Polyether Brevetoxin Derivatives as a Treatment for Cystic Fibrosis, Mucociliary Dysfunction, and Pulmonary Diseases

Abstract

Disclosed are compounds that are derivatives of brevetoxin, or PbTx, pharmaceutical formulations comprising the compounds, and methods of regulating mucus transport in a cell, treating mucociliary dysfunction and diseases related to decreased mucus transport, wherein the compounds are of the Formula (I), and Formula (III): wherein R, R 1 , R 2 , R 3 , A, n, and Y are as defined herein for each compound.

1 . A compound of the Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
 A is 
 
     
       
         
         
             
             
         
       
       R is C 1 -C 6  alkyl, C 3 -C 8  cycloalkylcarbonyl, C 2 -C 6  alkenyl, C 1 -C 6  alkyl ester, C 2 -C 6  alkenyl ester, amino, amido, aryl ester, cycloalkyl ester, cycloalkenyl ester, purinyl, pyrimidinyl, heterocyclyl, aryl, or heteroaryl; 
       R 1  is H or —(CO)CH 3 ; and 
       R 2  and R 3  at each occurrence are independently —CH 2 (CO)CH 3 , —CH 2 (CO)CH 2 CH 3 , —CH 2 (CO)CH(CH 3 ) 2 , —CH 2 (CO)CH 2 CH 2 CH 3 , 
       —CH 2 (CO)CH(CH 3 )CH 2 CH 3 , or —CH 2 (CO)CH 2 CH(CH 3 ) 2 , 
       or OR 2  and OR 3  can be taken together to form a six membered ring of the formula (Ia) 
     
     
       
         
         
             
             
         
       
       
         wherein X is CH 2 , C(O), or CH(CH 3 ); 
         wherein the bracketed-dashed bonds indicate attachment to backbone; 
       
       Y is CH═CH, C (O), CH(CH 3 ), or CH 2 ; 
       n is 1 or 0; and 
       with the proviso that when OR 2  and OR 3  are taken together to form a ring of the formula (Ia), X is C═O and the double bond is present; A is 
     
     
       
         
         
             
             
         
       
     
     Y is CH═CH, and R 1  is H, and n is 1, then R is not: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt, solvate, ester, amide, hydrate, complex, or combination thereof. 
     
   
   
       2 . The compound according to  claim 1 , wherein
 R is   
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       3 . The compound according to  claim 1 , wherein R 2  and R 3  are each independently 
     
       
         
         
             
             
         
       
     
   
   
       4 . The compound according to  claim 1 , wherein R 2  and R 3  are taken together to form a ring of formula (Ia). 
   
   
       5 . The compound according to  claim 4 , wherein R 2  and R 3  together form: 
     
       
         
         
             
             
         
       
     
     wherein the bracketed-dashed bonds indicate the point of attachment to the backbone. 
   
   
       6 . The compound according to  claim 1 , wherein the compound is of the Formula (II): 
     
       
         
         
             
             
         
       
     
     (II). 
   
   
       7 . A compound according to  claim 1 , wherein the compound is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein
 R is C 1 -C 6  alkanoyl, C 2 -C 6  alkenoyl, aroyl, cycloalkanoyl, cycloalkenoyl, purinoyl, or pyrimidinoyl; and 
 R 2  is 
 
     
       
         
         
             
             
         
       
     
   
   
       8 - 10 . (canceled) 
   
   
       11 . A compound of the Formula (III): 
     
       
         
         
             
             
         
       
     
     wherein
 R is H, OH, halogen, C 1 -C 6  lower alkyl, C 1 -C 6  alkyl ester, C 2 -C 6  alkenyl ester, amino, amido, aldehyde, aryl ester, cycloalkyl ester, cycloalkenyl ester, purinyl, pyrimidinyl, heterocyclyl, aryl, or heteroaryl; 
 Y is C═O, CH═CH, CHCH 3  or CH 2 ; and 
 n is 1 or 0; 
 or a pharmaceutically acceptable salt, solvate, hydrate, amide, ester, complex, or combination thereof. 
 
   
   
       12 . A compound according to  claim 11 , of the formula (IV): 
     
       
         
         
             
             
         
       
     
   
   
       13 - 18 . (canceled) 
   
   
       19 . A pharmaceutical formulation comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt, ester, amide, solvate, hydrate, complex, or combination thereof; and at least one pharmaceutically acceptable carrier, excipient, solvent, adjuvant or diluent. 
   
   
       20 . (canceled) 
   
   
       21 . A pharmaceutical formulation comprising a compound according to  claim 11 , or pharmaceutically acceptable salt, ester, amide, solvate, hydrate, complex, or combination thereof, and at least one pharmaceutically acceptable carrier, excipient, solvent, adjuvant or diluent. 
   
   
       22 . (canceled) 
   
   
       23 . A method of treating diseases associated with decreased mucus transport in a subject comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, ester, amide, complex, or combination thereof, where the compound according to  claim 1  has the formula: 
     
       
         
         
             
             
         
       
     
     wherein
 A is 
 
     
       
         
         
             
             
         
       
       R is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  alkyl ester, C 2 -C 6  alkenyl ester, amino, amido, aryl ester, cycloalkyl ester, cycloalkenyl ester, purinyl, pyrimidinyl, heterocyclyl, aryl, or heteroaryl; 
       R 1  is H or —(CO)CH 3 ; and 
       R 2  and R 3  at each occurrence are independently —CH 2 (CO)CH 3 , CH 2  (CO)CH 2 CH 3 , 
       —CH 2  (CO)CH(CH 3 ) 2 , —CH 2  (CO)CH 2 CH 2 CH 3 , —CH 2  (CO)CH(CH 3 ) CH 2 CH 3 , or —CH 2  (CO)CH 2 CH(CH 3 ) 2 , 
       or OR 2  and OR 3  can be taken together to form a six membered ring of the formula (Ia) 
     
     
       
         
         
             
             
         
       
       
         wherein X is CH, C═O, or CH(CH 3 ); 
         wherein the bracketed-dashed bonds indicate attachment to backbone; 
       
       Y is CH═CH, C═O, CHCH 3 , or CH 2 ; 
       n is 1 or 0. 
     
   
   
       24 . A method of treating diseases associated with decreased mucus transport in a subject comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to  claim 11 , or a pharmaceutically acceptable salt, solvate, hydrate, ester, amide, complex, or combination thereof. 
   
   
       25 - 27 . (canceled) 
   
   
       28 . A method of treating a subject who has, or is at increased risk of developing chronic airway obstruction, 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 according to  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, ester, amide, complex, or combination thereof, where the compound according to  claim 1  has the formula: 
     
       
         
         
             
             
         
       
     
     wherein
 A is 
 
     
       
         
         
             
             
         
       
       R is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  alkyl ester, C 2 -C 6  alkenyl ester, amino, amido, aryl ester, cycloalkyl ester, cycloalkenyl ester, purinyl, pyrimidinyl, heterocyclyl, aryl, or heteroaryl; 
       R 1  is H or —(CO)CH 3 ; and 
       R 2  and R 3  at each occurrence are independently —CH 2 (CO)CH 3 , —CH 2  (CO)CH 2 CH 3 , 
       —CH 2  (CO)CH(CH 3 ) 2 , —CH 2  (CO)CH 2 CH 2 CH 3 , —CH 2  (CO)CH(CH 3 )CH 2 CH 3 , or —CH 2  (CO)CH 2 CH(CH 3 ) 2 , 
       or OR 2  and OR 3  can be taken together to form a six membered ring of the formula (Ia) 
     
     
       
         
         
             
             
         
       
       
         wherein X is CH, C═O, or CH(CH 3 ); 
         wherein the bracketed-dashed bonds indicate attachment to backbone; 
       
       Y is CH═CH, C═O, CHCH 3 , or CH 2 ; 
       n is 1 or 0. 
     
   
   
       29 . A method of treating a subject who has, or is at increased risk of developing chronic airway obstruction, 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 according to  claim 11 , or a pharmaceutically acceptable salt, solvate, ester, amide, hydrate, complex, or combination thereof. 
   
   
       30 - 31 . (canceled) 
   
   
       32 . A method for regulating mucus transport in a cell, comprising contacting a cell with an effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, ester, amide, complex, or combination thereof, where the compound according to  claim 1  has the formula: 
     
       
         
         
             
             
         
       
     
     wherein
 A is 
 
     
       
         
         
             
             
         
       
       R is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  alkyl ester, C 2 -C 6  alkenyl ester, amino, amido, aryl ester, cycloalkyl ester, cycloalkenyl ester, purinyl, pyrimidinyl, heterocyclyl, aryl, or heteroaryl; 
       R 1  is H or —(CO)CH 3 ; and 
       R 2  and R 3  at each occurrence are independently —CH 2 (CO)CH 3 , CH 2  (CO)CH 2 CH 3 , 
       —CH 2 (CO)CH(CH 3 ) 2 , —CH 2 (CO)CH 2 CH 2 CH 3 , —CH 2 (CO)CH(CH 3 )CH 2 CH 3 , or —CH 2  (CO)CH 2 CH(CH 3 ) 2 , 
       or OR 2  and OR 3  can be taken together to form a six membered ring of the formula (Ia) 
     
     
       
         
         
             
             
         
       
       
         wherein X is CH, C═O, or CH(CH 3 ); 
         wherein the bracketed-dashed bonds indicate attachment to backbone; 
       
       Y is CH═CH, C═O, CHCH 3 , or CH 2 ; 
       n is 1 or 0. 
     
   
   
       33 . A method for regulating mucus transport in a cell, comprising contacting a cell with an effective amount of a compound according to  claim 11 , or pharmaceutically acceptable salt, solvate, ester, amide, hydrate, complex, or combination thereof. 
   
   
       34 . A method of treating diseases associated with mucociliary dysfunction in a subject comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, ester, amide, complex, or combination thereof, where the compound according to  claim 1  has the formula: 
     
       
         
         
             
             
         
       
     
     wherein
 A is 
 
     
       
         
         
             
             
         
       
       R is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  alkyl ester, C 2 -C 6  alkenyl ester, amino, amido, aryl ester, cycloalkyl ester, cycloalkenyl ester, purinyl, pyrimidinyl, heterocyclyl, aryl, or heteroaryl; 
       R 1  is H or —(CO)CH 3 ; and 
       R 2  and R 3  at each occurrence are independently —CH 2 (CO)CH 3 , —CH 2  (CO)CH 2 CH 3 , —CH 2  (CO)CH(CH 3 ) 2 , —CH 2  (CO)CH 2 CH 2 CH 3 , 
       —CH 2  (CO)CH(CH 3 )CH 2 CH 3 , or —CH 2  (CO)CH 2 CH(CH 3 ) 2 , 
       or OR 2  and OR 3  can be taken together to form a six membered ring of the formula (Ia) 
     
     
       
         
         
             
             
         
       
       
         wherein X is CH, C═O, or CH(CH 3 ); 
         wherein the bracketed-dashed bonds indicate attachment to backbone; 
       
       Y is CH═CH, C(O), CH(CH 3 ), or CH 2 ; 
       n is 1 or 0. 
     
   
   
       35 . A method of treating diseases associated with mucociliary dysfunction in a subject comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to  claim 11 , or pharmaceutically acceptable salt, solvate, ester, amide, hydrate, complex, or combination thereof. 
   
   
       36 . A compound of the formula: 
     
       
         
         
             
             
         
       
     
     wherein
 A is 
 
     
       
         
         
             
             
         
       
       R is aryl, or heteroaryl, each of which is substituted with up to five groups that are independently C 1 -C 10  alkyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkyl(C 1 -C 6 )alkyl, C 3 -C 8  cycloalkyl(C 1 -C 6 )alkoxy, C 1 -C 10  alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, amino(C 1 -C 6 )alkyl, mono(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl or di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl; 
       Y is CH═CH, C(O), CH(CH 3 ), or CH 2 ; 
       n is 1 or 0; and 
       or a pharmaceutically acceptable salt, solvate, amide, ester, hydrate, complex, or combination thereof. 
     
   
   
       37 - 42 . (canceled)