Rapamycin 40-O-Cyclic Hydrocarbon Esters, Compositions and Methods

Abstract

A new class of rapamycin 40-O-cyclic hydrocarbon esters is disclosed. The 40-O position of the rapamycin ester has the form 40-O—R, where R is C(O)—(CH 2 ) n —X, n is 0, 1 or 2, and X is a cyclic hydrocarbon having 3-8 carbons, optionally containing one or more unsaturated bonds, and one or more linear (CH 2 ) n ) and/or cyclic (X) carbon atoms may have an OH or halide group. Also disclosed are therapeutic compositions and methods that employ the novel analogs.

1 . A method of treating a disease selected from the group consisting of restenosis, wound healing, vascular injury, vascular inflammation, transplantation rejection, proliferative ophthalmic diseases (including wet age-related macular degeneration (AMD) and diabetic macular edema (DME)), uveitis and cancer in a mammal by administering an effective amount of a 40-O-cyclic hydrocarbon ester compound having the structure: 
       
         
           
           
               
               
           
         
         where R is C(O)—(CH 2 ) n —X, n is 0, 1 or 2, X is a cyclic hydrocarbon having 3-8 carbons, optionally containing one or more unsaturated bonds, one or more linear-chain or cyclic carbon atoms may contain an OH or halide substitution, and the rapamycin parent structure may contain substitutions at non-40 positions. 
       
     
     
         2 . The method of  claim 1 , wherein the 40-O-cyclic hydrocarbon ester compound is entrapped in microparticles and the microparticles are administered to the mammal. 
     
     
         3 . The method of  claim 1 , wherein the 40-O-cyclic hydrocarbon ester compound is administered from a drug coated balloon placed at the vascular injury site. 
     
     
         4 . A method of treating restenosis comprising applying the 40-O-cyclic hydrocarbon ester compound of  claim 1  to a surface of the inflatable balloon portion of a percutaneous vascular angioplasty balloon catheter as a coating in a manner that allows for the coating to separate from the surface of the inflatable balloon portion when placed adjacent to a vascular target lesion in an individual.