Patent EA-003605-B1 (EA)
Title: Camptothecin derivatives having antitumor activity
Inventor: PENCO SERGIO
IPC: A61P35/00
Filed: 2000-03-08
Abstract: 1. Compounds of formula (I) wherein: R1 is a -C(R5)=N-O(n)R4 group, wherein R4 is hydrogen or a C1-C8 linear or branched alkyl or C1-C8 linear or branched alkenyl group or C3-C10 cycloalkyl, or (C3-C10) cycloalkyl - (C1-C8) linear or branched alkyl group, or C6-C14 aryl, or (C6-C14) aryl - (C1-C8) linear or branched alkyl group, or a heterocyclic or heterocyclo - (C1-C8) linear or branched alkyl group, said heterocyclic group containing at least a heteroatom selected from the group consisting of nitrogen atom, optionally substituted with a (C1-C8) alkyl group, and/or oxygen and/or sulfur; said alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aryl-alkyl, heterocyclic or heterocyclo-alkyl groups, being optionally substituted with one or more groups selected from the group consisting of: halogen, hydroxy, C1-C8 alkyl, C1-C8 alkoxy, phenyl, cyano, nitro, -NR6R7, wherein R6 and R7, the same or different between them, are hydrogen, (C1-C8) linear or branched alkyl; the-COOH group or a pharmaceutically acceptable ester thereof; or the-CONR8R9 group, wherein R8 and R9, the same or different between them, are hydrogen, (C1-C8) linear or branched alkyl, phenyl; or R4 is a (C6-C10) aroyl or (C6-C10) arylsulfonyl group, optionally substituted with one or more groups selected from the group consisting of: halogen, hydroxy, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, phenyl, cyano, nitro, -NR10R11, wherein R10 and R11, the same or different between them are hydrogen, C1-C8 linear or branched alkyl; R4 is a polyaminoalkyl group of formula -(CH2)m-NR12-(CH2)p-NR13-(CH2)q-NH2, wherein m, p, are an integer from 2 to 6 and q is an integer from 0 to 6, extreme included and R12 and R13 are a (C1-C8) linear or branched alkyl, or R4 is a glycosyl group selected from 6-D-galactosyl, 6-D-glucosyl, D-galactopyranosyl, the glycosyl group being optionally protected with a suitable ketal group; n is the number 1; R5 is hydrogen, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkenyl, C3-C10 cycloalkyl, (C3-C10) cycloalkyl - (C1-C8) linear or branched alkyl, C6-C14 aryl, (C6-C14) aryl - (C1-C8) linear or branched alkyl; R2 and R3, the same or different between them are hydrogen, hydroxy, C1-C8 linear or branched alkoxy; their N1-oxides, their single isomers, in particular the syn and anti isomers of the-C(R5)=N-O(n) R4 group, their possible enantiomers, diastereoisomers and relative admixtures and the pharmaceutically acceptable salts thereof. 2. Compounds according to claim 1, selected from the group consisting of: -7-methoxyiminomethylcamptothecin; -7-methoxyiminomethyl-10-hydroxycamptothecin; -7-(ter-butoxycarbonyl-2-propoxy)iminomethylcamptothecin; -7-ethoxyiminomethylcamptothecin; -7-isopropoxyiminomethylcamptothecin; -7-(2-methylbutoxy)iminomethylcamptothecin; -7-t-butoxyiminomethylcamptothecin; -7-t-butoxyiminomethyl-10-hydroxycamptothecin; -7-t-butoxyiminomethyl-10-methoxycamptothecin; -7-(4-hydroxybutoxy)iminomethylcamptothecin; -7-triphenylmethoxyiminomethylcamptothecin; -7-carboxymethoxyiminomethylcamptothecini; -7-(2-amino)ethoxyiminomethylcamptothecin; -7-(2-N,N-dimethylamino)ethoxyiminomethylcamptothecin; -7-allyloxyiminomethylcamptothecin; -7-cyclohexyloxyiminomethylcamptothecin; -7-cyclohexylmethoxyiminomethylcamptothecin; -7-cyclooctyloxyiminomethylcamptothecin; -7-cyclooctylmethoxyiminomethylcamptothecin; -7-benzyloxyiminomethylcamptothecin; -7-[(1-benzyloxyimino)-2-phenylethyl]camptothecin; -7-(1-benzyloxyimino)ethylcamptothecin; -7-phenoxyiminomethylcamptothecin; -7-(1-t-butoxyimino)ethylcamptothecin; -7-p-nitrobenzyloxyiminomethylcamptothecin; -7-p-methylbenzyloxyiminomethylcamptothecin; -7-pentafluorobenzyloxyiminomethylcamptothecin; -7-p-phenylbenzyloxyiminomethylcamptothecin; -7-[2-(2,4-difluorophenyl)ethoxy]iminomethylcamptothecin; -7-(4-t-butylbenzyloxy)iminomethylcamptothecin; -7-(1-adamantyloxy)iminomethylcamptothecin; -7-(1-adamantylmethoxy)iminomethylcamptothecin; -7-(2-naphthyloxy)iminomethylcamptothecin; -7-(9-anthrylmethoxy)iminomethylcamptothecin; -7-oxiranylmethoxyiminomethylcamptothecin; -7-(6-uracyl)methoxyiminomethylcamptothecin; -7-[2-(1-uracyl)ethoxy]iminomethylcamptothecin; -7-(4-pyridyl)methoxyiminomethylcamptothecin; -7-(2-thienyl)methoxyiminomethylcamptothecin; -7-[(N-methyl)-4-piperidinyl]methoxyiminomethylcamptothecin; -7-[2-(4-morpholininyl]ethoxy]iminomethylcamptothecin; -7-(benzoyloxyiminomethyl)camptothecin; -7-[(1-hydroxyimino)-2-phenylethyl)camptothecin; -7-ter-butyloxyiminomethylcamptothecin N-oxide; -7-methoxyiminomethylcamptothecin N-oxide. 3. Compounds according to claim 1, selected from the group consisting of: -7-(N-(4-aminobutyl)-2-aminoethoxy]iminomethylcamptothecin; -7-[N-[N-(3-amino-1-propyl)-4-amino-1-butyl]-3-aminopropyl)iminomethyl-camptothecin. 4. Compounds according to claim 1, selected from the group consisting of: -7-(1,2:3,4-di-O-isopropylydene-D-galactopyranosyloxy)iminomethylcamptothecin; -7-(6-D-galactosyloxy)iminomethylcamptothecin; -7-(6-D-glucosyloxy)iminomethylcamptothecin. 5. Compounds according to claim 2, which is 7-(t-butoxy)iminomethylcamptothecin. 6. Compound according to claim 2, which is 7-benzyloxyiminomethylcamptothecin. 7. A process for the preparation of the compounds of claim 1, wherein n is 1 and R4 is as above defined, with the exception of aroyl and arylsulfonyl, comprising the reaction of a compound of formula (Ia) wherein R1 is the group -C(R5)(O and R5 is as defined for the formula (I), R2 and R3 are as defined in formula (I), with the compound of formula (IIa): R4O-NH2, wherein R4 is as above defined, to give compounds of formula (I), wherein R1 is the group -C(R5)=N-OR4, R4 is defined as in formula (I), except aroyl and arylsulfonyl. 8. Process according to claim 7, wherein the molar ratio between compound of formula (Ia) and compound of formula (IIa) is comprised between 1:3 and 3:1. 9. Process for the preparation of the compounds of the claim 1, wherein n is 1 and R4 is as above defined, with the exception of aroyl and arylsulfonyl, that comprises the reaction of a compound of formula (Ia) wherein R1 is the group -C(R5)(N-OH and R5 is as defined for formula (I), R2 and R3 are as defined in formula (I), with a halide R4-X, wherein X is a halogen and R4 is as above defined, to give compounds of formula (I), wherein R1 is the group - C(R5)=N-OR4, R4 is defined as in formula (I), except aroyl and arylsulfonyl. 10. Process for the preparation of the compounds of claim 1, wherein n is 1 and R4 is aroyl or arylsulfonyl, comprising the reaction of a compound of formula (Ia) wherein R1 is the group -C(R5)(N-OH, and R5 is as defined for formula (I), R2 and R3 are as defined in formula (I), with an acyl chloride R4-COCl, wherein R4 is aroyl or arylsulfonyl as above, to give compounds of formula (I), wherein R1 is the group - C(R5)=N-OR4, R4 is aroyl or arylsulfonyl. 11. Compounds according to any one of claims 1-6, as medicaments. 12. Pharmaceutical composition comprising a therapeutically effective amount of at least a compound of claims 1-6, in admixture with pharmaceutically acceptable vehicles and excipients. 13. Pharmaceutical composition comprising a therapeutically effective amount of at least a compound of claims 1-6, in admixture with pharmaceutically acceptable vehicles and excipients and optionally in combination with other active ingredients. 14. Pharmaceutical composition according to claim 13 wherein said other active ingredient is an antitumoral. 15. Use of a compound of claims 1-6, for the preparation of a medicament useful for the treatment of tumors. 16. Use of a compound of claims 1-6, for the preparation of a medicament useful for the treatment of viral infections. 17. Use of a compound of claims 1-6, for the preparation of a medicament having antiplasmodium falciparum activity. 18 Use of compounds of formula (Ia) wherein R1 is a group -C(R5)=N-OR4, wherein R4 is hydrogen, a group (C6-C10) aroyl or arylsulfonyl, optionally substituted with one or more groups selected from the group consisting of: halogen, hydroxy, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, phenyl, cyano, nitro, -NR10R11, wherein R10 and R11, the same or different between them, are hydrogen, C1-C8 linear or branched alkyl; R2 and R3, the same or different between them are hydrogen, hydroxy, C1-C8 linear or branched alkoxy; as intermediates in the process of claim 10. 19. Compounds of formula (Ia) wherein R1 is the group -C(R5)=O, and R5 is as defined for the formula (I), R2 and R3 are as defined in formula (I), as intermediates in the process of claim 7.