N-carboxyalkyl-auristatin and use thereof

Abstract

The present application relates to new derivatives of monomethylauristatin F, substituted on the N terminus by a carboxyalkyl group, processes for preparing these derivatives, their use for the treatment and/or prevention of diseases and to produce medication for the treatment and/or prevention of diseases, particularly hyperproliferative and/or angiogenic disorders such as cancer disorders, for example. Such treatments can occur as monotherapies or in combination with other medication or further therapeutic measures.

1 . Compound of the formula (I) 
       
         
           
           
               
               
           
         
         Wherein 
         L stands for a straight-chain (C 1 -C 12 )-alkandiyl, which may be substituted with methyl up to four times and in which (a) two carbon atoms may be connected to each other in 1,2-, 1,3- or 1,4 relation, if necessary including carbon atoms that are located between them to form a (C 3 -C 6 )-cycloalkyl-ring or a phenyl ring or (b) up to three CH 2  groups not adjacent to each other may be substituted for an O, 
         R 1  stands for hydrogen or methyl, 
         R 2  stands for isopropyl, isobutyl, sec.-butyl, tert.-butyl, 1-hydroxyethyl, phenyl, benzyl, 4-hydroxybenzyl, 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 both connected, form a 2-phenylcyclopropan-1,1-diyl group of the formula 
       
       
         
           
           
               
               
           
         
         Wherein
 # marks the points of attachment with other parts of the molecule, 
 
         And 
         T stands for a group with formula —C(═O)—OR 3 , —C(═O)—NR 4 R 5 , —C(═O)—NH—NH—R 6  or —CH 2 —O—R 7  in which
 R 3  stands for hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 10 )-cycloalkyl,
 wherein (C 1 -C 6 )-alkyl may be substituted with phenyl, naphthyl or (C 3 -C 10 )-cycloalkyl, 
 
 R 4  stands for hydrogen or (C 1 -C 6 )-alkyl, 
 R 5  stands for hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 10 )-cycloalkyl,
 wherein (C 1 -C 6 )-alkyl may be substituted with phenyl, 
 
 Or 
 R 4  and R 5  are connected to each other and, together with the nitrogen atom they are attached to, form a 5- to 7-membered, saturated aza-heterocyclic compound, which may contain a further ring-heteroatom such as >N—H, >N—CH 3  or —O—; and is located either at the 1,3- or 1,4-location in relation to the aforementioned nitrogen atom, 
 R 6  stands for (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkylcarbonyl, phenyl or benzoyl, and 
 R 7  stands for (C 1 -C 6 )-alkyl, which may be substituted with phenyl,
 Where phenyl may also be substituted with (C 1 -C 6 )-alkoxycarbonyl or carboxyl, 
 
 
         and also their salts, solvates and solvates of the salts. 
       
     
     
         2 . compound of the formula (I) as per  claim 1  wherein
 L stands for a straight-chain (C 1 -C 8 )-alkandiyl, in which (a) two carbon atoms are linked to each other in 1,3 or 1,4 relation including one or two carbon atoms located between them to form a phenyl ring or (b) up to two CH 2  groups not adjacent to each other which may be substituted for an O, 
 R 1  stands for hydrogen, 
 R 2  stands for benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl, 
 Or 
 R 1  and R 2 , together with the carbon atom to which they are both connected, form a 2-phenylcyclopropan-1,1-diyl group of the formula 
 
       
         
           
           
               
               
           
         
         Wherein
 # marks the points of attachment with other parts of the molecule, 
 
         And 
         T stands for a group with formula —C(═O)—OR 3 , —C(═O)—NR 4 R 5 , —C(═O)—NH—NH—R 6  or —CH 2 —O—R 7  in which
 R 3  stands for hydrogen or (C 1 -C 4 )-alkyl, which may be substituted with phenyl, naphthyl or (C 3 -C 10 )-cycloalkyl, 
 R 4  stands for hydrogen or methyl, 
 R 5  stands for hydrogen or (C 1 -C 4 )-alkyl, which may be substituted with phenyl, 
 Or 
 R 4  and R 5  are connected to each other and together with the nitrogen atom they are attached to, form a piperidine- or morpholine ring, 
 R 6  stands for (C 1 -C 4 )-alkylcarbonyl or benzoyl, 
 And 
 R 7  stands for (C 1 -C 4 )-alkyl or benzyl, which, in the phenyl group, may be substituted with (C 1 -C 4 )-alkoxycarbonyl or carboxyl, 
 
         and also their salts, solvates and solvates of the salts. 
       
     
     
         3 . compound of the formula (I) as per  claim 1  or  claim 2  wherein
 L stands for a straight-chain (C 1 -C 6 )-alkandiyl, 
 R 1  stands for hydrogen, 
 R 2  stands for benzyl, 1-phenylethyl or 1-H-indol-3-ylmethyl, 
 Or 
 R 1  and R 2 , together with the carbon atom they are both attached to, form a (S,2R)-2-phenylcyclopropan-1,1-diyl group of the formula 
 
       
         
           
           
               
               
           
         
         Wherein
 #1 marks the point of attachment with the adjacent nitrogen atom 
 And 
 #2 marks the point of attachment of group T, 
 
         And 
         T stands for a group with formula —C(═O)—OR 3 , —C(═O)—NR 4 R 5 , —C(═O)—NH—NH—R 6  or —CH 2 —O—R 7  in which
 R 3  stands for hydrogen, methyl, ethyl, n-propyl, benzyl or adamantylmethyl, 
 R 4  stands for hydrogen or methyl, 
 R 5  stands for hydrogen, methyl, ethyl, n-propyl or benzyl, 
 R 6  stands for benzoyl, 
 And 
 R 7  stands for benzyl, which may be substituted with methoxycarbonyl or 
 carboxyl in the phenyl group, 
 
         and also their salts, solvates and solvates of the salts. 
       
     
     
         4 . compound as per  claims 1 ,  2 , and  3  with formula (I A) 
       
         
           
           
               
               
           
         
         in which L, R 1 , R 2  and T are defined in  claim 1 ,  2 , or  3 , and that the radicals R 1  and R 2  supporting C X -carbon atom has the pictured configuration, 
         and also their salts, solvates and solvates of the salts. 
       
     
     
         5 . Method for manufacturing a compound of formula (I), as defined in  claims 1  to  4  which is characterized to that effect that a compound of formula (II) 
       
         
           
           
               
               
           
         
         Wherein R 1 , R 2  and T according to the meaning of  claims 1  to  4   
         Are coupled in an inert solvent either by 
         [A] base-induced alkylation with a compound of formula (III) 
       
       
         
           
           
               
               
           
         
         Wherein L has the meaning indicated in  claims 1  and  4 , 
         E 1  stands for hydrogen, (C 1 -C 4 )-alkyl or benzyl, 
         And 
         X stands for a leaving group such as chloride, bromide, iodide, mesylate, triflate or tosylate, 
         to a compound of formula (IV) 
       
       
         
           
           
               
               
           
         
         Wherein E 1 , L, R 1 , R 2  and T are defined as above, 
         and then, should E 1  stand for (C 1 -C 4 )-alkyl or benzyl, this ester radical is split off using common methods, so that, just as in the event in which E 1  in (III) stands for hydrogen, the carboxylic acid according to the invention of formula (I) 
       
       
         
           
           
               
               
           
         
         in which L, R 1 , R 2  and T are defined as above, 
         is preserved, 
         Or 
         [B] by treatment with a compound of formula (V) 
       
       
         
           
           
               
               
           
         
         Wherein 
         E 1  stands for hydrogen, (C 1 -C 4 )-alkyl or benzyl, 
         And 
         L A  according to the meaning of L described in  claims 1  to  4 , however, with the alkyl chain-length shortened by one CH 2 -unit, 
         in the presence of a suitable reducing agent to a compound of formula (VI) 
       
       
         
           
           
               
               
           
         
         Wherein E 1 , L A , R 1 , R 2  and T are defined as above, 
         and then, should E 1  stand for (C 1 -C 4 )-alkyl or benzyl, this ester radical is split off using common methods, so that, just as in the case in which E 1  in (V) stands for hydrogen, the carboxylic acid which complies with the invention of (I-B) 
       
       
         
           
           
               
               
           
         
         in which L A , R 1 , R 2  and T are defined as above, 
         is preserved, 
         And the resulting compounds of formula (I) and (I-B) may be, as required, separated into their enantiomers and/or diastereomers and/or converted using appropriate (i) solvents and/or (ii) bases or acids into their solvates, salts and/or solvates of the salts. 
       
     
     
         6 . Compound as defined in  claims 1  to  4  for treatment and/or prevention of diseases. 
     
     
         7 . Compound as defined in one of the  claims 1  to  4  for use in a procedure to treat and/or prevent cancer and tumor diseases. 
     
     
         8 . Use of a compound as defined in one of the  claims 1  to  4  for production of drug to treat and/or prevent cancer and tumor diseases. 
     
     
         9 . Drug which contains a compound as defined in one of the  claims 1  to  4 , in combination with one or more inert, non-toxic, pharmaceutically suitable agents. 
     
     
         10 . Drug which contains a compound as defined in one of the  claims 1  to  4 , in combination with one or more substances. 
     
     
         11 . Drug as per  claim 9  or  10  for treatment and/or prevention of cancer and tumor diseases. 
     
     
         12 . Method for treatment and/or prevention of cancer and tumor diseases in humans or animals using an effective amount of at least one compound as defined in one of the  claims 1  to  4 , or of a drug as defined in one of the  claims 9  to  11 .