Patent EA-004440-B1 (EA)
Title: 9-(3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro [3',4':6,7]-naphto [2,3-d] [1,3] dioxol-6(5ah)-one derivatives, their preparation process and pharmaceutical compositions containing them
Inventor: MONNERET CLAUDE
IPC: A61K31/70
Filed: 2000-10-27
Abstract: 1. A compound selected from those of formula (I): wherein: R represents: a group of formula (i): wherein: X and Y, which may be identical or different, each represent a group selected from hydrogen, hydroxy and amino, W represents hydrogen, linear or branched (C1-C6)alkyl, - or a group of formula (ii): -A-G (ii) wherein: A represents a single bond or a linear or branched (C1 -C6) alkylene chain optionally substituted by one or more hydroxy groups, G represents a group selected from hydrogen, -OR2, -NR3 R4, -NR2 C(O)-T2, -O-C(O)-O-T2, -O-C(O)-O-NR2-T2, and NR2SO2-T3, wherein: R2 represents hydrogen, linear or branched (C1-C6)alkyl, R3 and R4, which may be identical or different, each represent independently of the other: - hydrogen, linear or branched (C1-C6)alkyl, T2 represents a group selected from hydrogen, linear or branched (C1-C6) alkyl (optionally substituted by one or more halogen), aryl, aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, or T2 represents a linear or branched (C1-C6)alkylene chain, the chain being substituted by one or more identical or different groups selected from -NR3R4, wherein R3, R4 are as defined hereinbefore, T3 represents a group selected from linear or branched (C1-C20)alkyl, aryl, aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, heterocycloalkyl, heterocycloalkyl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, R1 represents a group selected from hydrogen, linear or branched (C1-C6)alkyl, arylcarbonyl, aryl-(C1-C6)alkylcarbonyl in which the alkyl moiety may be linear or branched, heterocycloalkylcarbonyl, linear or branched (C1-C6)alkylsulphonyl, aryloxycarbonyl and aryl-(C1-C6)alkoxycarbonyl in which the alkoxy moiety may be linear or branched, its isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base, wherein: aryl denotes phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl or indanyl, each of those groups optionally having one or more identical or different substituents selected from halogen, hydroxy, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, cyano, nitro, amino, linear or branched (C1-C6)alkylamino, di-(C1-C6)alkylamino in which each alkyl moiety may be linear or branched, linear or branched (C1-C6)alkylsulphonyl, linear or branched (C1-C6)alkylsulphonylamino, carboxy, linear or branched (C1-C6)alkoxycarbonyl, aryloxycarbonyl, aryl-(C1-C6)alkoxycarbonyl in which the alkoxy moiety may be linear or branched, linear or branched (C1-C6)hydroxyalkyl, linear or branched (C1-C6)trihaloalkyl, methylenedioxy, ethylenedioxy, morpholinyl, piperidyl, piperazinyl, linear or branched (C1-C6)alkylcarbonyloxy and linear or branched (C1-C6)alkylcarbonyl, heteroaryl denotes an aromatic monocyclic group, having 5 or 6 ring members and having one heteroatom, selected from oxygen and sulfur, it being possible for the said heteroaryl optionally to be substituted by the same substituents as those described in the case of the aryl group, heterocycloalkyl is to be understood as a monocyclic cycloalkyl or a bicyclic group that is saturated or unsaturated, but not of aromatic character, that contains from 3 to 10 carbon atoms containing one or two identical or different heteroatoms, selected from oxygen, nitrogen and sulphur, said heterocycloalkyl being optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)trihaloalkyl, hydroxy, linear or branched (C1-C6)hydroxyalkyl, amino, linear or branched (C1-C6)alkylamino, di-(C1-C6)-alkylamino in which each alkyl moiety may be linear or branched, piperidyl, piperazinyl and morpholinyl, with the proviso that R1 does not represent methyl when R represents a group -A-G in which A represents a single bond and G represents hydrogen. 2. Compound of claim 1, wherein R1 represents a group selected from hydrogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxycarbonyl, aryloxycarbonyl and aryl-(C1-C6)alkoxycarbonyl in which the alkoxy moiety may be linear or branched, its isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compound of claim 1, wherein R1 represents hydrogen, its isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compound of claim 1, wherein R represents a group of formula (i) as defined for formula (I), wherein: X represents amino, and Y represents hydroxy; or X and Y are identical and each represents hydroxy; or X represents hydrogen and Y represents amino, and W represents methyl, its isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 5. Compound of claim 1, wherein R represents a group of formula (i) such as: its isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 6. Compound of claim 1, wherein R represents a group of formula (ii) as defined for formula (I) wherein: A represents a single bond and G represents a group selected from -NR3 R4, -O-C(O)-NR2-T2, -NR2-SO2-T3, wherein in which T2, T3, R3, R4 are as defined for formula (I). its isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 7. Compound of either claim 1, wherein R represents a group of formula (ii) as defined for formula (I), wherein: A represents a single bond and G represents a group -O-C(O)-NR2-T2 wherein R2 and T2 are as defined for formula (I) and, advantageously, R2 represents hydrogen or linear or branched (C1-C6)alkyl and T2 represents an optionally substituted aryl group or a linear or branched (C1-C6)alkylene chain substituted by -NR3R4 wherein R3 and R4 are as defined for formula (I), its isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 8. Compound of claim 1 or 6, wherein R represents a group of formula (ii) as defined for formula (I) wherein: A represents a single bond and G represents -NR2-SO2-T3 wherein R2 and T3 are as defined for formula (I) and, advantageously, R2 represents hydrogen or linear or branched (C1-C6)alkyl and T3 represents linear or branched (C1-C6)alkyl, aryl or heteroaryl, its isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 9. Compound of claim 1 selected from the group consisting of: 9-(4-hydroxy-3,5-dimethoxyphenyl)-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4': 6,7]naphtho[2,3-d][1,3]dioxol-5-yl 4-fluorophenylcarbamate, 9-(4-hydroxy-3,5-dimethoxyphenyl)-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4': 6,7]naphtho[2,3-d][1,3]dioxol-5-yl 2-(dimethylamino)ethyl(methyl)carbamate, 9-(4-hydroxy-3,5-dimethoxyphenyl)-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4': 6,7]naphtho[2,3-d][1,3]-dioxol-5-yl 2-(dimethylamino)ethylcarbamate, 9-(4-hydroxy-3,5-dimethoxyphenyl)-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4': 6,7]naphtho[2,3-d][1,3]dioxol-5-yl 3-(dimethylamino)propyl(methyl)carbamate, and 9-(4-hydroxy-3,5-dimethoxyphenyl)-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4': 6,7]naphtho[2,3-d][1,3]dioxol-5-yl 3-(dimethylamino)propylcarbamate, and their isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 10. Compound of claim 1 selected from the group consisting of: (5R,5aR,8aS,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl 4-fluorophenylcarbamate, (5R,5aS,8aR,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-6-oxo-5,5a,6,8,8a,9-hexahydrofuro [3',4':6,7]naphtho [2,3-d][1,3]dioxol-5-yl 2-(dimethylamino)ethyl(methyl)carbamate, (5R,5aR,8aS,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]-dioxol-5-yl 2-(dimethylamino)ethylcarbamate, (5R,5aR,8aS,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl 3-(dimethylamino)propyl(methyl)carbamate and (5R,5aS,8aR,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl 3-(dimethylamino)propylcarbamate. 11. Method for preparing the compounds of formula (I), characterized in that the starting material hereon is compound of formula (II): hydroxy functional groups of which are protected by silyl protective group, ordinarily used in organic chemistry, in accordance to working conditions, ordinary in organic synthesis, to prepare the compounds of formula (III): where E is silyl protective group; compound of formula (III) is treated by reducing agent, resulting the compound of formula (IV): wherein E is such as defined before, compound of formula (IV) is subjected to reaction in base medium at the presence of tetrapropylammonia perrutenate, resulting the compound of formula (V): wherein E is such as defined before, compound of formula (V) is treated during few hours by tetrabutylammonia fluoride, resulting the compound of formula (I/a), particular case of compounds of formula (I): compound of formula (I/a) is subjected in basic reaction conditions with compound of formula (VII): R'1-X (VII) wherein R'1 is linear or branched (C1-C6)alkyl group, arylcarbonyl, aryl-(C1-C6)alkylcarbonyl, where the alkyl part can be linear or branched, heterocycloalkylcarbonyl, linear or branched (C1-C6)alkoxycarbonyl, aryloxy carbonyl, aryl-linear or branched (C1-C6) alkoxycarbonyl, where alkoxy group can be linear or branched, linear or branched(C1-C6) alkylsulfonyl, and X is hydrogen atom or halogen atom, resulting the compound of formula (I/b), particular case of compounds of formula (I): where R'1 is such as defined before, wherein the whole of compounds of formulas (I/a) and (I/b) are compounds of formula (I/c): where R1 is such as defined for formula (I), compound of formula (I/c) is subjected to reaction: - with compound of formula (VIII): where X, Y and W are such as defined for formula (I) and SiG represent a silyl protective group, usually used in sugar chemistry, in presence of boron trifluorid