Use of tellurium containing compounds as nerve protecting agents

Abstract

A novel neuroprotective agent is disclosed for the treatment and prevention of neurodegenerative disorders which is based on the administration of an effective amount of a tellurium compound which has a specific ability to induce the differentiation and interfere with apoptotic cell death pathways of neuronal PC-12 cells.

1 . A method for treating or preventing a neurodegenerative process in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one tellurium-containing compound, said at least one tellurium-containing compound comprising at least one tellurium dioxide moiety. 
     
     
         2 . The method of  claim 1 , wherein said neurodegenerative process is selected from the group consisting of stroke syndromes, subarachnoid hemorrhage, brain dysfunction post-brain surgery, and disorders of the nervous system. 
     
     
         3 . The method of  claim 2 , wherein said disorder of the nervous system is caused by a factor selected from the group consisting of hypoxia, hypoglycemia, central nervous system trauma, intoxication by drugs or gases, administration of chemotherapy, alcohol abuse, and neurodegenerative disease. 
     
     
         4 . The method of  claim 3 , wherein said central nervous system trauma comprises spinal cord injury. 
     
     
         5 . The method of  claim 3 , wherein said neurodegenerative disease is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, myasthenia gravis, HIV-related encephalitis, cervical spondylosis, multiple sclerosis, Down's syndrome, and Huntington's chorea. 
     
     
         6 . The method of  claim 1 , wherein said at least one tellurium-containing compound is selected from the group consisting of tellurium dioxide (TeO 2 ), an organic complex of TeO 2 , a compound having general Formula I: 
       
         
           
           
               
               
           
         
         a compound having general Formula II: 
       
       
         
           
           
               
               
           
         
         and 
         a compound having general Formula III: 
       
       
         
           
           
               
               
           
         
         wherein: 
         each of t, u and v is independently 0 or 1; 
         each of m and n is independently an integer from 0 to 3; 
         Y is selected from the group consisting of ammonium, phosphonium, potassium, sodium and lithium; 
         X is a halogen atom; and 
         each of R 1 -R 14  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. 
       
     
     
         7 . The method of  claim 6 , wherein said tellurium-containing compound has said general Formula I. 
     
     
         8 . The method of  claim 7 , wherein t, u and v are each 0. 
     
     
         9 . The method of  claim 8 , wherein each of R 1 , R 8 , R 9  and R 10  is hydrogen. 
     
     
         10 . The method of  claim 9 , wherein X is a halogen atom. 
     
     
         11 . The method of  claim 10 , wherein X is chloro. 
     
     
         12 . The method of  claim 11 , wherein Y is ammonium. 
     
     
         13 . The method of  claim 4 , wherein said administering is effected for a period of up to 21 days following said spinal cord injury. 
     
     
         14 . The method of  claim 1 , wherein said therapeutically effective amount ranges from about 0.1 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 pharmaceutical composition further comprises at least one additional active agent. 
     
     
         17 . The method of  claim 16 , wherein said additional active agent is selected from the group consisting of a neurotropic growth factor, an antispasticity agent, and an anti-inflammatory agent, a beta-adrenergic blocking agent and brimonidine. 
     
     
         18 . The method of  claim 16 , wherein said additional active agent is selected from the group consisting of methylprednisolone, Naloxone, Tirilazad, basic fibroblast growth factor, epithelial growth factor, insulin-like growth factor, brain-derived neurotrophic factor, interferon and glial-derived neurotrophic factor. 
     
     
         19 . A pharmaceutical composition comprising at least one tellurium-containing compound which comprises at least one tellurium dioxide moiety and a pharmaceutically acceptable carrier, the composition being packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment or prevention of a neurodegenerative process. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein said at least one tellurium-containing compound is selected from the group consisting of tellurium dioxide (TeO 2 ), an organic complex of TeO 2 , a compound having general Formula I: 
       
         
           
           
               
               
           
         
         a compound having general Formula II: 
       
       
         
           
           
               
               
           
         
         and 
         a compound having general Formula III: 
       
       
         
           
           
               
               
           
         
         wherein: 
         each of t, u and v is independently 0 or 1; 
         each of m and n is independently an integer from 0 to 3; 
         Y is selected from the group consisting of ammonium, phosphonium, potassium, sodium and lithium; 
         X is a halogen atom; and 
         each of R 1 -R 14  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. 
       
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein said tellurium-containing compound has said general Formula I. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein t, u and v are each 0. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein each of R 1 , R 8 , R 9  and R 10  is hydrogen. 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein X is a halogen atom. 
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein X is chloro. 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein Y is ammonium. 
     
     
         27 . The pharmaceutical composition of  claim 19 , wherein said neurodegenerative process is selected from the group consisting of stroke syndromes, subarachnoid hemorrhage, brain dysfunction post-brain surgery, and disorders of the nervous system. 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein said disorder of the nervous system is caused by a factor selected from the group consisting of hypoxia, hypoglycemia, central nervous system trauma, intoxication by drugs or gases, administration of chemotherapy, alcohol abuse, and neurodegenerative disease. 
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein said central nervous system trauma comprises spinal cord injury. 
     
     
         30 . The pharmaceutical composition of  claim 28 , wherein said neurodegenerative disease is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, myasthenia gravis, HIV-related encephalitis, cervical spondylosis, multiple sclerosis, Down's syndrome, and Huntington's chorea. 
     
     
         31 . The pharmaceutical composition of  claim 19 , further comprising at least one additional active agent. 
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein said additional active agent is selected from the group consisting of a neurotropic growth factor, an antispasticity agent, and an anti-inflammatory agent, a beta-adrenergic blocking agent and brimonidine. 
     
     
         33 . The pharmaceutical composition of  claim 31 , wherein said additional active agent is selected from the group consisting of methylprednisolone, Naloxone, Tirilazad, basic fibroblast growth factor, epithelial growth factor, insulin-like growth factor, brain-derived neurotrophic factor, interferon and glial-derived neurotrophic factor.