Patent EA-005200-B1 (EA)
Title: Carbamate and thiocarbamate podophyllotoxin derivatives, preparation method and pharmaceutical compositions containing them
Inventor: MONNERET CLAUDE
IPC: A61K31/36
Filed: 2001-06-19
Abstract: 1. Compounds of formula (I): wherein: R1 represents a hydrogen atom, R2 represents an oxygen atom, R3 a hydrogen atom or linear or branched (C1-C6)alkyl, X represents a linear or branched (C1-C6)alkylene group, R4 represents a group selected from: amino optionally substituted by one or two identical or different groups selected from linear or branched (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, a group of formula -N(R3)-X1-OR5 wherein R3 is as defined hereinbefore, X1 represents a linear or branched (C1-C6)alkylene group and R5 represents a group selected from hydrogen, linear or branched (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, a group of formula -N(R3)-X1-OR5 wherein R3 and X1 are as defined hereinbefore, their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base, isomers is to be understood as meaning the enantiomers and the diastereoisomers. 2. Compounds of formula (I) according to claim 1, characterised in that R1 represents a hydrogen atom, their isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compounds of formula (I) according to claim 1, characterised in that R4 represents a group -N(R3)-X1-OR5 or -O-X1-OR5, wherein R3 represents a hydrogen atom, X1 represents a linear -(C2-C4)alkylene group, and R5 represents a hydrogen atom, their isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to claim 1 that are: (5S,5aS,8aS,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-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, (5S,5aS,8aR,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-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, (5S,5aS,8aS,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl-3-(dimethylamino)propylcarbamate, (5S,5aS,8aS,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl 2-(2-hydroxyethoxy)ethylcarbamate, (5S,5aS,8aS,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexa-hydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl 2-[(2-hydroxyethyl)amino]ethylcarbamate, and (5S, 5aS,8aS,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl 2-(dimethylamino)ethylcarbamate, and their isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 5. Process for the preparation of the compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): which is subjected under basic conditions: or to the action of a compound of formula (V): G-L (V) wherein G represents a conventional protecting group for hydroxy functions and L represents a leaving group customary in organic chemistry, to yield the compounds of formula (IV/B): wherein G is as defined hereinbefore, which compound of formula (IV) is treated in basic medium with a compound of formula (VI)): Ph-O-C(R2)Cl (VI) wherein Ph represents an optionally substituted phenyl group and R2 represents an oxygen atom to yield the compounds of formula (VII): wherein G, Ph and R2 are as defined hereinbefore, which compound of formula (VII) is reacted in basic medium with a compound of formula (VIII): R4-X-NH-R3 (VIII) wherein R4, R3 and X are as defined for formula (I), to yield the compounds of formula (IX) wherein G, R2, R3, R4 and X are as defined hereinbefore, the hydroxy function of which compounds of formula (IX) is deprotected according to conventional methods of organic chemistry, a particular case of the compounds of formula (I): wherein R1, R2, R3, R4 and X are as defined for formula (I), which compounds are purified, if necessary, according to a conventional purification technique, may be separated, if desired according to a conventional separation technique, and are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base. 6. Pharmaceutical compositions comprising as active ingredient at least one compound according to any one of claims 1 to 4, alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers. 7. Pharmaceutical compositions according to claim 6, containing at least one active ingredient according to any one of claims 1 to 4, for use in the treatment of cancer.