Prodrug of an ice inhibitor

Abstract

This invention describes an ICE inhibitor prodrug (I) having good bioavailability. Compound I is useful for treating IL-1 mediated diseases such as rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory peritonitis, septic shock, pancreatitis, traumatic brain injury, organ transplant rejection, osteoarthritis, asthma, psoriasis, Alzheimer's disease, myocardial infarction, congestive heart failure, Huntington's disease, atherosclerosis, atopic dermatitis, leukemias and related disorders, myelodysplastic syndrome, uveitis or multiple myeloma.

1 .- 12 . (canceled) 
     
     
         13 . A topical formulation comprising an active ICE inhibitor II having a formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         14 . The topical formulation of  claim 13 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the active ICE inhibitor II, or the pharmaceutically acceptable salt thereof. 
     
     
         15 . The topical formulation of  claim 13 , wherein the topical formulation is an ointment. 
     
     
         16 . The topical formulation of  claim 15 , wherein the pharmaceutically acceptable carrier, adjuvant, or vehicle is a mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, or water, or a combination thereof. 
     
     
         17 . The topical formulation of  claim 13 , wherein the topical formulation is a cream or a lotion. 
     
     
         18 . The topical formulation of  claim 17 , wherein the pharmaceutically acceptable carrier, adjuvant, or vehicle is a mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, or water, or a combination thereof. 
     
     
         19 . The topical formulation of  claim 13 , wherein the active ICE inhibitor II, or the pharmaceutically acceptable salt thereof, is in an amount of about 5% w/w to about 95% w/w of the topical formulation. 
     
     
         20 . The topical formulation of  claim 13 , further comprising an additional agent, wherein the additional agent is an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin, an anti-vascular hyperproliferation compound, or a pharmaceutically acceptable adjuvant, or a combination thereof. 
     
     
         21 . A method of treating a disease in a subject in need thereof comprising the step of administering to said subject a pharmaceutical composition comprising an active ICE inhibitor II having a formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the disease is atopic dermatitis, psoriasis, acute dermatomyositis, eczema, or metastatic melanoma, or a combination thereof. 
       
     
     
         22 . The method of  claim 21 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the active ICE inhibitor II, or the pharmaceutically acceptable salt thereof. 
     
     
         23 . The method of  claim 21 , wherein the pharmaceutical composition is administered one to five times a day. 
     
     
         24 . The method of  claim 21 , wherein the active ICE inhibitor II, or pharmaceutically acceptable salt thereof is in an amount of about 5% w/w to about 95% w/w of the pharmaceutical composition. 
     
     
         25 . The method of  claim 21 , wherein the pharmaceutical composition is administered in combination with an additional agent, wherein the additional agent is an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin, an anti-vascular hyperproliferation compound, or a pharmaceutically acceptable adjuvant, or a combination thereof. 
     
     
         26 . The method of  claim 21 , wherein the pharmaceutical composition further comprises an additional agent, wherein the additional agent is an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin, an anti-vascular hyperproliferation compound, or a pharmaceutically acceptable adjuvant, or a combination thereof. 
     
     
         27 . The method of  claim 21 , wherein the pharmaceutical composition is a topical composition. 
     
     
         28 . The method of  claim 27 , wherein the topical composition is an ointment, a cream, or a lotion. 
     
     
         29 . A method of treating atopic dermatitis in a subject in need thereof comprising the step of administering to said subject a pharmaceutical composition comprising an active ICE inhibitor II having a formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
       
     
     
         30 . The method of  claim 29 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the active ICE inhibitor II, or the pharmaceutically acceptable salt thereof. 
     
     
         31 . The method of  claim 29 , wherein the pharmaceutical composition is administered one to five times a day. 
     
     
         32 . The method of  claim 29 , wherein the active ICE inhibitor II, the pharmaceutically acceptable derivative thereof, or the pharmaceutically acceptable salt thereof is in an amount of about 5% w/w to about 95% w/w of the pharmaceutical composition. 
     
     
         33 . The method of  claim 29 , wherein the pharmaceutical composition is a topical composition. 
     
     
         34 . The method of  claim 33 , wherein the topical pharmaceutical composition is an ointment, a cream or a lotion. 
     
     
         35 . The method of  claim 34 , wherein the topical pharmaceutical composition is administered in combination with an additional agent, wherein the additional agent is an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin, an anti-vascular hyperproliferation compound, or a pharmaceutically acceptable adjuvant, or a combination thereof. 
     
     
         36 . The method of  claim 29 , wherein the pharmaceutical composition further comprises an additional agent, wherein the additional agent is an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin, an anti-vascular hyperproliferation compound, or a pharmaceutically acceptable adjuvant, or a combination thereof.