Benzamide inhibitors of the P2X7 receptor

A method of treating an IL-1 mediated disease in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I:

• wherein R1 is (C1-C6)alkyl, optionally substituted by (C3-C10)cycloalkyl, or (C6-C10)aryl, wherein each of said (C1-C6)alkyl, (C3-C10)cycloalkyl, or (C6-C10)aryl, are optionally substituted by one to three moieties independently selected from the group consisting of hydroxy, halogen, —CN, (C1-C6)alkyl, HO(C1-C6)alkyl, (C1-C6)alkyl-NH(C═O)—, NH2(C═O)—, (C1-C6)alkoxy, and (C3-C10)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted by one or more moieties selected from halogen, or (C1-C6)alkyl-;
• R2 is hydrogen, halogen, —CN, and (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted by one to three moieties, independently selected from the group consisting of halo, hydroxy, amino, —CN, (C1-C6)alkyl, (C1-C6)alkoxy, —CF3, CF3O—, (C1-C6)alkyl-NH—, [(C1-C6)alkyl]2-N—, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-(SO2)—, (C1-C6)alkyl-O—(C═O)—, formyl, (C1-C6)alkyl-(C═O)—, and (C3-C6)cycloalkyl;
• R3 is a nitrogen linked (C1-C10)heterocyclyl of the formula:
• wherein R4 and R5 are independently selected from the group of substituents, consisting of hydrogen, halo, hydroxy, —CN, HO—(C1-C6)alkyl, and (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with one to three fluoro, (C1-C6)alkoxy optionally substituted with one to three fluoro, HO2C—, (C1-C6)alkyl-O—(C═O)—, R6R8N(O2S)—, (C1-C6)alkyl-(O2S)—NH—, (C1-C6)alkyl-O2S—[(C1-C6)alkyl-N]—, R6R8N(C═O)—, R6R8N(CH2)m—, (C6-C10)aryl, (C3-C8)cycloalkyl, C6-C10)aryl-O—, or (C3-C8)cycloalkyl-O—;
• and
• R7 is independently selected from the group of substituents consisting of hydrogen and (C1-C6)alkyl optionally substituted with one to three halogens, hydroxy, —CN, (C1-C6)alkoxy-, (C2-C6)alkenoxy, (C1-C6)alkyl-SO2—, NH2—, ((C1-C6)alkyl)n-N—, ((C2-C6)alkenyl)n-N—, ((C2-C6)alkynyl)n-N—, NH2(C═O)—, (C1-C6)alkyl-(C═O)N—, ((C1-C6)alkyl)n-N—(C═O)—, (C2-C6)alkenyl-(C═O)N—, ((C2-C6)alkenyl)n-N—(C═O)—, (C2-C6)alkynyl-(C═O)N—, ((C2-C6)alkynyl)n-N—(C═O)—, (C1-C6)alkyl-(C═O)—, (C2-C6)alkenyl-(C═O)—, (C2-C6)alkynyl-(C═O)—, (C3-C10)cycloalkyl-(C═O)—, (C6-C10)aryl-(C═O), (C1-C6)alkyl-(C═O)O—, (C2-C6)alkenyl-(C═O)O—, (C2-C6)alkynyl-(C═O)O—, (C1-C6)alkyl-O(C═O)—, (C2-C6)alkenyl-O—(C═O)—, (C2-C6)alkynyl-O—(C═O)—, and (C3-C10)cycloalkyl;
• wherein R4, R5 and R7 may each be optionally substituted on any aliphatic or aromatic carbon atom by one to three moieties, independently selected from the group consisting of halo, hydroxy, amino, —CN, (C1-C6)alkyl, (C1-C6)alkoxy, —CF3, CF3O—, (C1-C6)alkyl-NH—, [(C1-C6)alkyl]2-N—, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)—, (C1-C6)alkyl-(SO2)—, (C1-C6)alkyl-O—(C═O)—, formyl, (C1-C6)alkyl-(C═O)—, and (C3-C6)cycloalkyl;
• R6 and R8 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, HO—(C2-C6)alkyl and (C3-C8)cycloalkyl;
• n is an integer from zero to two;
• and
• m is an integer from one to two;
• or a pharmaceutically acceptable salt thereof;
• wherein said IL-1 mediated disease is selected from the group consisting of:
• arthritis, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, acute synovitis, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, psoriasis, allergic dermatitis, hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, peripheral neuropathy, and pain.