Texaphyrin coordination compounds and uses thereof

Abstract

Novel coordination polymers, their pharmaceutical formulations, useful for treating atheroma, tumors and other neoplastic tissue, as well as other conditions that are responsive to the induction of targeted oxidative stress, are disclosed.

1 - 33 . (canceled)  
     
     
         34 . A method for localizing a texaphyrin at a desired site in a patient comprising administering to the patient a reducing agent and a compound having the structure:  
       
         
           
           
               
               
           
         
         its hydrate, pharmaceutically acceptable salt or prodrug form thereof, wherein:  
         M represents H or a metal cation;  
         Q represents an integer of from about −5 to about +5;  
         L represents a charge balancing species;  
         n represents an integer of from 0 to +5;  
         Z 1 , Z 2  and Z 3  independently represent N, O, CH or S;  
         R 1 , R 1a , R 2 , R 3 , R 4 , R 4a , R 7 , and R 8  are independently selected from acyl, acyloxy, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, carboxyl, (optionally substituted alkoxy)carbonyl, (optionally substituted amino)carbonyl, (optionally substituted alkoxy)carbonyloxy, (optionally substituted amino)carbonyloxy, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, halogen, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclooxy, hydrogen, hydroxyl, nitro, optionally substituted azo, S—R 31 , SO—R 31 , SO 2 —R 31 , and the moiety X—Y;  
         R 6  and R 9  are independently selected from acyl, acyloxy, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, carboxyl, (optionally substituted alkoxy)carbonyl, (optionally substituted amino)carbonyl, (optionally substituted alkoxy)carbonyloxy, (optionally substituted amino)carbonyloxy, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, fluoro, chloro, bromo, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclooxy, hydrogen, hydroxyl, nitro, optionally substituted azo, sulfanyl, sulfinyl, sulfonyl, and the moiety X—Y;  
         R 5 , R 10 , R 11  and R 12  are independently selected from acyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aryl, halo, hydrogen, hydroxy, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;  
         X is a covalent bond or a linker;  
         Y is a catalytic group, a chemotherapeutic agent or a site-directing group;  
         R 31  represents acyl, optionally substituted alkenyl, optionally substituted alky, optionally substituted alkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkynyl, optionally substituted aminocarbonyl, optionally substituted aryl, carboxy, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.  
       
     
     
         35 . The method of  claim 34 , wherein the desired site is a tumor or plaque in the patient.  
     
     
         36 . The method of  claim 34 , wherein the compound has the structure:  
       
         
           
           
               
               
           
         
         its hydrate, pharmaceutically acceptable salt or prodrug form thereof, wherein:  
         M represents a metal cation selected from Gd(III) and Lu(III);  
         Q represents an integer of 2;  
         L represents a charge balancing species selected from OAc, NO 2 , Cl, and PO 4 ;  
         n represents an integer of 2;  
         Z 1 , Z 2  and Z 3  independently represent N;  
         R 1  and R 1a  independently represent (CH 2 ) 3 OH;  
         R 2  and R 3  independently represent C 2 H 5 ;  
         R 4  and R 4a  independently represent CH 3 ;  
         R 7  and R 8  independently represent O—(CH 2 —CH 2 —O) 3 —CH 3 ; and  
         R 5 , R 6 , R 9 , R 10 , R 11  and R 12  independently represent H.  
       
     
     
         37 . The method of  claim 34  wherein the reducing agent is selected from ascorbic acid, dehydroascorbate, dihydrolipoate, NADH, folate, glyoxal, glyoxalate, oxamate, dimethyloxalate, oxamide, NADPH, glutathione, nacetylcystein and pyruvate.  
     
     
         38 . The method of  claim 34 , wherein the compound has the structure:  
       
         
           
           
               
               
           
         
       
       wherein M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III); AL is an apical ligand; and n represents an integer from 1 to 3.  
     
     
         39 . The method of  claim 34 , wherein the reducing agent and the compound are intravenously administered to the patient.  
     
     
         40 . The method of  claim 34 , wherein the reducing agent is administered before the compound is administered.  
     
     
         41 . The method of  claim 34 , wherein the reducing agent and the compound are administered simultaneously.  
     
     
         42 . The method of  claim 34 , wherein the patient is administered a mixture of the reducing agent and the compound.  
     
     
         43 . The method of  claim 34 , wherein the reducing agent is administered before the compound is administered.  
     
     
         44 . The method of  claim 34 , wherein administration of the reducing agent enhances cellular uptake of the texaphyrin.  
     
     
         45 . The method of  claim 34 , wherein the patient has a disease or condition selected from the group consisting of sarcoma, lymphoma, leukemia, carcinoma, brain metastases, glioma, glioblastoma, cancer of the prostate, melanoma, atherosclerosis, intimal hyperplasia, restenosis, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, non-specific vasculitis, Kawasaki's disease, psoriasis, Type I diabetes, pemphigus vulgaris, multiple sclerosis, tuberculosis, sarcoidosis, lymphomatoid granulomatosis, Wegener's granulomatosus, interstitial pneumonitis, asthma, inflammatory bowel disease, inflammatory arthritis, transplant rejection, and age-related macular degeneration.  
     
     
         46 . A method for providing intracellular oxidative stress comprising administering to a patient a reducing agent and a compound having the structure:  
       
         
           
           
               
               
           
         
         its hydrate, pharmaceutically acceptable salt or prodrug form thereof, wherein:  
         M represents H or a metal cation;  
         Q represents an integer of from about −5 to about +5;  
         L represents a charge balancing species;  
         n represents an integer of from 0 to +5;  
         Z 1 , Z 2  and Z 3  independently represent N, O, CH or S;  
         R 1 , R 1a , R 2 , R 3 , R 4 , R 4a , R 7 , and R 8  are independently selected from acyl, acyloxy, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, carboxyl, (optionally substituted alkoxy)carbonyl, (optionally substituted amino)carbonyl, (optionally substituted alkoxy)carbonyloxy, (optionally substituted amino)carbonyloxy, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, halogen, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclooxy, hydrogen, hydroxyl, nitro, optionally substituted azo, S—R 31 , SO—R 31 , SO 2 —R 31 , and the moiety X—Y;  
         R 6  and R 9  are independently selected from acyl, acyloxy, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, carboxyl, (optionally substituted alkoxy)carbonyl, (optionally substituted amino)carbonyl, (optionally substituted alkoxy)carbonyloxy, (optionally substituted amino)carbonyloxy, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, fluoro, chloro, bromo, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclooxy, hydrogen, hydroxyl, nitro, optionally substituted azo, sulfanyl, sulfinyl, sulfonyl, and the moiety X—Y;  
         R 5 , R 10 , R 11  and R 12  are independently selected from acyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aryl, halo, hydrogen, hydroxy, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;  
         X is a covalent bond or a linker;  
         Y is a catalytic group, a chemotherapeutic agent or a site-directing group;  
         R 31  represents acyl, optionally substituted alkenyl, optionally substituted alky, optionally substituted alkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkynyl, optionally substituted aminocarbonyl, optionally substituted aryl, carboxy, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.  
       
     
     
         47 . The method of  claim 46 , wherein the desired site is selected from a tumor or plaque.  
     
     
         48 . The method of  claim 46 , wherein the compound has the structure:  
       
         
           
           
               
               
           
         
         its hydrate, pharmaceutically acceptable salt or prodrug form thereof, wherein:  
         M represents a metal cation selected from Gd(III) and Lu(III);  
         Q represents an integer of 2;  
         L represents a charge balancing species selected from OAc, NO 2 , Cl, and PO 4 ;  
         n represents an integer of 2;  
         Z 1 , Z 2  and Z 3  independently represent N;  
         R 1  and R 1a  independently represent (CH 2 ) 3 OH;  
         R 2  and R 3  independently represent C 2 H 5 ;  
         R 4  and R 4a  independently represent CH 3 ;  
         R 7  and R 8  independently represent O—(CH 2 —CH 2 —O) 3 —CH 3 ; and  
         R 5 , R 6 , R 9 , R 10 , R 11  and R 12  independently represent H.  
       
     
     
         49 . The method of  claim 46 , wherein the reducing agent is selected from ascorbic acid, dehydroascorbate, dihydrolipoate, NADH, folate, glyoxal, glyoxalate, oxamate, dimethyloxalate, oxamide, NADPH, glutathione, nacetylcystein and pyruvate.  
     
     
         50 . The method of  claim 46 , wherein the compounds has the structure:  
       
         
           
           
               
               
           
         
       
       wherein M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III); AL is an apical ligand; and n represents an integer from 1 to 3.  
     
     
         51 . The method of  claim 46 , wherein the reducing agent and the texaphyrin metal complex are intravenously administered to the patient.  
     
     
         52 . The method of  claim 46 , wherein the reducing agent is administered before the texaphyrin metal complex is administered.  
     
     
         53 . The method of  claim 46 , wherein the reducing agent and the texaphyrin metal complex are administered simultaneously.  
     
     
         54 . The method of  claim 46 , wherein the patient is administered a mixture of the reducing agent and the texaphyrin metal complex.  
     
     
         55 . The method of  claim 46 , wherein the reducing agent is administered before the texaphyrin metal complex is administered.  
     
     
         56 . The method of  claim 46 , wherein the patient has a disease or condition selected from the group consisting of sarcoma, lymphoma, leukemia, carcinoma, brain metastases, glioma, glioblastoma, cancer of the prostate, melanoma, atherosclerosis, intimal hyperplasia, restenosis, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, non-specific vasculitis, Kawasaki's disease, psoriasis, Type I diabetes, pemphigus vulgaris, multiple sclerosis, tuberculosis, sarcoidosis, lymphomatoid granulomatosis, Wegener's granulomatosus, interstitial pneumonitis, asthma, inflammatory bowel disease, inflammatory arthritis, transplant rejection, and age-related macular degeneration.