Patent DE-102004004787-A1 (DE)
Title: New effector-linker and effector-recognition unit conjugates derived from epothilones, useful as targeted drugs for treating proliferative diseases, e.g. tumors or neurodegenerative disease
Inventor: KLAR ULRICH
IPC: C07K16/00
Filed: 2004-01-30
Abstract: New effector conjugates (I) consist of an epothilone (or derivative) as effector, conjugated with a linker (III) containing a di- or tripeptide residue. Effector conjugates of formula (I) (as individual isomers or mixtures of different isomers) and their salts are new. R1a>, R1b>H, 1-10C alkyl, aryl or aralkyl; or together form (CH2)m; R2a>, R2b>H, 1-10C alkyl, aryl, aralkyl, 2-10C alkenyl or 2-10C alkynyl; or together form (CH2)n; R3>H, 1-10C alkyl, aryl or aralkyl; R4a>, R4b>H, 1-10C alkyl, aryl or aralkyl; or together form (CH2)p; m, n, p : 2-5; R5>H, 1-10C alkyl, aryl, aralkyl, COOH, alkoxycarbonyl, CH2OH, alkoxymethyl, acyloxymethyl, CN, CH2NH2 (optionally N-substituted by 1 or 2 of alkyl and acyl) or halomethyl; G : O or CH2; D-E : CH2CH2, CH=CH, CC, CH(OH)CH(OH), CH(OH)CH2, CH2CH(OH), oxirane-2,3-diyl or OCH2; or may also be OCH2 if G = CH2; W : C(X)R8> or bi- or tricyclic (hetero)aromatic group; L3>H; or forms a group -O-L4 or -N(R25>)-L4> together with a hydroxy or amino group respectively contained in W; R25>H or 1-10C alkyl; X : O, (OR20>)2, 2-10C alkylenedioxy, H/OR9> or CR10>R11>; R8>H, 1-10C alkyl, aryl, aralkyl, halo or CN; R9>H or protecting group; R10>, R11>H, 1-20C alkyl, aryl or aralkyl; or together complete a 5-7 membered carbocycle; Z : O or protecting group; A-Y : O-C(O), O-CH2, CH2-C(O), NR21>-C(O) or NR21>-SO2; R20>1-20C alkyl; R21>H or 1-10C alkyl; L1>, L2>, L4>H, -CO-Cl, -CS-Cl, protecting group or L, provided that at least one of L1>, L2>, L4> = L; L : linker of formula (III); T : halo, OH, alkoxy, COOH, alkoxycarbonyl, NHR23>, NO2, N3, CN, 1-20C alkyl, 1-20C acyl or 1-20C acyloxy; U : direct bond, O or NR24a>; o : 0-5; V : O or NR24b>; Aa1direct bond or aminoacid residue of formula -C(O)-CH(Ra>)-N(R24c>)- (IV); Aa2, Aa3(IV); Ra>alpha -substituent of a natural or non-natural aminoacid; R22>H, 1-10C alkyl, aryl or aralkyl; R23>H, 1-10C alkyl or 1-10C acyl; R24a>, R24b>, R24c>H or 1-10C alkyl; q : 1-20; FG1>1-10C alkyl-S3, phthalimido, -CO-CH=CH2, -CO-C(Br)=CH2, -CO-C(Cl)=CH2, -SO2-CH=CH2 or COOH; R6>, R7>H; R6>+R7>bond, O, NH, N(alkyl) or CH2. Independent claims are included for: (1) new effector-recognition unit conjugates (A) (as individual isomers or mixtures of different isomers) and their salts, where (A) are as for (I) but with at least one FG1> group replaced by -FG2a>-RU or -FG2b>-RU; (2) new linkers of formula RG-L (III'); and (3) the preparation of (I) and (A). FG2a>-S-S-, 3-thio-2,5-dioxo-pyrrolidino, -CO-CH2CH2-S-, -CO-CH(Br)-CH2-S-, -CO-CH(Cl)-CH2-S- or -SO2-CH2CH2-S-; RU : recognition unit, bonded to the S of FG2a> or the N of FG2b>, selected from peptides, soluble receptors, cytokines, lymphokines, aptamers, spiegelmers, recombinant proteins, new framework structures, monoclonal antibodies and monoclonal antibody fragments; RG : NCO, halo-C(O)-CHR22>-, halo-C(O)-CHR22>-NR23>-C(O)-, R26>-C(O)-O-C(O)-CHR22>-, R26>-C(O)-O-C(O)-CHR22>-NR23>-C(O)-, OH, NHR24a> or COOH; R26>1-10C alkyl, aryl, aralkyl; FG2b>CONH. [Image] [Image] ACTIVITY : Cytostatic; Antiinflammatory; Neuroprotective; Nootropic; Antirheumatic; Antiarthritic; Ophthalmological. MECHANISM OF ACTION : None given in the source material.