New effector conjugates, process for their production and their pharmaceutical use

An effector recognition unit conjugate of formula (I),

• in which
• R1a, R1b, independently of one another, are hydrogen, C1-C10 alkyl, aryl, aralkyl, or together a —CH2)m group, in which m is 2 to 5,
• R2a, R2b, independently of one another, are hydrogen, C1-C10 alkyl, aryl, aralkyl, or together a —(CH2)n group, in which n is 2 to 5, or C2-C10 alkenyl, or C2-C10 alkynyl,
• R3 is hydrogen, C1-C10 alkyl, aryl or aralkyl, and
• R4a, R4b, independently of one another, are hydrogen, C1-C10 alkyl, aryl, aralkyl, or together a —CH2)p group, in which p is 2 to 5,
• R5 is hydrogen, C1-C10 alkyl, aryl, aralkyl, CO2H, CO2alkyl, CH2OH, CH2Oalkyl, CH2Oacyl, CN, CH2NH2, CH2N(alkyl, acyl)1,2, or CH2Hal,
• Hal is a halogen atom,
• R6, R7 in each case are hydrogen, or together an additional bond, or together an oxygen atom, or together an NH group, or together an N-alkyl group, or together a CH2 group, and
• G is an oxygen atom or CH2,
• D-E is a group H2C—CH2, HC═CH, C≡C, CH(OH)—CH(OH), CH(OH)—CH2, CH2—CH(OH),
• O—CH2, or, if G represents a CH2 group, D-E is CH2—O,
• W is a group C(═X)R8, or a bicyclic or tricyclic aromatic or heteroaromatic radical,
• L3 is hydrogen, or, if a radical in W contains a hydroxyl group, forms a group O-L4 with the latter, or, if a radical in W contains an amino group, forms a group
• NR25-L4 with the latter,
• R25 is hydrogen or C1-C10 alkyl,
• X is an oxygen atom, or two OR20 groups, or a C2-C10 alkylenedioxy group that may be straight or branched, or H and OR9, or a CR10R11 group,
• R8 is hydrogen, C1-C10 alkyl, aryl, aralkyl, halogen or CN, and
• R9 is hydrogen or a protective group PGX,
• R10, R11, in each case independently of one another, are hydrogen, C1-C20 alkyl, aryl, aralkyl, or together with a methylene carbon atom form a 5- to 7-membered carbocyclic ring,
• Z can represent oxygen or H and OR12,
• R12 can represent hydrogen or a protective group PGZ,
• A-Y can represent a group O—C(═O), O—CH2, CH2—C(═O), NR21—C(═O) or NR21—SO2,
• R20 can represent C1-C20 alkyl,
• R21 can represent a hydrogen atom or C1-C10 alkyl,
• PGX, PGY, and PGZ can represent a protective group PG, and
• L1, L2, and L4, independently of one another, can represent hydrogen, a group C(═O)Cl, a group C(═S)Cl, a group PGY or a linker of general formula (III) or (IV);
• provided that at least one substituent L1, L2 or L4 represents a linker of general formula (III) or (IV);
• the linker of general formula (III) has the following structure,
• in which
• T can represent oxygen or sulfur,
• U can represent oxygen, CHR22, CHR22—NR23—C(═O)—, O—C(═O)—CHR22—NR23—C(═O)—, O—C(═O)—CHR22—NR23—C(═S)—, CHR22—NR23—C(═S)— or NR24a,
• o can represent 0 to 15,
• V can represent a bond, aryl, a group
• or a group
• s can represent 0 to 4,
• Q can represent a bond, O—C(═O)—NR24c, O—C(═S)—NR24c,
• R22 can represent hydrogen, C1-C10 alkyl, aryl or aralkyl,
• R23 can represent hydrogen or C1-C10 alkyl,
• R24a, R24b, and R24c, independently of one another, can represent hydrogen or
• C1-C10 alkyl,
• q can represent 0 to 15,
• FG1 can represent C1-C10 alkyl-S3,
• or CO2H;
• and
• the linker of general formula (IV) has the following structure,
• in which
• T can represent oxygen or sulfur,
• W1, W2 are the same or different and can represent oxygen or NR24a,
• o can represent 0 to 5,
• R24a can represent hydrogen or C1-C10 alkyl,
• R27 can represent halogen, CN, NO2, CO2R28, or OR28,
• R28 can represent hydrogen, C1-C10 alkyl, aryl or aralkyl,
• q can represent 0 to 5,
• U can represent oxygen, CHR22, CHR22—NR23—C(═O)—, CHR22—NR23—C(═S)— or
• C1-C20 alkyl,
• R22 can represent hydrogen, C1-C10 alkyl, aryl or aralkyl,
• R23 can represent hydrogen or C1-C10 alkyl,
• r can represent 0 to 20,
• FG1 can represent C1-C10 alkyl-S3,
• or CO2H,
• and wherein
• at least one group FG1 is not as defined above, but instead is a group FG2a or FG2b, wherein
• FG2a is —S—S—,
• FG2b is —CONH—;
• wherein
• a recognition unit is conjugated via a sulfur atom with group FG2a or via an amide function with group FG 2b;
• and wherein the recognition unit is selected from peptides, soluble receptors, cytokines, lymphokines, aptamers, spiegelmers, recombinant proteins, new framework structures, monoclonal antibodies and fragments of monoclonal antibodies;
• or
• a single isomer or a mixture of different isomers or a pharmaceutically acceptable salt thereof.