Compounds and methods for the treatment of erb b2/neu positive diseases

Abstract

Disclosed herein are anti-ERB B2/NEU antibodies conjugated with maytansinoid drugs for targeted delivery to disease tissues. Methods relating to the preparation and uses of such drug conjugates to treat ERB B2/NEU positive cells in cancers are provided.

1 . A compound of Formula Ia: 
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein 
         X is hydrogen or halo; 
         Y is selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, and —C(═O)R 5 ; 
         R 1  is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5  and —OR 5 ; 
         R 2  is hydrogen or C 1 -C 6  alkyl; 
         R 3  is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ; 
         R 4  is —OH or —SH; 
         R 5  is C 1 -C 6  alkyl or benzyl; 
         R 6  is C 1 -C 6  alkyl, phenyl or benzyl; 
         R 7  is hydrogen, C 1 -C 6  alkyl or an amino acid side chain; 
         R 8  is hydrogen or C 1-6  alkyl; 
         n is 0, 1, 2, 3, 4, 5, 6, 7 or 8; 
         p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; and 
         Anti-HER2 is an anti-ERB B2/NEU (HER2) antibody. 
       
     
     
         2 . The compound of  claim 1 , which is a compound of Formula Ib 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         3 . The compound of  claim 1 , which is a compound of Formula Ic 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, 
         wherein Anti-HER2 is an anti-ERB B2/NEU (HER2) antibody. 
       
     
     
         4 . The compound of  claim 3 , wherein the compound connected to anti-ERB B2/NEU (HER2) antibody is N2′-deacetyl-N2′-(6-maleimido-1-oxo-hexyl)maytansine). 
     
     
         5 . The compound of  claim 1 , wherein the anti-Erb B2/neu antibody is an antibody comprising trastuzumab or pertuzumab or an equivalent thereof. 
     
     
         6 . A pharmaceutical composition comprising a compound of  claim 1 . 
     
     
         7 . A method of treating a proliferative, inflammatory or immunologic disease or condition in a patient in need thereof comprising administering an effective amount of a compound of  claim 1 . 
     
     
         8 . A method of treating a proliferative, inflammatory or immunologic disease or condition characterized by Erb B2/neu positive cells in a patient in need thereof comprising administering an effective amount of a compound of Formula IVa: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein the compound of Formula IVa is generated as a result of a metabolic chemical reaction following administration of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, to the patient, wherein AA is an amino acid or thiolated amino acid, 
     
     
         9 . A method of treating a proliferative, inflammatory or immunologic disease or condition characterized by Erb B2/neu positive cells in a patient in need thereof comprising administering an effective amount of a compound of Formula IVb: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein the compound of Formula IVb is generated as a result of a metabolic chemical reaction following administration of a compound of  claim 2 , or a pharmaceutically acceptable salt thereof, to the patient, wherein AA is an amino acid or thiolated amino acid. 
     
     
         10 . A method of treating a proliferative, inflammatory or immunologic disease or condition characterized by Erb B2/neu positive cells in a patient in need thereof comprising administering an effective amount of a compound of Formula IVc: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein the compound of Formula IVc is generated as a result of a metabolic chemical reaction following administration of a compound of  claim 3 , or a pharmaceutically acceptable salt thereof, to the patient, wherein AA is an amino acid or thiolated amino acid. 
     
     
         11 . The method of  claim 8 , wherein AA is 
       
         
           
           
               
               
           
         
       
       wherein   represents point of connection to the rest of the molecule. 
     
     
         12 . The compound of  claim 1 , wherein:
 X is halo;   Y is C 1 -C 6  alkyl;   R 1  is hydrogen;   R 2  is C 1 -C 6  alkyl;   R 3  is methyl;   R 4  is —OH;   R 7  is C 1 -C 6  alkyl; and   R 8  is C 1-6  alkyl.   
     
     
         13 . The compound of  claim 1 , wherein:
 X is Cl;   Y is C 1 -C 6  alkyl;   R 1  is hydrogen;   R 2  is C 1 -C 6  alkyl;   R 3  is methyl;   R 4  is —OH;   R 7  is C 1 -C 6  alkyl; and   R 8  is C 1-6  alkyl.   
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 13 . 
     
     
         15 . A method of treating a proliferative, inflammatory or immunologic disease or condition in a patient in need thereof comprising administering an effective amount of a compound of  claim 13 . 
     
     
         16 . The pharmaceutical composition of  claim 6 , wherein the pharmaceutical composition is suitable for injection or infusion. 
     
     
         17 . The pharmaceutical composition of  claim 14 , wherein the pharmaceutical composition is suitable for injection or infusion.