Phosphate transport inhibitors

Abstract

Disclosed are compounds which have been identified as inhibitors of phosphate transport. Many of the compounds are represented by Structural Formula (I): Ar 1 —W—X—Y—Ar 2 ; or a pharmaceutically acceptable salt thereof. Ar 1 and Ar 2 are independently a substituted or unsubstituted aryl group or an optionally substituted five membered or six membered non-aromatic heterocylic group fused to an optionally substituted monocylic aryl group. W and Y are independently a covalent bond or a C1-C3 substituted or unsubstituted alkylene group. X is a heteroatom-containing functional group, an aromatic heterocyclic group, substituted aromatic heterocyclic group, non-aromatic heterocyclic group, substituted non-aromatic heterocyclic group, an olefin group or a substituted olefin group. Also disclosed are methods of treating a subject with a disease associated with hyperphosphatemia, as well as a disease mediated by phosphate-transport function. The methods comprise the step of administering an effective amount of the one of the compounds described above.

1 - 13 . (canceled)  
   
   
       14 . A method of inhibiting phosphate transport in a subject in need of phosphate transport inhibition, said method comprising the step of administering an effective amount of a compound represented by the following structural formula:  
       Ar 1 —W—X—Y—Ar 2 ;  
     or a pharmaceutically acceptable salt thereof, wherein: 
 Ar 1  and Ar 2  are independently a substituted or unsubstituted aryl group or an optionally substituted five membered or six membered non-aromatic heterocyclic group fused to an optionally substituted monocyclic aryl group;  
 W and Y are independently a covalent bond or a C1-C3 substituted or unsubstituted alkylene group; and  
 X is —S(O) 2 —, —S(O) 2 CR 1 R 2 —, —S(O) 2 NR 1 S(O) 2 —, —C(O)NR 1 C(O)—, —NR 1 C(O)NR 2 —, —NR 1 C(NR 3 )NR 2 —, —(CH 2 ) n —, —C(O)—, —P(O)(OH)—, —NR 1 —, —NR 1 R 2 —, or a group represented by a structural formula selected from the group consisting of:  
                     
 wherein R 1 , R 2  and R 3  are independently a hydrogen, lower alkyl group, substituted lower alkyl group, heteroalkyl group, substituted heteroalkyl group, cycloalkyl group, substituted cycloalkyl group, aralkyl group, substituted aralkyl, heteroaralkyl group, or substituted heteroaralkyl.  
 
   
   
       15 . The method of  claim 14  wherein said subject is in need of treatment for hyperphosphatemia, chronic renal failure, disorders of phosphate metabolism or impaired phosphate transport function, hyperparathyroidism, uremic bone disease, soft tissue calcification or osteoporosis.  
   
   
       16 - 18 . (canceled)  
   
   
       19 . The method of  claim 14  wherein the method further comprises co-administering one or more phosphate sequesterants to the subject.  
   
   
       20 . (canceled)  
   
   
       21 . The method of  claim 15  wherein W and Y are covalent bonds.  
   
   
       22 . The method of  claim 21  wherein Ar 1  and Ar 2  are independently a phenyl group, a substituted phenyl group, a furyl group, a substituted furyl group, a thienyl group, a substituted thienyl group, a thiazolyl group, a substituted thiazolyl group, a triazinyl group, a substituted triazinyl group, a pyridyl group, a substituted pyridyl group, a pyrrolyl group, a substituted pyrrolyl group, an imidazolyl group, a substituted imidazolyl group, a pyrimidyl group, a substituted pyrimidyl group, a pyrazolyl group or a substituted pyrazolyl group.  
   
   
       23 . (canceled)  
   
   
       24 . The method of  claim 22  wherein Ar 1  and Ar 2  are independently a phenyl group, a substituted phenyl group, a furyl group or a substituted furyl group.  
   
   
       25 . The method of  claim 24  wherein Ar 1  and Ar 2  are independently a phenyl group substituted with one or more substituents selected from the group consisting of: a halogen, a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an alkoxy group, a substituted alkoxy group, —C(O)NR 4 R 5 , —C(O)OR 6 , —P(O)(OR 6 ) 2 , —NO 2 , —SO 3 , —S(O) 2 R 6 , —C(O)R 7  or —CR 7 ═NR 4 ; 
 R 4 , R 5  and R 6  are independently a hydrogen, lower alkyl group, substituted lower alkyl group, heteroalkyl group, substituted heteroalkyl group, a heteroaryl group, a substituted heteroaryl group, cycloalkyl group, substituted cycloalkyl group, aralkyl group, substituted aralkyl, heteroaralkyl group, or substituted heteroaralkyl, or R 4  and R 5  taken together with the atom to which they are bonded, form an aromatic heterocyclic group, substituted aromatic heterocyclic group, non-aromatic heterocyclic group, or substituted non-aromatic heterocyclic group; and    R 7  is a hydrogen, lower alkyl group, substituted lower alkyl group, heteroalkyl group, substituted heteroalkyl group, cycloalkyl group, substituted cycloalkyl group, aralkyl group, substituted aralkyl, heteroaralkyl group, substituted heteroaralkyl, —OR 6  or —NR 4 R 5 .    
   
   
       26 . The method of  claim 24  wherein X is —NHC(O)NH—.  
   
   
       27 . The method of  claim 26  wherein Ar 2  is a group represented by a structural formula selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 12  and R 13  are independently a hydrogen, a halogen, a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an alkoxy group, a substituted alkoxy group, —C(O)NR 4 R 5 , —C(O)OR 6 , —P(O)(OR 6 ) 2 , —NO 2 , —SO 3 , —S(O) 2 R 6 , —C(O)R 7  or —CR 7 ═NR 4 ;  
 R 4 , R 5  and R 6  are independently a hydrogen, lower alkyl group, substituted lower alkyl group, heteroalkyl group, substituted heteroalkyl group, a heteroaryl group, a substituted heteroaryl group, cycloalkyl group, substituted cycloalkyl group, aralkyl group, substituted aralkyl, heteroaralkyl group, or substituted heteroaralkyl, or R 4  and R 5  taken together with the atom to which they are bonded, form an aromatic heterocyclic group, substituted aromatic heterocyclic group, non-aromatic heterocyclic group, or substituted non-aromatic heterocyclic group;  
 R 7  is a hydrogen, lower alkyl group, substituted lower alkyl group, heteroalkyl group, substituted heteroalkyl group, cycloalkyl group, substituted cycloalkyl group, aralkyl group, substituted aralkyl, heteroaralkyl group, substituted heteroaralkyl, —OR 6  or —NR 4 R 5 ; and  
 Ring A is optionally substituted with one or more substituents other than R 12 .  
 
   
   
       28 . The method of  claim 27  wherein Ar 2  is a group represented by the following structural formula:  
     
       
         
         
             
             
         
       
       wherein R 12  is —C(O)NR 4 R 5 , —C(O)OR 6 , —P(O)(O 6 ) 2 , —NO 2 , SO 3 , —S(O) 2 R 6 , —C(O)R 7  or —CR 7 ═NR 4 .  
     
   
   
       29 . The method of  claim 27  wherein Ar 2  is a group represented by the following structural formula:  
     
       
         
         
             
             
         
       
       wherein R 13  is hydrogen, a halogen, a lower alkyl group, a substituted lower alkyl group, an alkoxy group or a substituted alkoxy group or —NO 2 .  
     
   
   
       30 . The method of  claim 27  wherein Ar 1  is a group represented by the following structural formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 15  is a hydrogen, a halogen, a lower alkyl group, a substituted lower alkyl group, an alkoxy group or a substituted alkoxy group or —NO 2 ; and  
 Ring B is optionally substituted with one or more other substituents other than R 15 .  
 
   
   
       31 . The method of  claim 30  wherein Ar 1  is a group represented by a structural formula selected from:  
     
       
         
         
             
             
         
       
       wherein R 16  and R 17  are independently hydrogen, a halogen, a lower alkyl group, a substituted lower alkyl group, an alkoxy group, a substituted alkoxy group or —NO 2 .  
     
   
   
       32 . The method of  claim 31  wherein R 15  is a fluoroalkyl group or a nitro group.  
   
   
       33 . The method of  claim 32  wherein Ar 2  is represented by the structural formula:  
     
       
         
         
             
             
         
       
     
     wherein R 13  is a halogen or a haloalkyl group and R 14  is hydrogen or a halogen.  
   
   
       34 . The method of  claim 24  wherein X is —NR 1 C(NR 3 )NR 2 —.  
   
   
       35 . The method of  claim 34  wherein R 1 , R 2  and R 3  are each hydrogen.  
   
   
       36 . The method of  claim 35  wherein Ar 1  is represented by the structural formula:  
     
       
         
         
             
             
         
       
     
     wherein R 15 , R 16  and R 17  are each independently a halogen or a substituted alkyl group.  
   
   
       37 . The method of  claim 36  wherein Ar 2  is represented by the structural formula:  
     
       
         
         
             
             
         
       
     
     wherein R 13  and R 14  are each independently a halogen or a substituted alkyl group.  
   
   
       38 . The method of  claim 37  wherein R 13 , R 14 , R 15  and R 16  are each independently a halogen or a haloalkyl group.  
   
   
       39 - 52 . (canceled)