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

摘要

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, R1bH, 1-10C alkyl, aryl or aralkyl; or together form (CH2)m; R2a, R2bH, 1-10C alkyl, aryl, aralkyl, 2-10C alkenyl or 2-10C alkynyl; or together form (CH2)n; R3H, 1-10C alkyl, aryl or aralkyl; R4a, R4bH, 1-10C alkyl, aryl or aralkyl; or together form (CH2)p; m, n, p : 2-5; R5H, 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; L3H; or forms a group -O-L4 or -N(R25)-L4 together with a hydroxy or amino group respectively contained in W; R25H or 1-10C alkyl; X : O, (OR20)2, 2-10C alkylenedioxy, H/OR9 or CR10R11; R8H, 1-10C alkyl, aryl, aralkyl, halo or CN; R9H or protecting group; R10, R11H, 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; R201-20C alkyl; R21H or 1-10C alkyl; L1, L2, L4H, -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); Raalpha -substituent of a natural or non-natural aminoacid; R22H, 1-10C alkyl, aryl or aralkyl; R23H, 1-10C alkyl or 1-10C acyl; R24a, R24b, R24cH or 1-10C alkyl; q : 1-20; FG11-10C alkyl-S3, phthalimido, -CO-CH=CH2, -CO-C(Br)=CH2, -CO-C(Cl)=CH2, -SO2-CH=CH2 or COOH; R6, R7H; R6+R7bond, 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; R261-10C alkyl, aryl, aralkyl; FG2bCONH. [Image] [Image] ACTIVITY : Cytostatic; Antiinflammatory; Neuroprotective; Nootropic; Antirheumatic; Antiarthritic; Ophthalmological. MECHANISM OF ACTION : None given in the source material.