Macrocyclic lactone compounds and methods for their use

Abstract

The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula: wherein R 1 , R 2 , R 3 , R 5 , R 6 and R 8 are each independently a member selected from the group consisting of H, C 1-6 alkyl and OH; R 4 , R 7 and R 9 are each independently selected from the group consisting of C 1-6 alkoxy and OH; R 10 is a member selected from the group consisting of H, —OH, —OP(O)Me 2 , —O—(CH 2 ) n —OH and —O—(CH 2 ) m —O—(CH 2 ) o —CH 3 , wherein subscripts n and m are each independently from 2 to 8 and subscript o is from 1 to 6; each of L 1 and L 4 are independently selected from the group consisting of: each of L 2 and L 3 are independently selected from the group consisting of: and salts, hydrates, isomers, metabolites and prodrugs thereof.

1 .- 76 . (canceled) 
     
     
         77 . A method of inhibiting cell proliferation or cytokine production, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein:
 R 4  is —OH; 
 R 7  and R 9  are each independently —OH or —OCH 3 ; and 
 R 10  is selected from the group consisting of H, —OH, —OP(O)Me 2 , 
 
       
         
           
           
               
               
           
         
       
       —O—(CH 2 ) n —OH and —O—(CH 2 ) m —O—(CH 2 ) o —CH 3 , wherein subscripts n and m are each independently from 2 to 8 and subscript o is from 1 to 6;
 or a salt or isomer thereof. 
 
     
     
         78 . The method of  claim 77 , wherein the compound is administered systemically or locally, or a combination thereof. 
     
     
         79 . The method of  claim 77 , wherein the compound is administered orally, topically, parenterally, intravascularly, intravenously, intraperitoneally, intramuscularly, intralesionally, intranasally, pulmonarily, mucosally, transdermally, ophthalmically, subcutaneously, intrathecally, or as a suppository. 
     
     
         80 . The method of  claim 77 , wherein the compound is administered via delivery from a temporary device or an implant. 
     
     
         81 . The method of  claim 80 , wherein the temporary device is a catheter or a porous balloon. 
     
     
         82 . The method of  claim 80 , wherein the implant is a vascular prosthesis. 
     
     
         83 . The method of  claim 82 , wherein the vascular prosthesis comprises an expandable structure. 
     
     
         84 . The method of  claim 82 , wherein the vascular prosthesis comprises a scaffold formed at least in part from an open lattice. 
     
     
         85 . The method of  claim 82 , wherein the vascular prosthesis comprises a stent. 
     
     
         86 . The method of  claim 82 , wherein the vascular prosthesis comprises a graft. 
     
     
         87 . The method of  claim 82 , wherein the vascular prosthesis has a luminal surface and a tissue-facing surface, and wherein the compound is associated with at least one of the luminal and tissue-facing surfaces. 
     
     
         88 . The method of  claim 80 , wherein the amount of the compound associated with the temporary device or implant is from about 1 nanogram/cm 2  to about 1000 micrograms/cm 2 . 
     
     
         89 . The method of  claim 80 , wherein the amount of the compound associated with the temporary device or implant is from about 1 microgram/cm 2  to about 500 micrograms/cm 2 . 
     
     
         90 . The method of  claim 80 , wherein the amount of the compound associated with the temporary device or implant is from about 10 micrograms/cm 2  to about 400 micrograms/cm 2 . 
     
     
         91 . The method of  claim 80 , wherein the temporary device or implant is configured to release the compound to a body lumen or organ in a mammalian body. 
     
     
         92 . The method of  claim 80 , wherein the concentration of the compound in tissue adjacent to the temporary device or implant is from about 0.001 ng/gm tissue to about 1000 ug/gm tissue. 
     
     
         93 . The method of  claim 80 , wherein the concentration of the compound in tissue adjacent to the temporary device or implant is from about 1 ng/gm tissue to about 500 ug/gm tissue. 
     
     
         94 . The method of  claim 80 , wherein the concentration of the compound in tissue adjacent to the temporary device or implant is from about 100 ng/gm tissue to about 100 ug/gm tissue. 
     
     
         95 . The method of  claim 80 , wherein at least 75% of the compound is released from the temporary device or implant in a period from about 1 day to about 2 years. 
     
     
         96 . The method of  claim 80 , wherein at least 90% of the compound is released from the temporary device or implant in a period from about 3 days to about 6 months. 
     
     
         97 . The method of  claim 80 , wherein at least 90% of the compound is released from the temporary device or implant in a period from about 1 week to about 3 months. 
     
     
         98 . The method of  claim 77 , wherein the compound is administered with a pharmaceutically acceptable excipient. 
     
     
         99 . The method of  claim 98 , wherein the pharmaceutically acceptable excipient is selected from the group consisting of polymers, solvents, stabilizers, antioxidants, binders, fillers, disintegrants, lubricants, glidants, wetting agents, emulsifying agents, suspending agents, dispensing agents, acidifying agents, preserving agents, sweeteners, flavors, colorants, perfuming agents, coatings, metals, semi-metals, and ceramics. 
     
     
         100 . The method of  claim 99 , wherein the pharmaceutically acceptable excipient is a polymer. 
     
     
         101 . The method of  claim 100 , wherein the polymer is selected from the group consisting of polyurethanes, polyethylene imines, ethylene-vinyl alcohol copolymers, poly(ethylene-vinyl acetate), silicone, C-flex, nylons, polyamides, polyimides, polytetrafluoroethylene (PTFE), parylene, parylast, polymethacrylates, poly(methyl methacrylate), poly(n-butyl methacrylate), poly(2-hydroxyethyl methacrylate), poly(ethylene glycol-methacrylate), blends or copolymers of poly(butyl methacrylate) and poly(ethylene-vinyl acetate), poly(vinyl chloride), poly(dimethyl siloxane), polycarbonates, poly(ethylene carbonate), polyacrylamide gels, poly(L-lactide-glycolide) copolymers, poly(L-lactide-trimethylene carbonate) copolymers, and poly(L-lactide). 
     
     
         102 . The method of  claim 100 , wherein the polymer is selected from the group consisting of poly(ethylene carbonate), poly(L-lactide-glycolide) copolymers, and poly(n-butyl methacrylate). 
     
     
         103 . The method of  claim 100 , wherein the compound is present in an amount of at least 25% (w/w) in a mixture of the compound and the polymer. 
     
     
         104 . The method of  claim 100 , wherein the compound is present in an amount of at least 50% (w/w) in a mixture of the compound and the polymer. 
     
     
         105 . The method of  claim 100 , wherein the compound is present in an amount of at least 75% (w/w) in a mixture of the compound and the polymer. 
     
     
         106 . The method of  claim 77 , wherein the compound is administered with a pharmaceutically acceptable excipient via a vascular prosthesis, and wherein the pharmaceutically acceptable excipient comprises a polymer selected from the group consisting of poly(ethylene carbonate), poly(L-lactide-glycolide) copolymers, and poly(n-butyl methacrylate). 
     
     
         107 . The method of  claim 77 , further comprising administering an additional therapeutic agent. 
     
     
         108 . The method of  claim 107 , wherein the additional therapeutic agent is selected from the group consisting of anti-platelet agents, anti-thrombotic agents, anti-inflammatory agents, anti-proliferative agents, immunosuppressant agents, and anti-cancer agents. 
     
     
         109 . The method of  claim 77 , wherein the compound is racemic at the C-16 position. 
     
     
         110 . The method of  claim 77 , wherein the compound has an (R)-stereochemistry at the C-16 position. 
     
     
         111 . The method of  claim 77 , wherein the compound has an (S)-stereochemistry at the C-16 position. 
     
     
         112 . The method of  claim 77 , wherein the effective dose of the compound is from about 0.1 mg to about 20 mg. 
     
     
         113 . The method of  claim 77 , wherein the effective dose of the compound is from about 0.5 mg to about 10 mg. 
     
     
         114 . The method of  claim 77 , wherein the effective dose of the compound is from about 1 mg to about 5 mg. 
     
     
         115 . The method of  claim 77 , wherein the cell proliferation is a smooth muscle cell proliferation.