Patent DE-102006005936-A1 (DE)
Title: New fredericamycin derivatives are topoisomerase I inhibitors useful to treat tumor, parasite, immunosupression and neurodermititis
Inventor: SIMON WERNER
IPC: C07D221/02
Filed: 2006-02-09
Abstract: Fredericamycin derivatives (I) and their stereoisomers, tautomers and salts are new. Fredericamycin derivatives (I) of formula (Ia) or (Ib) and their stereoisomers, tautomers and salts are new. R1 : H, 1-6C-cycloalkyl, cycloalkyl or 1-4C-alkyl-cycloalkyl; R2 : H, 1-4C-alkyl, 2-14C-alkenyl, (hetero)aryl 1-4C-alkyl-aryl, 1-4C-alkenyl-heteroaryl, (hetero)cycloalkyl, 1-4C-alkyl-cycloalkyl, C mH 2m+o-pY1 p, (CH 2) rCH 2NHCOR21, (CH 2) rCH 2OCOR21, (CH 2) rCH 2NHCSR21, (CH 2) rCH 2S(O) nR21, (CH 2) rCH 2SCOR21, (CH 2) rCH 2OSO 2-R21, (CH 2) rCHO, CH 2-O-N=CH-(het)aryl, CH 2-O-N=CH-R21, CH 2-O-N=CR21R22, CH 2-O-N=CH=cycloalkyl, CH=N-S-(het)aryl, (CH 2) rCH=NOH, (CH 2) rCH(OH)R21, (CH 2) rCH=NOR21, (CH 2) rCH=NOCOR21, (CH 2) rCH=NOCH 2CONR21R22, (CH 2) rCH=NOCH(CH 3)CONR21R22, (CH 2) rCH=NOC(CH 3) 2CONR21R22, (CH 2) rCH=N-NHCOR23, (CH 2) rCH=N-NHC(O)NH-R23, (CH 2) rCH=N-NHC(S)NH-R23, (CH 2) rCH=N-NHC(NH)NH-R23, (CH 2) rCH=N-CH 2NHCOR21, (CH 2) rCH=N-NHCS-R23, (CH 2) rCH=CR24R25 (cis or trans), (CH 2) rCOOH, (CH 2) rCOOR21, (CH 2) rCONR21R22, (CH 2) rCH=NR21, hydrazine compound of formula (1), (CH 2) rCH=N-NR21R22, (CH 2) r-long chain group such as (CH 2) rCH=N-N-(1-3C-alkyl-NX1R211R212R213); m : 1-6 (for o is 1, p is 1-2m+o), 2-6 (for o is -1, p is 1-2m+o) or 4-6 (for o is -2, p is 1-2m+o); Y1 : halo, OH, OR21, NH 2, NHR21, NR21R22, SH or SR21; X1 : NR215, O or S; R211-R215 : H, 1-6C-alkyl or (CH 2) rCH=N-NHSO 2-(hetero)aryl; r : 0-5, preferably 0; R21, R22 : 1-14C-alkyl, 1-14C-alkanoyl, 1-6C-alkylhydroxy, 1-8C-alkylamino, 1-6C-alkylamino-1-6C-alkyl, 1-6C-alkylamino-di-1-6C-alkyl, (hetero)cycloalkyl, 1-4C-alkyl-(hetero)cycloalkyl, cycloalkanoyl, 1-4C-alkyanoyl-cycloalkyl, (hetero)cycloalkanoyl, 1-4C-alkanoyl-heterocycloalkyl, 1-4C-alkanoyl-(hetero)aryl or mono-/di- sugar residue (glucuronic acid and its optical stereoisomers C-atom, aldopentose, aldohexose or its deoxy compound such as glucose, deoxyglucose, ribose or deoxyribose), which is linked by C-atom that carries a OH-group; R23 : R21, CH 2-pyridinium salt or CH 2tri-1-6C-alkylammonium-salt; either R24, R25 : R21, H, CN, COCH 3, COOH, COOR21, CONR21R22, NH 2or NHCOR21; or R24+R25 : 4-8C-cyloalkyl; R3 : H, F, Cl, Br, I, OH, OR31, NO 2, NH 2, NHR31, NR31R32, NHCHO, NHCOR31, NHCOCF 3, CH 3-mhal m(where hal is Cl or F (preferred) and m is 1-3), OCOR31, SCN, CN, N 3, CH 2NR331R332, CH 2OH, CH 2OR33, CH 2SR33, 2-14C-alkyl, 2-14C-alkenyl, 2-14C-alkynyl, (hetero)aryl, 1-4C-alkyl-aryl, 1-4C-alkyl-heteroaryl (where (hetero)aryl is substituted with (hetero)aryl, 1-4C-alkyl-(hetero)aryl, O-aryl, 1-4C-alkyl-O-aryl, O-heteroayl or 1-4C-alkyl-O-heteroaryl), (hetero)cycloalkyl, 1-4C-alkyl-(hetero)cycloalkyl, C mH 2m +o-pY2 p(where m is 2-6 (for o is -1, p is 1-2m+o) or 4-6 (for o is -2, p is 1-2m+o)), CH 2NHCOR31, CH 2NHCSR31, CH 2S(O) nR31 (where n is 0-2), CH 2SCOR31, CH 2OSO 2-R31, CHO, CH=NOH, CH(OH)R31, -CH=NOR31, -CH=NOCOR31, -CH=NOCH 2CONR31R32, -CH=NOCH(CH 3)CONR31R32, -CH=NOC(CH 3) 2CONR31R32, -CH=N-NHCO-R33, -CH=N-NHCO-CH 2NHCOR31, -CH=N-O-CH 2NHCOR31, -CH=N-NHCS-R33, -CH=CR34R35 (trans or cis), COOH, COOR31, CONR31R32, -CH=NR31, -CH=N-NR31R32, hydrazine compound of formula (2), CH=N-NHSO 2-aryl, -CH=N-NHSO-2-heteroaryl, SCN, CN, N 3, CH 2NR331R332 or CH 2SR33; X2 : NR315, O or S; R311-R315 : H or 1-6C-alkyl; R331, R332 : R33; Y2 : halo, OH, OR31, NH 2, NHR31, NR31R32, SH or SR31; R31, R32 : 1-14C alkyl, 1-14C alkanoyl, 1-6C alkylhydroxy, 1-6C alkylamino, 1-6C alkylamino-1-6C-alkyl, 1-6C-alkylannino-di-1-6C-alkyl, cycloalkyl, 1-4C-alkyl-cycloalkyl, heterocycloalkyl, 1-4C-alkyl-heterocycloalkyl, aryl, aryloyl, 1-4C-alkyl-aryl, heteroaryl, heteroaryloyl, 1-4C alkyl-heteroaryl, cycloalkanoyl, 1-4C alkanoyl-cycloalkyl, heterocycloalkanoyl, 1-4C alkanoyl-heterocycloalkyl, 1-4C-alkanoyl-aryl, 1-4C-alkanoyl-heteroaryl, mono- and di- sugar residues (that are connected over carbon atom, where the sugar carries an OH group and the sugar residues are glucuronic acid and its stereoisomers at all optical carbon atoms, aldopentose, aldohexose including its deoxy compound (like glucose, deoxyglucose, ribose, deoxyribose)); R33 : R31, CH 2pyridinium salt or CH 2tri-1-6C-alkylammonmium-salt; R34 : R31, H, CN, COCH 3, COOH, COOR21, CONR31R32, NH 2or NHCOR31; R35 : R31, H, CN, COCH 3, COOH, COOR31, CONR31R32, NH 2or NHCOR31; R34R35 : 4-8C cycloalkyl; R5 : H, 1-6C alkyl, cycloalkyl, 1-4C-alkyl-cycloalkyl, heterocycloalkyl, 1-4C alkyl-heterocycloalkyl, aryl, 1-4C-alkyl-aryl, heteroaryl, 1-4C-alkylheteroaryl; R4,R6,R7 : H, 1-6C alkyl or CO-R41; R41 : R21; either X : O, S, NH or N-R8; or X-R5 : H, F, Cl, Br, I, N 3or W 1>-R51; either R8 : R5; or NR8R5 : 4-8 membered heterocycloalkyl ring, optionally contains further heteroatoms such as N, O or S; Y 1>F, Cl, Br, I, N 3, CN, CH 2NRY3RY4, CH2OH, CH2ORY3, CH2SRY4, SCN, aryl or hetaryl; either RY3, RY4 : R23; or NRY3RY4 : 4-8 membered heterocycloalkyl ring, optionally contains further heteroatoms such as N, O or S; W 1>O, S, NH or N-R81; either R81, R51 : R5; or NR81R51 : 4-8 membered heterocycloalkyl ring, optionally contains further heteroatoms such as N, O or S; Z : O, S or NR9; and R9 : H or 1-6C alkyl. [Image] [Image] ACTIVITY : Cytostatic; Antiparasitic; Immunosuppressive; Antiinflammatory; Neuroprotective. MECHANISM OF ACTION : Topoisomerase I inhibitor; Topoisomerase II inhibitor. The cytotoxic effect of (I) was tested in breast cancer cell (MCF7). The results showed that (I) exhibited median inhibitory concentration of 0.19 mu M.