Methods of using diaminopyrimidine p2x3 and p2x2/3 receptor modulators for treatment of respiratory and gastrointestinal diseases

Abstract

Methods for treating respiratory and gastrointestinal diseases mediated by a P2X 3 and/or a P2X 2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein D, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein.

What is claimed is: 
     
         1 . A method for treating a respiratory or gastrointestinal disease mediated by a P2X 3  or P2X 2/3  receptor antagonist, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 X is: —CH 2 —; —O—; —C(O)—; —CHOH—; —S(O)—; or —NR c — wherein n is from 0 to 2 and R c  is hydrogen or alkyl; 
 Y is: hydrogen; or —NR d R e  wherein one of R d  and R e  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalky; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; 
 D is an optional oxygen; 
 R 1  is: alkyl; alkenyl; cycloalkyl; cycloalkenyl; halo; haloalkyl; hydroxyalkyl; or alkoxy; 
 R 2 , R 3 , R 4  and R 5  each independently is: hydrogen; alkyl; alkenyl; amino; aminosulfonyl; halo; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; arylsulfonyl; cyano; aryl; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; optionally substituted phenoxy; —(CH 2 ) m —(Z) n —(CO)—R f  or —(CH 2 ) m —(Z) n —SO 2 —(NR g )—R f  where m and n each independently is 0 or 1, Z is O or NR g , R f  is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl, and each R g  is independently hydrogen or alkyl; or R 3  and R 4  may together form an alkylene dioxy; or R 3  and R 4  together with the atoms to which they are attached may form a five or six-membered ring that optionally includes one or two heteroatoms selected from O, S and N; or R 2  and R 3  may together form an alkylene dioxy; or R 2  and R 3  together with the atoms to which they are attached may form a five or six-membered ring that optionally includes one or two heteroatoms selected from O, S and N; 
 R 6  is: hydrogen; alkyl; halo; haloalkyl; amino; or alkoxy; and 
 one of R 7  and R 8  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalky; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. 
 
       
     
     
         2 . The method of  claim 1 , wherein X is: —CH 2 — or —O—. 
     
     
         3 . The method of  claim 2 , wherein Y is —NR d R e . 
     
     
         4 . The method of  claim 3 , wherein R 1  is alkyl, alkenyl or cycloalkyl. 
     
     
         5 . The method of  claim 4 , wherein R 5  and R 6  are hydrogen. 
     
     
         6 . The method of  claim 5 , wherein R 2  is hydrogen. 
     
     
         7 . The method of  claim 6 , wherein one of R 7  and R 8  is hydrogen and the other is hydrogen, alkyl, hydroxyalkyl or haloalkyl. 
     
     
         8 . The method of  claim 6 , wherein one of R d  and R e  is hydrogen and the other is hydrogen, alkyl, hydroxyalkyl or haloalkyl. 
     
     
         9 . The method of  claim 6 , wherein R 3  and R 4  each independently is halo, alkoxy, hydroxy, haloalkoxy; aminosulfonyl; or alkylsulfonyl. 
     
     
         10 . The method of  claim 6 , wherein R 7 , R 8 , R d  and R e  are hydrogen. 
     
     
         11 . The method of  claim 9 , wherein R 1  is isopropyl. 
     
     
         12 . The method of  claim 1 , wherein R 4  is heteroaryl. 
     
     
         13 . The method of  claim 1 , wherein R 3  and R 4  together with the atoms to which they are attached form a five or six membered ring that includes one or two heteroatoms selected from O, N and S. 
     
     
         14 . The method of  claim 1 , wherein R 2  and R 3  together with the atoms to which they are attached form a five or six membered ring that includes one or two heteroatoms selected from O, N and S. 
     
     
         15 . The method of  claim 1  wherein said compound is of the formula (II): 
       
         
           
           
               
               
           
         
         wherein:
 X is: —CH 2 —; or —O—; 
 R 1  is: alkyl; alkenyl; cycloalkyl; cycloalkenyl; or halo; 
 R 3  and R 4  each independently is: alkyl; alkenyl; amino; aminosulfonyl; halo; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; arylsulfonyl; cyano; aryl; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; optionally substituted phenoxy; —(CH 2 ) m —(Z) n —(CO)—R f  or —(CH 2 ) m —(Z) n —SO 2 —(NR g ) n —R f  where m and n each independently is 0 or 1, Z is O or NR g , R f  is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl, and each R g  is independently hydrogen or alkyl; or R 3  and R 4  may together form an alkylene dioxy; or R 3  and R 4  together with the atoms to which they are attached may form a five or six-membered ring that optionally includes one or two heteroatoms selected from O, S and N; 
 one of R 7  and R 8  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; and 
 one of R d  and R e  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. 
 
       
     
     
         16 . The method of  claim 15 , wherein R 1  is isopropyl. 
     
     
         17 . The method of  claim 16 , wherein R 3  is halo, alkoxy, haloalkoxy or hydroxy. 
     
     
         18 . The method of  claim 17 , wherein R 4  is halo, alkoxy, alkylsulfonyl, aminosulfonyl or heteroaryl. 
     
     
         19 . The method of  claim 1  wherein said compound is of the formula (III): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is: isopropyl, isopropenyl, cyclopropyl or iodo 
 R 3  and R 4  each independently is: alkyl; alkenyl; amino; aminosulfonyl; halo; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; arylsulfonyl; cyano; aryl; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; optionally substituted phenoxy; —(CH 2 ) m —(Z) n —(CO)—R f  or —(CH 2 ) m —(Z)—SO 2 —(NR g ) n —R f  where m and n each independently is 0 or 1, Z is O or NR g , R f  is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl, and each R g  is independently hydrogen or alkyl; or R 3  and R 4  may together form an alkylene dioxy; or R 3  and R 4  together with the atoms to which they are attached may form a five or six-membered ring that optionally includes one or two heteroatoms selected from O, S and N; 
 one of R 7  and R 8  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; and 
 one of R d  and R e  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. 
 
       
     
     
         20 . The method of  claim 1 , wherein said compound is of the formula (IV): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is: alkyl; alkenyl; cycloalkyl; cycloalkenyl; or halo; 
 R 3  and R 4  each independently is: alkyl; alkenyl; amino; aminosulfonyl; halo; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; arylsulfonyl; cyano; aryl; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; optionally substituted phenoxy; —(CH 2 ) m —(Z) n —(CO)—R f  or —(CH 2 ) m —(Z) n —SO 2 —(NR g ) n —R f  where m and n each independently is 0 or 1, Z is O or NR g , R f  is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl, and each R g  is independently hydrogen or alkyl; or R 3  and R 4  may together form an alkylene dioxy; or R 3  and R 4  together with the atoms to which they are attached may form a five or six-membered ring that optionally includes one or two heteroatoms selected from O, S and N; 
 one of R 7  and R 8  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; and 
 one of R d  and R e  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. 
 
       
     
     
         21 . The method of  claim 1 , wherein said compound is of the formula (V): 
       
         
           
           
               
               
           
         
         wherein:
 R 3  and R 4  each independently is: alkyl; alkenyl; amino; aminosulfonyl; halo; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; arylsulfonyl; cyano; aryl; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; optionally substituted phenoxy; —(CH 2 ) m —(Z) n —(CO)—R f  or —(CH 2 ) m —(Z) n —SO 2 —(NR g ) n —R f  where m and n each independently is 0 or 1, Z is O or NR g , R f  is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl, and each R g  is independently hydrogen or alkyl; or R 3  and R 4  may together form an alkylene dioxy; or R 3  and R 4  together with the atoms to which they are attached may form a five or six-membered ring that optionally includes one or two heteroatoms selected from O, S and N; 
 one of R 7  and R 8  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; and 
 one of R d  and R e  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. 
 
       
     
     
         22 . The method of  claim 1 , wherein said compound is of the formula (VI): 
       
         
           
           
               
               
           
         
         wherein:
 R 3  and R 4  each independently is: alkyl; alkenyl; amino; aminosulfonyl; halo; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; arylsulfonyl; cyano; aryl; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; optionally substituted phenoxy; —(CH 2 ) m —(Z) n —(CO)—R f  or —(CH 2 ) m —(Z) n —SO 2 —(NR g ) n —R f  where m and n each independently is 0 or 1, Z is O or NR g , R f  is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl, and each R g  is independently hydrogen or alkyl; or R 3  and R 4  may together form an alkylene dioxy; or R 3  and R 4  together with the atoms to which they are attached may form a five or six-membered ring that optionally includes one or two heteroatoms selected from O, S and N; 
 one of R 7  and R 8  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; and 
 one of R d  and R e  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. 
 
       
     
     
         23 . The method of  claim 22 , wherein R 3  is halo, alkoxy, haloalkoxy or hydroxy. 
     
     
         24 . The method of  claim 23 , wherein R 4  is halo, alkoxy, alkylsulfonyl or aminosulfonyl. 
     
     
         25 . The method of  claim 13 , wherein said compound is of the formula (VII): 
       
         
           
           
               
               
           
         
         wherein:
 X is: —CH 2 —; or —O—; 
 R 1  is: alkyl; alkenyl; cycloalkyl; or cycloalkenyl; or halo; 
 R 2  is: hydrogen; alkyl; alkenyl; amino; aminosulfonyl; halo; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; arylsulfonyl; cyano; aryl; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; optionally substituted phenoxy; or —(CH 2 ) m —(Z) n —(CO)—R f  or —(CH 2 ) m —(Z) n —SO 2 —(NR g ) n —R f  where m and n each independently is 0 or 1, Z is O or NR g , R f  is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl, and each R g  is independently hydrogen or alkyl; 
 one of R 7  and R 8  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; 
 one of R d  and R e  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; 
 Q is CR 9 , one of A and E is O, S or NR 10  and the other is CR 9  or N; or 
 Q is N, one of A and E is NR 10  and the other is CR 9 ; 
 each R 9  is independently hydrogen, alkyl, halo or alkoxy; and 
 R 10  is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, —(CH 2 ) m —(Z) n —(CO)—R f , or —(CH 2 ) m —(Z) n —SO 2 —(NR g ) n —R f . 
 
       
     
     
         26 . The method of  claim 14 , wherein said compound is of the formula (VIII): 
       
         
           
           
               
               
           
         
         wherein:
 X is: —CH 2 —; or —O—; 
 R 1  is: alkyl; alkenyl; cycloalkyl; or cycloalkenyl; or halo; 
 R 4  is: hydrogen; alkyl; alkenyl; amino; aminosulfonyl; halo; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; arylsulfonyl; cyano; aryl; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; optionally substituted phenoxy; or —(CH 2 ) m —(Z) n —(CO)—R f  or —(CH 2 ) m —(Z) n —SO 2 —(NR g ) n —R f  where m and n each independently is 0 or 1, Z is O or NR g , R f  is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl, and each R g  is independently hydrogen or alkyl; 
 one of R 7  and R 8  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; 
 one of R d  and R e  is hydrogen, and the other is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; 
 Q is CR 9 , one of A and E is O, S or NR 10  and the other is CR 9  or N; or 
 Q is N, one of A and E is NR 10  and the other is CR 9 ; 
 each R 9  is independently hydrogen, alkyl, halo or alkoxy; and 
 R 10  is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, —(CH 2 ) m —(Z) n —(CO)—R f , or —(CH 2 ) m —(Z) n —SO 2 —(NR g ) n —R f . 
 
       
     
     
         27 . The method of  claim 1 , wherein said disease is a respiratory disease selected from chronic obstructive pulmonary disease (COPD), asthma and bronchospasm. 
     
     
         28 . The method of  claim 1 , wherein said disease is a gastrointestinal disease selected from: Irritable Bowel Syndrome, Inflammatory Bowel Disease, biliary colic, renal colic, diarrhea-dominant irritable bowel syndrome, and pain associated with GI distension.