Patent EA-000218-B1 (EA)
Title: 5h,1oh-imidazo[1,2-a]indeno[1,2-e]pyrazin-4one derivatives, preparation thereof, and drugs containing said derivatives and indanone compounds as intermediate products
Inventor: ALOUP JEAN-CLAUDE
IPC: A61P3/08
Filed: 1996-04-02
Abstract: 1. 5H,1OH- imidazo [1,2-a]indeno[1,2-e]pyrazin-4one derivatives of formula (1):   wherein R is a hydrogen atom or a carboxy, alkoxycarbonyl, -CO-NR4 R5, -PO3 H2 or -CH2 OH; R1 is an -alk-NH2, -alk-NH-CO-R3, -alk-COOR4, -alk-CO-NR5R6 or -CO-NH-R7 R3 is alkyl, phenyl, phenylalkyl, cycloalkyl or -NR6R8; R4 is a hydrogen atom or alkyl radical; R5 is a hydrogen atom, alkyl, phenyl, cycloalkyl, or phenylalkyl; R6 is a hydrogen atom or alkyl; or R5 and R6 together with a nitrogen atom with which they are bound form mono- or polycyclic, saturated or unsaturated, heterocycle, comprising 1-6 carbon atoms and, possibly, one or several other heteroatoms chosen from O, S, N; R7 is phenyl, phenylalkyl or -alk-COOR4; R8 is a hydrogen atom, alkyl, cycloalkyl or phenylalkyl; wherein "alk" is alkylen radicalin in case that alcoxy, alkyl or alkylene radicals and portions comprise 1-6 carbon atoms and have linear or ramified chain, and cycloalkyl radicals comprise 3-6 carbon atoms; salts thereof, enantiomeres and diastereoisomeres. 2. Derivatives of formula (1) according to Claim 1, in which, when R5 and R6 together with a nitrogen atom with which they are bound form heterocycle, and said heterocycle represents azetidin, pyrrolidin, piperidin, piperazin or morpholin cycle 3. Derivatives of formula (1) according to Claim 1 or 2, in which substituent R1 is in position 8 or 9. 4. Derivatives of formula (1) according to Claim 1, in which R is a hydrogen atom or carboxy radical, R1 is -alk-NH-CO-R3, -alk-COOR4, -alk-CO-NR5R6 or -CO-NH-R7, R3 is alkyl radical or -NR6R; R4 is a hydrogen atom; R5 is a hydrogen atom; R6 is alkyl radical; R7 is phenylalkyl radical or -alk-COOR4; salts thereof, enantiomeres and diastereoisomeres. 5. Derivatives of formula (1) according to Claim 1, representing the following compounds: - (4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-9-yl) acetic acid; - N-methyl-2-(4,5-dihydro-4-oxo-1OH-imidazo[1,2-a]indeno-[1,2-e]pyrazin-9-yl) acetamid - N-[(4,5-dihydro-4-oxo-1OH-imidazo[1,2-a]indeno-[1,2-e]pyrazin-9yl) methyl] acetamid - 9-[(3-methylureido)methyl]-5H, 10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one; -N-methyl-(4,5-dihydro-4-oxo-1OH-imidazo[1,2-a]indeno-[1,2-e]pyrazin-8-yl) acetamid; - 8-N-methylcarboxamidomethyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-2 carboxylic acid; - 8-carboxymethyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-2-carboxylicacid; - 8-(3-methylureido)methyl-5H, 10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one; - 9-carboxymethyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1.2-elpyrazin-2-carboxylic acid; - N--benzyl-(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl) carboxamid; - N-[(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl)carbonyl]glycin. - N-benzyl-(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl) carboxamid; - 8-(N-ethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno [1,2-e]pyrazin-2-carboxylic acid; - 8-(N-ethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno [1,2-e]pyrazin-2-ethylcarboxylate; - 9-N-benzylcarbamoyl-4,5-dihydro-4-oxo-10H-imidazo[1,2--a]indeno[1,2-e]pyrazin-2-carboxylic acid - 8-(2-carboxyethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-elpyrazin-2-carboxylc acid - 9-[(3-methylureido)methyl]-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid - 9-carboxymethyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-phosphonic acid - 9-N-methylaminocarbonylmethyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid. - 9-(1-carboxyethyl)- 4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid salts thereof, enantiomeres and diastereoisomeres. 6. Procedure for preparation 5H, 1OH- imidazo [1,2-a]indeno[1,2-e]pyrazin-4one derivatives of formula (I) as claimed in Claim 1, wherein in the presence of acetate ammonium a compound of formula (II) is cycled       in which R and R1 have values, given in Claim 1 and "alk" isalkyl radical, the product is separated and, if necessary, said product is transformed in salt. 7. Procedure for preparation of compounds of formula (I) as claimed in Claim 1, in which R is carboxy and/or R1 is -alk-COOR4 radical, where R4 is a hydrogen atom, or -CO-NH-R7,in which R7 is -alk-COOR4 radical, in which R4 is a hydrogen atom, wherein a corresponding compound of formula (I) is hydrolyzed, in which R is alcoxycarbonyl and/or R1 is -alk-COOR4 radical. where R4 is alkyl radical or -CO-NH-R7 radical, in which R7 is -alk-COOR4 radical, where R4 is alkylene radical, the product is separated and, if necessary, said product is transformed in salt. 8. Procedure for preparation of compounds of formula (I) as claimed in Claim 1, in which R is -PO3H2, wherein a compound of formula (V)is hydrolyzed:   in which R1 has values, given in Claim 1 and Ra is methyl, ethyl or benzyl, the product is separated and, if necessary, said product is transformed in salt. 9. Procedure for preparation of compounds of formula (I) as claimed in Claim 1, in which R is -CH2OH, wherein a corresponding compound of formula (I) is restored, in which R is alcoxycarbonyl, the product is separated and, if necessary, said product is transformed in salt. 10. Procedure for preparation of compounds of formula (I) as claimed in Claim 1, in which R is -CO-NR4R5, wherein a complex aluminium compound, formed by trialkylaluminium and chlorhydrate amine HNR4R5 is interacted with the corresponding compound of formula (I), in which R is alcoxycarbonyl, the product is separated and, if necessary, said product is transformed in salt. 11. Procedure for preparation of compounds of formula (I) as claimed in Claim 1, in which R1 is -alk-NH-CO-R3 radical, in which R3 is alkyl radical (one carbon atom), wherein a corresponding compound of formula (I), in which R1 is -alk-NH2 radical is interacted with anhydride acetic, the product is separated and, if necessary, said product is transformed in salt. 12. Procedure for preparation of compounds of formula (I) as claimed in Claim 1, in which R1 is -alk-NH-CO-R3 radical, in which R3 is -NR6R8, where R6 is a hydrogen atom and R8 is a hydrogen atom or alkyl radical, wherein a corresponding compound of formula (I), in which R1 is -alk-NH2, are interacted with isocyanate Rb-, NCO in which Rb is trimethylsilyl, alkyl, cycloalkyl or phenylalkyl,and, if necessary, with further hydrolysis of silyl compound, the product is separated and, if necessary, said product is transformed in salt. 13. Procedure for preparation of compounds of formula (I) as claimed in Claim 1, in which R1 is -alk-NH-CO-R3 radical, in which R3 is -NR6R8, where R6 is a hydrogen atom and R8 is alkyl, cycloalkyl or phenylalkyl, wherein a corresponding compound of formula (I), in which R1 is -alk-NH2, are interacted with a compound of formula (VI)   in which Rc is alkyl, cycloalkyl or phenylalkyl, the product is separated and, if necessary, said product is transformed in salt. 14. Procedure for preparation of compounds of formula (I) as claimed in Claim 1, in which R1 is -alk-NH-CO-R3 radical, in which R3 is alkyl, phenyl, phenylalkyl, cycloalkyl or -NR6R8, radical, where R6 is alkyl radical and R8 is alkyl, cycloalkyl or phenylalkyl, wherein a corresponding compound of formula (I), in which R1 is -alk-NH2, radical are interacted with a compound Hal-CO-R3, in which Hal is a hlogen atom and R3 has the above values, the product is separated and, if necessary, said product is transformed in salt. 15. Procedure for preparation of compounds of formula (I) as claimed in Claim 1, in which R1 is -alk-NH-CO-R3 radical, wherein a corresponding compound of formula (I), in which R1 is -alk COOR4, or, when R4 is a hydrogen atom, reactive compound of this acid are interacted with amine HNR5R6, the product is separated and, if necessary, said product is transformed eventually into salt. 16. Procedure for preparation of compounds of formula (I) as claimed in Claim 1, in which R1 is -alk (1 C)-NH2, wherein a compound of formula (VII) is hydrolyzed:   in which R has a value, given in formula (I), the product is separated and, if necessary, said product is transformed in salt. 17. Medicinal, being antagonists of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and the N-methyl-D-aspartate (NMDA) receptors, comprising as an active means at least one compound of formula(I) as claimed in one of Claims 1-5 or salt of such compound. 18. A compound of formula (II)   in which R and R1 have values given in Claim 1 and "alk"is a linear or ramified C1-6 alkyl