Rapamycin carbohydrate derivatives

Abstract

This invention provides modified rapamycins that have specific monosaccharide(s), oligosaccharide(s), pseudosugar(s) or derivatives thereof attached through a linker to create rapamycin carbohydrate derivatives having enhanced pharmacokinetic and/or pharmacodynamic profiles. For example, administration of the rapamycin carbohydrate derivative results in altered pharmacokinetic profiles and reduced toxicities. Thus, the present invention provides compounds with characteristics that are distinct from other drugs in its class such as rapamycin.

1 - 24 . (canceled)  
     
     
         25 . A medical device comprising a rapamycin carbohydrate derivative having the structure of formula (I):  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently hydrogen or —X-Z;  
         wherein n=0 or 1; and  
         wherein each X is a linker selected from the group consisting of —C(O)— and —SO 2 —;  
         wherein each Z is a carbohydrate moiety selected from the group consisting of fructose, fucitol and allose;  
         wherein Z is attached to X through a hydroxyl oxygen atom of Z;  
         with the proviso that R 1  and R 2  are not both hydrogen.  
       
     
     
         26 . The medical device of  claim 25 , further comprising a pharmaceutically acceptable carrier.  
     
     
         27 . The medical device of  claim 26  wherein the pharmaceutically acceptable carrier is a solid carrier.  
     
     
         28 . The medical device of  claim 27  wherein the solid carrier is selected from the group consisting of calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.  
     
     
         29 . The medical device of  claim 25  further comprising a second compound selected from the group consisting of a cyclosporine, ISA TX 247, prednisone, prednisolone, methylprednisolone, azothioprine, mycophenolic acid, mycophenolate mofitil and leflunomide.  
     
     
         30 . The medical device of  claim 29  further comprising a pharmaceutically acceptable carrier.  
     
     
         31 . The medical device of  claim 30  wherein the pharmaceutically acceptable carrier is a solid carrier.  
     
     
         32 . The medical device of  claim 31  wherein the solid carrier is selected from the group consisting of calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.  
     
     
         33 . The medical device of  claim 29  wherein the second compound is ISA TX 247.  
     
     
         34 . The medical device of  claim 33  further comprising a pharmaceutically acceptable carrier.  
     
     
         35 . The medical device of  claim 34  wherein the pharmaceutically acceptable carrier is a solid carrier.  
     
     
         36 . The medical device of  claim 35  wherein the solid carrier is selected from the group consisting of calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.  
     
     
         37 . The medical device of  claim 25  further comprising a second compound wherein the second compound is an antibody.  
     
     
         38 . The medical device of  claim 37  wherein the antibody is selected from the group comprising α-LFA-1, α-ICAM-1, thimoglobuline, basiliximab, daclizumab, alemtuzumab, Orthoclone OKT3, and muromonab CD3.  
     
     
         39 . The medical device of  claim 25  wherein the medical device is selected from the group consisting of intravascular stent, catheter, pump, drug-eluting bead and drug-eluting disc.  
     
     
         40 . The medical device of  claim 39  further comprising a second compound selected from the group consisting of a cyclosporine, ISA TX 247, prednisone, prednisolone, methylprednisolone, azothioprine, mycophenolic acid, mycophenolate mofitil and leflunomide.  
     
     
         41 . The medical device of  claim 40  further comprising a pharmaceutically acceptable carrier.  
     
     
         42 . The medical device of  claim 41  wherein the pharmaceutically acceptable carrier is a solid carrier.  
     
     
         43 . The medical device of  claim 42  wherein the solid carrier is selected from the group consisting of calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.  
     
     
         44 . The medical device of  claim 40  wherein the second compound is ISA TX 247.