Thiotungstate analogues and uses thereof

Abstract

The current invention provides novel thiotungstate derivatives, methods of making novel thiotungstate derivatives, pharmaceutical compositions of novel thiotungstate derivatives, methods of using novel thiotungstate derivatives to treat diseases associated with aberrant vascularization, copper metabolism disorders and obesity and methods of using pharmaceutical compositions of thiotungstate derivatives to treat diseases associated with aberrant vascularization, copper metabolism disorders, neurodegenerative disorders, obesity or NF-κB dysregulation.

1 . A compound of structural formula (I): 
       
         
           
           
               
               
           
         
       
       or a solvate or hydrate thereof wherein:
 R 1 , R 2 , R 3 , R 5 , R 6  and R 7  are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl; 
 R 4  and R 8  are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl or are absent when N is part of an aromatic ring; 
 optionally, R 1  and R 2  taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl; 
 optionally, R 5  and R 6  taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl; 
 optionally, R 1  and R 2  taken together, R 2  and R 3  taken together and R 2  and R 4  taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl; 
 optionally, R 5  and R 6  taken together, R 6  and R 7  taken together and R 6  and R 8  taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl; 
 optionally, R 3  and R 7  taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl; and 
 Y −2  is (W 2 S 12 ) −2 , (W 2 S 9 ) −2 , (W 2 S 7 ) −2 , (W 2 S 8 ) −2 , (W 2 S 11 ) −2 , (W 2 S 6 ) −2  or (W 2 S 13 ) −2 . 
 
     
     
         2 . A compound of structural formula (I): 
       
         
           
           
               
               
           
         
       
       or a solvate or hydrate thereof wherein:
 Y −2  is (WS 4 ) −2 ; and 
 a) wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
 
       
         
           
           
               
               
           
         
         
           wherein R 1 (R 2 )(R 3 )N has the structure: 
         
       
       
         
           
           
               
               
           
         
         b) wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
       
         
           
           
               
               
           
         
         wherein R 9  is n-C 8 H 17 , n-C 9 H 19 , n-C 10 H 21 , n-C 11 H 23 , n-C 12 H 25 , n-C 13 H 27 , n-C 14 H 29 , n-C 15 H 31 , n-C 16 H 33 , n-C 17 H 35  or n-C 18 H 37 ; 
         c) wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
       
         
           
           
               
               
           
         
         d) wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
       
         
           
           
               
               
           
         
         e) wherein R 1 (R 2 )(R 3 )N has the structure: 
       
       
         
           
           
               
               
           
         
         f) wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
       
         
           
           
               
               
           
         
         
           wherein R 5 , R 6  and R 7  are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl; 
         
         R 8  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl or are absent when N is part of an aromatic ring; 
         optionally, R 5  and R 6  taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl; and 
         optionally, R 5  and R 6  taken together, R 6  and R 7  taken together and R 6  and R 8  taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl. 
       
     
     
         3 . The compound of  claim 2 , wherein 
       
         
           
           
               
               
           
         
         a) wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
       
         
           
           
               
               
           
         
         
           wherein R 1 (R 2 )(R 3 )N has the structure: 
         
       
       
         
           
           
               
               
           
         
         b) wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
       
         
           
           
               
               
           
         
         wherein R 9  is n-C 8 H 17 , n-C 9 H 19 , n-C 10 H 21 , n-C 11 H 23 , n-C 12 H 25 , n-C 13 H 27 , n-C 14 H 29 , n-C 15 H 31 , n-C 16 H 33 , n-C 17 H 35  or n-C 18 H 37 ; 
         c) wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
       
         
           
           
               
               
           
         
         d) wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
       
         
           
           
               
               
           
         
         e) wherein R 1 (R 2 )(R 3 )N has the structure: 
       
       
         
           
           
               
               
           
         
         f) wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 2 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
         
           
           
               
               
           
         
         wherein R 1 (R 2 )(R 3 )N has the structure: 
       
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 2 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
         
           
           
               
               
           
         
         wherein R 9  is n-C 8 H 17 , n-C 9 H 19 , n-C 10 H 21 , n-C 11 H 23 , n-C 12 H 25 , n-C 13 H 27 , n-C 14 H 29 , n-n-C 15 H 31 , n-C 16 H 33 , n-C 17 H 35  or n-C 18 H 37 . 
       
     
     
         6 . The compound of  claim 2 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 2 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 2 , wherein R 1 (R 2 )(R 3 )N has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 2 , wherein R 1 (R 2 )(R 3 )N has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         10 - 35 . (canceled) 
     
     
         36 . A pharmaceutical composition comprising the compound of  claim 2  and a pharmaceutically acceptable diluent, excipient or adjuvant. 
     
     
         37 . A method for treating cancer in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 2 . 
     
     
         38 . A method for treating cancer in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of  claim 36 . 
     
     
         39 . The method of  claim 37  further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-cancer agent or a pharmaceutical composition comprising i) said another anti-cancer agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant. 
     
     
         40 . The method of  claim 38  further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-cancer agent or a pharmaceutical composition comprising i) said another anti-cancer agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant. 
     
     
         41 . The method of  claim 37  further comprising administering to the patient in need of such treatment a therapeutically effective amount of zinc or a pharmaceutical composition comprising i) zinc and ii) a pharmaceutically acceptable diluent, excipient or adjuvant. 
     
     
         42 . The method of  claim 38  further comprising administering to the patient in need of such treatment a therapeutically effective amount of zinc or a pharmaceutical composition comprising i) zinc and ii) a pharmaceutically acceptable diluent, excipient or adjuvant. 
     
     
         43 . The method of  claim 37 , wherein the cancer is breast cancer, renal cancer, brain cancer, colon cancer, prostrate cancer, chondrosarcoma or angiosarcoma. 
     
     
         44 . A method for treating wet type macular degeneration or rheumatoid arthritis in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 2 . 
     
     
         45 . A method for treating wet type macular degeneration or rheumatoid arthritis in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of  claim 36 . 
     
     
         46 . A method for treating aberrant vascularization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 2 . 
     
     
         47 . A method for treating aberrant vascularization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of  claim 36 . 
     
     
         48 . A method for treating excess copper levels in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 2 . 
     
     
         49 . A method for treating excess copper levels in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of  claim 36 . 
     
     
         50 . A method for treating obesity in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 2 . 
     
     
         51 . A method for treating obesity in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of  claim 36 . 
     
     
         52 . The method of  claim 50  further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-obesity agent or a pharmaceutical composition comprising i) said another anti-obesity agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant. 
     
     
         53 . The method of  claim 51  further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-obesity agent or a pharmaceutical composition comprising i) said another anti-obesity agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant. 
     
     
         54 . A method for treating neurodegenerative disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 2 . 
     
     
         55 . A method for treating neurodegenerative disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of  claim 36 . 
     
     
         56 . The method of  claim 54 , wherein the neurodegenerative disease is Alzheimer's disease, amyotrophic lateral sclerosis or prion disease. 
     
     
         57 . The method of  claim 55 , wherein the neurodegenerative disease is Alzheimer's disease, amyotrophic lateral sclerosis or prion disease. 
     
     
         58 . The method of  claim 38 , wherein the cancer is breast cancer, renal cancer, brain cancer, colon cancer, prostrate cancer, chondrosarcoma or angiosarcoma. 
     
     
         59 . The compound of  claim 6 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
         
           
           
               
               
           
         
         and wherein R 1 (R 2 )(R 3 )(R 4 )N═R 5 (R 6 )(R 7 )(R 8 )N 
       
     
     
         60 . A pharmaceutical composition comprising the compound of  claim 59  and a pharmaceutically acceptable diluent, excipient or adjuvant. 
     
     
         61 . The compound of  claim 4 , wherein R 1 (R 2 )(R 3 )(R 4 )N═R 5 (R 6 )(R 7 )(R 8 )N or R 1 (R 2 )(R 3 )N═R 5 (R 6 )(R 7 )N. 
     
     
         62 . The compound of  claim 5 , wherein R 1 (R 2 )(R 3 )(R 4 )N═R 5 (R 6 )(R 7 )(R 8 )N. 
     
     
         63 . The compound of  claim 7 , wherein R 1 (R 2 )(R 3 )(R 4 )N has the structure: 
       
         
           
           
               
               
           
         
         and wherein R 1 (R 2 )(R 3 )(R 4 )N═R 5 (R 6 )(R 7 )(R 8 )N. 
       
     
     
         64 . The compound of  claim 8 , wherein R 1 (R 2 )(R 3 )(R 4 )N═R 5 (R 6 )(R 7 )(R 8 )N. 
     
     
         65 . The compound of  claim 9 , wherein R 1 (R 2 )(R 3 )(R 4 )N═R 5 (R 6 )(R 7 )(R 8 )N. 
     
     
         66 . A method for treating cancer in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 59 . 
     
     
         67 . The method of  claim 66  further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-cancer agent or a pharmaceutical composition comprising i) said another anti-cancer agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant. 
     
     
         68 . The method of  claim 66  further comprising administering to the patient in need of such treatment a therapeutically effective amount of zinc or a pharmaceutical composition comprising i) zinc and ii) a pharmaceutically acceptable diluent, excipient or adjuvant. 
     
     
         69 . The method of  claim 66 , wherein the cancer is breast cancer, renal cancer, brain cancer, colon cancer, prostrate cancer, chondrosarcoma or angiosarcoma. 
     
     
         70 . A method for treating wet type macular degeneration or rheumatoid arthritis in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 59 . 
     
     
         71 . A method for treating aberrant vascularization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 59 . 
     
     
         72 . A method for treating excess copper levels in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 59 . 
     
     
         73 . A method for treating obesity in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 59 . 
     
     
         74 . The method of  claim 73  further comprising administering to the patient in need of such treatment a therapeutically effective amount of another anti-obesity agent or a pharmaceutical composition comprising i) said another anti-obesity agent and ii) a pharmaceutically acceptable diluent, excipient or adjuvant. 
     
     
         75 . A method for treating neurodegenerative disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 59 . 
     
     
         76 . The method of  claim 75 , wherein the neurodegenerative disease is Alzheimer's disease, amyotrophic lateral sclerosis or prion disease. 
     
     
         77 . A method for treating cancer, aberrant vascularization, wet type macular degeneration, rheumatoid arthritis, obesity or neurodegenerative disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 1 .