Method for treating a mammal by administration of a compound having the ability to release CO, compounds having the ability to release CO and pharmaceutical compositions thereof

Abstract

Several classes of in vivo carbon monoxide-releasing compounds are useful for the treatment and/or prevention of diseases, such as chronic inflammatory, e.g., rheumatoid arthritis, and of diseases with a strong inflammatory component, such as atherosclerosis, stroke, coronary disease, and Alzheimers disease. The in vivo carbon monoxide-releasing compounds can be attached to known drug vectors and/or known anti-inflammatory drugs, such as aspirin.

1 . A method for treating or preventing a disease in a mammal, comprising administering to the mammal an organic substance that is capable of releasing CO by an enzymatic process or by decarbonylation; provided that the organic substance is not CH 2 Cl 2 , bis-(2,4-dinitrophenyl)oxalate, formic acid, a formate ester, a formate amide, oxalic acid, an oxalate ester, or an oxalate amide.  
   
   
       2 . The method of  claim 1 , wherein the organic substance releases CO upon treatment with a base, an acid, or a radical initiator.  
   
   
       3 . The method of  claim 1 , wherein the organic substance is selected from the group consisting of: 
 CH n X y X′ 4−(n+y) , wherein n is 0-3, y is 0-4, and X and X′ are each independently F, Cl, Br, or I; trichloroacetic acid, or a salt, ester, or sulfinate thereof; triaryl carboxylic acid; an α-hydroxyacid or an ester or salt thereof; an α-ketoacid or an ester or salt thereof; a trialkylbenzaldehyde; a trialkoxybenzaldehyde; and an aliphatic aldehyde.    
   
   
       4 . The method of  claim 1 , wherein the organic substance is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       wherein R is H, alkyl, or aryl;  
       
         
           
           
               
               
           
         
       
       wherein Ar′ is  
       
         
           
           
               
               
           
         
       
       and R is H, alkyl, or aryl;  
       
         
           
           
               
               
           
         
       
       wherein R and R′ are each independently alkyl;  
       
         
           
           
               
               
           
         
       
       wherein R and R′ are each independently H, alkyl, or perfluoroalkyl.  
     
   
   
       5 . The method of  claim 1 , wherein the disease is an inflammatory disease, a disease with a strong inflammatory component, asthma, injury, infarction, or a circulatory disease.  
   
   
       6 . The method of  claim 5 , wherein the disease with a strong inflammatory component is atherosclerosis, stroke, coronary disease, or Alzheimer's disease.  
   
   
       7 . The method of  claim 1 , wherein the disease is a chronic inflammatory disease.  
   
   
       8 . The method of  claim 7 , wherein the chronic inflammatory disease is arthritis.  
   
   
       9 . The method of  claim 1 , wherein the mammal is a human.  
   
   
       10 . A method for treating or preventing a disease in a mammal, comprising administering to the mammal an organic substance that is capable of releasing CO by an enzymatic process or by decarbonylation, wherein the organic substance is encapsulated in a support.  
   
   
       11 . The method of  claim 10 , wherein the support is an organic support.  
   
   
       12 . The method of  claim 10 , wherein the support is a host-guest supermolecule, a liposome, a cyclodextrin, or a polymeric material.  
   
   
       13 . The method of  claim 10 , wherein the organic substance releases CO upon treatment with a base, an acid, or a radical initiator.  
   
   
       14 . The method of  claim 10 , wherein the organic substance is selected from the group consisting of: 
 CH n X y X′ 4−(n+y) , wherein n is 0-3, y is 0-4, and X and X′are each independently F, Cl, Br, or I; trichloroacetic acid, or a salt, ester, or sulfinate thereof; triaryl carboxylic acid; an α-hydroxyacid or an ester or salt thereof; an α-ketoacid or an ester or salt thereof; a trialkylbenzaldehyde; a trialkoxybenzaldehyde; and an aliphatic aldehyde.    
   
   
       15 . The method of  claim 10 , wherein the organic substance is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       wherein R is H, alkyl, or aryl;  
       
         
           
           
               
               
           
         
       
       wherein Ar′ is  
       
         
           
           
               
               
           
         
       
       and R is H, alkyl, or aryl;  
       
         
           
           
               
               
           
         
       
       wherein R and R′ are each independently alkyl;  
       
         
           
           
               
               
           
         
       
       wherein R and R′ are each independently H, alkyl, or perfluoroalkyl.  
     
   
   
       16 . The method of  claim 10 , wherein the disease is an inflammatory disease, a disease with a strong inflammatory component, asthma, injury, infarction, or a circulatory disease.  
   
   
       17 . The method of  claim 16 , wherein the disease with a strong inflammatory component is atherosclerosis, stroke, coronary disease, or Alzheimer's disease.  
   
   
       18 . The method of  claim 10 , wherein the disease is a chronic inflammatory disease.  
   
   
       19 . The method of  claim 18 , wherein the chronic inflammatory disease is arthritis.  
   
   
       20 . The method of  claim 10 , wherein the mammal is a human.  
   
   
       21 . A compound comprising an organic substance that is capable of releasing CO by an enzymatic process or by decarbonylation; provided that the organic substance is not CH 2 Cl 2 , bis-(2,4-dinitrophenyl)oxalate, formic acid, a formate ester, a formate amide, oxalic acid, an oxalate ester, or an oxalate amide; and a second moiety.  
   
   
       22 . The compound of  claim 21 , wherein the organic substance releases CO upon treatment with a base, an acid, or a radical initiator.  
   
   
       23 . The compound of  claim 21 , wherein the organic substance is selected from the group consisting of: 
 CH n X y X′ 4−(n+y) , wherein n is 0-3, y is 0-4, and X and X′ are each independently F, Cl, Br, or I; trichloroacetic acid, or a salt, ester, or sulfinate thereof; triaryl carboxylic acid; an α-hydroxyacid or an ester or salt thereof; an α-ketoacid or an ester or salt thereof; a trialkylbenzaldehyde; a trialkoxybenzaldehyde; and an aliphatic aldehyde.    
   
   
       24 . The compound of  claim 21 , wherein the organic substance is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       wherein R is H, alkyl, or aryl;  
       
         
           
           
               
               
           
         
       
       wherein Ar′ is  
       
         
           
           
               
               
           
         
       
       and R is H, alkyl, or aryl;  
       
         
           
           
               
               
           
         
       
       wherein R and R′ are each independently alkyl;  
       
         
           
           
               
               
           
         
       
       wherein R and R′ are each independently H, alkyl, or perfluoroalkyl.  
     
   
   
       25 . The compound of  claim 21 , further comprising a spacer linking the organic substance and the second moiety.  
   
   
       26 . The compound of  claim 21 , wherein the second moiety is a drug carrier or a drug.  
   
   
       27 . The compound of  claim 26 , wherein the drug is an anti-inflammatory agent.  
   
   
       28 . The compound of  claim 27 , wherein the anti-inflammatory agent is a cyclooxygenase inhibitor or a phosphodiesterase inhibitor.  
   
   
       29 . The compound of  claim 28 , wherein the cyclooxygenase inhibitor is aspirin, nimesulide, or naproxen.  
   
   
       30 . The compound of  claim 26 , wherein the drug is a biphosphonate or biphosphonate derivative.  
   
   
       31 . A pharmaceutical composition comprising the compound of  claim 21 .  
   
   
       32 . A compound comprising an organic substance that is capable of releasing CO by an enzymatic process or by decarbonylation, wherein the organic substance is encapsulated in a support; and a second moiety.  
   
   
       33 . The compound of  claim 32 , wherein the organic substance releases CO upon treatment with a base, an acid, or a radical initiator.  
   
   
       34 . The compound of  claim 32 , wherein the organic substance is selected from the group consisting of: 
 CH n X y X′ 4−(n+y) , wherein n is 0-3, y is 0-4, and X and X′ are each independently F, Cl, Br, or I; trichloroacetic acid, or a salt, ester, or sulfinate thereof; triaryl carboxylic acid; oxalic acid; an α-hydroxyacid or an ester or salt thereof; an α-ketoacid or an ester or salt thereof; a trialkylbenzaldehyde; a trialkoxybenzaldehyde; and an aliphatic aldehyde.    
   
   
       35 . The compound of  claim 32 , wherein the organic substance is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       wherein R is H, alkyl, or aryl;  
       
         
           
           
               
               
           
         
       
       wherein Ar′ is  
       
         
           
           
               
               
           
         
       
       and R is H, alkyl, or aryl;  
       
         
           
           
               
               
           
         
       
       wherein R and R′ are each independently alkyl;  
       
         
           
           
               
               
           
         
       
       wherein R and R′ are each independently H, alkyl, or perfluoroalkyl.  
     
   
   
       36 . The compound of  claim 32 , further comprising a spacer linking the organic substance and the second moiety.  
   
   
       37 . The compound of  claim 32 , wherein the second moiety is a drug carrier or a drug.  
   
   
       38 . The compound of  claim 37 , wherein the drug is an anti-inflammatory agent.  
   
   
       39 . The compound of  claim 38 , wherein the anti-inflammatory agent is a cyclooxygenase inhibitor or a phosphodiesterase inhibitor.  
   
   
       40 . The compound of  claim 39 , wherein the cyclooxygenase inhibitor is aspirin, nimesulide, or naproxen.  
   
   
       41 . The compound of  claim 37 , wherein the drug is a biphosphonate or biphosphonate derivative.  
   
   
       42 . A pharmaceutical composition comprising the compound of  claim 32.