Patent EA-002203-B1 (EA)
Title: Fluoro 19 labelled anthracyclinone and anthracycline derivatives, pharmaceutical composition based thereon, use thereof for treating or amyloidosis diagnostics
Inventor: BANDIERA TIZIANO
IPC: C07D405/12
Filed: 1997-06-18
Abstract: 1. A use of a fluoro<19> tagged compounds, which are anthracycline or anthracyclinone derivatives of general formula wherein R1 is hydrogen, hydroxy, halogen, C1-C8 alkoxy, amino which may be substituted by benzyl, acyl or trifluoracetyl, or OSO2(R4) wherein R4 is alkyl or aryl each of which is unsubstituted or substituted by one or more fluorine atoms; R2 is hydrogen, or hydroxy; R3 is hydrogen, or hydroxy, amino which may be mono- or di-substituted by C1-C16 alkyl, aryl, aralkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl which is unsubstituted or substituted by one or more fluorine atoms or trifluoromethyl groups, morpholino which may be substituted by C1-C16 alkyl, aryl, aralkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl which is unsubstituted and/or substituted by one or more fluorine atoms or trifluoromethyl groups, piperazino which may be substituted by trifluoroacyl or trifluoromethanesulfonyl or aryl(trifluoromethyl), tetrahydropyridine, a group of formula B or C   wherein R5 is hydrogen or C1-C6 alkyl, R6 represents COCF3 or SO2CF3, n and m, which are the same or different, are each an integer of from 1 to 4; or a saccharide of formula D:   wherein R7 is hydrogen, hydroxy, amino which is unsubstituted or substituted by acyl, trifluoracetyl, trifluoromethanesulfonyl, a residue of a naturally occurring amino acid, or a synthetic amino acid or a residue of di- or tri-peptide; R8 and R9 are both hydrogen or one of R8 or R9 is hydroxy , C1-C4 alkoxy, tetrahydropyranyl, halogen or OSO2(R4) wherein R4 is defined above and the other of R8 and R9 is hydrogen or amino which is unsubstituted or substituted by acyl, trifluoracetyl or trifluoromethanesulfonyl; Y is hydrogen, hydroxy, C1-C16 alkoxy, amino which may be unsubstituted or substituted by acyl, trifluoracetyl, C1-C16 alkyl, aryl, or aralkyl which are unsubstituted and/or substituted by one or more fluorine atoms, morpholino, piperazino which may be substituted by trifluoroacyl or trifluoromethanesulfonyl, tetrahydropyridine, a group of formula B or C as defined above, or saccharide of formula D as defined above; and Z is C=O, CHOH, or CH2; wherein at least one fluorine atom is linked to the anthracyclinone or anthracycline skeleton or is carried by groups linked at different positions of the molecule; wherein aryl is a monocyclic or bicyclic aromatic group, comprising 6 to 10 carbon atoms, and aralkyl is an alkyl group substituted with aryl as said above, or a pharmaceutically acceptable salt thereof for diagnostics of amyloidosis. 2. The use of Claim 1, wherein R1 is hydrogen, hydroxy, fluorine, methoxy, amino, aminotrifluormethanesulfonyl (NHSCO2CF3), aminotrifluoracetyl, or O-mesyl [OSO2CH3]; R2 is hydroxy; R3 is C1-C6 mono- or bis-alkylamino which is unsubstituted or substituted by one or more fluorine atoms or trifluoromethyl groups, benzyltrifluoroethylamino, morpholinyl, trifluoromethanesulfonylpiperazinyl, trifluoroacetylpiperazinyl, tetrahydropyridinyl, a group of the formula B or C as defined above, wherein R5 is hydrogen or methyl or ethyl, R6 is COCF3 or SO2CF3, n is 2 or 3, or m is 2 or 3, or a saccharide of formula D, wherein R7 is amino, aminotrifluoroacetyl, aminotrifluoromethanesulfonyl, or α- or ε-N-trifluoroacetyllysine; R8 is hydroxy, iodine, or O-mesyl, R9 is hydrogen; Y is hydrogen, hydroxy, methoxy, amino, C1-C6 mono-bis-alkylamino which is unsubstituted or substituted by one or more fluorine atoms, Benzyltrifluoroethylamino, morpholinyl, trifluoroacetylpiperazinyl, trifluoromethanesulfonylpiperazinyl, tetrahydropyridinyl, a group of formula B or C as defined above, wherein R5 is hydrogen or methyl or ethyl, R6 is COCF3 or SO2CF3 n is 2 or 3, m is 2 or 3, or a saccharide of formula D, wherein R7 is amino, aminotrifluoroacetyl, aminotrifluoromethanesulfonyl, α- or ε-(N-trifluoroacetyl)lysine, or  α- or ε-(N-trifluoromethanesulfonyl)lysine; R8 is hydroxy, iodine, or O-mesyl [OSO2CH3]; R9 is hydrogen; and Z is C=O, or CHOH. 3. The use according to Claim 1 wherein R1 is hydrogen or methoxy; R2 is hydroxy; R3 is hydrogen, hydroxy, hexafluorodiethylamine, benzyltrifluoroethylamino, morpholino, trifluoromethanesulfonylpiperazinyl, trifluoroacylpiperazino, tetrahydropyridine, a group of formula B or C, wherein R5 is hydrogen or methyl, R6 is COCF3, n is 2 or 3, m is 2 or 3, a saccharide of formula D, wherein R7 is selected from the group consisting of amino, aminotrifluoroacetyl, aminotrifluoromethanesulfonyl, α- or ε-N-trifluoracetyllysine; R8 is iodine; R9 is hydrogen; Y is hydrogen, hydroxy, hexafluorodiethylamine, benzyltrifluoroethylamino, morpholino, trifluoromethanesulfonylpiperazinyl, trifluoroacetylpiperazino, or a saccharide of formula D, wherein R7 is amino, aminotrifluoroacetyl, α- or ε-(N-trifluoroacetyl)lysine, R8 is iodine; R9 is hydrogen; and Z is C=O. 4. The use of Claim 1, wherein R1 is methoxy; R2 is hydroxy; R3 is hydrogen, hydroxy, hexafluorodiethylamine, benzyltrifluoroethylamino, morpholino, trifluoroacylpiperazino, or tetrahydropyridino, Y is hydrogen, hydroxy, trifluoroacetylpiperazino, trifluoromethanesulfonylpiperazino,  a group of the formula B or C, wherein R5 is hydrogen, R6 is COCF3, n is 3, m is 2, or a saccharide of formula D, wherein R7 is amino, aminotrifluoroacetyl, or α- or ε-N-trifluoroacetyllysine; R8 is iodine; R9 is hydrogen; and Z is C=O. 5. A compound according to Claim 1, wherein R3 is amino which is mono- or di-substituted by C1-C16 alkyl, aryl, aralkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl which is substituted by one or more fluorine atoms or trifluoromethyl groups, morpholino which is substituted by C1-C16 alkyl, aryl, aralkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl which is substituted by one or more fluorine atoms or trifluoromethyl groups, piperazino which is substituted by trifluoroacyl or trifluoromethanesulfonyl or tetrahydropyridine, or the group of formula B and C   wherein R5 is hydrogen or C1-C6 alkyl, R6 represents COCF3 or SO2CF3, n and m, which are the same or different, are each an integer of from 1 to 4. 6. The compound of Claim 1, which is N-trifluoroacetyl-4'-iododoxorubicin, 14-(4-trifluoroacetylpiperazin-1-yl)daunomycinone, 14-(4-trifluoromethanesulphonylpiperazin-1-yl)daunomycinone, 14-[4-(3-trifluoromethylphenyl)piperazin-1-yl]daunomycinone, 14-[N-ethyl-N-(3,5-bis-trifluoromethylphenyl)methyl]daunomycinone, 14-[N-benzyl-N-(2,2,2-trifluoroethyl)]aminodaunomycinone, or 14-(1,2,3,6-tetrahydropyridin-1-yl)-4'-dezoxy-4'-iodo-3'-N-trifluoracetyldaunorubicin. 7. A use of compound according to Claim 5 or 6 for of treating amyloidosis. 8. A use of compound according to Claim 1 while obtaining a composition for amyloidosis diagnostics. 9. A pharmaceutical composition, comprising as an active ingredient the compound of Claim 5 or 6 and a pharmaceutically acceptable carrier or diluent.