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US 2004/0176362 A1Published application
Hydroxamic and carboxylic acid derivatives
OwnerDuncan Batty, Verity Margaret Sabin +6inventors
InventorsDuncan Batty, Verity Margaret Sabin, Robert John Watson, Hazel Joan Dyke, Andrew Sharpe, Richard John Davenport, David Alan Owen, Andrew Douglas Baxter
Life of this patent
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Abstract
The invention relates to hydroxamic and carboxylic acid derivatives. Compounds of the formula: 1 are disclosed. These compounds are useful for the treatment of diseases mediated by inhibitors of matrix metalloproteinase, ADAM, ADAM-TS enzymes, and/or TNFα-mediated diseases including degenerative diseases and certain cancers.
Claims15
A compound of formula (I)
- 7
- wherein
- R1 is the OH or NHOH;
- R2 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo or heterocycloalkyl (any of which may be optionally substituted with one or more substituents selected from R6, W and WR6);
- and
- R3 is H or alkyl;
- or R2, R3 and the carbon atom to which they are attached together represent a carbocyclic or heterocyclic ring (either of which may be substituted with one or more substituents selected from R6, W and WR6);
- R4 is alkyl, cycloalkyl, OR9, CO2R14, COR10, S(O)qR10 where q is 0, 1 or 2, CONR7R8, CN or S(O)qNR7R8, two R4 substituents may be attached to the same carbon atom to form C(R4)2, where each R4 is the same or different, or C(R4)2 may represent C═O;
- R5 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, CF3, OR9, CO2R10, S(O)qR10, CO2R14, CONR7R8, S(O)qNR7R8, halogen, NR10R11 or CN, or two adjacent R5 substituents may be combined to form a heterocyclic ring;
- R6 is OR9, COR10, CO2R15, CONR7R8, NR10R11, S(O)qR10, S(O)qNR7R8, ═O, ═NOR10, succinimido or the group
- 8
- R7 and R8, which may the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl, or R7 and R8 and the nitrogen to which they are attached together represent a heterocyclic ring;
- R9 is H, alkyl, CF3, CHF2, CH2F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- R10 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- and
- R11 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR12, CONR7R8, S(O)qR12 or S(O)qNR7R8;
- or R10 and R11 and the nitrogen to which they are attached together represent a heterocyclic ring;
- R12 is OR9 or R13;
- R13 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- R14 is H, alkyl or cycloalkyl;
- R15 is H, alkyl, cycloalkyl, arylalkyl or heteroarylalkyl;
- X is a bond (i.e. is absent), —O—, —C(O)—, —S(O)q—, —N(R11)—, —N(R11)C(R16)2—, —S(O)qC(R16)2—, —C(R6)2N(R1 I)_, C(R16)2S(O)q—, —C(R16)═N—, —N═C(R16)—, —N(R11)SO2—, —SO2N(R11)—, —N(R11)CO— or —CON(R11)—;
- and the R16 groups in C(R16)2 may be the same or different;
- Y is a bond (i.e. is absent), —O—, —C(O)—, —S(O)q—, —N(R11)—, —N(R11)C(R16)2—, —S(O)qC(R16)2—, —C(R16)2N(R11)—, C(R16)2S(O)q—, —C(R16)═N—, —N═C(R16)_, N(R11 1)SO2—, SO2N(R11)—, —N(R11)CO— or —CON(R11)—;
- and the R16 groups in C(R16)2 may be the same or different;
- R16 is H, alkyl, cycloalkyl, OR9, CO2R14, COR10, S(O)qR10, CONR7R8, CN or S(O)qNR7R8;
- R17 is H or alkyl;
- W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl;
- represents a single or double bond;
- each k and m is independently 0, 1, 2 or 3;
- n is 0, 1 or 2;
- and
- p is 0, 1 or 2, provided that n+p does not exceed 3;
- or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid thereof.
31 more elements
A pharmaceutical composition for use in therapy, comprising a compound of formula (I)
- 9
- wherein
- R1 is the OH or NHOH;
- R2 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo or heterocycloalkyl (any of which may be optionally substituted with one or more substituents selected from R6, W and WR6);
- and
- R3 is H or alkyl;
- or R2, R3 and the carbon atom to which they are attached together represent a carbocyclic or heterocyclic ring (either of which may be substituted with one or more substituents selected from R6, W and WR6);
- R4 is alkyl, cycloalkyl, OR9, CO2R14, COR10, S(O)qR10 where q is 0, 1 or 2, CONR7R8, CN or S(O)qNR7R8;
- two R4 substituents may be attached to the same carbon atom to form C(R4)2, where each R4 is the same or different, or C(R4)2 may represent C═O;
- R5 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, CF3, OR9, COR10, S(O)qR10, CO2R4, CONR7R8, S(O)qNR7R8, halogen, NR10R11 or CN, or two adjacent R5 substituents may be combined to form a heterocyclic ring;
- R6 is OR9, COR10, CO2R15, CONR7R8, NR10R11, S(O)qR10, S(O)qNR7R8, ═O, ═NOR10, succinimido or the group
- 10
- R7 and R8, which may the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl, or R7 and R8 and the nitrogen to which they are attached together represent a heterocyclic ring;
- R9 is H, alkyl, CF3, CHF2, CH2F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- R9 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- and
- R11 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR12, CONR7R8, S(O)qR12 or S(O)qNR7R8;
- or R10 and R11 and the nitrogen to which they are attached together represent a heterocyclic ring;
- R12 is OR9 or R13;
- R13 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- R14 is H, alkyl or cycloalkyl;
- R15 is H, alkyl, cycloalkyl, arylalkyl or heteroarylalkyl;
- X is a bond (i.e. is absent), —O—, —C(O)—, —S(O)q—, —N(R11)—, —N(R1)C(R16)2—, —S(O)qC(R16)2—, C(R16)2N(R11)—, C(R16)2S(O)q—, —C(R6)═N—, —N═C(R16)—, —N(R11)SO2—, —SO2N(R11)—, —N(R11)CO— or —CON(R11)—;
- and the R16 groups in C(R16)2 may be the same or different;
- Y is a bond (i.e. is absent), —O—, —C(O)—, —S(O)q—, —N(R11)—, —N(R11)C(R16)2—, —S(O)qC(R16)2—, —C(R16)2N(R11)—, —C(R16)2S(O)q—, —C(R116)═N—, —N═C(R16)—, N(R11)SO2—, SO2N(R11)—, —N(R11)CO— or —CON(R11)—;
- and the R16 groups in C(R16)2 may be the same or different;
- R16 is H, alkyl, cycloalkyl, OR9, CO2R14, COR10, S(O)qR10, CONR7R8, CN or S(O)qNR7R8;
- R17 is H or alkyl;
- W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl;
- =represents a single or double bond;
- each k and m is independently 0, 1, 2 or 3;
- n is 0, 1 or 2;
- and
- p is 0, 1 or 2, provided that n+p does not exceed 3;
- or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid thereof;
- and a pharmaceutically-acceptable diluent or carrier.
33 more elements
A method for the treatment of cancer;
- inflamation;
- or an autoimmune, infectious or ocular disease;
- wherein said method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I)
- 11
- wherein
- R1 is the OH or NHOH;
- R2 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo or heterocycloalkyl (any of which may be optionally substituted with one or more substituents selected from R6, W and WR6);
- and
- R3 is H or alkyl;
- or R2, R3 and the carbon atom to which they are attached together represent a carbocyclic or, heterocyclic ring (either of which may be substituted with one or more substituents selected from R6, W and WR6);
- R4 is alkyl, cycloalkyl, OR9, CO2R14, COR11, S(O)qR10 where q is 0, 1 or 2, CONR7R8, CN or S(O)qNR7R8;
- two R4 substituents may be attached to the same carbon atom to form C(R4)2, where each R4 is the same or different, or C(R4)2 may represent C═O;
- R5 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, CF3, OR9, COR10, S(O)qR11, CO2R14, CONR7R8, S(O)qNR7R8, halogen, NR10R11 or CN, or two adjacent R5 substituents may be combined to form a heterocyclic ring;
- R6 is OR9, COR10, CO2R15, CONR7R8, NRIOR11, S(O)qR10, S(O)qNR7R8, ═O, ═NOR10, succinimido or the group
- 12
- R7 and R8, which may the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl, or R7 and R8 and the nitrogen to which they are attached together represent a heterocyclic ring;
- R9 is H, alkyl, CF3, CHF2, CH2F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- R10 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- and
- R11 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR12, CONR7R8, S(O)qR12 or S(O)qNR7R8;
- or R10 and R11 and the nitrogen to which they are attached together represent a heterocyclic ring;
- R12 is OR9 or R13;
- R13 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- R14 is H, alkyl or cycloalkyl;
- R15 is H, alkyl, cycloalkyl, arylalkyl or heteroarylalkyl;
- X is a bond (i.e. is absent), —O—, —C(O)—, —S(O)q—, —N(R11)—, —N(R11)C(R16)2—, —S(O)qC(R16)2—, —C(R16)2N(R11)—, C(R16)2S(O)q—, —C(R16)═N—, —N═C(R16)_, —N(R11)SO2—, —SO2N(R11)—, —N(R11)CO— or —CON(R11)—;
- and the R16 groups in C(R16)2 may be the same or different;
- Y is a bond (i.e. is absent), —O—, —C(O)—, —S(O)q—, —N(R11)—, —N(R11)C(R16)2—, —S(O)qC(R16)2 —, —C(R16)2N(R11)—, —C(R16)2S(O)q—, —C(R16)═N—, —N═C(R16)—, N(R11)SO2—,
- SO2N(R11)—, —N(R11)CO— or —CON(R11)—;
- and the R16 groups in C(R16)2 may be the same or different;
- R16 is H, alkyl, cycloalkyl, OR9, CO2R14, COR10, S(O)qR10, CONR7R8, CN or S(O)qNR7R8;
- R17 is H or alkyl;
- W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl;
- represents a single or double bond;
- each k and m is independently 0, 1, 2 or 3;
- n is 0, 1 or 2;
- and
- p is 0, 1 or 2, provided that n+p does not exceed 3;
- or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid thereof.
36 more elements
Dependencies are inferred from the claim text.