New binder-drug conjugates (adcs) and use thereof

Abstract

The present application relates to new binder-drug conjugates (ADCs) of N,N-dialkylauristatins that are directed against the target C4.4a, to active metabolites of these ADCs, to processes for preparing these ADCs, to the use of these ADCs for treating and/or preventing illnesses, and also to the use of these ADCs for producing medicaments for treating and/or preventing illnesses, more particularly hyperproliferative and/or angiogenic diseases such as, for example, cancer diseases. Such treatments may be practised as a monotherapy or else in combination with other medicaments or further therapeutic measures.

1 . Binder-drug conjugates of the general formula (Ia) 
       
         
           
           
               
               
           
         
         in which 
         n is a number from 1 to 50, 
         AK is a binder, 
         the group §-G-L 1 -B-L 2 -§§ is a linker,
 where 
 § marks the linkage site with the group AK and 
 §§ marks the linkage site with the nitrogen atom, 
 
         D is a group of the formula 
       
       
         
           
           
               
               
           
         
         
           
             where 
           
           # 3  marks the linkage site with the nitrogen atom, 
           R 1  is hydrogen or methyl, 
           R 2  is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3 ylmethyl, 
           or 
           R 1  and R 2  together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula 
         
       
       
         
           
           
               
               
           
         
         
           
             in which 
             # 4  marks the linkage site with the adjacent nitrogen atom, 
             # 5  marks the linkage site with the carbonyl group, 
           
           the ring A with the N—O moiety present therein is a mono- or bicyclic, 
           optionally substituted heterocycle of the formula 
         
       
       
         
           
           
               
               
           
         
         
           
             in which 
             # 6  marks the linkage site with the carbonyl group, 
             R 6  is hydrogen, hydroxy or benzyloxy, 
           
           R 3  is hydrogen or methyl, 
           R 4  is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3 ylmethyl, 
           or 
           R 3  and R 4  together with the carbon atom to which they are bonded form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula 
         
       
       
         
           
           
               
               
           
         
         
           
             in which 
             # 7  marks the linkage site with the adjacent nitrogen atom, 
             # 8  marks the linkage site with the group T1, 
           
         
         T 1  is a group of the formula —C(═O)—OR 7 , —C(═O)—NR 8 R 9 , —C(═O)—NH—NH—R 10  or —CH 2 —O—R 11 ,
 in which 
 R 7  is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl, 
 R 8  is hydrogen or methyl, 
 R 9  is hydrogen, methyl, ethyl, n-propyl or benzyl, 
 or 
 R 8  and R 9  together with the nitrogen atom to which they are bonded form a 4- to 7-membered heterocycle, 
 R 10  is benzoyl, 
 R 11  is benzyl, which may be substituted in the phenyl group by methoxycarbonyl or carboxyl, 
 
         R 5  is hydrogen, methyl or a group of the formula 
       
       
         
           
           
               
               
           
         
         
           in which 
           # 9  marks the linkage site with —CHC(R 26 )-T 2 , 
           R 12  is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula —S(O)2OH, 
           R 13  is phenyl which may be substituted by methoxycarbonyl or 10 carboxyl, 
         
         R 26  is hydrogen or hydroxy, 
         T 2  is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, 
         R 35  is methyl or hydroxy, 
         and also their salts, solvates and solvates of the salts. 
       
     
     
         2 - 55 . (canceled)