End-capped poly(ester amide) copolymers

Abstract

This invention relates to poly(ester amide)s (PEAs) comprising inactivated terminal amino and carboxyl groups, methods of synthesizing the inactivated PEAs and uses for them in the treatment of vascular diseases.

1 - 16 . (canceled) 
     
     
         17 . An implantable medical device which is formed of a material or comprises a coating, wherein the material or the coating comprises a polymer of formula:
 PEA—Inactivated Terminal Amino Group
 or 
   Inactivated Terminal Carboxyl Group—PEA;
 wherein PEA comprises formula I: 
   
       
         
           
           
               
               
           
         
         wherein: 
         m is an integer; 
         n is 0 or an integer; 
         X, Y, Z 1  and Z 2  are each independently branched or straight chain alkylene, cycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, or heterocycloalkylene; 
         Inactivated Terminal Carboxyl Group is: —C(O)NR 1 R 2 , wherein R 1  and R 2  are H, 2 to 12 carbon alkyl, alkyl ether, or alkyl hydroxyl; or —C(O)SR, wherein R is 2 to 12 carbon alkyl; and 
         Inactivated Terminal Amino Group is: —NR 3   + X − , wherein X is Br, Cl, or I, and each R is a primary or secondary alkyl radical having 2 to 12 carbon atoms; —NHC(O)R, wherein R is a primary or secondary alkyl radical having 2 to 12 carbon atoms; —NHR, wherein R is a primary or secondary alkyl radical having 2 to 12 carbon atoms; —N(C(R) 3 ) 2 , wherein each R is hydrogen or a primary or secondary alkyl radical having 2 to 12 carbon atoms; —CH═CH 2 ; —NO 2 ; —NHC(O)R, wherein R is cycloalkyl, aryl, or a saturated, linear or branched alkyl; —NHCH 2 CH(OH)R, wherein R is cycloalkyl, aryl, or a saturated, linear or branched alkyl; —NHC(O)NHR, wherein R is cycloalkyl, aryl, or a saturated, linear or branched alkyl; —NHC(S)NHR, wherein R is cycloalkyl, aryl, or a saturated, linear or branched alkyl; or —NHCH 2 CH 2 C(O)R, wherein R is hydrogen, a primary or secondary alkyl radical having 2 to 12 carbon atoms, or OR′, wherein R′ is a primary or secondary alkyl radical having 2 to 12 carbon atoms. 
       
     
     
         18 . The implantable medical device of  claim 17 , which is formed of the material, wherein the material further comprises a bioactive agent. 
     
     
         19 . The implantable medical device of  claim 17 , which comprises the coating, wherein the coating further comprises a bioactive agent. 
     
     
         20 . The implantable medical device of  claim 18 , wherein the bioactive agent is selected from the group consisting of paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide dismutase, super oxide dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, 40-O-(2-hydroxyl)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propylrapamycin, 40-O-[2-(2-hydroxyl)ethoxy]ethylrapamycin, 40-O-tetrazole-rapamycin, ABT-578, clobetasol, progenitor cell capturing antibody, and a combination thereof. 
     
     
         21 . The implantable medical device of  claim 19 , wherein the bioactive agent is selected from the group consisting of paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide dismutase, super oxide dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, 40-O-(2-hydroxyl)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propylrapamycin, 40-O-[2-(2-hydroxyl)ethoxy]ethylrapamycin, 40-O-tetrazole-rapamycin, ABT-578, clobetasol, progenitor cell capturing antibody, and a combination thereof. 
     
     
         22 . The implantable medical device of  claim 17 , which is a stent. 
     
     
         23 . The implantable medical device of  claim 17 , which is formed of the material wherein the material further comprises a biocompatible polymer. 
     
     
         24 . The implantable medical device of  claim 17 , which comprises a coating wherein the coating further comprises a biocompatible polymer. 
     
     
         25 . The implantable medical device of  claim 23 , wherein the biocompatible polymer is selected from the group consisting of poly(hydroxyvalerate), poly(L-lactic acid), poly(L-lactide), poly(D,L-lactide), poly(L-lactide-co-D,L-lactide), polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(D,L-lactide-co-glycolide) (PDLLAGA), poly(glycolic acid-co-trimethylene carbonate), poly(trimethylene carbonate), poly(butylene terephthalate-co-PEG-terephthalate), and a combination thereof. 
     
     
         26 . The implantable medical device of  claim 24 , wherein the biocompatible polymer is selected from the group consisting of poly(hydroxyvalerate), poly(L-lactic acid), poly(L-lactide), poly(D,L-lactide), poly(L-lactide-co-D,L-lactide), polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(D,L-lactide-co-glycolide) (PDLLAGA), poly(glycolic acid-co-trimethylene carbonate), poly(trimethylene carbonate), poly(butylene terephthalate-co-PEG-terephthalate), and a combination thereof. 
     
     
         27 . A method of treating or preventing a disorder in a patient in need thereof comprising implanting in the patient an implantable device of  claim 17 , wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and a combination thereof.