Adenosine analogs and their use

Abstract

The invention provides adenosine analog compounds that act at P2Y receptors, e.g., the P2Y 2 receptor, including pharmaceutical compositions; and uses thereof to treat or prevent diseases associated with that receptor, e.g., disorders relating to mucus secretion, such as cystic fibrosis, chronic obstructive pulmonary disorder (COPD), asthma, constipation, chronic idiopathic constipation, dry mouth (xerostomia), gum disease, and gastrointestinal problems caused by radiation and chemotherapy for cancer.

1 - 32 . (canceled) 
     
     
         33 : A method of treating cystic fibrosis, sinusitis, otitis media, ventilator associated pneumonia, chronic bronchitis, chronic obstructive pulmonary disorder, primary ciliary dyskinesia, asthma, bronchiectasis, post-operative atelectasis, Kartagener's syndrome, constipation, chronic idiopathic constipation, dry mouth, mouth ulcer, gum disease, mycositis, gastro-esophageal reflux disease, peptic ulcer, heartburn, esophagitis, Sjogren's syndrome, inflammatory bowel disease, constipation, gastrointestinal problems caused by radiation or chemotherapy for cancer, or a disease associated with expression or activity of a P2Y receptor in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula IIIA: 
       
         
           
           
               
               
           
         
       
       or enantiomers, diastereomers, enantiomerically enriched mixtures, racemic mixtures, crystalline forms, non-crystalline forms, amorphous forms, and a pharmaceutically acceptable salt thereof, wherein:
 A is phenyl or pyridyl; 
 X 1  is O, NH, N(alkyl), —N(alkyl)-C(O)—, —C(O)N(alkyl)-, —N(alkyl)-CH 2 —, —CH 2 —N(alkyl)-, —CH 2 N(alkyl)-C(O)—, or —C(O)N(alkyl)-CH 2 —; 
 R′ represents independently for each occurrence a halo, hydroxy, alkyl, alkoxy, carboxy, cyano, nitro, sulfonamido, sulfonate, amino, alkylamino, or di-alkylamino group; and 
 t is 0, 1, 2, or 3. 
 
     
     
         34 : The method of  claim 33 , wherein the subject is a human. 
     
     
         35 : A method of treating cystic fibrosis, sinusitis, otitis media, ventilator associated pneumonia, chronic bronchitis, chronic obstructive pulmonary disorder, primary ciliary dyskinesia, asthma, bronchiectasis, post-operative atelectasis, Kartagener's syndrome, constipation, chronic idiopathic constipation, dry mouth, mouth ulcer, gum disease, mycositis, gastro-esophageal reflux disease, peptic ulcer, heartburn, esophagitis, Sjogren's syndrome, inflammatory bowel disease, constipation, gastrointestinal problems caused by radiation or chemotherapy for cancer, or a disease associated with expression or activity of a P2Y receptor in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by one of the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         36 : The method of  claim 35 , wherein the subject is a human. 
     
     
         37 : A method of treating cystic fibrosis, sinusitis, otitis media, ventilator associated pneumonia, chronic bronchitis, chronic obstructive pulmonary disorder, primary ciliary dyskinesia, asthma, bronchiectasis, post-operative atelectasis, Kartagener's syndrome, dry mouth, mouth ulcer, gum disease, mycositis, gastro-esophageal reflux disease, peptic ulcer, heartburn, esophagitis, Sjogren's syndrome, inflammatory bowel disease, constipation, gastrointestinal problems caused by radiation or chemotherapy for cancer, or a disease associated with expression or activity of a P2Y receptor in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula IA: 
       
         
           
           
               
               
           
         
       
       or enantiomers, diastereomers, enantiomerically enriched mixtures, racemic mixtures, crystalline forms, non-crystalline forms, amorphous forms, or pharmaceutically acceptable salts thereof, wherein:
 Ar is an aryl, alkyl, cycloalkyl, aralkyl, or a heteroaryl or fused heteroaryl group containing 1-4 heteroatoms; each of which is optionally substituted with one or more of a halo, hydroxy, alkyl, alkoxy, carboxy, cyano, nitro, sulfonamido, sulfonate, amino, imino, alkylamino, or di-alkylamino group or groups; provided that when X is O, Ar is neither unsubstituted phenyl, anilino, nor 4-nitrophenyl; 
 X is a bond or is selected from the group consisting of O, S, S(O), S(O 2 ), N(R′), —C(O)N(R′)—, and —(CH 2 ) m X 1 —; 
 X 1  is O, S, S(O), S(O 2 ), or N(R′); 
 R′ is H, alkyl, or aralkyl; 
 Q is selected from the group consisting of H; OH; lower alkoxy; halo; mono-, di- or trihalomethyl; amino; lower alkylamino; and lower dialkylamino group; 
 U and V each represent independently for each occurrence O; NH; a lower alkylamino diradical; methylene; or mono- or dihalomethylene; 
 Y 1 , Y 2 , and Y 3  each represent independently for each occurrence O, O − ; 
 
       S − ; or substituted or unsubstituted lower alkoxy, aryloxy, aralkyloxy, or cycloalkyloxy groups;
 Z is O, NH, or a lower alkylamino diradical; 
 m and n are independently 0, 1 or 2; 
 W is P; and 
 M is H or a salt-forming cation. 
 
     
     
         38 : The method of  claim 37 , wherein the subject is a human. 
     
     
         39 : A method of treating cystic fibrosis, sinusitis, otitis media, ventilator associated pneumonia, chronic bronchitis, chronic obstructive pulmonary disorder, primary ciliary dyskinesia, asthma, bronchiectasis, post-operative atelectasis, Kartagener's syndrome, dry mouth, mouth ulcer, gum disease, mycositis, gastro-esophageal reflux disease, peptic ulcer, heartburn, esophagitis, Sjogren's syndrome, inflammatory bowel disease, gastrointestinal problems caused by radiation or chemotherapy for cancer, or a disease associated with expression or activity of a P2Y receptor in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula IIA: 
       
         
           
           
               
               
           
         
         or enantiomers, diastereomers, enantiomerically enriched mixtures, racemic mixtures, crystalline forms, non-crystalline forms, amorphous forms, or pharmaceutically acceptable salts thereof, wherein: 
         A, D, and E are independently N, C(R 5 ), or CH; 
         F is N or C(R 4 ); 
         R 1  is an H, oxo, lower alkoxy, lower alkylamino, lower dialkylamino, imino, lower alkyl-substituted imino, lower thioalkyl, aryl, substituted or unsubstituted lower alkyl, or lower alkyl-substituted aryl group; 
         R 2  is absent or is selected from the group consisting of a lower alkyl, lower alkoxy, lower alkyl-substituted aryl, aralkyl, and cycloalkyl group; 
         R 3  and R 4  are independently an H, lower thioalkyl, substituted lower alkyl, or unsubstituted lower alkyl group; 
         R 5  is a lower alkyl, lower alkoxy, lower alkyl-substituted aryl, aralkyl, or cycloalkyl group; 
         Ar is an aryl, alkyl, cycloalkyl, arylalkyl, or a heteroaryl or fused heteroaryl group containing 1-4 heteroatoms; each of which is optionally substituted with one or more of a halo, hydroxy, alkyl, alkoxy, carboxy, cyano, nitro, sulfonamido, sulfonate, amino, alkylamino, or di-alkylamino group or groups; provided that when X is O, Ar is neither unsubstituted phenyl, anilino, nor 4-nitrophenyl; 
         X is a bond or is selected from the group consisting of O, S, S(O), S(O 2 ), N(R′), —C(O)N(R′)—, and —(CH 2 ) m X 1 —; 
         X 1  is O, S, S(O), S(O 2 ), or N(R′); 
         R′ is H, alkyl, or aralkyl; 
         Q represents independently for each occurrence an H; OH; lower alkoxy; halo; mono-, di- or trihalomethyl; amino; lower alkylamino, or lower dialkylamino group; 
         U and V each represent independently for each occurrence O; NH; a lower alkylamino diradical; methylene; or mono- or dihalomethylene; 
         Y 2  and Y 3  each represent independently for each occurrence O, O − ; S − ; or a substituted or unsubstituted lower alkoxy, aryloxy, aralkyloxy, or cycloalkyloxy group; 
         M is H or a salt-forming cation; 
         Z represents independently for each occurrence O, NH, or a lower alkylamino diradical; 
         m and n are independently 0, 1 or 2; and 
         W is P. 
       
     
     
         40 : The method of  claim 39 , wherein the compound administered has the formula IIA-1: 
       
         
           
           
               
               
           
         
       
     
     
         41 : The method of  claim 39 , wherein the compound administered has the formula IIA-2: 
       
         
           
           
               
               
           
         
       
     
     
         42 : The method of  claim 39 , wherein the subject is a human. 
     
     
         43 : A method of treating cystic fibrosis, sinusitis, otitis media, ventilator associated pneumonia, chronic bronchitis, chronic obstructive pulmonary disorder, primary ciliary dyskinesia, asthma, bronchiectasis, post-operative atelectasis, Kartagener's syndrome, dry mouth, mouth ulcer, gum disease, mycositis, gastro-esophageal reflux disease, peptic ulcer, heartburn, esophagitis, Sjogren's syndrome, inflammatory bowel disease, gastrointestinal problems caused by radiation or chemotherapy for cancer, or a disease associated with expression or activity of a P2Y receptor in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula IIB: 
       
         
           
           
               
               
           
         
         or enantiomers, diastereomers, enantiomerically enriched mixtures, racemic mixtures, crystalline forms, non-crystalline forms, amorphous forms, or pharmaceutically acceptable salts thereof, wherein: 
         Ar is an aryl, alkyl, cycloalkyl, arylalkyl, or a heteroaryl or fused heteroaryl group containing 1-4 heteroatoms; each of which is optionally substituted with one or more of a halo, hydroxy, alkyl, alkoxy, carboxy, cyano, nitro, sulfonamido, sulfonate, amino, alkylamino, or di-alkylamino group or groups; provided that when X is O, Ar is neither unsubstituted phenyl, anilino, nor 4-nitrophenyl; 
         X is a bond or is selected from the group consisting of O, S, S(O), S(O 2 ), N(R′), —C(O)N(R′)—, and —(CH 2 ) m X 1 —; 
         X 1  is O, S, S(O), S(O 2 ), or N(R′); 
         R′ is H, alkyl, or aralkyl; 
         Q represents independently for each occurrence an H; OH; lower alkoxy; halo; mono-, di- or trihalomethyl; amino; lower alkylamino; or lower dialkylamino group; 
         U and V each represent independently for each occurrence O; NH; a lower alkylamino diradical; a lower dialkylamino diradical; methylene; or mono- or dihalomethylene; 
         Y 1  is CH 2  or NH; 
         Y 2  and Y 3  each represent independently for each occurrence O, O − ; S − ; or a substituted or unsubstituted lower alkoxy, aryloxy, aralkyloxy, or cycloalkyloxy group; 
         M is H or a salt-forming cation; 
         Z represents independently for each occurrence O, NH, or a lower alkylamino diradical; 
         m and n are independently 0, 1 or 2; 
         W is P. 
       
     
     
         44 : The method of  claim 44 , wherein the subject is a human.