 1 but starting from 8.9 g of 1-methyl-8-oxo-6- (4-trifluoromethylphenyl) -7,8-dihydro-imidazo bromide [1, 2-a ] pyrazinium and 40 g imidazole. The crude product (5 g) is dissolved in 170 cm ³ of boiling ethanol and the solution, supplemented with bleaching black, is filtered hot and stored for 16 hours at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed with 25 cm ³ of a mixture of water and methanol (50-50 by volume) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 70 ° C. 3 g of 6- (4-trifluoromethylphenyl) -7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 290 ° C. NMR spectrum: (200 MHz; (CD ₃ ) ₂ SO d6; δ in ppm): 7.54 and 7.84 (2d, J = 1 Hz, 1 H each: -H of imidazole); 7.90 and 8.00 (2d, J = 8.5 Hz, 2H each: -H aromatic); 8.08 (s, 1H: = CH-N); 11.67 (mf, 1H: -CONH-).

1-methyl-8-oxo-6- (4-trifluoromethylphenyl) -7,8-dihydro-imidazo [1,2-a] pyrazinium bromide can be prepared as in Example 1 for the preparation 1-methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide but from 10.2 g of 2-bromo-4'-trifluorome- 80% thylacetophenone and 3.2 g of 1-methylimidazole-2-carboxamide in 100 cm ³ of acetonitrile. 8.9 g of 1-methyl-8-oxo-6- (4-trifluoromethylphenyl) -7,8-dihydro-imidazo [1, 2-a] pyrazinium- bromide are thus obtained.

2-Bromo-4'-trifluoromethylacetophenone can be prepared as described by W. T. CALDWELL and G. C. SCHWEIKER, J. Am. Chem. Soc, 75, 5884 (1953).

EXAMPLE 12

The procedure is as in Example 1 but starting with 1.9 g of 1-methyl-8-oxo-6- (4-trifluoromethoxyphenyl) -7,8-dihydro-imidazo bromide [1, 2-a ] pyrazinium and 9 g imidazole. The crude product (1.15 g) is chromatographed on 60 g of neutral silica gel (0.020-0.045 mm) contained in a column 2.9 cm in diameter, eluting under pressure with a mixture of dichloromethane and methanol (93-7 by volume) and collecting 15 cm ³ fractions. Fractions 12 to 24 are concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 50 ° C. The product obtained (0.5 g) is dissolved in 15 cm ³ of boiling isopropanol and the solution, supplemented with bleaching black, is filtered hot. The filter is washed with 5 cm ³ of boiling isopropanol, then the filtrate and the washing are combined, concentrated under reduced pressure (15 mm Hg; 2 kPa) at 40 ° C so as to reduce their volume to 5 cm ³ and stored for 16 hours at a temperature close to 5 ° C. The crystals are separated by filtration, washed with 2 cm ³ of ice-cold isopropanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60 ° C. 0.44 g of 6- (4-trifluoromethoxyphenyl) -7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 235 ° C. NMR spectrum ^" : (200 MHz; (CD ₃ ) ₂ SO d6; δ in ppm): 7.51 (d, J = 8 Hz, 2H: -H in 3 and -H in 5 of phenyl); 7, 52 and 7.83 (2d, J = 1 Hz, 1 H each: -JH of imidazole); 7.79 (d, J = 8 Hz, 2H: -Jd in 2 and -H in 6 of phenyl) ; 7.92 (s, 1H: = CH-N); 11.60 (mf, 1H: -CONH-).

1-methyl-8-oxo-6- (4-trifluoromethoxyphenyl) -7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide can be prepared as in Example 1 for the preparation 1-methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide but from 2 g of 2-bromo-4'-trifluoromethoxyoxyetophenone and 0.75 g of 1-methylimidazole-2-carboxamide in 25 cm ³ of acetonitrile. 1.9 g of 1-methyl-8-oxo 6- (4-trifluoromethoxyphenyl) -7,8-dihydro-imidazo [1,2-a] pyrazinium are thus obtained.

EXAMPLE 13

The procedure is as in Example 1 but starting with 5.4 g of bromide

1-methyl-6- (4-methoxyphenyl) -8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium and 24 g of imidazole. The crude product (3.9 g) is chromatographed on 135 g of neutral silica gel (0.020-0.045 mm) contained in a column 3.6 cm in diameter, eluting under pressure with a mixture of dichloromethane and methanol (93 -7 by volume) and collecting 40 cm ³ fractions. Fractions 25 to 150 are concentrated to dryness under reduced pressure (15 mm Hg;

2 kPa) at 50 ° C. The product obtained (0.5 g) is dissolved in 75 cm ³ of boiling methanol and the solution, supplemented with bleaching black, is filtered hot. The filter is washed with 10 cm ³ of boiling methanol, then the filtrate and the washing are combined, concentrated under reduced pressure (15 mm Hg; 2 kPa) at 40 ° C so as to reduce their volume to 10 cm ³ and kept for 16 hours at a temperature close to 5 ° C. The crystals are separated by filtration, washed with 5 cm ³ of ice-cold methanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60 ° C. 0.38 g of 6- (4-methoxyphenyl) -7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 288 ° C (decomposition). NMR spectrum: (200 MHz; (CD _g ) ₂ SO d6; δ in ppm): 3.80 (s, 3H: -OCHg); 7.05 (d, J = 8.5 Hz, 2H: -JH in 3 and -H in 5 of phenyl); 7.52 and 7.80 (2d, J = 1 Hz, 1 H each: -H of imidazole); 7.62 (d, J = 8.5 Hz, 2H: -Jd in 2 and -H in 6 of phenyl); 7.79 (s, 1H: = CH-N); 11.40 (mf, 1H: -CONH-).

1-methyl-6- (4-methoxyphenyl) -8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide can be prepared as in Example 1 for the preparation 1-methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide but from 4.5 g of 2-bromo-4'-methoxyaceous- tophenone and 2 g of 1-methylimidazole-2-carboxamide in 60 cm ³ of acetonitrile. 5.4 g of 1-methyl-6- (4-methoxyphenyl) -8-oxo-7,8-dihydro-imidazo [1,2-a] pyrazinium are thus obtained.

EXAMPLE 14

A stirred solution of 5.7 g of 2-bromo-2 ', 4'-dichloroacetophenone at 90% and 2 g of 1-methylimidazole-2-carboxamide in 60 cm ³ of acetonitrile is kept at boiling point for 20 hours and cooled to 15 ° C. The crystals are separated by filtration, washed with ethyl ether and dried under reduced pressure. The product obtained (4.9 g) is heated for 24 hours at 175 ° C in 24 g of imidazole and the mixture, cooled to 100 ° C, is poured onto a mixture of 75 g of ice and 75 g of distilled water. The insoluble material is separated by filtration, washed twice with 20 cm ³ in total of distilled water and dried under reduced pressure. The product obtained (3.8 g) is dissolved in 300 cm ³ of boiling isopropanol and the solution, supplemented with bleaching black, is filtered hot. The filtrate is concentrated under reduced pressure (15 mm Hg; 2 kPa) at 40 ° C so as to reduce the volume to 75 cm ³ and stored for 16 hours at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed with 5 cm ³ of ice-cold isopropanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60 ° C. 2 g of 6- (2,4-dichlorophenyl) -7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 256 ° C. NMR spectrum: (300 MHz; (CD ₃ ) ₂ SO d6; δ in ppm): 7.53 and 7.90 (2s, 1 H each: -Jd imidazole); 7.60 (dd, J = 8.5 and 1 Hz, 1 H: -Jd in 5 of phenyl); 7.67 (d, J = 8.5 Hz, 1H: -H 6 of phenyl); 7.68 (s, 1H: = CM-N); 7.88 (d, J = 1 Hz, 1 H: -M 3 of phenyl); 11.52 (mf, 1H: -CONJJ-).

2-bromo-2 ', 4'-dichloroacetophenone can be prepared as described in patent WO 91/09857.

EXAMPLE 15

A stirred solution of 5.3 g of 2-bromo-3 ', 4'-dichloroacetophenone at 95% and of 2 g of 1-methylimidazole-2-carboxamide in 60 cm ³ of acetonitrile is kept at boiling point for 20 hours and cooled to 15 ° C. The crystals are separated by filtration, washed with ethyl ether and dried under reduced pressure. The product obtained (4.3 g) is heated for 24 hours at 175 ° C in 24 g of imidazole and the mixture, cooled to 100 ° C, is poured onto a mixture of 75 g of ice and 75 g of distilled water. The insoluble material which appears is separated by filtration, washed twice with 20 cm ³ in total of distilled water and dried under reduced pressure. The product obtained (2.8 g) is dissolved in 250 cm ³ of boiling methanol and the solution, supplemented with bleaching black, is filtered hot and stored for 16 hours at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed with 5 cm ³ of ice-cold methanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60 ° C. 0.97 g of 6- (3,4-dichlorophenyl) -7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 315 ° C. NMR spectrum: (300 MHz; (CD ₃ ) ₂ SO d6; δ in ppm): 7.55 and 7.82 (2d, J = 1 Hz, 1 H each: -Jd of imidazole); 7.70 (dd, J = 8.5 and 2.5 Hz, 1H: -H 6 of phenyl); 7.77 (d, J = 8.5 Hz, 1H: -H at 5 of phenyl); 7.99 (s, 1H: = CH-N); 8.01 (d, J = 2.5 Hz, 1 H: -d 2 in phenyl); 11.52 (mf, 1H. -CONH-).

2-bromo-3 ', 4'-dichloroacetophenone can be prepared as described by R. FUCHS, J. Am. Chem. Soc, 78, 5612 (1956).

EXAMPLE 16

A stirred solution of 4.75 g of 2-bromo-2'-acetonaphtone and 2 g of 1-methylimidazole-2-carboxamide in 60 cm ³ of acetonitrile is kept boiling for 48 hours and cooled to 15 °. vs. The crystals are separated by filtration, washed with ethyl ether and dried under reduced pressure. The product obtained (5.45 g) is heated for 24 hours at 175 ° C in 24 g of imidazole and the mixture, cooled to 100 ° C, is poured onto a mixture of 75 g of ice and 75 g of distilled water. The insoluble material is separated by filtration, washed with 50 cm ³ of distilled water and dried under reduced pressure. The product obtained (5 g) is dissolved in 25 cm ³ of boiling dimethylformamide and the solution, supplemented with bleaching black, is filtered hot. The filter is washed twice with 20 cm ³ in total of boiling dimethylformamide, then the filtrate and the washing are combined and stored for 16 hours at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed successively with 10 cm ³ of ice-cold dimethylformamide, with 10 cm ³ of distilled water and with 10 cm ³ of ice-cold ethanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) to 60 ° C. 2.4 g of 6- (2-naphthyl) -7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 297 ° C. (decomposition). NMR spectrum: (300 MHz; (CD ₃ ) ₂ SO d6; δ in ppm): 7.55 and 7.90 (2s wide, 1 H each: -H of imidazole); 7.60 and 8.00 (2mt, 2H each: -JH in 5, -Jd in 6 - -H in 7 and -H in 8 of naphthyl); 7.82 (dd, J = 8.5 and 1 Hz, 1H: -H in 3 of naphthyl); 8.05 (d, J = 8.5 Hz, 1H: -H in 4 of naphthyl); 8.09 (s, 1H: = CH-N); 8.32 (d, J = 1 Hz, 1 H: -H in 1 of naphthyl); 11.65 (mf, 1H: -CONH-).

EXAMPLE 17

A stirred solution maintained under a nitrogen atmosphere of 11.6 g of 1-methyl-8-oxo-6- (2-pyridyl) -7,8-dihydro-imidazo [1, 2-a] pyra zinium bromide in 55 g of imidazole is heated for 6 hours at 175 ° C, cooled to 95 ° C, added with 50 cm ³ of ethanol, cooled to a temperature in the region of 20 ° C then added with 50 cm ³ of acetone. The solid is separated by filtration, washed with acetone and dried under reduced pressure. The product obtained (5.6 g) is suspended in 1200 cm ³ of boiling distilled water and the mixture, supplemented with bleaching black, is filtered hot then the filter is washed twice with 500 cm ³ in total of boiling distilled water. The filtrate and the washing are combined and stored for 30 minutes at a temperature in the region of 5 ° C. The crystals are separated by filtration, and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 80 ° C. 1.1 g of 6- (2-pyridyl) -7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 305 ° C. NMR spectrum: [300 MHz; (CD ₃ ) ₂ SO d6; δ in ppm]: 7.48 (dd, J = 9 and 6.5 Hz, 1 H: -Jd ₅ of pyridine); 7.55 and 7.93 (2 seconds wide, 1 hour each: -Jd of imidazole); 8.00 (dt, J = 9 and 3 Hz, 1 H: -Jd ₄ of pyridine); 8.05 (d, J = 9 Hz, 1 H: -JH ₃ of pyridine); 8.48 (s, 1H: = CJd-N); 8.70 (dd, J = 6.5 and 3 Hz, 1 H: -Jd ₆ of pyridine); 11.00 (mf, 1H: -CONH-).

1-Methyl-8-oxo-6- (2-pyridyl) -7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide can be prepared as follows: a solution stirred and kept under an atmosphere of nitrogen of 29 g of 2-bromoacetylpyridine hydrobromide and 10 g of 1-methylimidazole-2-carboxamide in 300 cm ³ of dimethylformamide is heated for 30 hours to 120 ° C, cooled to a temperature in the region of 20 ° C and added of 60 cm ³ of ethyl ether. After cooling to 5 ° C, the crystals are separated by filtration, washed with 20 cm ³ of acetone and dried under reduced pressure. 11.5 g of 1-methyl-8-oxo-6- (2-pyridyl) -7,8-dihydro-imidazo [1, 2-a] pyra zinium bromide hydrobromide are thus obtained.

2-Bromoacetylpyridine hydrobromide can be prepared as described by K. SCHANK, Chem. Ber., 102, 385 (1969).

EXAMPLE 18

A solution stirred and maintained under a nitrogen atmosphere of 4.5 g of 6- (2-furyl) -1-methyl-8-oxo-7,8-dihydro-imidazo bro¬ mure [1, 2-a] pyrazinium in 20 g of imidazole is heated for 6 hours at 175 ° C, cooled to 90 ° C, supplemented with 50 cm ³ of distilled water and then poured onto 100 cm ³ of distilled water. After cooling to a temperature in the region of 20 ° C., the solid is separated by filtration, washed with distilled water and dried under reduced pressure. The product obtained (2.5 g) is dissolved in 200 cm ³ of boiling ethanol and the solution, supplemented with bleaching black, is filtered hot, cooled and stored for 1 hour at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed with 10 cm ³ of ice-cold ethanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 50 ° C. 1.1 g of 6- (2-furyl) -7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 270 ° C. NMR spectrum: [200 MHz; (CD ₃ ) ₂ SO d6; δ in ppm: 6.65 (dd, J = 3.5 and 2 Hz, 1 H: -H ₄ of furan); 7.23 (d, J = 3.5 Hz, 1 H: -H ₃ of furan); 7.49 and 7.87 (2 d, J = 1 Hz, 1 H each: -H of imidazole); 7.83 (d, J = 2 Hz, 1 H: -H ₅ of furan); 7.95 (s, 1H: = CH-N); 11.57 (mf, 1H: -CONH-). 6- (2-furyl) -1-methyl-8-oxo-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide can be prepared as in Example 1 for the preparation of bromide 1 -methyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium but from 4.5 g of 2-bromoacetylfuran and 3 g of 1 -methylimida-zole-2 -carboxamide in 100 cm ³ of acetonitrile. 5.6 g of 6- (2-furyl) -1-methyl-8-oxo-7,8-dihydro-imidazo [1,2-a] pyrazinium bromide are thus obtained.

2-bromoacetylfuran can be prepared as described by A. ARCORIA, J. Het. Chem., 12, 385 (1975).

EXAMPLE 19

A solution stirred and maintained under a nitrogen atmosphere of 11.2 g of 1,5-dimethyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium bromide in 50 g of imidazole is heated for 20 hours at 160 ° C and for 4 hours at 175 ° C, cooled to 100 ° C and then poured over 150 g of a mixture of water and ice (50-50 in weight). The mixture is extracted 6 times with 700 cm ³ in total of chloroform and the organic extracts are combined, dried over magnesium sulphate and concentrated to dryness under reduced pressure (15 mm Hg; 2kPa) at 35 ° C. The product obtained (14.7 g) is dissolved in 110 cm ³ of boiling isopropanol and the solution, supplemented with bleaching black, is filtered hot. The filter is washed with 20 cm ³ of boiling isopropanol, then the filtrate and the washing are combined, cooled and stored for 16 hours at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed twice with 50 cm ³ in total of iced isopropanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60 ° C. The product obtained (6.5 g) is dissolved in 100 cm ³ of boiling isopropanol and the solution, supplemented with bleaching black, is filtered hot. The filter is washed twice with 50 cm ³ in total of boiling isopropanol, then the filtrate and the washing are combined, cooled and stored for 16 hours at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed twice with 30 cm ³ in total of iced isopropanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60 ° C. Of the 4.6 g of product obtained in total, 4 g are chromatographed on 250 g of neutral silica gel (0.020-0.045 mm) contained in a column of 4.4 cm in diameter, eluting under pressure with a mixture of dichloromethane and methanol (95-5 by volume) and collecting 60 cm ³ fractions. Fractions 34 to 59 are combined and concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 40 ° C. The product obtained (3.2 g) is dissolved in 90 cm ³ of boiling isopropanol and the solution, supplemented with bleaching black, is filtered hot. The filter is washed with 20 cm ³ of boiling isopropanol, then the filtrate and the washing are combined, cooled and stored for 16 hours at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed with 10 cm ³ of ice-cold isopropanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60 ° C. 2.4 g of 5-methyl-6-phenyl-7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 232 ° C. NMR spectrum: [300 MHz; (CD ₃ ) ₂ SO d6; δ in ppm]: 2.27 (s, 3H: -CJd ₃ ); 7.50 (s, 5H: -Jd of phenyl); 7.57 and 7.90 (2s wide, 1 H each: -JH imidazole); 11.35 (mf, 1H: -CONH-).

1,5-dimethyl-8-oxo-6-phenyl-7,8-dihydro-imidazo [1, 2-a] pyrazinium can be prepared as follows: a solution stirred and maintained under a nitrogen atmosphere of 22 , 5 g of 2-bromopropiophenone and 10 g of 1-methylimidazole-2-carboxamide in 300 cm ³ of dimethylformamide is heated for 10 hours at 115 ° C and then concentrated under reduced pressure (1 mm Hg; 0.13 kPa) to 70 ° C. The product obtained (38.4 g) is dissolved in 650 cm ³ of isopropanol and the solution, supplemented with 3 liters of ethyl acetate, is stirred for 30 minutes at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed with 50 cm ³ of ethyl acetate and dried under reduced pressure. 11.5 g of 1,5-dimethyl-8-oxo-6- (phenyl) -7,8-dihydro-imidazo [1,2-a] pyrazinium are thus obtained.

EXAMPLE 20

A stirred solution of 8 g of 2-bromo-2-phenyl-acetophenone and 3 g of 1-methylimidazole-2-carboxamide in 90 cm ³ of acetonitrile is kept boiling for 20 hours and cooled to a neighboring temperature 20 ° C. The crystals are separated by filtration, washed with acetonitrile then with ethyl ether and dried under reduced pressure. The product obtained (3.3 g) is dissolved in 17 g of molten imidazole and the solution, maintained under a nitrogen atmosphere, is heated for 20 hours at 175 ° C, cooled to 100 ° C and then poured over 100 cm ³ distilled water. The solid is separated by filtration, washed twice with 20 cm ³ in total of distilled water and dried under reduced pressure. The product obtained (2 g) is dissolved in 100 cm ³ of boiling ethanol and the solution, supplemented with bleaching black, is filtered hot, cooled and stored for 1 hour at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed with 10 cm ³ of ice-cold ethanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 50 ° C. 1.1 g of 5,6-diphenyl-7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at 305 ° C. NMR spectrum: [200 MHz; (CD ₃ ) ₂ SO d6; δ in ppm): 7.18 and 7.50 (2d, J = 1 Hz, 1 H each: -H of imidazole); 7.31 and 7.42 (2 mt, 5H each: -H of phenyls); 11.65 (mf, 1H: -CONH-).

EXAMPLE 21

A stirred solution of 5.22 g of 2-bromo-4-phenylacetophenone and 2 g of 1-methylimidazole-2-carboxamide in 60 cm ³ of acetonitrile is kept boiling for 29 hours and cooled to 15 ° C . The crystals are separated by filtration, washed with 20 cm ³ of acetonitrile and then with 30 cm ³ of ethyl ether and dried under reduced pressure. The product thus obtained (5.63 g) is heated for 20 hours at 175 ° C in 21 g of imidazole and the mixture cooled to 100 ° C is poured onto 120 g of a mixture of water and ice (50 -50 by weight). The solid is separated by filtration, washed with 30 cm ³ of distilled water and dried under reduced pressure. The product (4.36 g) is dissolved in 75 cm ³ of boiling dimethylformamide and the solution, supplemented with bleaching black, is filtered hot, cooled and stored for 16 hours at a temperature in the region of 5 ° C. The crystals are separated by filtration, washed twice with 30 cm ³ of distilled water and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 45 ° C. 1.6 g of 6- (4-biphenyl) -7H-imidazo [1, 2-a] pyrazine-8-one are thus obtained, melting at a temperature above 260 ° C. NMR spectrum: (200 MHz; (CD ₃ ) ₂ SO d6; δ in ppm): 7.42 (wide t, J = 8 Hz, 1 H: -JH in 4 of the monosubstituted phenyl); 7.52 (wide t, J = 8 Hz, 2H: -Jd in 3 and -JH in 5 of the monosubstituted phenyl); 7.54 and 7.86 (2d, J = 1 Hz, 1 H each: -H of imidazole); 7.76 (d, J = 8 Hz, 2H: -H in 2 and -H in 6 of the monosubstituted phenyl); 7.82 (s, 4H: -H aromatic); 7.96 (s, 1H: = CH-N); 11.58 (mf, 1H. -CONH-). The medicaments according to the invention consist of at least one compound of formula (I) in free form or in the form of a salt, 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, capsules) 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, sucrose, lactose or silica, under a stream of argon. These compositions can also include substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, 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 l 'paraffin oil. These compositions may 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, suspen¬ sions 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 other organic solvents can be used. suitable. 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 of an NMDA receptor antagonist. These compounds are therefore useful for treating or preventing all ischemias (such as focal or global ischemia) consecutive to cerebrovascular accidents, cardiac arrest, hypotension, cerebral palsy, cardiac or pulmonary surgical intervention or severe hypoglycemia. . They are also useful in the treatment of effects due to anoxia, whether perinatal or following drowning, suffocation or CO poisoning or cerebrospinal damage. These compounds are also useful for treating or preventing the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, senile dementia, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and Parkinson's disease. These compounds can also be used vis-à-vis epileptogenic and / or convulsive manifestations, for the treatment of cerebral or spinal traumas, to combat poisoning due to toxins agonists of glutamatergic receptors, of anxiety, of depression, schizophrenia, as analgesics, antianorexics, antimigraine, antiemetics and to treat poisonings by neurotoxins or other substances agonists of the receptor NMDA, as well as the neurological disorders associated with viral diseases such as AIDS, rabies, measles and tetanus. These compounds are also useful for preventing symptoms of abstinence drugs and alcohol and the inhibition of addiction and opioid dependence.

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 according to 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 cm ³ - Sodium benzoate 80 mg

- 95% ethanol 0.4 cm ³

- Sodium hydroxide 24 mg

- Propylene glycol 1.6 cm ³

- Water q.s.p. 4 cm3

Claims

1 - Medicines containing as active ingredient at least one compound of formula:

in which

R- | represents a hydrogen atom or an alkyl or phenyl radical and

R ₂ represents (a) a phenyl radical, (b) a phenyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals, (c) a naphthyl radical, (d) a naphthyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals, (e) a 2-, 3- or 4-pyhdyle, (f) a 2-, 3- or 4-pyridyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals, (g ) a 2- or 3-furyl radical, (h) a 2- or 3-furyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals or a salt of such a compound.

2 - Medicines containing as active ingredient at least one of the following compounds:

- 6-phenyl-7H-imidazo [1, 2-a] pyrazine-8-one,

- 6- (4-chlorophenyl) -7H-imidazo [1, 2-a] pyrazine-8-one,

- 6- (2-pyridyl) -7H-imidazo [1, 2-a] pyrazine-8-one, - 6- (2-furyl) -7H-imidazo [1, 2-a] pyrazine-8-one,

- 5-methyl-6-phenyl-7H-imidazo [1, 2-a] pyrazine-8-one

- 6- (3,4-dichlorophenyl) -7H-imidazo [1, 2-a] pyrazine-8-one,

- 5,6-diphenyl-7H-imidazo [1, 2-a] pyrazine-8-one. or their salts.

3 - Compounds of formula:

in which R- | represents a hydrogen atom or an alkyl or phenyl radical and

R ₂ represents (a) a phenyl radical, (b) a phenyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals, (c) a naphthyl radical, (d) a naphthyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals, (e) a 2-, 3- or 4-pyridyl, (f) a 2-, 3- or 4-pyridyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals, (g ) a 2- or 3-furyl radical, (h) a 2- or 3-furyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, phenyl, nitro or cyano radicals or a salt of such a compound, with the exception of 6-p hényl-7H-imidazo [1, 2- a] pyrazine-8-one.

4 - The following compounds:

- 6- (4-chlorophenyl) -7H-imidazo [1, 2-a] pyrazine-8-one,

- 6- (2-pyridyl) -7H-imidazo [1, 2-a] pyrazine-8-one,

- 6- (2-furyl) -7H-imidazo [1, 2-a] pyrazine-8-one,

- 5-methyl-6-phenyl-7H-imidazo [1, 2-a] pyrazine-8-one, - 6- (3,4-dichlorophenyl) -7H-imidazo [1, 2-a] pyrazine-8- one,

- 5,6-diphenyl-7H-imidazo [1, 2-a] pyrazine-8-one.

5 - Process for the preparation of the compounds of formula (I) according to claim 3 characterized in that one dealkylates and desalifies a derivative of formula:

in which R- | and R have the same meanings as in claim 3, alk represents an alkyl radical and Hal represents a halogen atom, isolates the product and optionally transforms it into a salt.