1-benzyl-3-hydroxymethylindazole derivatives and use thereof in the treatment of diseases based on the expression of MCP-1 and CX3CR1

A method for treating a disease based on the expression of MCP-1 or CX3CR1, comprising administering an effective amount of a pharmaceutical composition, which comprises a compound represented by formula (I):

• wherein:
• A is —X1— or —X1—O—X2—, in which
• X1 is an alkylene group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms or one or more alkoxy groups having from 1 to 3 carbon atoms, and
• X2 is an alkylene group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms,
• Y is hydrogen, —OH, —N(R11)(R12), or —N(R11)O(R12), wherein
• R11 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, or an alkoxy group having from 1 to 3 carbon atoms, or R11 together with R12 forms a 4- to 7-membered heterocycle,
• R12 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an aryl group, a heteroaryl group, an alkylaryl group, an alkylheteroaryl group, —COR′, —COOR′, or —CON(R′)(R″), wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R12 together with R11, forms a 4- to 7-membered heterocycle,
• R1 and R2, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
• R3, R4 and R8, which may be identical or different from each other, are each independently hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, —CN, —CONR′R″, —SO2NR′R″, —SO2R′, nitro or trifluoromethyl;
• wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
• R5 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, nitro or trifluoromethyl, or R5 together with one of either R6 or R7 forms a ring having 5 or 6 carbon atoms;
• wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
• R6 and R7, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R6 and R7 together form a group C═O, or one of either R6 or R7, together with R5, forms a ring having 5 or 6 carbon atoms,
• a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, and at least one pharmaceutically acceptable vehicle, to a subject in need thereof.

A method for treating a disease based on the expression of MCP-1 or CX3CR1, comprising administering an effective amount of a compound represented by formula (I):

• wherein:
• A is —X1—O—X2—, in which
• X1 is an alkylene group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms or one or more alkoxy groups having from 1 to 3 carbon atoms, and
• X2 is an alkylene group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms,
• Y is hydrogen, —OH, —N(R11)(R12), or —N(R11)O(R12), wherein
• R11 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, or an alkoxy group having from 1 to 3 carbon atoms, or R11 together with R12 forms a 4- to 7-membered heterocycle,
• R12 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an aryl group, a heteroaryl group, an alkylaryl group, an alkylheteroaryl group, —COR′, —COOR′, or —CON(R′)(R″), wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R12 together with R11, forms a 4- to 7-membered heterocycle,
• R1 and R2, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
• R3, R4 and R8, which may be identical or different from each other, are each independently hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, —CN, —CONR′R″, —SO2NR′R″, —SO2R′, nitro or trifluoromethyl;
• wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
• R5 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, nitro or trifluoromethyl, or R5 together with one of either R6 or R7 forms a ring having 5 or 6 carbon atoms;
• wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
• R6 and R7, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R6 and R7 together form a group C═O, or one of either R6 or R7, together with R5, forms a ring having 5 or 6 carbon atoms,
• a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, to a subject in need thereof.

A method for treating a disease based on the expression of MCP-1 or CX3CR1, comprising administering an effective amount of a pharmaceutical composition, which comprises a compound represented by formula (I):

• wherein:
• A is —X1—O—X2—, in which
• X1 is an alkylene grout having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms or one or more alkoxy groups having from 1 to 3 carbon atoms, and
• X2 is an alkylene group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms,
• Y is hydrogen, —OH, —N(R11)(R12), or —N(R11)O(R12), wherein
• R11 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, or an alkoxy group having from 1 to 3 carbon atoms, or R11 together with R12 forms a 4- to 7-membered heterocycle,
• R12 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an aryl group, a heteroaryl group, an alkylaryl group, an alkylheteroaryl group, —COR′, —COOR′, or —CON(R′)(R″), wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R12 together with R11, forms a 4- to 7-membered heterocycle,
• R1 and R2, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
• R3, R4 and R8, which may be identical or different from each other, are each independently hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, —CN, —CONR′R″, —SO2NR′R″, —SO2R′, nitro or trifluoromethyl;
• wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
• R5 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, nitro or trifluoromethyl, or R5 together with one of either R6 or R7 forms a ring having 5 or 6 carbon atoms;
• wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
• R6 and R7, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R6 and R7 together form a group C═O, or one of either R6 or R7, together with R5, forms a ring having 5 or 6 carbon atoms,
• a pharmaceutically acceptable salt thereof, or a pharmaceutically ester thereof, and at least one pharmaceutically acceptable vehicle, to a subject in need thereof.