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US 6,787,536 B2Granted
Hydroxamic acid derivatives
AssigneeDarwin Discovery, Ltd.
InventorsDuncan Robert Hannah, Hazel Joan Dyke, Andrew Sharpe, Andrew Douglas Baxter
Life of this patent
Estimating the term…
Abstract
The invention encompasses novel compounds which are inhibitors of matrix metalloproteinase, ADAM or ADAM-TS enzymes, and which are useful for the treatment of diseases mediated by those enzymes, including degenerative diseases and certain cancers.
Claims18
A compound of formula (I)
- wherein R2 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl or cycloalkyl (any of which may be optionally substituted with one or more substituents selected from R4, W and WR4);
- 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 chosen from R4, W and WR4);
- and
- A is a heterocyclic ring (attached to SO2 through a nitrogen atom) optionally substituted with R4;
- B is an aryl or heteroaryl ring, optionally substituted with one or more R5;
- D is an aryl or heteroaryl ring, optionally substituted with one or more R5, or a heterocyclic ring (attached through a carbon atom) optionally substituted with R4 at any available carbon atom or with R14 at any available nitrogen atom;
- provided that B and D are not both phenyl;
- R4 is OR6, COR10, CO2R9, CONR7R8, NR10R11, S(O)qR10, S(O)qNR7R8, CN, ═O or ═NOR10, provided that R4 is not ═O or NOR10 if a substituent on an aromatic ring;
- R5 is alkyl, cycloalkyl, CF3, OR6, COR10, S(O)qR10, CO2R9, CONR7R8, S(O)qNR7R8, halogen, NR10R11 or CN;
- R6 is H, alkyl, CF3, CHF2, CH2F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- R7 and R8, which may be the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, or R7 and R8 and the nitrogen to which they are attached together represent a heterocyclic ring;
- R9 is H, alkyl or cycloalkyl;
- 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 atom to which they are attached together represent a heterocyclic ring optionally substituted by R13;
- R12 or OR6 or R13;
- R13 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- R14 is H, alkyl or cycloalkyl
- q is O, 1 or 2;
- W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl;
- and
- X is —O—, —CO—, S(O)q—, —N(R10)—, or is absent;
- or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof.
23 more elements
A pharmaceutical composition, comprising a therapeutically effective amount of a compound of formula (I)
- wherein R2 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl or cycloalkyl (any of which may be optionally substituted with one or more substituents selected from R4, W and WR4);
- 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 substitients chosen from R4, W and WR4);
- A is a heterocyclic ring (attached to SO2 through a nitrogen atom) optionally substituted with R4;
- B is an aryl or heteroaryl ring, optionally substituted with one or more R5;
- D is an aryl or heteroaryl ring, optionally substituted with one or more R5, or a heterocyclic ring (attached through a carbon atom) optionally substituted with R4 at any available carbon atom or with R14 at any available nitrogen atom;
- provided that B and D are not both phenyl;
- R4 is OR6, COR10, CO2R9, CONR7R8, NR10R11, S(O)qR10, S(O)qNR7R8, CN, ═O or ═NOR10, provided that R4 is not ═O or NOR10 if a substituent on an aromatic ring;
- R5 is alkyl, cycloalkyl, CF3, OR6, COR10, S(O)qR10, CO2R9, CONR7R8, S(O)qNR7R8, halogen, NR10R11 or CN;
- R6 is H, alkyl, CF3, CHF2, CH2F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- R7 and R8, which may be the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, or R7 and R8 and the nitrogen to which they are attached together represent a heterocyclic ring;
- R9 is H, alkyl or cycloalkyl;
- 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 atom to which they are attached together represent a heterocyclic ring optionally substituted by R13;
- R12 or OR6 or R13;
- R13 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- R14 is H, alkyl or cycloalkyl
- q is O, 1 or 2;
- W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl;
- and
- X is —O—, —CO—, S(O)q—, —N(R10)—, or is absent;
- or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof;
- and a pharmaceutically-acceptable diluent or carrier.
23 more elements
A method for the treatment of asthma, wherein said method comprises administering to a patient in need of such treatment a compound of formula (I)
- wherein R2 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl or cycloalkyl (any of which may be optionally substituted with one or more substituents selected from R4, W and WR4);
- 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 substitients chosen from R4, W and WR4);
- A is a heterocyclic ring (attached to SO2 through a nitrogen atom) optionally substituted with R4;
- B is an aryl or heteroaryl ring, optionally substituted with one or more R5;
- D is an aryl or heteroaryl ring, optionally substituted with one or more R5, or a heterocyclic ring (attached through a carbon atom) optionally substituted with R4 at any available carbon atom or with R14 at any available nitrogen atom;
- provided that B and D are not both phenyl;
- R4 is OR6, COR10, CO2R9, CONR7R8, NR10R11, S(O)qR10, S(O)qNR7R8, CN, ═O or ═NOR10, provided that R4 is not ═O or NOR10 if a substituent on an aromatic ring;
- R5 is alkyl, cycloalkyl, CF3, OR6, COR10, S(O)qR10, CO2R9, CONR7R8, S(O)qNR7R8, halogen, NR10R11 or CN;
- R6 is H, alkyl, CF3, CHF2, CH2F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- R7 and R8, which may be the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, or R7 and R8 and the nitrogen to which they are attached together represent a heterocyclic ring;
- R9 is H, alkyl or cycloalkyl;
- 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 atom to which they are attached together represent a heterocyclic ring optionally substituted by R13;
- R12 or OR6 or R13;
- R13 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
- R14 is H, alkyl or cycloalkyl
- q is O, 1 or 2;
- W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl;
- and
- X is —O—, —CO—, S(O)q—, —N(R10)—, or is absent;
- or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof.
22 more elements
Dependencies are inferred from the claim text.