Novel tellurium compounds and their use as immunomodulators

Abstract

Novel tellurium-containing compounds and uses thereof as immunomodulators are disclosed.

1 . A method of treating or preventing a condition in which inhibition of interleukin-1β-converting enzyme is beneficial, the method comprising administering to a subject in need thereof a therapeutically effective amount of a tellurium-containing compound having the general formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         each of m and n is independently an integer from 0 to 3; and 
         each of R 1 —R 8  is independently selected from the group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate and sulfoneamido. 
       
     
     
         2 . The method of  claim 1 , wherein n and m are each 0. 
     
     
         3 . The method of  claim 2 , wherein each of R 1 —R 8  is independently selected from the group consisting of hydrogen, hydroxy, thiohydroxy, halogen and cyano. 
     
     
         4 . The method of  claim 2 , wherein each of R 1 , R 4 , R 5  and R 8  is hydrogen. 
     
     
         5 . The method of  claim 1 , wherein said condition is selected from the group consisting of an IL-1 mediated disease, an inflammatory disease, an autoimmune disease, an ischemic disease, a destructive bone disorder, a proliferative disorder, an infectious disease, a neurodegenerative disease, a disease associated with cell death, an excess dietary alcohol intake disease, retinal disorders, uveitis, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma, glomerulonephritis, diabetes, inflammatory bowel disease, Crohn's disease, atopic dermatitis, scarring, graft vs host disease, organ transplant rejection, organ apoptosis after burn injury, osteoporosis, leukemia and related disorders, myelodysplastic syndrome, multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, haemorrhagic shock, sepsis, burns, Shigellosis, Huntington's disease, Kennedy's disease, prion disease, epilepsy, acute and chronic heart disease, myocardial infarction, congestive heart failure, atherosclerosis, coronary artery bypass graft, spinal muscular atrophy, HIV-related encephalitis, aging, neurological damage due to stroke, traumatic brain injury, spinal cord injury, yellow fever, dengue fever, Japanese encephalitis, liver disease, renal disease, polycystic kidney disease,  H. pylori -associated gastric and duodenal ulcer disease, HIV infection, tuberculosis, an immunotherapy for the treatment of various forms of cancer, organ failure, meningitis, obesity and related diseases, diabetes, hyperglycemia, hyperinsulinemia and a complication associated with coronary artery bypass grafts. 
     
     
         6 . The method of  claim 5 , wherein said inflammatory disease is selected from the group consisting of septic shock, septicemia, adult respiratory distress syndrome, arthritis, cholangitis, colitis, encephalitis, hepatitis, pancreatitis and reperfusion injury. 
     
     
         7 . The method of  claim 5 , wherein said ischemic disease is selected from the group consisting of cerebral ischemia, myocardial ischemia, myocardial infarction, stroke, ischemic kidney disease; an immune based diseases, and hypersensitivity. 
     
     
         8 . The method of  claim 5 , wherein said neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and primary lateral sclerosis. 
     
     
         9 . The method of  claim 8 , wherein said neurodegenerative disease is caused by trauma. 
     
     
         10 . The method of  claim 9 , wherein said trauma comprises spinal cord injury. 
     
     
         11 . The method of  claim 5 , wherein said autoimmune disease is selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, throbocytopenia, chronic active hepatitis, myasthenia gravis and multiple sclerosis. 
     
     
         12 . The method of  claim 1 , wherein said administering is effected by a route selected from the group consisting of the oral, parenteral, rectal, nasal, topical and inhalation routes. 
     
     
         13 . The method of  claim 12 , wherein said oral administration comprises administration of a dose of from about 1 mg to about 150 mg per day. 
     
     
         14 . The method of  claim 1 , wherein said therapeutically effective amount of said compound ranges from about 1 mg/m 2 /day to about 20 mg/m 2 /day. 
     
     
         15 . The method of  claim 1 , wherein said at least one tellurium-containing compound forms a part of a pharmaceutical composition, said pharmaceutical composition further comprising a pharmaceutically acceptable carrier. 
     
     
         16 . The method of  claim 15 , wherein said administration comprises application of from about 0.01 weight percentages to about 40 weight percentages of said compound in said carrier. 
     
     
         17 . The method of  claim 15 , wherein said pharmaceutical composition further comprises an additional active agent. 
     
     
         18 . The method of  claim 17 , wherein said additional active agent is selected from the group consisting of an antibiotic agent, an anti-diabetic agent, an antihyperglemic agent, an antimicrobial agent, an anti-obesity agent, an anesthetic agent, an anti-oxidant, a chemotherapeutic agent, an antidepressant, an anti-histamine, a vitamin, and a hormone. 
     
     
         19 . A method of treating or preventing obesity and related disorders, the method comprising administering to a subject in need thereof a therapeutically effective amount of a tellurium-containing compound having the general formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         each of m and n is independently an integer from 0 to 3; and 
         each of R 1 —R 8  is independently selected from the group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate and sulfoneamido. 
       
     
     
         20 . The method of  claim 19 , wherein n and m are each 0. 
     
     
         21 . The method of  claim 20 , wherein each of R 1 —R 8  is independently selected from the group consisting of hydrogen, hydroxy, thiohydroxy, halogen and cyano. 
     
     
         22 . The method of  claim 20 , wherein each of R 1 , R 4 , R 5  and R 8  is hydrogen. 
     
     
         23 . The method of  claim 19 , wherein said administering is effected by a route selected from the group consisting of the oral, parenteral, rectal, nasal, topical and inhalation routes. 
     
     
         24 . The method of  claim 23 , wherein said oral administration comprises administration of a dose of from about 1 mg to about 150 mg per day. 
     
     
         25 . The method of  claim 19 , wherein said therapeutically effective amount of said compound ranges from about 1 mg/m 2 /day to about 20 mg/m 2 /day. 
     
     
         26 . The method of  claim 19 , wherein said at least one tellurium-containing compound forms a part of a pharmaceutical composition, said pharmaceutical composition further comprising a pharmaceutically acceptable carrier. 
     
     
         27 . The method of  claim 26 , wherein said administration comprises application of from about 0.01 weight percentages to about 40 weight percentages of said compound in said carrier. 
     
     
         28 . The method of  claim 26 , wherein said pharmaceutical composition further comprises an additional active agent. 
     
     
         29 . The method of  claim 28 , wherein said additional active agent is selected from the group consisting of an antibiotic agent, an anti-diabetic agent, an antihyperglemic agent, an antimicrobial agent, an anti-obesity agent, an anesthetic agent, an anti-oxidant, a chemotherapeutic agent, an antidepressant, an anti-histamine, a vitamin, and a hormone.