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 rapamycin carbohydrate derivative having the structure of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is hydrogen and R 2  is —X-Z, 
 wherein n=0 or 1; and  
 wherein each X is a linker, and each Z is a carbohydrate moiety independently selected from the group consisting of a monosaccharide, oligosaccharide and pseudosugar, 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 rapamycin carbohydrate derivative of  claim 25 , wherein X is selected from the group consisting of: 
 (i) —R 3 C(O)—;    (ii) —C(O)R 3 —;    (iii) —R 3 S(O) 2 —; and    (iv) —S(O) 2 R 3 —;    wherein R 3  is selected from the group consisting of: 
 (a) —(CH 2 ) p — where p is an integer from 1 to 18;  
 (b) —(CH 2 ) n —O—(CH 2 ) m — where n and m are each independently an integer from 2 to 6; and  
 (c) a bond.  
   
   
   
       27 . The rapamycin carbohydrate derivative of  claim 26 , wherein X is selected from the group consisting of —C(O)— and —SO 2 —.  
   
   
       28 . The rapamycin carbohydrate derivative of  claim 26 , wherein Z is selected from the group consisting of fructose, fucitol and allose.  
   
   
       29 . The rapamycin carbohydrate derivative of  claim 26 , wherein Z is D-fructose.  
   
   
       30 . A pharmaceutical composition comprising the rapamycin carbohydrate derivative of  claim 25  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
   
   
       31 . A pharmaceutical composition comprising the rapamycin carbohydrate derivative of  claim 26  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
   
   
       32 . A pharmaceutical composition comprising the rapamycin carbohydrate derivative of  claim 27  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
   
   
       33 . A pharmaceutical composition comprising the rapamycin carbohydrate derivative of  claim 28  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
   
   
       34 . A pharmaceutical composition comprising the rapamycin carbohydrate derivative of  claim 29  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
   
   
       35 . A method for treating a disease, wherein the disease is selected from the group consisting of transplantation rejection, host vs. graft disease, leukemia, lymphoma, hyperproliferative vascular disorders, autoimmune disease, diseases of inflammation, solid tumors, and fungal infections, comprising comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 30  to a subject in need thereof.  
   
   
       36 . A method for treating a disease, wherein the disease is selected from the group consisting of transplantation rejection, host vs. graft disease, leukemia, lymphoma, hyperproliferative vascular disorders, autoimmune disease, diseases of inflammation, solid tumors, and fungal infections, comprising comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 31  to a subject in need thereof.  
   
   
       37 . A method for treating a disease, wherein the disease is selected from the group consisting of transplantation rejection, host vs. graft disease, leukemia, lymphoma, hyperproliferative vascular disorders, autoimmune disease, diseases of inflammation, solid tumors, and fungal infections, comprising comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 32  to a subject in need thereof.  
   
   
       38 . A method for treating a disease, wherein the disease is selected from the group consisting of transplantation rejection, host vs. graft disease, leukemia, lymphoma, hyperproliferative vascular disorders, autoimmune disease, diseases of inflammation, solid tumors, and fungal infections, comprising comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 33  to a subject in need thereof.  
   
   
       39 . A method for treating a disease, wherein the disease is selected from the group consisting of transplantation rejection, host vs. graft disease, leukemia, lymphoma, hyperproliferative vascular disorders, autoimmune disease, diseases of inflammation, solid tumors, and fungal infections, comprising comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 34  to a subject in need thereof.  
   
   
       40 . A medical device wherein said medical device is coated with a rapamycin carbohydrate derivative of  claim 25 .  
   
   
       41 . The medical device of  claim 40 , wherein the medical device is selected from the group consisting of stents, grafts, and implants.  
   
   
       42 . A medical device wherein said medical device is coated with a rapamycin carbohydrate derivative of  claim 26 .  
   
   
       43 . The medical device of  claim 42 , wherein the medical device is selected from the group consisting of stents, grafts, and implants.  
   
   
       44 . A medical device wherein said medical device is coated with a rapamycin carbohydrate derivative of  claim 27 .  
   
   
       45 . The medical device of  claim 44 , wherein the medical device is selected from the group consisting of stents, grafts, and implants.  
   
   
       46 . A medical device wherein said medical device is coated with a rapamycin carbohydrate derivative of  claim 28 .  
   
   
       47 . The medical device of  claim 46 , wherein the medical device is selected from the group consisting of stents, grafts, and implants.  
   
   
       48 . A medical device wherein said medical device is coated with a rapamycin carbohydrate derivative of  claim 29 .  
   
   
       49 . The medical device of  claim 48 , wherein the medical device is selected from the group consisting of stents, grafts, and implants.  
   
   
       50 . A method for treating a disease wherein the disease is selected from the group consisting of transplantation rejection, host vs. graft disease, leukemia, lymphoma, hyperproliferative vascular disorders, autoimmune disease, diseases of inflammation, solid tumors, and fungal infections, comprising coadministering a therapeutically effective amount of a pharmaceutical composition of  claim 30  to a subject in need thereof with a pharmaceutical composition comprising a compound selected from the group consisting of a cyclosporine or cyclosporine derivative, a steroid, or an immunomodulatory compound.  
   
   
       51 . A method for treating a disease wherein the disease is selected from the group consisting of transplantation rejection, host vs. graft disease, leukemia, lymphoma, hyperproliferative vascular disorders, autoimmune disease, diseases of inflammation, solid tumors, and fungal infections, comprising coadministering a therapeutically effective amount of a pharmaceutical composition of  claim 31  to a subject in need thereof with a pharmaceutical composition comprising a compound selected from the group consisting of a cyclosporine or cyclosporine derivative, a steroid, or an immunomodulatory compound.  
   
   
       51 . A method for treating a disease wherein the disease is selected from the group consisting of transplantation rejection, host vs. graft disease, leukemia, lymphoma, hyperproliferative vascular disorders, autoimmune disease, diseases of inflammation, solid tumors, and fungal infections, comprising coadministering a therapeutically effective amount of a pharmaceutical composition of  claim 32  to a subject in need thereof with a pharmaceutical composition comprising a compound selected from the group consisting of a cyclosporine or cyclosporine derivative, a steroid, or an immunomodulatory compound.  
   
   
       52 . A method for treating a disease wherein the disease is selected from the group consisting of transplantation rejection, host vs. graft disease, leukemia, lymphoma, hyperproliferative vascular disorders, autoimmune disease, diseases of inflammation, solid tumors, and fungal infections, comprising coadministering a therapeutically effective amount of a pharmaceutical composition of  claim 33  to a subject in need thereof with a pharmaceutical composition comprising a compound selected from the group consisting of a cyclosporine or cyclosporine derivative, a steroid, or an immunomodulatory compound.  
   
   
       53 . A method for treating a disease wherein the disease is selected from the group consisting of transplantation rejection, host vs. graft disease, leukemia, lymphoma, hyperproliferative vascular disorders, autoimmune disease, diseases of inflammation, solid tumors, and fungal infections, comprising coadministering a therapeutically effective amount of a pharmaceutical composition of  claim 34  to a subject in need thereof with a pharmaceutical composition comprising a compound selected from the group consisting of a cyclosporine or cyclosporine derivative, a steroid, or an immunomodulatory compound.