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

A method for treating a respiratory or gastrointestinal disease mediated by a P2X3 or P2X2/3 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:
• —CH2—;
• —O—;
• —C(O)—;
• —CHOH—;
• —S(O)n—;
• or —NRc— wherein n is from 0 to 2 and Rc is hydrogen or alkyl;
• Y is:
• hydrogen;
• or —NRdRe wherein one of Rd and Re 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;
• R1 is:
• alkyl;
• alkenyl;
• cycloalkyl;
• cycloalkenyl;
• halo;
• haloalkyl;
• hydroxyalkyl;
• or alkoxy;
• R2, R3, R4 and R5 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;
• —(CH2)m—(Z)n—(CO)—Rf or —(CH2)m—(Z)—SO2—(NRg)n—Rf where m and n each independently is 0 or 1, Z is O or NRg, Rf is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl, and each Rg is independently hydrogen or alkyl;
• or R3 and R4 may together form an alkylene dioxy;
• or R3 and R4 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 R2 and R3 may together form an alkylene dioxy;
• or R2 and R3 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;
• R6 is:
• hydrogen;
• alkyl;
• halo;
• haloalkyl;
• amino;
• or alkoxy;
• and
• one of R7 and R8 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.