5-substituted-2-phenylamino benzamides as MEK inhibitors

A method for treating a disease for which MEK inhibition is effective, wherein the method comprises administering to a patient in need of treatment for the disease a pharmaceutically effective dose of a composition that comprises as an active ingredient a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

• wherein
• R1 represents a halogen atom, an alkenyl group, or an alkynyl group;
• R2 represents a halogen atom or an alkyl group;
• the alkyl group is optionally substituted by a hydroxyl group;
• R3 represents a hydrogen atom or a halogen atom;
• R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group;
• the alkyl group, the alkenyl group, and the alkynyl group optionally have one to three substituents selected from the group consisting of —ORa, —NRaRb, —NRaCORb, a heterocyclic group, and a heteroaryl group;
• the heterocyclic group and the heteroaryl group optionally have one to three substituents selected from the group consisting of a C1-5 alkyl group, —ORa, and —NRaRb;
• X represents a group represented by the following formula (i):
• wherein
• Y represents —O—, —NR8O—, —ONR8—, —NR8CO—, or —NR8SO2—;
• Z represents a C1-8 alkylene chain which is optionally substituted by one to three groups represented by W′;
• where R8 represents a hydrogen atom, an alkyl group, —ORa, or —COR9;
• and the alkyl group is optionally substituted by a halogen atom, —ORa, or —NRaRb;
• R9 represents a hydrogen atom, an alkyl group, or —ORa;
• and the alkyl group is optionally substituted by a halogen atom, —ORa, or —NRaRb;
• R8 and R9 are optionally linked to the alkylene chain of Z or form a heterocyclic group through a linkage to the substituent represented by Ra or Rb of W,
• or alternatively,
• X represents a group represented by the following formula (ii):
• wherein
• Y1 and Y2, which may be the same or different, each represent a single bond, —CO—, —COO—, —O—, —OCO—, —NRa—, or —SO2—;
• Z′ represents a C1-5 alkylene chain which is optionally substituted by one to three groups represented by W′;
• wherein, in the above formulae (i) and (ii),
• W and W′, which may be the same or different, each represent a C1-5 alkyl group, a halogen atom, an oxo group, —ORa, —COORa, —COOCORa, —CO-halogen atom, —OCORa, —CONRaRb, —SRa, —SORa, —SO2Ra, —NRaRb, —NRaCORb, —NRaSO2Rb, —SO2NRaRb, a heterocyclic group, or a heteroaryl group;
• the heterocyclic group and the heteroaryl group optionally have a substituent selected from the group consisting of a C1-5 alkyl group, —ORa, and —NRaRb;
• the alkyl group is optionally substituted by a hydroxyl group, a C1-5 alkoxy group, or an amino group;
• the above substituents except the oxo group and the halogen atom are optionally linked to each other to form a cycloalkyl group or a heterocyclic group;
• the cycloalkyl group or the heterocyclic group optionally has a substituent selected from the group consisting of —ORa, —NRaRb, and a C1-5 alkyl group that is optionally substituted with —ORa;
• Ra and Rb, which may be the same or different, each represent a hydrogen atom or a C1-5 alkyl group;
• the alkyl group is optionally substituted by one to three groups selected from the group consisting of a hydroxyl group, a C1-5 alkoxy group, and an amino group;
• provided that, when X is the group represented by the above formula (i) and Y is not —O—, W is a hydrogen atom or any of the groups assigned to W defined above.

A method for treating a joint disorder with inflammation, wherein the method comprises administering to a patient in need of treatment for the joint disorder with inflammation a pharmaceutically effective dose of a composition that comprises as an active ingredient a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof

• wherein
• R1 represents a halogen atom, an alkenyl group, or an alkynyl group;
• R2 represents a halogen atom or an alkyl group;
• the alkyl group is optionally substituted by a hydroxyl group;
• R3 represents a hydrogen atom or a halogen atom;
• R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group;
• the alkyl group, the alkenyl group, and the alkynyl group optionally have one to three substituents selected from the group consisting of —ORa, —NRaRb, —NRaCORb, a heterocyclic group, and a heteroaryl group;
• the heterocyclic group and the heteroaryl group optionally have one to three substituents selected from the group consisting of a C1-5 alkyl group, —ORa, and —NRaRb;
• X represents a group represented by the following formula (i):
• wherein
• Y represents —O—, —NR8O—, —ONR8—, —NR8CO—, or —NR8SO2—;
• Z represents a C1-8 alkylene chain which is optionally substituted by one to three groups represented by W′;
• where R8 represents a hydrogen atom, an alkyl group, —ORa, or —COR9;
• and the alkyl group is optionally substituted by a halogen atom, —ORa, or —NRaRb;
• R9 represents a hydrogen atom, an alkyl group, or —ORa;
• and the alkyl group is optionally substituted by a halogen atom, —ORa, or —NRaRb;
• R8 and R9 are optionally linked to the alkylene chain of Z or form a heterocyclic group through a linkage to the substituent represented by Ra or Rb of W,
• or alternatively,
• X represents a group represented by the following formula (ii):
• wherein
• Y1 and Y2, which may be the same or different, each represent a single bond, —CO—, —COO—, —O—, —OCO—, —NRa—, or —SO2—;
• Z′ represents a C1-5 alkylene chain which is optionally substituted by one to three groups represented by W′;
• wherein, in the above formulae (i) and (ii),
• W and W′, which may be the same or different, each represent a C1-5 alkyl group, a halogen atom, an oxo group, —ORa, —COORa, —COOCORa, —CO-halogen atom, —OCORa, —CONRaRb, —SRa, —SORa, —SO2Ra, —NRaRb, —NRaCORb, —NRaSO2Rb, —SO2NRaRb, a heterocyclic group, or a heteroaryl group;
• the heterocyclic group and the heteroaryl group optionally have a substituent selected from the group consisting of a C1-5 alkyl group, —ORa, and —NRaRb;
• the alkyl group is optionally substituted by a hydroxyl group, a C1-5 alkoxy group, or an amino group;
• the above substituents except the oxo group and the halogen atom are optionally linked to each other to form a cycloalkyl group or a heterocyclic group;
• the cycloalkyl group or the heterocyclic group optionally has a substituent selected from the group consisting of —ORa, —NRaRb, and a C1-5 alkyl group that is optionally substituted with —ORa;
• Ra and Rb, which may be the same or different, each represent a hydrogen atom or a C1-5 alkyl group;
• the alkyl group is optionally substituted by one to three groups selected from the group consisting of a hydroxyl group, a C1-5 alkoxy group, and an amino group;
• provided that, when X is the group represented by the above formula (i) and Y is not —O—, W is a hydrogen atom or any of the groups assigned to W defined above.

A method for treating osteoarthritis or rheumatoid arthritis, wherein the method comprises administering to a patient who needs treatment for osteoarthritis or rheumatoid arthritis a pharmaceutically effective dose of a composition that comprises as an active ingredient a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

• wherein
• R1 represents a halogen atom, an alkenyl group, or an alkynyl group;
• R2 represents a halogen atom or an alkyl group;
• the alkyl group is optionally substituted by a hydroxyl group;
• R3 represents a hydrogen atom or a halogen atom;
• R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group;
• the alkyl group, the alkenyl group, and the alkynyl group optionally have one to three substituents selected from the group consisting of —ORa, —NRaRb, —NRaCORb, a heterocyclic group, and a heteroaryl group;
• the heterocyclic group and the heteroaryl group optionally have one to three substituents selected from the group consisting of a C1-5 alkyl group, —ORa, and —NRaRb;
• X represents a group represented by the following formula (i):
• wherein
• Y represents —O—, —NR8O—, —ONR8—, —NR8CO—, or —NR8SO2—;
• Z represents a C1-8 alkylene chain which is optionally substituted by one to three groups represented by W′;
• where R8 represents a hydrogen atom, an alkyl group, —ORa, or —COR9;
• and the alkyl group is optionally substituted by a halogen atom, —ORa, or —NRaRb;
• R9 represents a hydrogen atom, an alkyl group, or —ORa;
• and the alkyl group is optionally substituted by a halogen atom, —ORa, or —NRaRb;
• R8 and R9 are optionally linked to the alkylene chain of Z or form a heterocyclic group through a linkage to the substituent represented by Ra or Rb of W,
• or alternatively,
• X represents a group represented by the following formula (ii):
• wherein
• Y1 and Y2, which may be the same or different, each represent a single bond, —CO—, —COO—, —O—, —OCO—, —NRa—, or —SO2—;
• Z′ represents a C1-5 alkylene chain which is optionally substituted by one to three groups represented by W′;
• wherein, in the above formulae (i) and (ii),
• W and W′, which may be the same or different, each represent a C1-5 alkyl group, a halogen atom, an oxo group, —ORa, —COORa, —COOCORa, —CO-halogen atom, —OCORa, —CONRaRb, —SRa, —SORa, —SO2Ra, —NRaRb, —NRaCORb, —NRaSO2Rb, —SO2NRaRb, a heterocyclic group, or a heteroaryl group;
• the heterocyclic group and the heteroaryl group optionally have a substituent selected from the group consisting of a C1-5 alkyl group, —ORa, and —NRaRb;
• the alkyl group is optionally substituted by a hydroxyl group, a C1-5 alkoxy group, or an amino group;
• the above substituents except the oxo group and the halogen atom are optionally linked to each other to form a cycloalkyl group or a heterocyclic group;
• the cycloalkyl group or the heterocyclic group optionally has a substituent selected from the group consisting of —ORa, —NRaRb, and a C1-5 alkyl group that is optionally substituted with —ORa;
• Ra and Rb, which may be the same or different, each represent a hydrogen atom or a C1-5 alkyl group;
• the alkyl group is optionally substituted by one to three groups selected from the group consisting of a hydroxyl group, a C1-5 alkoxy group, and an amino group;
• provided that, when X is the group represented by the above formula (i) and Y is not —O—, W is a hydrogen atom or any of the groups assigned to W defined above.