Leptomycin derivatives

Abstract

Leptomycin derivatives having a moiety, such as a sulfide or a disulfide, that can conjugate to a cell binding reagent such as an antibody are disclosed. The therapeutic use of such leptomycin derivative conjugates is also described; such conjugates have therapeutic use because they can deliver cytotoxic leptomycin derivatives to a specific cell population in a targeted fashion.

1 . A therapeutic agent for inhibiting the growth of selected cell population comprising:
 (a) a cytotoxic amount of a leptomycin derivative of formula (I) linked to a cell binding agent,   
       
         
           
           
               
               
           
         
       
       wherein:
 Ra and R′a are independently H or a linear or branched C 1 -C 20  alkyl; 
 R17 is alkyl optionally substituted by OR, CN, NRR′, or perfluoroalkyl; 
 R9 is alkyl optionally substituted by OR, CN, NRR′, or perfluoroalkyl; 
 X is —NR—; 
 Y is a linear or branched C 1 -C 20  alkyl; 
 T represents H or a thiol protecting group or T represents 
 
       
         
           
           
               
               
           
         
       
       where:
 Ra, R′a, R17, R9, X, and Y are defined as above; and 
 R and R′, which may be identical or different, are H or a linear or branched C 1 -C 20  alkyl; or a pharmaceutically acceptable salt thereof; 
 
       and
 (b) a pharmaceutically acceptable carrier, diluent or excipient 
 
     
     
         2 . The therapeutic agent according to  claim 1 , wherein the thiol protecting group is Ac, R 1  or SR 1 , where R 1  is H, methyl or a linear or branched C 1 -C 20  alkyl. 
     
     
         3 . The therapeutic agent according to  claim 1 , wherein Ra is a linear or branched C 1 -C 20  alkyl and R′a is H. 
     
     
         4 . The therapeutic agent according to  claim 1 . wherein Ra is a linear or branched C 1 -C 20  alkyl and R′a is H. 
     
     
         5 . The therapeutic agent according to  claim 1 , wherein R17 is a linear or branched C 1 -C 20  alkyl. 
     
     
         6 . The therapeutic agent according to  claim 1 , wherein R17 is a linear or branched C 1 -C 20  alkyl. 
     
     
         7 . The therapeutic agent according to  claim 1 , wherein R9 is a linear or branched C 1 -C 20  alkyl. 
     
     
         8 . The therapeutic agent according to  claim 1 , wherein R9 is a linear or branched C 1 -C 20  alkyl. 
     
     
         9 . The therapeutic agent according to  claim 1 , wherein T is H or SR 1  where R 1  is a linear or branched C 1 -C 20  alkyl. 
     
     
         10 . The therapeutic agent according to  claim 1 , wherein:
 Ra is a linear or branched C 1 -C 20  alkyl;   R′a is H;   R17 is a linear or branched C 1 -C 20  alkyl;   R9 is a linear or branched C 1 -C 20  alkyl; and   T is H or SR 1  where R 1  is a linear or branched C 1 -C 20  alkyl.   
     
     
         11 . The therapeutic agent according to  claim 1 , wherein the leptomycin derivative is:
 (2-Methylsulfanyl-ethyl)-amide of (2E,10E,12E,16Z,18E)-(R)-6-Hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid;   Bis-[(2-mercaptoethyl)-amide of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid];   (2-Mercapto-ethyl)-amide of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid;   (2-Methyldisulfanyl-ethyl)-amide of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid;   (2-Methyl-2-methyldisulfanyl-propyl)-amide of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid; or   (2-Mercapto-2-methyl-propyl)-amide of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid;   or a pharmaceutically acceptable salt thereof.   
     
     
         12 . The therapeutic agent according to  claim 1 , wherein the selected cell population is a malignancy. 
     
     
         13 . The therapeutic agent according to  claim 12 , wherein the malignancy is cancer of lung, breast, colon, prostate, kidney, pancreas, ovary, lymphatic organ or melanoma. 
     
     
         14 . The therapeutic agent according to  claim 1 , wherein the cell binding agent is a modified cell binding agent comprising a function reactive towards the linking group of the leptomycin derivative, so that the derivative and the cell binding agent are linked together via said linker comprising said linking group. 
     
     
         15 . The therapeutic agent according to  claim 14 , wherein the cell binding agent is modified with SMCC, SSNPB, LC-SMCC, STAB, SIA, SBA or SBAP. 
     
     
         16 . The therapeutic agent according to  claim 14 , wherein the cell binding agent is an antibody or peptide. 
     
     
         17 . The therapeutic agent according to  claim 16 , wherein the cell binding agent is modified by SPP, SMPT, SDPB, SPDP, SMCC, SSNPB, 2-iminothiolate, or S-acetylsuccinic anhydride. 
     
     
         18 . A leptomycin derivative of formula (I) linked to a cell binding agent, 
       
         
           
           
               
               
           
         
       
       wherein:
 Ra and R′a are independently H or a linear or branched C 1 -C 20  alkyl; 
 R17 is alkyl optionally substituted by OR, CN, NRR′, or perfluoroalkyl; 
 R9 is alkyl optionally substituted by OR, CN, NRR′, or perfluoroalkyl; 
 X is —NR—; 
 Y is a linear or branched C 1 -C 20  alkyl; 
 T represents H or a thiol protecting group or T represents 
 
       
         
           
           
               
               
           
         
       
       where:
 Ra, R′a, R17, R9, X, and Y are defined as above; and 
 R and R′, which may be identical or different, are H or a linear or branched C 1 -C 20  alkyl; or a pharmaceutically acceptable salt thereof.