Imidazo (1,2-A)pyrazine-4-one derivatives/useful as antagonists

Details Imidazo (1,2-A)pyrazine-4-one derivatives/useful as antagonists Imidazo (1,2-A)pyrazine-4-one derivatives/useful as antagonists

1996-01-16

1997-09-30

Grumbling, Matthew V.

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

514249, C07D24136

Patent

active

056727054

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/FR94/00865 dated Jul. 11, 1994 published as WO95/02602 Jan. 26, 1995.
The present invention relates to the compounds of formula: ##STR2## to their salts, to their preparation and to the medicaments containing them.
In the formula (I), or halogen atoms or alkyl, alkoxy, amino, acylamino, --NH--CO--NH--Ar, --N.dbd.CH--N(alk)alk', nitro, cyano, phenyl, imidazolyl or SO.sub.3 H radicals, alk.
In the preceding and following definitions, except when otherwise mentioned, the alkyl and alkoxy radicals contain 1 to 4 carbon atoms in a straight or branched chain, the acyl radicals and portions contain 2 to 5 carbon atoms and the halogen atoms are chosen from fluorine, chlorine, bromine and iodine.
The compounds of formula (I) in which R.sub.1 and/or R.sub.2 represent an --N.vertline.CH--N(alk)alk' radical have isomeric forms (E and Z). These isomers and their mixtures form part of the invention.
The compounds of formula (I) in which R represents an oxygen atom can be prepared by dealkylation, dehydration and desalification of the derivatives of formula: ##STR3## in which R.sub.1 and R.sub.2 have the same meanings as in the formula (I), R.sub.3 represents an alkyl radical and Hal represents a halogen atom. Hal preferably represents a bromine atom.
This reaction is preferably carried out in the presence of imidazole, by heating at a temperature between 100.degree. and 200.degree. C.
The derivatives of formula (II) can be obtained by reacting the 1-alkyl-1H-imidazole-2-carboxamide with a derivative of formula: ##STR4## in which R.sub.1 and R.sub.2 have the same meanings as in the formula (I) and Hal represents a halogen atom. Hal preferably represents a bromine atom.
This reaction is generally carried out in an inert solvent, such as acetonitrile, at the boiling temperature of the reaction mixture.
1-Alkyl-1H-imidazole-2-carboxamides can be obtained by application or adaptation of the method described by D. D. Davey, J. Org. Chem., 52, 4379 (1987).
The derivatives of formula (III) can be obtained by halogenation of the corresponding 3-coumaranones, by means of a halogenating agent, in an inert solvent such as a chlorinated solvent (methylene chloride or chloroform, for example), at a temperature in the range of -15.degree. C. Bromine or chlorine is preferably used.
3-Coumaranones are marketed or can be obtained by application or adaptation of the method described by A. R. Deshpande et al., Synth. Commun., 20 (6), 809 (1990) and G. Schenk et al., Tetrahedron Lett., (19), 2375 (1968).
The compounds of formula (I) in which R represents a sulphur atom can be prepared by cyclization of a derivative of formula: ##STR5## in which R.sub.1 and R.sub.2 have the same meanings as in the formula (I).
This cyclization is generally carried out by means of an acid such as hydrochloric acid in aqueous solution, at a temperature in the region of 20.degree. C.
The derivatives of formula (IV) can be obtained by reacting ammonia with a derivative of formula: ##STR6## in which R.sub.1 and R.sub.2 have the same meanings as in the formula (I).
This reaction is generally carried out in an inert solvent, such as an alcohol, at a temperature between 20.degree. C. and the boiling temperature of the reaction mixture.
The derivatives of formula (V) can be obtained by condensation of ethyl imidazole-2-carboxylate with a derivative of formula: ##STR7## in which R.sub.1 and R.sub.2 have the same meanings as in the formula (I) and Hal represents a halogen atom and preferably a bromine atom.
This reaction is carried out in an inert solvent, such as an alcohol (methanol or ethanol, for example), at the boiling temperature of the reaction mixture.
Ethyl imidazole-2-carboxylate can be obtained according to the method described in U.S. Pat. No. 3,600,399.
The derivatives of formula (VI) can be obtained by application or adaptation of the method described by Z. I. Miroshnichenko and M. A. Al'Perovich, J. Gen. Chem. USSR, 32, 1218 (1962).
The compounds of formula (I) in which R represents an NH radical can be prepared by hydro

REFERENCES:
patent: 5182279 (1993-01-01), Jorgensen et al.
McQuaid et al., "Synthesis and Excitatory Amino Acid Pharmacology of a Series of Heterocyclic-Fused Quinoxalinones and Quinazolines", Journal of Medicinal Chemistry, 35(18):3319-3324 (1992).

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