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 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 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, 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 , —OH 2 -phenyl, or —OH 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. A method according to claim 1 , wherein the compound is administered as a component of a pharmaceutical composition comprising the compound and at least one pharmaceutically acceptable carrier, excipient, solvent, adjuvant, diluent, or mixtures thereof.
3. 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 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, 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.
4. A method according to claim 3 , wherein the compound is administered as a component of a pharmaceutical composition comprising the compound and at least one pharmaceutically acceptable carrier, excipient, solvent, adjuvant, diluent, or mixtures thereof.
5. 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 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, 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.
6. A method according to claim 5 , wherein the compound is administered as a component of a pharmaceutical composition comprising the compound and at least one pharmaceutically acceptable carrier, excipient, solvent, adjuvant, diluent, or mixtures thereof.
7. The method according to claim 6 , wherein the compound is administered in a dosage of between about 0.1 pg to about 100 mg per day.
8. The method according to claim 6 , wherein the compound is administered in a dosage of between about 0.1 mg to about 10 mg per day.
9. A method of treating a subject who has, or is at increased risk of developing pulmonary disease, or pulmonary infection, comprising administering to a subject in need of such treatment a therapeutically effective amount of 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, 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.
10. A method according to claim 9 , wherein the compound is administered as a component of a pharmaceutical composition comprising the compound and at least one pharmaceutically acceptable carrier, excipient, solvent, adjuvant, diluent, or mixtures thereof.
11. A method for regulating mucus clearance in a cell, comprising contacting a cell with an effective amount of 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, 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.
12. A method according to claim 11 , wherein the compound is administered as a component of a pharmaceutical composition comprising the compound and at least one pharmaceutically acceptable carrier, excipient, solvent, adjuvant, diluent, or mixtures thereof.
13. A method of treating an industrial disease comprising administering a pharmaceutically acceptable amount of 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, 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.
14. A method of treatment according to claim 13 , wherein the industrial disease is caused or exacerbated by inhaling gases, particles of textiles, grit, or other industrial particles or fumes.
15. 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 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, 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.