Caspase inhibitor prodrugs

Abstract

The present invention relates to compounds of formula I which are prodrugs of caspase inhibitors and pharmaceutically acceptable salts thereof. This invention further relates to the release of caspase inhibitors from these compounds through selective bond cleavage. This invention further relates to pharmaceutical compositions comprising these compounds, which are particularly well-suited for treatment of caspase-mediated diseases, including inflammatory and degenerative diseases. This invention further relates to methods for preparing compounds of this invention.

1 . A compound of the formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is a saturated or unsaturated, straight-chain or branched, substituted or unsubstituted hydrocarbon chain; 
 R 2  is B or a phospholipid head group; 
 X is a direct covalent bond or a group C(O)LR 3 ; 
 
       wherein L is a saturated or unsaturated, straight-chain or branched, substituted or unsubstituted hydrocarbon chain having from 2 to 15 carbon atoms, which optionally includes cyclic elements, and is optionally interrupted by one or more atoms selected from the group consisting of oxygen, sulfur and N(R 4 ), R 3  is selected from the group consisting of O, S and N(R 4 ); 
       wherein R 4  is a saturated or unsaturated hydrocarbon chain having 1 to 6 carbon atoms; and
 Y is a residue of a caspase inhibitor. 
 
     
     
         2 . The compound of  claim 1 , wherein the R 1  hydrocarbon chain has from 2 to 30 carbon atoms. 
     
     
         3 . The compound of  claim 2 , wherein the R 1  hydrocarbon chain has from 2 to 24 carbon atoms. 
     
     
         4 . The compound of  claim 1 , wherein R 2  is a phospholipid head group. 
     
     
         5 . The compound of  claim 4 , wherein the phospholipid head group is choline. 
     
     
         6 . The compound of  claim 1 , wherein X is a direct covalent bond. 
     
     
         7 . The compound of  claim 1 , wherein Y is a reversible caspase inhibitor. 
     
     
         8 . The compound of  claim 1 , wherein Y is an irreversible caspase inhibitor. 
     
     
         9 . The compound of  claim 1 , wherein the caspase inhibitor is any one of the caspase inhibitors depicted in  FIGS. 1-20 . 
     
     
         10 . The compound of  claim 1 , wherein the caspase inhibitor is selected from a structure in Table 1 below: 
       
         
           
                 
               
                   TABLE 1 
                 
                     
                 
                   Structures of Selected Caspase 
                 
                   Inhibitors 
                 
                 
                 
               
                   Comp. 
                     
                 
                   No. 
                   Structure 
                 
                     
                 
                 
                 
               
                   1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   2 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   3 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   4 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   5 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   6 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   7 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   8 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   9 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   10 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   11 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   12 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   13 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   14 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   15 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   16 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   17 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   18 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   19 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   20 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
               
               
                
                
                
               
            
             
                
                
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         11 . A pharmaceutical composition comprising:
 a) a compound according to any one of  claims 1 - 10 ; and   b) a pharmaceutically acceptable carrier.   
     
     
         12 . A method for inhibiting caspase activity in a mammal in need thereof comprising administering to said mammal a compound according to any one of  claims 1 - 10  or a composition according to  claim 11 . 
     
     
         13 . A method for treating or preventing a disease selected from the group consisting of an IL-1 mediated disease, an apoptosis mediated disease, an inflammatory disease, an autoimmune disease, a destructive bone disorder, a proliferative disorder, an infectious disease, a degenerative disease, a disease associated with cell death, an excess dietary alcohol intake disease, a viral mediated disease, uveitis, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, scarring, graft vs. host disease, organ transplant rejection, osteoporosis, leukemias and related disorders, myelodysplastic syndrome, multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, hemorrhagic shock, sepsis, septic shock, burns, Shigellosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Kennedy's disease, prion disease, cerebral ischemia, epilepsy, myocardial ischemia, acute and chronic heart disease, myocardial infarction, congestive heart failure, arteriosclerosis, coronary artery bypass graft, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, traumatic brain injury, spinal cord injury, hepatitis-B, hepatitis-C, hepatitis-G, yellow fever, dengue fever, or Japanese encephalitis, various forms of liver disease, renal disease, polyaptic kidney disease,  H. pylori -associated gastric and duodenal ulcer disease, HIV infection, tuberculosis, and meningitis in a mammal comprising administering to said mammal a compound according to any one of  claims 1 - 10  or a composition according to  claim 11 . 
     
     
         14 . A method for treating complications associated with coronary artery bypass grafts in a mammal comprising administering to said mammal a compound according to any one of  claims 1 - 10  or a composition according to  claim 11 . 
     
     
         15 . A method for treating cancer in a mammal comprising administering to said mammal a compound according to any one of  claims 1 - 10  or a composition according to  claim 11 , wherein said compound or composition is used as a component of immunotherapy. 
     
     
         16 . The method according to any one of  claims 12 - 15 , wherein said mammal is a human. 
     
     
         17 . A method for preserving cells comprising treating the cells with a solution comprising an effective amount of a compound according to any one of  claims 1 - 10  or a composition according to  claim 11 . 
     
     
         18 . The method according to  claim 17 , wherein said compound or composition is used for an organ transplant or for preserving blood products. 
     
     
         19 . The method according to any one of  claims 12 - 15 , wherein said compound or composition is administered with an additional therapeutic agent. 
     
     
         20 . The method according to  claim 19 , wherein said additional therapeutic agent is a thrombolytic agent. 
     
     
         21 . The method according to  claim 20 , wherein said thrombolytic agent is selected from the group consisting of tissue plasminogen activator and streptokinase. 
     
     
         22 . A method for decreasing IGIF or IFN-γ production in a mammal in need thereof comprising administering to said mammal a compound according to any one of  claims 1 - 10  or a composition according to  claim 11 .