Back to results
US 7,071,223 B1Granted
Benzamide inhibitors of the P2X7 receptor
AssigneePfizer Inc.
InventorsMark A Dombroski, Allen J. Duplantier, Chakrapani Subramanyam
Life of this patent
Estimating the term…
Abstract
The present invention provides benzamide inhibitors of the P2X7 receptor of the formula: wherein R1–R3 are as defined herein. The compounds of the invention are useful in the treatment of IL-1 mediated disorders, including, without limitation, inflammatory diseases such as osteoarthritis and rheumatoid arthritis; allergies, asthma, COPD, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.
Claims9
A compound of the formula
- 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, or (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;
- and
- R3 is a substituted nitrogen linked (C1–C10)heterocyclyl of the formula:
- or the pharmaceutically acceptable salts or solvates thereof.
2 more elements
A compound of the formula
- 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 the pharmaceutically acceptable salts or solvates thereof.
9 more elements
A compound of any one of the preceding claims wherein R2 is chloro, methyl or ethyl.
A compound of any of the preceding claims wherein R3 is a nitrogen linked (C1–C10)heterocyclyl of formula (IV):
- R4 is hydrogen or methyl,
- and R7 is selected from the group consisting of:
A compound selected from the group consisting of:
- 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methoxy-ethyl)-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;
- 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-benzamide;
- 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-benzamide;
- 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;
- 2-Chloro-5-(4-cyanomethyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide;
- 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methoxy-ethyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;
- 2-Chloro-5-(4-cyanomethyl-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-N-(1-hydroxy-cycloheptyl methyl)-benzamide;
- 2-Chloro-N-(1-hydroxy-3,3-dimethyl-cyclohexylmethyl)-5-(3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-benzamide;
- 5-(4-Carbamoylmethyl-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide;
- 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;
- 5-[4-(2-Amino-ethyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide;
- 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;
- 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;
- and
- 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-methyl-propyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide, or the pharmaceutically acceptable salts or solvates thereof.
12 more elements
Dependencies are inferred from the claim text.