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US 6,310,088 B1Granted
Hydroxamic and carboxylic acid derivatives having MMP and TNF inhibitory activity
AssigneeDarwin Discovery, Ltd.
InventorsAndrew Douglas Baxter, David Alan Owen, John Gary Montana, Elizabeth Jane Reed Nicholson
Life of this patent
Estimating the term…
Abstract
Compounds of formula (I) are useful therapeutic agents, by virtue of having MMP and TNF inhibitory activity.
Claims60
A compound, represented by formula (I):
- wherein
- n is 1-2;
- X is O or S(O)0-2;
- Y is NHOH;
- W is CR3 or (when X is SO2) N;
- R1 is H or a substituent selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, heterocycloalkyl, C1-6 alkyl-heterocycloalkyl, cycloalkyl, and C1-6 alkyl-cycloalkyl, wherein said substituent is optionally substituted with R14, and
- R2 is H or C1-6 alkyl, or
- CR1R2 is a cycloalkyl or heterocycloalkyl ring, optionally substituted with R14 or a substituent (optionally substituted with R14) selected from the group consisting of C1-6 alkyl, aryl, C1-6 alkyl-aryl;
- R3, R4 and R5 are independently H or C1-6 alkyl, or R3 and R4 may together represent a bond;
- R6, R7, R8, and R9 are independently H, R10, or a group (optionally substituted with R10) selected from the group consisting of C1-6 alkyl, aryl, C1-6 alkyl-aryl, C1-6 alkyl-heteroaryl, heteroaryl, and heterocycloalkyl, or
- R6 and R7, R7 and R8, R8 and R9, or when n=1, R5 and R6, and the carbons to which they are independently attached may alternatively form an aryl, heteroaryl, cycloalkenyl or hetercycloalkenyl ring, wherein said ring is optionally substituted with R10 or R11;
- R10 is selected from the group consisting of C1-6 alkyl, Br, I, F, CN, NO2, N(R11)2, OR11, COR11, CO2R15, CON(R11)2, C═NOR11, NR11R12, S(O)0-2R11, and SO2N(R11)2;
- R11 is selected from the group consisting of H, C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, cycloalkyl, C1-6 alkyl-cycloalkyl, heterocyloalkyl, and C1-6 alkyl-heterocycloalkyl, wherein said group is optionally substituted with R13, COR13, SO0-2R13, CO2R13, OR13, CONR15R13, NR15R13, halogen, CN, SO2NR15R13 or NO2, and for each case of N(R11)2 the R11 groups are the same or different or N(R11)2 is heterocycloalkyl optionally substituted with a substituent selected from the group consisting of R13, COR13, SO0-2R13, CO2R13, OR13, CONR15R13, NR15R13, halogen, CN, SO2R15R13, and NO2;
- R12 is selected from the group consisting of COR11, CON(R11)2, CO2R13, and SO2R13;
- R13 is selected from the group consisting of C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, and C1-6 alkyl-heteroaryl;
- R14 is selected from the group consisting of OR11, COR11, CO2R15, CON(R11)2, NR11R12, S(O)0-2R13, SO2N(R11)2, halogen, CN, NO2, and cycloimidyl (optionally substituted with R15);
- and
- R15 is H or C1-6 alkyl;
- and salts, solvates, hydrates, N-oxides, protected amino, protected carboxy, and protected hydroxamic acid derivatives thereof.
16 more elements
A method for the treatment of a condition associated with matrix metalloproteinases or that is mediated by TNFα or enzymes involved in the shedding of L-selectin, CD23, the TNF receptors, IL-6 receptors, or IL-1 receptors, wherein said method comprises administration of an effective amount of a composition comprising a compound represented by formula (I):
- wherein
- n is 1-2;
- X is O or S(O)1-2;
- Y is OH or NHOH;
- W is CR3 or (when X is SO2) N;
- R1 is H or a substituent selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, heterocycloalkyl, C1-6 alkyl-heterocycloalkyl, cycloalkyl, and C1-6 alkyl-cycloalkyl, wherein said substitutent is optionally substituted with R14,
- R2 is H or C1-6 alkyl, or
- CR1R2 is a cycloalkyl or heterocycloalkyl ring, optionally substituted with R14 or a substituent (optionally substituted with R14) selected from the group consisting of C1-6 alkyl, aryl, C1-6 alkyl-aryl;
- R3, R4 and R5 are independently H or C1-6 alkyl, or R3 and R4 may together represent a bond;
- R6, R7, R8, and R9 are independently H, R10, or a group (optionally substituted with R10) selected from the group consisting of C1-6 alkyl, aryl, C1-6 alkyl-aryl, C1-6 alkyl-heteroaryl, heteroaryl, and heterocycloalkyl, or
- R6 and R7, R7 and R8, R8 and R9, or when n=1, R5 and R6, and the carbons to which they are independently attached may alternatively form an aryl, heteroaryl, cycloalkenyl or hetercycloalkenyl ring, wherein said ring is optionally substituted with R10 or R11;
- R10 is selected from the group consisting of C1-6 alkyl, halogen, CN, NO2, N(R11)2, OR11, COR11, CO2R15, CON(R11)2, C═NOR11, NR11R12, S(O)0-2R11, and SO2N(R11)2;
- R11 is selected from the group consisting of H, C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, cycloalkyl, C1-6 alkyl-cycloalkyl, heterocyloalkyl, and C1-6 alkyl-heterocycloalkyl, wherein said group is optionally substituted with R13, COR13, SO0-2R13, CO2R13, OR13, CONR15R13, NR15R13, halogen, CN, SO2NR15R13 or NO2, and for each case of N(R11)2 the R11 groups are the same or different or N(R11)2 is heterocycloalkyl optionally substituted with a substituent selected from the group consisting of R13, COR13, SO0-2R13, CO2R13, OR13, CONR15R13, NR15R13, halogen, CN, SO2R15R13, and NO2;
- R12 is selected from the group consisting of COR11, CON(R11)2, CO2R13, and SO2R13;
- R13 is selected from the group consisting of C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, and C1-6 alkyl-heteroaryl;
- R14 is selected from the group consisting of OR11, COR11, CO2R15, CON(R11)2, NR11R12, S(O)0-2R13, SO2N(R11)2, halogen, CN, NO2, and cycloimidyl (optionally substituted with R15);
- and
- R15 is H or C1-6 alkyl;
- and salts, solvates, hydrates, N-oxides, protected amino, protected carboxy, and protected hydroxamic acid derivatives thereof.
16 more elements
A compound, represented by formula (I):
- wherein
- n is 1-2;
- X is O or S(O)1-2;
- Y is NHOH;
- W is CR3 or (when X is SO2) N;
- R1 is H or a substituent selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, heterocycloalkyl, C1-6 alkyl-heterocycloalkyl, cycloalkyl, and C1-6 alkyl-cycloalkyl, wherein said substituent is optionally substituted with R14, and
- R2 is H or C1-6 alkyl, or
- CR1R2 is a cycloalkyl or heterocycloalkyl ring, optionally substituted with R14 or a substituent (optionally substituted with R14) selected from the group consisting of C1-6 alkyl, aryl, C1-6 alkyl-aryl;
- R3, R4 and R5 are independently H or C1-6 alkyl, or R3 and R4 may together represent a bond;
- R6, R7, R8, and R9 are independently H, R10, or a group (optionally substituted with R10) selected from the group consisting of C1-6 alkyl, aryl, C1-6 alkyl-aryl, C1-6 alkyl-heteroaryl, heteroaryl, and heterocycloalkyl, or
- R6 and R7, R7 and R8, R8 and R9, or when n=1, R5 and R6, and the carbons to which they are independently attached may alternatively form an aryl, heteroaryl, cycloalkenyl or hetercycloalkenyl ring, wherein said ring is optionally substituted with R10 or R11;
- R10 is selected from the group consisting of C1-6 alkyl, halogen, CN, NO2, N(R11)2, OR11, COR11, CO2R15, CON(R11)2, C═NOR11, NR11R12, S(O)0-2R11, and SO2N(R11)2;
- R11 is selected from the group consisting of H, C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, cycloalkyl, C1-6 alkyl-cycloalkyl, heterocyloalkyl, and C1-6 alkyl-heterocycloalkyl, wherein said group is optionally substituted with R13, COR13, SO0-2R13, CO2R13, OR13, CONR15R13, NR15R13, halogen, CN, SO2NR15R13 or NO2, and for each case of N(R11)2 the R11 groups are the same or different or N(R11)2 is heterocycloalkyl optionally substituted with a substituent selected from the group consisting of R13, COR13, SO0-2R13, CO2R13, OR13, CONR15R13, NR15R13, halogen, CN, SO2R15R13, and NO2;
- R12 is selected from the group consisting of COR11, CON(R11)2, CO2R13, and SO2R13;
- R13 is selected from the group consisting of C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, and C1-6 alkyl-heteroaryl;
- R14 is selected from the group consisting of OR11, COR11, CO2R15, CON(R11)2, NR11R12, S(O)0-2R13, SO2N(R11)2, halogen, CN, NO2, and cycloimidyl (optionally substituted with R15);
- and
- R15 is H or C1-6 alkyl;
- and salts, solvates, hydrates, N-oxides, protected amino, protected carboxy, and protected hydroxamic acid derivatives thereof.
16 more elements
A method for the treatment of a condition associated with matrix metalloproteinases or that is mediated by TNFα or enzymes involved in the shedding of L-selectin, CD23, the TNF receptors, IL-6 receptors, or IL-1 receptors, wherein said method comprises administration of an effective amount of a composition comprising a compound represented by formula (I):
- wherein
- n is 1-2;
- X is O or S(O)0-2;
- Y is NHOH;
- W is CR3 or (when X is SO2) N;
- R1 is H or a substituent selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, heterocycloalkyl, C1-6 alkyl-heterocycloalkyl, cycloalkyl, and C1-6 alkyl-cycloalkyl, wherein said substituent is optionally substituted with R14,
- R2 is H or C1-6 alkyl, or
- CR1R2 is a cycloalkyl or heterocycloalkyl ring, optionally substituted with R14 or a substituent (optionally substituted with R14) selected from the group consisting of C1-6 alkyl, aryl, C1-6 alkyl-aryl;
- R3, R4 and R5 are independently H or C1-6 alkyl, or R3 and R4 may together represent a bond;
- R6, R7, R8, and R9 are independently H, R10, or a group (optionally substituted with R10) selected from the group consisting of C1-6 alkyl, aryl, C1-6 alkyl-aryl, C1-6 alkyl-heteroaryl, heteroaryl, and heterocycloalkyl, or
- R6 and R7, R7 and R8, R8 and R9, or when n=1, R5 and R6, and the carbons to which they are independently attached may alternatively form an aryl, heteroaryl, cycloalkenyl or hetercycloalkenyl ring, wherein said ring is optionally substituted with R10 or R11;
- R10 is selected from the group consisting of C1-6 alkyl, Br, I, F, CN, NO2, N(R11)2, OR11, COR11, CO2R15, CON(R11)2, C═NOR11, NR11R12, S(O)0-2R11, and SO2N(R11)2;
- R11 is selected from the group consisting of H, C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, cycloalkyl, C1-6 alkyl-cycloalkyl, heterocyloalkyl, and C1-6 alkyl-heterocycloalkyl, wherein said group is optionally substituted with R13, COR13, SO0-2R13, CO2R13, OR13, CONR15R13, NR15R13, halogen, CN, SO2NR15R13 or NO2, and for each case of N(R11)2 the R11 groups are the same or different or N(R11)2 is heterocycloalkyl optionally substituted with a substituent selected from the group consisting of R13, COR13, SO0-2R13, CO2R13, OR13, CONR15R13, NR15R13, halogen, CN, SO2R15R13, and NO2;
- R12 is selected from the group consisting of COR11, CON(R11)2, CO2R13, and SO2R13;
- R13 is selected from the group consisting of C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, and C1-6 alkyl-heteroaryl;
- R14 is selected from the group consisting of OR11, COR11, CO2R15, CON(R11)2, NR11R12, S(O)0-2R13, SO2N(R11)2, halogen, CN, NO2, and cycloimidyl (optionally substituted with R15);
- and
- R15 is H or C1-6 alkyl;
- and salts, solvates, hydrates, N-oxides, protected amino, protected carboxy, and protected hydroxamic acid derivatives thereof.
16 more elements
Dependencies are inferred from the claim text.