Agonizing dimeric cell-surface receptors with a receptor binding moiety and chelating metal

Abstract

Invented are metal chelated dimeric cell-surface receptor ligands, pharmaceutical compositions containing these compounds, and methods of using these compounds as agonist of dimeric cell-surface receptors. Also invented are novel processes used in preparing these compounds. Also invented are novel receptor binding moieties of the invented metal chelated cell-surface receptor ligands.

What is claimed is:  
     
         1 . A method for agonizing dimeric cell-surface receptors in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a metal chelated dimeric cell-surface receptor ligand.  
     
     
         2 . The method of  claim 1  wherein said metal is selected from the group consisting of zinc, iron, nickel, copper, manganese, magnesium, calcium, cobalt, cadmium, silver, paladium, ruthenium, chromium, vanadium, molybdenum and niobium.  
     
     
         3 . A method for agonizing a dimeric cell surface receptor in a subject in need thereof which comprises co-administering to the subject a therapeutically effective amount of a receptor binding moiety and an amount of metal sufficient to form a metal chelate with said receptor binding moiety, wherein said receptor binding moiety is a ligand for said dimeric cell surface receptor when it is in metal chelated form.  
     
     
         4 . The method of  claim 3  wherein said metal is zinc.  
     
     
         5 . The method of  claim 3  wherein said dimeric cell surface receptor is selected from the group consisting of granulocyte colony-stimulating factor (G-CSF) receptor, erythropoeitin (EPO) receptor, macrophage-colony-stimulating factor (M-CSF) receptor, growth hormone (GRH) receptor, thrombopoietin (TPO) receptor, interferon (IFN) alpha receptor, interferon (IFN) beta receptor, and a tyrosine kinase (TRK) receptor.  
     
     
         6 . The method of  claim 5  wherein said cell surface receptor is a G-CSF receptor.  
     
     
         7 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a receptor binding moiety, and an amount of metal sufficient to form a metal chelate of said receptor binding moiety, wherein said receptor binding moiety and said metal are separated in said composition, and further wherein said receptor binding moiety is a ligand for a dimeric cell surface receptor when it is in metal chelated form.  
     
     
         8 . The pharmaceutical composition of  claim 7  wherein said metal is zinc.  
     
     
         9 . The pharmaceutical composition of  claim 7  wherein said cell surface receptor is selected from the group consisting of granulocyte colony-stimulating factor (G-CSF) receptor, erythropoeitin (EPO) receptor, macrophage-colony-stimulating factor (M-CSF) receptor, growth hormone (GRH) receptor, thrombopoietin (TPO) receptor, interferon (IFN) alpha receptor, interferon (IFN) beta receptor, and a tyrosine kinase (TRK) receptor.  
     
     
         10 . The pharmaceutical composition of  claim 9  wherein said cell surface receptor is a G-CSF receptor.  
     
     
         11 . A pharmaceutical composition for use in enhancing leukocyte production which comprises the pharmaceutical composition of  claim 10 .  
     
     
         12 . A pharmaceutical composition for use in treating bacterial infections which comprises the pharmaceutical composition of  claim 10 .  
     
     
         13 . A pharmaceutical composition for use in treating bacterial infections which comprises the pharmaceutical composition of  claim 10 .  
     
     
         14 . A pharmaceutical composition for use in treating fungal infections which comprises the pharmaceutical composition of  claim 10 .  
     
     
         15 . The pharmaceutical composition of  claim 10 , wherein said receptor binding moiety is selected from: 
 Bis {2,5-bis[2-benzimidazolylimino]-3a,6a-bis(2-pyridyl)-1,2,3,3a,4,5,6,6a-octahydroimidazo[4,5-d]imidazole-N,N′}-zinc(II);    Bis {2,5-bis [2-benzimidazolylimino]-3a,6a-diphenyl-1,2,3,3a,4,5,6,6a-octahydroimidazo[4,5-d]imidazole-N,N′}-zinc(II);    Bis {5-(2-benzimidazolylimino)-2-[(5-methyl-2-benzimidazolyl)imino]-3a,6a-bis(2-pyridyl)-1,2,3,3a,4,5,6,6a-octahydroimidazo[4,5-d]imidazole-N,N′}-zinc(II); and    Bis {2,5-bis[(5-methyl-2-benzimidazolyl)imino]-3a,6a-bis(2-pyridyl)-1,2,3,3a,4,5,6,6a-octahydroimidazo[4,5-d]imidazole-N,N′}-zinc(II).    
     
     
         16 . The method of  claim 1  wherein said metal chelated dimeric cell-surface receptor ligand comprises a symmetrical multimer of a receptor binding moiety.  
     
     
         17 . The method of  claim 1  wherein said metal chelated dimeric cell-surface receptor ligand comprises a symmetrical dimer of a receptor binding moiety.  
     
     
         18 . A method for agonizing dimeric cell-surface receptors in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of an organic molecule having a molecular weight from about 100 to about 850, containing of from 1 to 4 metal binding motifs.  
     
     
         19 . The method of  claim 18  wherein the each metal binding motif forms at least two coordinate bonds to a metal ion.  
     
     
         20 . A method for identifying agonists of dimeric cell-surface receptors which comprises contacting the receptor with dimeric cell-surface receptor ligand candidates in the presence of a metal ion source, and selecting ligand candidates which bind to the receptor.  
     
     
         21 . A process for the preparation of a metal chelated dimeric cell-surface receptor ligand which comprises reacting one or more receptor binding moieties and a metal ion source followed by optional isolation of the metal chelated dimeric cell-surface receptor ligand.  
     
     
         22 . A metal chelated cell-surface receptor ligand prepared by the process of  claim 21 .  
     
     
         23 . A metal chelated cell-surface receptor ligand.  
     
     
         24 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 22 .  
     
     
         25 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 23 .  
     
     
         26 . A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of  claim 22  which process comprises bringing the compound of  claim 22  into association with the pharmaceutically acceptable carrier or diluent.  
     
     
         27 . A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of  claim 23  which process comprises bringing the compound of  claim 23  into association with the pharmaceutically acceptable carrier or diluent.  
     
     
         28 . An isolated dimeric cell-surface receptor binding moiety of a metal chelated cell-surface receptor ligand.  
     
     
         29 . A dimeric cell-surface receptor binding moiety.  
     
     
         30 . A method for agonizing a dimeric cell surface receptor selected from the group consisting of granulocyte colony-stimulating factor (G-CSF) receptor, erythropoeitin (EPO) receptor, macrophage-colony-stimulating factor (M-CSF) receptor, growth hormone (GRH) receptor, thrombopoietin (TPO) receptor, interferon (IFN) alpha receptor, interferon (IFN) beta receptor, and a tyrosine kinase (TRK) receptor, in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of  claim 22 .  
     
     
         31 . A method for agonizing a dimeric cell surface receptor selected from the group consisting of granulocyte colony-stimulating factor (G-CSF) receptor, erythropoeitin (EPO) receptor, macrophage-colony-stimulating factor (M-CSF) receptor, growth hormone (GRH) receptor, thrombopoietin (TPO) receptor, interferon (IFN) alpha receptor, interferon (IFN) beta receptor, and a tyrosine kinase (TRK) receptor, in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of  claim 23 .  
     
     
         32 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 22 .  
     
     
         33 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 23 .  
     
     
         34 . A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of  claim 22  which process comprises bringing the compound of  claim 22  into association with the pharmaceutically acceptable carrier or diluent.  
     
     
         35 . A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of a compound of  claim 23  which process comprises bringing the compound of  claim 23  into association with the pharmaceutically acceptable carrier or diluent.  
     
     
         36 . A method for agonizing dimeric cell-surface receptors in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of  claim 22 .  
     
     
         37 . A method for agonizing dimeric cell-surface receptors in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of  claim 23 .  
     
     
         38 . The method of  claim 3  wherein said dimeric cell surface receptor is selected from the group consisting of the insulin receptor and the leptin receptor.  
     
     
         39 . The composition of  claim 7  wherein said dimeric cell surface receptor is selected from the group consisting of the insulin receptor and the leptin receptor.  
     
     
         40 . A method for agonizing a dimeric cell surface receptor selected from the group consisting of the insulin receptor and the leptin receptor, in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of  claim 22 .  
     
     
         41 . A method for agonizing a dimeric cell surface receptor selected from the group consisting of the insulin receptor and the leptin receptor, in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim  23 .