Patent EA-003275-B1 (EA)
Title: Novel aromatic amides, preparation method and application as medicines
Inventor: HAESSLEN JEAN-LUC
IPC: A61K31/70
Filed: 1999-01-07
Abstract: 1. The compounds of formula (I): in which: -Y represents an oxygen atom, or anN-Nhalk1 or Noalk2 radical in which alk1 and alk2 represent an alkyl radical, containing up to 12 carbon atoms optionally interrupted by one or more oxygen, sulphur or nitrogen atoms, optionally substituted by one or more halogen atoms, by an aryl radical optionally substituted by one or more halogen atoms, by a heterocyclic radical, by one or more radicals in which Ra and Rb identical to or different from one another represent a hydrogen atom, an optionally substituted alkyl radical containing up to 8 carbon atoms, or Ra and Rb form together with the nitrogen atom to which they are joined, a heterocycle which can contain in addition another heteroatom chosen from oxygen, sulphur or nitrogen, X represents a hydrogen atom, a hydroxyl radical, a linear, branched or cyclic alkyl, alkenyl or alkynyl radical optionally interrupted by one or more oxygen, sulphur and or nitrogen atoms, containing up to 12 carbon atoms, optionally substituted by one or more halogen atoms, by a heterocyclic radical, one or more free or esterified OH, C [triple bond] N, NO2 radicals in which Ra and Rb, identical or different, represent a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, or Ra and Rb form together with the nitrogen atom to which they are linked a heterocycle optionally containing another heteroatom chosen from nitrogen, sulphur or oxygen, or X represents an alkoxy radical or a radical in which Re represents an alkyl radical containing up to 8 carbon atoms, optionally substituted by one or more of the substituents indicated above, or X represents an NRcRd radical in which Re and Rd identical or different, represent a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, optionally substituted by one or more of the substituents indicated above, or Re and Rd form together with the nitrogen atom to which they are linked a heterocycle optionally containing another heteroatom chosen from nitrogen, sulphur or oxygen, - Z represents a hydrogen or halogen atom or a free, etherified or esterified OH radical, - R2 represents a hydrogen or halogen atom, - R3 represents a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or a halogen atom, - R represents a hydrogen atom or an alkyl radical containing up to 4 carbon atoms, - R1 represents a hydrogen atom, a linear, branched or cyclic alkyl, alkenyl or alkynyl radical containing up to 8 carbon atoms, optionally substituted by one or more halogen atoms, a C [triple bond] N radical, an aryl radical containing up to 14 carbon atoms, - R5 represents a hydrogen atom, an 0-alkyl radical containing up to 4 carbon atoms, - either R6 represents an alkyl or CH2-O-alkyl radical, in which alkyl represents an alkyl radical containing up to 8 carbon atoms, as well as ethynyl and propynyl. - R7; represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, - or R6 and R7 form together with the carbon atom which carries them a ring containing up to 8 carbon atoms, as well as the salts of the compound of formula (I), when the compounds of formula (I) have a basic function. 2. The compounds of formula (I) defined in claim 1, in which Y represents an oxygen atom. 3. The compounds of formula (I) in which Y represents an NO-alkyl radical in which the alkyl radical contains up to 4 carbon atoms. 4. The compounds of formula (I) defined in claim 3, in which Y represents the NOC2H5 radical. 5. The compounds of formula (I) defined in any one of claims 1 to 4 in which X represents an alkyl radical containing up to 4 carbon atoms and in particular the CH3 radical. 6. The compounds of formula (I) defined in any one of claims 1 to 4, in which X represents an NH2 radical. 7. The compounds of formula (I) defined in any one of claims 1 to 4 in which X represents the radical: 8. The compounds of formula (I) defined in any one of claims 1 to 7 in which R1 represents a radical: 9. The compounds of formula (I) defined in any one of claims 1 to 8 in which R represents a hydrogen atom. 10. The compounds of formula (I) defined in any one of claims 1 to 9 in which Ra represents a methyl radical. 11. The compounds of formula (I) defined in any one of claims 1 to 10 in which Z represents a hydrogen atom. 12. The compounds of formula (I) defined in any one of claims 1 to 11 in which R2 represents a hydrogen atom. 13. The compounds of formula (I) defined in any one of claims 1 to 12 in which R5 represents an OCH3 radical. 14. The compounds of formula (I) defined any one of claims 1 to 13 in which R6 represents a methyl radical. 15. The compounds of formula (I) defined in any one of claims 1 to 14 in which R7 represents a methyl radical. 16. The compounds of formula (I) defined in any one of claims 1 to 14 in which R7 represents an ethyl radical. 17. The compounds of formula (I), defined in any one of claims 1 to 13 in which R6 and R7 form with the carbon atom which carries them a cyclopentyl radical. 18. The compounds of formula (I) defined in claim 1 the names of which follow: (2-propynyloxy)carbamic acid 3'-ester of 7-[[6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl ] oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxamide, (2-propynyloxy)-carbamic acid 3'-ester of 7-[[6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl) oxy]-4-hydroxy-8-methyl-N-[2-(4-morpholinyl)ethyl]-2-oxo-2H-1-benzopyran-3-carboxamide, (2-propynyloxy)-carbamic acid 3'-ester of 7-[[6-deoxy-S-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl] oxy]-4-hydroxy-3-[1-(methoxyimino) ethyl] -8-methyl-2H-1-benzopyran-2-one, (2-propynyloxy)-carbamic acid 3'-ester of 7-[(6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyL) oxy]-3-[l-(ethoxyimino) ethyl]-4-hydroxy-8-methyl-2H-1-benzopyran-2-one. 19. The compounds of formula (I) the names of which follow: (2-propynyloxy)-carbamic acid 3'-ester of 7-[(6-deoxy-5-C-ethyl-4-O-methyl-beta-D-gulopyranosyl) oxy]-4-hydroxy-3-[1-(methoxyimino) ethyl]-8-methyl-2H-1-benzopyran-2-one, [7R-(7-alpha, 8-beta, 9-beta, 10-alpha)]-(2-propynyloxy)-carbamate of 8-hydroxy-7-[4-hydroxy-3-[1-(methoxyimino) ethyl]-8-methyl-2-oxo-2H-1-benzopyran-7-yl]-10-methoxy-6-oxaspiro [4,5]decan-9-yl. 20. As medicaments, the compounds of formula (I) defined in any one of Claims 1 to 18 as well as their pharmaceutically acceptable salts. 21. As medicaments the compounds of formula (I) defined in Claim 19 as well as their pharmaceutically acceptable salts. 22. A pharmaceutical composition containing at least one medicament defined in claims 20 or 21 as active ingredient. 23. Process for the preparation of the compounds of formula (I) defined in any one of Claims 1 to 19 characterized in that a compound of formula (II) in which the R2, R3, Z, R5, R6 and R7 radicals retain their previous meaning, OW represents a blocked hydroxyl group and W` represents an alkyl or O-alkyl radical containing up to 4 carbon atoms, is subjected - to the action of an agent capable of introducing the radical or of a series of operations capable of introducing the radical R and R1 retaining their previous meaning, - to the action of an agent capable of releasing the hydroxyl radical from the OW radical, - to the optional action of an agent capable of replacing W` by the X radical which is different from alkyl or O-alkyl, - to the optional action of an agent capable of introducing the Y radical which is different from oxygen, - to the optional action of a salification agent. 24. Use of the compounds of formula (II) as defined in Claim 23 as intermediate compounds. 25. Process according to claim 23 characterized in that the product of formula (II) is prepared by the action of a compound of formula (III) in which R5, R6 and R7 retain their previous meaning on a compound of formula (IV) in which R2, R3 and Z retain their previous meaning, then of a blocking agent of the free hydroxyl radical. 26. Use of the compounds of formula (III) as defined in Claim 25 as intermediate compounds.