Patent EA-003996-B1 (EA)
Title: NEW DIHYDROFURO{3,4-b}QUINOLIN-1-ONE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
Inventor: HUSSON HENRI-PHILIPPE
IPC: C07D495/16
Filed: 2000-11-23
Abstract: 1. Compound of formula (I): wherein: ----- represents a single or double bond, R0 represents hydrogen, hydroxy or linear or branched (C1-C6)alkoxy, R1 and R2, which are identical or different, each represents: - a hydrogen atom, - a linear or branched (C1-C6)alkyl group, - a linear or branched (C1-C6)alkoxy group, - a hydroxy group, - or form together with the carbon atoms carrying them an aromatic or non-aromatic. mono- or bi-cyclic group having from 5 to 12 ring members, optionally containing 1 or 2 hetero atoms selected from O, S and N, R3 represents a hydrogen atom or a group of formula R4 wherein R4 represents: x an aryl group, x a linear or branched (C1-C6)alkyl group optionally substituted by an aryl group, by a heteroaryl group, by a hydroxy group, or by a group of formula NR5R6 wherein R5 and R6, which are identical or different, each represents a linear or branched (C1-C6)alkyl group or a linear or branched (C1-C6), x or a group of formula COR7, wherein R7 represents linear or branched (C1-C6)alkyl (optionally substituted by a group of formula NR8R9 wherein R8 and R9, which are identical or different, each represents a linear or branched (C1-C6)alkyl group or a linear or branched (C1-C6)hydroxyalkyl group, X represents an oxygen or sulphur atom or a -CH2- or -CH2-CH2- group, Ar represents an aryl, heteroaryl or aryl-(C1-C6)alkyl group in which alkyl is linear or branched, it being understood that a least one of R0, R1, or R2 is other than hydrogen; their optical isomers, their hydrates, solvates and also addition salts thereof with a pharmaceutically acceptable acid, wherein aryl is to be understood as phenyl, biphenyl, naphthyl or tetrahydronaphthyl, each of those groups being optionally substituted by one or more identical or different atoms or groups selected from halogen atoms and the groups linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6))alkoxy, linear or branched (C1-C6)polyhaloalkyl, amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups), nitro, linear or branched (C1-C6)acyl and (C1-C2)alkylenedioxy, heteroaryl is to be understood as an aromatic, mono-cyclic group having from 5 to 6 ring members and containing one hetero atom, selected from oxygen, nitrogen and sulphur, wherein the heteroaryl group may be optionally substituted by one or more identical or different atoms or groups selected from halogen and linear or branched (C1-C6)alkyl, a hydroxy group, linear or branched (C1-C6)alkoxy group, linear or branched (C1-C6)polyhaloalkyl, and amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups). 2. Compound of formula (I) according to claim 1, wherein ----- represents a double bond. 3. Compound of formula (I) according to any one of claims 1 or 2, wherein R0 represents a hydrogen atom. 4. Compound of formula (I) according to any one of claims 1 to 3, wherein R1 and R2, which are identical or different, each represents: - a hydrogen atom, - a linear or branched (C1-C6)alkyl group, - a linear or branched (C1-C6)alkoxy group, - a hydroxy group. 5. Compound of formula (I) according to any one of claims 1 to 3, wherein R1 and R2 form together with the carbon atoms carrying them an aromatic or non-aromatic, mono- or bi-cyclic group having from 5 to 12 ring members and optionally containing 1 or 2 hetero atoms selected from O, S and N. 6. Compound of formula (I) according to claim 5, wherein R1 and R2 form together with the carbon atoms carrying them a group of formula G3 or G4: 7. Compound of formula (I) according to claim 5, wherein R and R; form together with the carbon atoms carrying them a phenylene group. 8. Compound of formula (I) according to any one of claims 1 to 7, wherein X represents an oxygen atom. 9. Compound of formula (I) according to any one of claims 1 to 7, wherein X represents a sulphur atom. 10. Compound of formula (I) according to any one of claims 1 to 7, wherein X represents a -CH2- or -CH2-CH2- group. 11. Compound of formula (I) according to any one of claims 1 to 10, wherein Ar represents an aryl group. 12. Compound of formula (I) according to any one of claims 1 to 10, wherein Ar represents a heteroaryl group. 13. Compound of formula (I) according to claim 11, wherein Ar represents a phenyl group. 14. Compound of formula (I) according to claim 1 that is (+-)-4-methyl-6,7-methylenedioxy-9-(3,4,5-trimemoxyphenyl)-4,9-dihydrofuro[3,4-b]quinolin-1(3H)-one, and also its optical isomers and its hydrates and solvates. 15. Compound of formula (I) according to claim 1 that is (+-)-6,7-methylenedioxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydrofuro[3,4-b]quinolin-1(3H)-one, its optical isomers, its hydrates, solvates, and also its addition salts with a pharmaceutically acceptable acid. 16. Compound of formula (I) according to claim 1 that is (+-)-6-methoxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydrofuro[3,4-b]quinolin-1(3H)-one, its optical isomers, its hydrates, solvates, and also its addition salts with a pharmaceutically acceptable acid. 17. Compound of formula (I) according to claim 1 that is (+-)-7-(3,4,5-trimethoxyphenyl)-7,11-dihydrobenzo[h]furo[3,4-b]quinolin-8(10H)-one, its optical isomers, its hydrates, solvates, and also its addition salts with a pharmaceutically acceptable acid. 18. Compound of formula (I) according to claim 1 that is (+-)-6,7-methylenedioxy-9-(3,4,5-trimethoxyphenyl)-2,3,4,9-tetrahydrocyclopenta[b]quinolin-1-one, its optical isomers, its hydrates, solvates, and also its addition salts with a pharmaceutically acceptable acid. 19. Compound of formula (I) according to claim 1 that is (+-)-6,7-ethylenedioxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydrofuro[3,4-b]quinolin-1(3H)-one, its optical isomers, its hydrates, solvates, and also its addition salts with a pharmaceutically acceptable acid. 20. Compound of formula (I) according to claim 1 that is (+-)-7-(3,4,5-trimethoxyphenyl)-7,9,10,11-tetrahydro-8H-benzo[h]cyclopenta[b]quinohn-8-one, its optical isomers, its hydrates, solvates, and also its addition salts with a pharmaceutically acceptable acid. 21. Process for the preparation of the compounds of formula (I) according to claim 1, characterised in that a compound of formula (II): wherein R0, R1, R2 and R3 have the same meanings as for formula (I), is reacted with a compound of formula (III): wherein X and Ar have the same meanings as for formula (I), to yield a compound of formula (Ia), a particular case of the compounds of formula (I): wherein R0, R1, R2, R3, X and Ar are as defined hereinbefore, which is then reduced, if desired, to a compound of formula (Ib), a particular case of the compounds of formula (I): wherein R0, R1, R2, R3, X and Ar are as defined hereinbefore, which compounds of formulae (Ia) and (Ib), which constitute the totality of the compounds of formula (I), are purified, if necessary, according to a conventional purification technique, are separated, if desired, into their optical isomers according to a conventional separation technique, and are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid. 22. Process for the preparation of the compounds of formula (I) according to claim 1, characterised in that there are reacted in the same pot a compound of formula (II): wherein R0, R1, R2, and R3 have the same meanings as for formula (I), a compound of formula (VIII): wherein Ar has the same meanings as for formula (I), and a compound of formula (IX): wherein X has the same meanings as for formula (I), to yield a compound of formula (Ia), a particular case of the compounds of formula (I): wherein R0, R1, R2, R3, X and Ar are as defined hereinbefore, which is then reduced, if desired, to a compound of formula (Ib), a particular case of the compounds of formula (I) : wherein R0, R1, R2, R3, X and Ar are as defined hereinbefore, which compounds of formulae (Ia) and (Ib), which constitute the totality of the compounds of formula (I), are purified, if necessary, according to a conventional purification technique, are separated, if desired, into their optical isomers according to a conventional separation technique, and are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid. 23. Pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 20, alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers. 24. Pharmaceutical composition according to claim 23, for use in the manufacture of anti-cancer medicaments.