Fused Pentacyclic Polyethers

Abstract

Disclosed are polycyclic polyether compounds of formula I and pharmaceutical compositions comprising such compounds. wherein R, OR 1 , and R 2 are as defined herein. Also disclosed are methods of regulating mucus clearance in a cell, and methods of treating decreased mucus clearance or mucociliary dysfunction.

1 . A compound of the Formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R is C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 1 -C 12  alkyl esters, C 1 -C 12  alkyl amides, C 4 -C 12  alkenyl esters, C 1 -C 12  alkylaryl esters, C 4 -C 12  alkenylaryl esters, C 4 -C 12  alkenyl amides, C 1 -C 12  alkoxy, formylC 1 -C 12 alkyl, formylC 2 -C 12 alkenyl, alkanoylC 1 -C 12 alkyl, alkanoylC 2 -C 12 alkenyl, carboxyC 1 -C 12 alkyl, carboxyC 2 -C 12 alkenyl, wherein the alkyl and alkenyl groups are optionally substituted with 1-6 substituent groups selected from the group consisting of: C 3 -C 12  cycloalkyl, C 3 -C 12  heterocyclyl, aryl, heteroaryl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen, C 2 -C 6  alkenyl, OH, nucleosides, nucleotides, purines, pyrimidincs, aromatic esters, aryl esters, cycloalkyl esters, cycloalkenyl esters, purines, or pyrimidines; 
 OR 1  is OH or —O(CO)CH 3 ; 
 R 2  is —CH═CHCH═CH 2 , —CH 2 -phenyl, or —CH 2 -pyridyl, wherein the phenyl and pyridyl groups are optionally substituted at each substitutable position with a group that is independently C 1 -C 6  alkyl, C 1 -C 6  alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, halogen, —CO 2 H, C 1 -C 6  alkoxycarbonyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6  alkyl), or —C(O)N(C 1 -C 6  alkyl)(C 1 -C 6  alkyl); or a pharmaceutically acceptable salt, solvate, ester, amide, or hydrate thereof. 
 
     
     
         2 - 3 . (canceled) 
     
     
         4 . A pharmaceutical composition comprising a therapeutically effective amount of at least one compound, pharmaceutically acceptable salt, solvate, hydrate, ester, amide, or isomer of  claim 1 , and at least one pharmaceutically acceptable carrier, excipient, solvent, adjuvant, diluent, or mixtures thereof. 
     
     
         5 - 6 . (canceled) 
     
     
         7 . A method of treating mucociliary dysfunction in a subject comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or pharmaceutically acceptable salts, solvates, hydrates, esters, amides, or isomers thereof. 
     
     
         8 . A method of treating mucociliary dysfunction in a subject comprising administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition of  claim 4 . 
     
     
         9 . A method of treating, preventing, or treating and preventing diseases associated with decreased mucus clearance in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1  or pharmaceutically acceptable salts, solvates, hydrates, esters, amides, or isomers thereof. 
     
     
         10 . A method of treating, preventing, or treating and preventing diseases associated with decreased mucus clearance in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a pharmaceutical composition of  claim 4 . 
     
     
         11 . A method of treating diseases associated with decreased mucus clearance in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1  or pharmaceutically acceptable salts, solvates, hydrates, esters, amides, or isomers thereof. 
     
     
         12 . A method of treating diseases associated with decreased mucus clearance in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a pharmaceutical composition of  claim 4 . 
     
     
         13 . The method according to  claim 12 , wherein the therapeutically effective amount is administered in a dosage of between about 0.1 pg to about 100 mg per day. 
     
     
         14 . The method according to  claim 12 , wherein the therapeutically effective amount comprises a dosage of between about 0.1 mg to about 10 mg per day. 
     
     
         15 . A method of treating a subject who has, or is at increased risk of developing chronic obstructive pulmonary disease, asthma, pulmonary disease, pulmonary infection, or cystic fibrosis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of  claim 1  or pharmaceutically acceptable salts, solvates, hydrates, esters, amides, or isomers thereof. 
     
     
         16 . A method of treating a subject who has, or is at increased risk of developing chronic obstructive pulmonary disease, asthma, pulmonary disease, pulmonary infection, or cystic fibrosis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition of  claim 4 . 
     
     
         17 . A method for regulating mucus clearance in a cell, comprising contacting a cell with an effective amount of a compound of  claim 1  or pharmaceutically acceptable salts, solvates, hydrates, esters, amides, or isomers thereof. 
     
     
         18 . A method for regulating mucus clearance in a cell, comprising contacting a cell with an effective amount of a pharmaceutical composition of  claim 4 . 
     
     
         19 . A compound of  claim 1 , wherein 
       R is 
       
         
           
           
               
               
           
         
       
       and 
       R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         20 . A compound according to  claim 19 , wherein R 1  is H. 
     
     
         21 . A compound according to claim  2 , wherein R 2  is —CH═CHCH═CH 2 . 
     
     
         22 . A method of treating an industrial disease comprising administering a pharmaceutically acceptable amount of a compound of  claim 1 , or pharmaceutically acceptable salts, solvates, hydrates, esters, amides, or isomers thereof, to a subject in need of such treatment. 
     
     
         23 . A method of treatment according to  claim 22 , wherein the industrial disease is caused or exacerbated by inhaling gases, particles of textiles, grit, or other industrial particles or fumes. 
     
     
         24 . A method of treating a disease or condition that results from inhalation of bacterial or other pathogenic particles comprising administering a pharmaceutically acceptable amount of a compound of  claim 1 , or pharmaceutically acceptable salts, solvates, hydrates, esters, amides, or isomers thereof, to a subject in need of such treatment.