Fused pentacyclic polyethers
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, or 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, aryl esters, cycloalkyl esters, cycloalkenyl esters, and
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
pharmaceutically acceptable salts, solvates, esters, amides, or combinations thereof.
2. The compound according to claim 1 , wherein
R is
wherein
Hal is chloro, fluoro, iodo, or bromo;
R 3 is selected from H, OH, NH 2 , halogen, and NO 2 , and
Y is selected from CH, N, O, and S.
3. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
4. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound, pharmaceutically acceptable salt, solvate, ester, amide, or isomer of claim 1 , and at least one pharmaceutically acceptable carrier, excipient, solvent, adjuvant, diluent, or mixtures thereof.
5. A pharmaceutical composition of claim 4 , wherein the pharmaceutical composition is in unit dosage form.
6. The pharmaceutical composition in unit dosage form according to claim 5 , wherein the compound is present in an amount of about 1 pg to about 100 mg.
7. A compound of claim 1 , wherein
8. A compound according to claim 7 , wherein R 1 is H.
9. A compound according to claim 2 , wherein R 2 is —CH═CHCH═CH 2 .