Patent EA-004737-B1 (EA)
Title: 12,13-(PYRANOZYL)-INDOLO[2,3-alpha]PYRROLO[3,4-c]CARBAZOLE AND 12,13 PYRANOZYL-FURO[3,4-c]INDOLO[2,3-alpha]CARBAZOLE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
Inventor: PRUDHOMME MICHELLE
IPC: C07H19/23
Filed: 2000-11-16
Abstract: 1-Compounds of formula (I): wherein: R1 and R2, which may be identical or different, each independently of the other represents a group of formula U-V wherein: U represents a single bond or a linear or branched (C1-C6)alkylene chain, optionally substituted by one or more hydroxy groups, V represents a group selected from a hydrogen atom, a halogen atom, a nitro group, a linear or branched (C1-6)alkyl group, a hydroxy group, formyl, NraRb, -C(O)-T1, -C(O)-NRa-T1, -C(O)-O-T1, wherein: Ra and Rb, which may be identical or different, each represents a group selected from a hydrogen atom, a linear or branched (C1-C6)alkyl group, T1 represents a group selected from linear or branched (C1-C6)alkyl, a linear or branched (C1-C6)alkylene chain substituted by a group selected from -ORa, -NRaRb, wherein Ra and Rb are as defined hereinbefore, G represents an oxygen atom or an NR3 group wherein R3 represents a group selected from a hydrogen atom, a linear or branched (C1-C6)alkyl group, an -ORa group, an -NRaRb group, an -NH-C(O)-Ra group and a linear or branched (C1-C6)alkylene chain substituted by one or more identical or different groups selected from -ORa, -NRaRb, wherein Ra and Rb being as defined hereinbefore, X represents a hydrogen atom, a hydroxy group, Y represents a hydrogen atom, or X and Y together with the carbon atom carrying them form a carbonyl group, X1 represents a hydrogen atom, Y1 represents a hydrogen atom, or X1 and Y1 together with the carbon atom carrying them form a carbonyl group, R4 represents a group selected from a hydroxy group and a-O-C(O)-Rc group, wherein Rc represents a direct or branched (C1-C6)alkyl group(optionally substituted by one or more groups selected from halogen and amino) R5 represents a direct (C1-C6)alkoxy group, R6 represents a group of formula -U1-R`4 wherein U1 represents a single bond or a methylene group, and R`4 is as defined hereinbefore, or represents a group selected from a halogen atom, an azido group or a NraRb group, wherein Ra and Rb are as defined hereinbefore, or R4, R5 and R6 taken in pairs in adjacent or non-adjacent positions form with the carbon atoms carrying them a ring system having from 3 to 6 ring members, containing one or two oxygen atoms, with the remaining group R4, R5 or R6 has the meaning R5 given hereinbefore, their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base, provided that the compounds of formula (I) are other than the following compounds: -1,11-dichloro-12,13-[1,2-(4-0-methyl-p-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo-[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione, -12,13-[1,2-(4-0-methyl-P-D-mannopyranosyl)-6,7,12,13-tetrahydro-(5H)-indolo-[2,3-a]-pyrrolo[3,4-c]carbazole-5,7-dione, -12,13-[1,2-(4-0-methyl-p-D-mannopyranosyl)-6,7,12,13-tetrahydro-(5H)-indolo-[2,3-a]-pyrrolo[3,4-c]carbazol-5-one, and -12,13-[1,2-(4-0-methyl-p-D-mannopyranosyl)-5,6,12,13-tetrahydro-(7H)-indolo-[2,3-a]-pyrrolo [3,4-c]-carbazol-7-one. 2. Compounds of formula (I) according to claim 1, characterised in that G represents an NR3 group wherein R3 is as defined for formula (I), their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compounds of formula (I) according to claim 1, characterised in that X and Y together with the carbon atom carrying them form a carbonyl group, and X1 and Y1 together with the carbon atom carrying them form a carbonyl group, their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to claim 1, characterised in that they represent compounds of formula (I bis): wherein R1, R2, R3, R4, R5 and R6 are as defined for formula (I), their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to claim 1 or claim 4, characterised in that R1 and R2, which may be identical or different, represent a group of formula U-V wherein U represents a single bond and V represents a group selected from a halogen atom, a hydrogen atom, a nitro group, a formyl group, a hydroxy group, and a linear or branched (C1-C6)alkylene chain substituted by a hydroxy group, their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 6. Compounds of formula (I) according to claim 1 or claim 4, characterised in that R1 and R2 are identical, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 7. Compounds of formula (I) according to claim 1 or claim 4, characterised in that R3 represents a hydrogen atom, a hydroxy group or a linear or branched (C1-C6) alkylene chain substituted by a group selected from NRaRb and ORa wherein Ra and Rb are as defined for formula (I), their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 8. Compounds of formula (I) according to claim 1 or claim 4, characterised in that they represent compounds of formula (I ter): wherein R1, R2, R3 and R6 are as defined for formula (I), their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 9. Compounds of formula (I) which are: -3,9-diformyl-12,13-[1,2-(4-O-methyl-beta-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo [2,3-alpha]pyrrolo [3,4-c] carbazole-5,7-dione, -3,9-dinitro-12,13-[1,2-(4-O-methyl-p-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-alpha]pyrrolo[3,4-c]carbazole-5,7-dione, -3-nitro-12,13-[1,2-(4-O-methyl-beta-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo [2,3-alpha]pyrrolo[3,4-c] carbazole-5,7-dione, -9-nitro-12,13-[1,2-(4-O-methyl-beta-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-alpha]pyrrolo[3,4-c]carbazole-5,7-dione, -6-hydroxy-12,13-[1,2-(4-O-methyl-beta-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo [2,3-alpha]pyrrolo [3,4-c] carbazole-5,7-dione, -3,9-di-(hydroxymethyl)-12,13-[1,2-(4-O-methyl-beta-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-alpha]pyrrolo[3,4-c]carbazole-5,7-dione, -3,9-dinitro-12,13-[1,2-(3,6-anhydro-4-O-methyl-beta-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo [2,3-alpha]pyrrolo [3,4-c] carbazole-5,7-dione, -3,9-dihydroxy-12,13-[1,2-(4-O-methyl-beta-D-mannopyranosyl)]-6,7,12.13-tetrahydro-(5H)-indolo[2,3-alpha]pyrrolo[3,4-c]carbazole-5,7-dione, -3,9-dibromo-12,13-[1,2-(4-O-methyl-beta-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-alpha]pyrrolo[3,4-c]carbazole-5,7-dione, and -6-diethylaminoethyl-12,13-[1,2-(4-O-methyl-beta-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-alpha]pyrrolo[3,4-c]carbazole-5,7-dione, and its hydrochloride, their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 10. Process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): wherein X, Y, X1, Y1, R4, R5 and R6 are as defined for formula (I), which is treated in a basic medium with a toluenesulphonic acid, to yield a compound of formula (III): wherein X, Y, X1, Y1, R4, R5 and R6 are as defined hereinbefore, which compound of formula (III) is reacted with sodium azide, to yield principally a compound of formula (I/a), a particular case of the compounds of formula (I): wherein X, Y, X1, Y1, R4, R5 and R6 are as defined hereinbefore, which compound of formula (I/a) is subjected to conditions of hydrogenolysis, to yield a compound of formula (I/b), a particular case of the compounds of formula (I): wherein X, Y, X1, Y1, R4, R5 and R6 are as defined hereinbefore, which compound of formula (I/b) is treated with aqueous sodium hydroxide solution and then treated with hydrochloric acid, to yield a compound of formula (I/c), a particular case of the compounds of formula (I): wherein X, Y, X1, Y1, R4, R5 and R6 are as defined hereinbefore, which compound of formula (I/c) is subjected to the action of a compound of formula (IV): R3aNH2 (IV) wherein R3a has the same definitions as R3 with the exception of a hydrogen atom, to yield a compound of formula (I/d), a particular case of the compounds of formula (I): wherein X, Y, X1, Y1, R3a, R4, R5 and R6 are as defined hereinbefore, the totality of the compounds of formulae (I/b) to (I/d) constituting the compounds of formula (I/e): wherein G, X, Y, X1, Y1, R4, R5 and R6 are as defined for formula (I), which compound of formula (I/e) is subjected to an electrophilic aromatic addition reaction or to a nucleophilic aromatic addition reaction, according to conventional conditions of organic synthesis well known to the person skilled in the art, to yield a compound of formula (I/f), a particular case of the compounds of formula (I): wherein G, X, Y, X1, Y1, R4, R5 and R6 are as defined hereinbefore, and R1a and R2a have the same definitions as R1 and R2, respectively, except that R1a and R2a cannot simultaneously represent a hydrogen atom, which compounds of formulae (I/a) to (I/f) constitute the totality of the compounds of formula (I), which are purified, if necessary, according to conventional purification techniques, which may, if desired, be separated into their different isomers according to a conventional separation technique, the substituents R4, R5 and R6 of which are adjusted according to conventional methods of organic synthesis used in the field of sugar chemistry, and which are converted, if desired, to addition salts thereof with a pharmaceutically acceptable acid or base. 11. Pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) according to any one of claims 1 to 9, on its own or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers. 12. Pharmaceutical compositions according to claim 10 for use as anti-tumour agents in the treatment of cancers.