Substituted Tricyclics and Method of Use

Abstract

The present invention provides for compounds of formula (I) wherein X, Y, and R 1 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions mediated and modulated by CFTR, including cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).

We claim: 
     
         1 . A pharmaceutical composition comprising
 i) trans-4-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, and   ii) one potentiator.   
     
     
         2 . The composition of  claim 1  further comprising one additional corrector. 
     
     
         3 . A method of treating cystic fibrosis in a subject comprising administering a therapeutically effective amount of a composition of  claim 1 . 
     
     
         4 . A pharmaceutical composition comprising
 i) 1-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclopropane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.   ii) one potentiator.   
     
     
         5 . The composition of  claim 4  further comprising one additional corrector. 
     
     
         6 . A method of treating cystic fibrosis in a subject comprising administering a therapeutically effective amount of a composition of  claim 4 . 
     
     
         7 . A pharmaceutical composition comprising
 i) trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, and   ii) one potentiator.   
     
     
         8 . The composition of  claim 7  further comprising one additional corrector. 
     
     
         9 . A method of treating cystic fibrosis in a subject comprising administering a therapeutically effective amount of a composition of  claim 7 . 
     
     
         10 . A pharmaceutical composition comprising
 i) trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, and   ii) one potentiator.   
     
     
         11 . The composition of  claim 10  further comprising one additional corrector. 
     
     
         12 . A method of treating cystic fibrosis in a subject comprising administering a therapeutically effective amount of a composition of  claim 10 . 
     
     
         13 . A pharmaceutical composition comprising
 i) trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, and   ii) one potentiator.   
     
     
         14 . The composition of  claim 13  further comprising one additional corrector. 
     
     
         15 . A method of treating cystic fibrosis in a subject comprising administering a therapeutically effective amount of a composition of  claim 13 .