Isosorbide nitrates

Abstract

The present invention relates to new 3-substituted 6-nitrooxy-hexahydrofuro[3,2-b]furane derivatives possessing a superior pharmacological activity in thrombosis and in coronary ischemia models.

1 ) A compound of formula (I), a tautomer, a pharmaceutically acceptable salt, a prodrug, or a solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 G is a —(C═O)—S— group or a —S(O) n — group; 
 n is 0, 1, or 2; and 
 R is a C 1 -C 3  alkyl or a C 3  alkenyl, with the proviso that when R is a methyl group, the R-G- and —ONO 2  groups have a cis orientation relative to each other. 
 
     
     
         2 ) The compound of  claim 1 , wherein:
 G is a —S(O) n — group;   n is 1 or 2; and   R is a C 2 -C 3  alkyl group or a C 3  alkenyl group.   
     
     
         3 ) The compound of  claim 2 , wherein R is an ethyl group, an n-propyl group, or an allyl group. 
     
     
         4 ) The compound of  claim 2 , wherein n is 1. 
     
     
         5 ) The compound of  claim 4 , wherein R is an n-propyl group. 
     
     
         6 ) The compound of  claim 4 , wherein R is an allyl group. 
     
     
         7 ) The compound of  claim 2 , wherein n is 2. 
     
     
         8 ) The compound of  claim 7 , wherein R is an ethyl group. 
     
     
         9 ) The compound of  claim 7 , wherein R is an n-propyl group. 
     
     
         10 ) The compound of  claim 7 , wherein R is an allyl group. 
     
     
         11 ) The compound of  claim 1 , wherein R is a methyl group. 
     
     
         12 ) The compound of  claim 1 , wherein G is a —(C═O)—S— group and R is a methyl group. 
     
     
         13 ) The compound of  claim 1 , wherein:
 G is a —S(O) n — group;   n is 0; and   R is a C 2 -C 3  alkyl group or a C 3  alkenyl group.   
     
     
         14 ) The compound of  claim 13 , wherein R is a an ethyl group, an n-propyl group, or an allyl group. 
     
     
         15 ) A pharmaceutical composition, comprising:
 a compound of  claim 1 ; and   a pharmacologically acceptable excipient.   
     
     
         16 ) The pharmaceutical composition of  claim 15 , further comprising:
 at least one additional active ingredient selected from the group consisting of a thrombolytic agent, an anticoagulant agent, an antithrombotic agent, an immunoglobulin, a fragment of an immunoglobulin, a hypolipemiant agent, and an antioxidant/free radical scavenging agent.   
     
     
         17 ) A method of treating, preventing, or treating and preventing a condition selected from the group consisting of atherosclerosis, cardiac allograft vasculopathy, platelet activation, thrombosis, stroke, tissue damage due to ischemia, tissue damage due to ischemia-reperfusion, a pathological condition where oxidative stress plays an important role in their pathogenesis, and a pathological condition where a deficit of NO plays an important role in their pathogenesis, the method comprising:
 administering an effective amount of the composition of  claim 15  to a subject in need thereof.   
     
     
         18 ) The method of  claim 17 , wherein the composition further comprises at least one additional active ingredient selected from the group consisting of a thrombolytic agent, an anticoagulant agent, an antithrombotic agent, an immunoglobulin, a fragment of an immunoglobulin, a hypolipemiant agent, and an antioxidant/free radical scavenging agent. 
     
     
         19 ) A method of treating a condition selected from the group consisting of atherosclerosis, cardiac allograft vasculopathy, platelet activation, thrombosis, stroke, tissue damage due to ischemia, tissue damage due to ischemia-reperfusion, a pathological condition where oxidative stress plays an important role in their pathogenesis, and a pathological condition where a deficit of NO plays an important role in their pathogenesis, the method comprising:
 administering an effective amount of a compound of  claim 1  to a subject in need thereof.   
     
     
         20 ) A method of preventing a condition selected from the group consisting of atherosclerosis, cardiac allograft vasculopathy, platelet activation, thrombosis, stroke, tissue damage due to ischemia, tissue damage due to ischemia-reperfusion, a pathological condition where oxidative stress plays an important role in their pathogenesis, and a pathological condition where a deficit of NO plays an important role in their pathogenesis, the method comprising:
 administering an effective amount of a compound of  claim 1  to a subject in need thereof.