Diaminopyrimidines as P2X
Compounds and methods for treating 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, solvate or prodrug 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.
1. A compound of formula (I):
or pharmaceutically acceptable salts thereof,
wherein:
X is: —CH 2 —;
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; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl;
D is an optional oxygen;
R 1 is: isopropyl;
R 2 and R 5 each independently is: hydrogen; alkyl; alkenyl; amino; halo; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; amino; 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;
R 3 and R 4 together with the atoms to which they are attached 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 compound of claim 1 , wherein Y is —NR d R e .
3. The compound of claim 2 , wherein R 5 and R 6 are hydrogen.
4. The compound of claim 3 , wherein R 2 is hydrogen.
5. The compound of claim 4 , wherein one of R 7 and R 8 is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl.
6. The compound of claim 4 , wherein one of R d and R e is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl.
7. The compound of claim 1 , wherein R 7 , R 8 , R d and R e are hydrogen.
8. The compound of claim 1 , wherein said compound is of the formula (II):
wherein:
R 3 and R 4 together with the atoms to which they are attached 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.
9. The compound of claim 1 , wherein said compound is of the formula (VII):
wherein:
X is: —CH 2 —;
R 1 is: isopropyl;
R 2 is: hydrogen; alkyl; alkenyl; amino; 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 .