Auristatin tyramine phosphate salts and auristatin aminoquinoline derivatives and prodrugs thereof

Abstract

The present invention relates to new auristatin compounds and prodrugs thereof, compositions comprising them and uses thereof.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         R 1  and R 2  are independently alkyl or a Linker Unit; 
         R 3  and R 4  are independently selected from the group consisting of lithium (Li + ), sodium (Na + ), potassium (K + ), hydrogen (H), morpholine, quinine, tris(hydroxymethyl)aminomethane (TRIS), serine, nitroarginine and a Linker Unit; and 
         each R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl and a Linker Unit. 
       
     
     
         2 . The compound of  claim 1 , wherein R is: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein R 3  and R 4  are sodium. 
     
     
         4 . The compound of  claim 3 , wherein R 5  is H. 
     
     
         5 . The compound of  claim 1 , wherein R is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein R is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , wherein R 1  is methyl and R 2  is methyl. 
     
     
         8 . The compound of  claim 1 , wherein one of R 1  or R 2  is a Linker Unit. 
     
     
         9 . The compound of  claim 8 , wherein the Linker Unit comprises an antibody. 
     
     
         10 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         11 . (canceled) 
     
     
         12 . The pharmaceutical composition of  claim 10 , further comprising a therapeutically effective amount of chemotherapeutic agent selected from the group consisting of a tubulin-forming inhibitor, a topoisomerase inhibitor, and a DNA binder. 
     
     
         13 . A method for killing or inhibiting the proliferation of tumor cells or cancer cells comprising treating tumor cells or cancer cells with a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, in an amount effective to kill or inhibit the proliferation of the tumor cells or cancer cells. 
     
     
         14 . A method for treating cancer in a patient comprising administering to the patient a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered in an amount effective to treat cancer. 
     
     
         15 . The method of  claim 14 , further comprising administering an effective amount of a chemotherapeutic agent. 
     
     
         16 . A method for treating an autoimmune disease in a patient, comprising administering to the patient an effective amount of a compound having formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof 
         wherein R is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         R 1  and R 2  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl and a Linker Unit; 
         R 3  and R 4  are independently selected from the group consisting of lithium (Li + ), sodium (Na + ), potassium (K + ), hydrogen (H), morpholine, quinine, tris(hydroxymethyl)aminomethane (TRIS), serine, nitroarginine and a Linker Unit; and 
         each R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl and a Linker Unit. 
       
     
     
         17 . A method for treating an infectious disease in a patient, comprising administering to the patient an effective amount of a compound having formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof 
         wherein R is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         R 1  and R 2  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl and a Linker Unit; 
         R 3  and R 4  are independently selected from the group consisting of lithium (Li + ), sodium (Na + ), potassium (K + ), hydrogen (H), morpholine, quinine, tris(hydroxymethyl)aminomethane (TRIS), serine, nitroarginine and a Linker Unit; and 
         each R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl and a Linker Unit. 
       
     
     
         18 . The method of  claim 16 , wherein the compound is in a formulation comprising a pharmaceutically acceptable carrier. 
     
     
         19 .- 22 . (canceled) 
     
     
         23 . A method of determining inhibition of cellular proliferation by a compound, comprising contacting cells in a cell culture medium with the compound having formula I, 
       
         
           
           
               
               
           
         
       
       (I),
 or a pharmaceutically acceptable salt or solvate thereof 
 wherein R is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         R 1  and R 2  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl and a Linker Unit; 
         R 3  and R 4  are independently selected from the group consisting of lithium (Li + ), sodium (Na + ), potassium (K + ), hydrogen (H), morpholine, quinine, tris(hydroxymethyl)aminomethane (TRIS), serine, nitroarginine and a Linker Unit; and 
         each R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl and a Linker Unit and measuring the cytotoxic activity of the compound, whereby proliferation of the cells is inhibited. 
       
     
     
         24 . The method of  claim 23 , further comprising culturing the cells for a period from about 6 hours to about 5 days. 
     
     
         25 . A method of inhibiting the growth of tumor cells that overexpress a tumor-associated antigen comprising administering to a patient the compound of  claim 1  conjugated to an antibody that is specific for said tumor-associated antigen, and optionally a chemotherapeutic agent wherein the compound and said chemotherapeutic agent are each administered in amounts effective to inhibit growth of tumor cells in the patient. 
     
     
         26 .- 31 . (canceled) 
     
     
         32 . The method of  claim 17 , wherein the compound is in a formulation comprising a pharmaceutically acceptable carrier. 
     
     
         33 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein R is 
       
       
         
           
           
               
               
           
         
         R 1  and R 2  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl and a Linker Unit; 
         R 3  and R 4  are independently selected from the group consisting of lithium (Li + ), sodium (Na + ), potassium (K + ), hydrogen (H), morpholine, quinine, tris(hydroxymethyl)aminomethane (TRIS), serine, nitroarginine and a Linker Unit, wherein one of R 3  and R 4  is a Linker Unit; and 
         each R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl and a Linker Unit. 
       
     
     
         34 . The compound of  claim 33 , wherein each R 5  is H. 
     
     
         35 . The compound of  claim 33 , wherein one R 5  is a Linker Unit and the others are H. 
     
     
         36 . The compound of  claim 33 , wherein R 1  and R 2  are independently alkyl or a Linker Unit.