Amide derivative and use thereof as medicine

1. An amide derivative represented by formula (I)

wherein A is a 5-membered heteroarylene containing 1-3 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom or phenylene or a 6-membered heteroarylene represented by the formula

wherein Z 4 , Z 5 , Z 6 and Z 7 are each a carbon atom or a nitrogen atom,

the phenylene and heteroarylene are optionally substituted by one or the same or different 2 or 3 substituents selected from a halogen atom; a hydroxyl group; nitro; cyano; mercapto; C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 2 -C 6 alkenyl; C 2 C 6 alkynyl; C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group or amino; C 6 -C 10 aryl optionally substituted by substituent B shown below; heteroaryl containing 1 -6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5 -10 ring-constituting atoms, which is optionally substituted by substituent B shown below; C 1 -C 6 alkoxy optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 2 -C 7 acyloxy; C 1 -C 6 alkylthio wherein the alkyl moiety is optionally substituted by a halogen atom or a hydroxyl group; C 1 -C 6 alkylsulfinyl wherein the alkyl moiety is optionally substituted by a halogen atom or a hydroxyl group; C 1 -C 6 alkylsulfonyl wherein the alkyl moiety is optionally substituted by a halogen atom or a hydroxyl group; C 3 -C 6 cycloalkylthio; C 3 -C 6 cycloalkylsulfinyl; C 3 -C 6 cycloalkylsulfonyl; amino optionally mono- or di-substituted by C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; C 2 -C 7 acylamino wherein the amino moiety is optionally substituted by C 1 - C 6 alkyl; aminocarbonyl wherein the amino moiety is optionally mono- or di-substituted by C 1 -C 6 alkyl (wherein C 1 -C 6 alkyl is optionally substituted by a halogen atom, a hydroxyl group, cyano, C 1 -C 6 alkoxy, amino optionally mono- or di-substituted by C 1 -C 6 alkyl, C 6 -C 10 aryl optionally substituted by substituent B shown below or heteroaryl containing 1-6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5-10 ring-constituting atoms, which is optionally substituted by substituent B shown below), C 3 -C 6 cycloalkyl (wherein C 3 -C 6 cycloalkyl is optionally substituted by substituent B shown below), C 2 -C 7 alkoxycarbonyl, C 6 -C 10 aryl optionally substituted by substituent B shown below, heteroaryl containing 1-6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5-10 ring-constituting atoms, which is optionally substituted by substituent B shown below, or a nonaromatic heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 3-7 ring-constituting atoms, which is optionally substituted by substituent B shown below; C 1 -C 6 alkylsulfonylamino wherein the amino moiety is optionally substituted by C 1 -C 6 alkyl; C 3 -C 6 cycloalkylsulfonylamino wherein the amino moiety is optionally substituted by C 1 -C 6 alkyl; a nonaromatic heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3-7 ring-constituting atoms, which is optionally substituted by a halogen atom, a hydroxyl group, oxo, dioxo, C 1 -C 6 alkyl (which is optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group, C 1 -C 6 alkoxy, arylalkyl wherein the C 6 -C 10 aryl moiety is optionally substituted by substituent B shown below and the alkyl moiety has 1-6 carbon atoms, arylalkyloxy wherein the C 6 -C 10 aryl moiety is optionally substituted by substituent B shown below and the alkyl moiety has 1-6 carbon atoms, heteroarylalkyl wherein the heteroaryl moiety containing 1-6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 5-10 ring-constituting atoms is optionally substituted by substituent B shown below and the alkyl moiety has 1-6 carbon atoms or heteroarylalkyloxy wherein the heteroaryl moiety containing 1-6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 5-10 ring-constituting atoms is optionally substituted by substituent B shown below and the alkyl moiety has 1-6 carbon atoms), C 1 -C 6 alkoxy (which is optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy) or C 2 -C 7 acyl; carbonyl substituted by a nonaromatic heterocyclic group containing at least one nitrogen atom and 0-3 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3-7 ring-constituting atoms, which is optionally substituted by substituent B shown below (wherein the carbonyl is bonded to a nitrogen atom on a nonaromatic heterocyclic group); and R′—NH—CO—NH— (wherein R′ is C 1 -C 6 alkyl optionally substituted by a halogen atom; C 3 -C 6 cycloalkyl optionally substituted by a halogen atom; a nonaromatic heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3-7 ring-constituting atoms, which is optionally substituted by a halogen atom; C 6 -C 10 aryl optionally substituted by substituent B shown below; or heteroaryl containing 1-6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5-10 ring-constituting atoms, which is optionally substituted by substituent B shown below), the right bond is bonded to carbonyl, and the left bond is bonded to substituent W,

R 1 is a hydroxyl group; cyano; C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group or amino; C 6 -C 10 aryl optionally substituted by substituent B shown below; heteroaryl containing 1-6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5-10 ring-constituting atoms, which is optionally substituted by substituent B shown below; C 1 -C 6 alkoxy optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 2 -C 7 alkoxycarbonyl; carboxy; C 1 -C 6 alkylthio wherein the alkyl moiety is optionally substituted by a halogen atom or a hydroxyl group; C 1 -C 6 alkylsulfinyl wherein the alkyl moiety is optionally substituted by a halogen atom or a hydroxyl group; C 1 -C 6 alkylsulfonyl wherein the alkyl moiety is optionally substituted by a halogen atom or a hydroxyl group; amino optionally mono- or di-substituted by C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; C 2 -C 7 acylamino wherein the amino moiety is optionally substituted by C 1 -C 6 alkyl; C 1 -C 6 alkylsulfonylamino wherein the amino moiety is optionally substituted by C 1 -C 6 alkyl; or C 3 -C 6 cycloalkylsulfonylamino wherein the amino moiety is optionally substituted by C 1 -C 6 alkyl,

R 2 is a halogen atom; a hydroxyl group; nitro; cyano; C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group or amino; C 6 -C 10 aryl optionally substituted by substituent B shown below; heteroaryl containing 1-6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5-10 ring-constituting atoms, which is optionally substituted by substituent B shown below; C 1 -C 6 alkylthio wherein the alkyl moiety is optionally substituted by a halogen atom or a hydroxyl group; C 1 -C 6 alkylsulfinyl wherein the alkyl moiety is optionally substituted by a halogen atom or a hydroxyl group; C 1 -C 6 alkylsulfonyl wherein the alkyl moiety is optionally substituted by a halogen atom or a hydroxyl group; amino optionally mono- or di-substituted by C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; C 2 -C 7 acylamino wherein the amino moiety is optionally substituted by C 1 -C 6 alkyl; C 1 -C 6 alkylsulfonylamino wherein the amino moiety is optionally substituted by C 1 -C 6 alkyl; or C 3 -C 6 cycloalkylsulfonylamino wherein the amino moiety is optionally substituted by C 1 -C 6 alkyl,

R 3 is a hydrogen atom; a halogen atom; a hydroxyl group; nitro; cyano; C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group or amino; C 1 -C 6 alkoxy optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 2 -C 7 alkoxycarbonyl; or carboxy,

R 4a , R 4b and R 4c are the same or different and each is a hydrogen atom, C 1 -C 6 alkyl, oxo or C 1 -C 6 alkoxy,

W is a bond, C 1 -C 6 alkylene or C 3 -C 6 cycloalkylidene,

X is a carbon atom (any of R 4a , R 4b and R 4C may be bonded to the carbon atom, but the carbon atom is not substituted by oxo) or a nitrogen atom (when Y is a bond, the nitrogen atom may be oxidized to form N-oxide),

Y is a bond, carbonyl, C 1 -C 6 alkylene, an oxygen atom or —NH—,

m is 1or 2,

Z 1 , Z 2 and Z 3 are the same or different and each is a carbon atom or a nitrogen atom, wherein Z 1 , Z 2 and Z 3 are not nitrogen atoms at the same time,

R a and R b , together with the adjacent nitrogen atom, form a nitrogen-containing cyclic group selected from

which is optionally substituted with C 1 -C 6 alkoxy, oxo, or C 1 -C 6 alkyl optionally substituted with a hydroxyl group,

when the formula (I) is

then R 1 and R 2 are not methyl groups at the same time, and

wherein substituent B is

a halogen atom; a hydroxyl group; cyano; C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group or amino; C 1 -C 6 alkoxy optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; amino optionally mono- or di-substituted by C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; aminocarbonyl wherein the amino moiety is optionally mono- or di-substituted by C 1 -C 6 alkyl or C 3 C 6 cycloalkyl; or carbonyl which is substituted by a nonaromatic heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 3-7 ring-constituting atoms and optionally substituted by a halogen atom, a hydroxyl group, oxo, dioxo, C 1 -C 6 alkyl or C 1 -C 6 alkoxy,

or a pharmacologically acceptable salt thereof.

2. The amide derivative according to claim 1 , wherein X is a nitrogen atom or N-oxide wherein nitrogen atom is oxidized and Y is a bond, or a pharmacologically acceptable salt thereof.

3. The amide derivative according to claim 1 , wherein A is 5-membered heteroarylene containing 1-3 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or phenylene or 6-membered heteroarylene represented by the formula

wherein Z 4 , Z 5 , Z 6 and Z 7 are each a carbon atom or a nitrogen atom,

the phenylene and heteroarylene are optionally substituted by one or the same or different 2 or 3 substituents selected from

a halogen atom; a hydroxyl group; nitro; cyano; mercapto; C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group or amino; C 6 -C 10 aryl optionally substituted by substituent B shown below; heteroaryl containing 1-6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5-10 ring-constituting atoms, which is optionally substituted by substituent B shown below; C 1 -C 6 alkoxy optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 2 -C 7 acyloxy; C 1 -C 6 alkylthio wherein the alkyl moiety is optionally substituted by a halogen atom or a hydroxyl group; C 1 -C 6 alkylsulfinyl wherein the alkyl moiety is optionally substituted by a halogen atom or a hydroxyl group; C 1 -C 6 alkylsulfonyl wherein the alkyl moiety is optionally substituted by a halogen atom or a hydroxyl group; C 3 -C 6 cycloalkylthio; C 3 -C 6 cycloalkylsulfinyl; C 3 -C 6 cycloalkylsulfonyl; amino optionally mono- or di-substituted by C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; C 2 -C 7 acylamino wherein the amino moiety is optionally substituted by C 1 -C 6 alkyl; aminocarbonyl wherein the amino moiety is optionally mono- or di-substituted by C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; C 1 -C 6 alkylsulfonylamino wherein the amino moiety is optionally substituted by C 1 -C 6 alkyl; C 3 -C 6 cycloalkylsulfonylamino wherein the amino moiety is optionally substituted by C 1 -C 6 alkyl; a nonaromatic heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3-7 ring-constituting atoms, which is optionally substituted by a halogen atom, a hydroxyl group, oxo, dioxo, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; and R′ —NH—CO—NH— (wherein R′ is C 1 -C 6 alkyl optionally substituted by a halogen atom; C 3 -C 6 cycloalkyl optionally substituted by a halogen atom; a nonaromatic heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3-7 ring-constituting atoms, which is optionally substituted by a halogen atom; C 6 -C 10 aryl optionally substituted by substituent B shown below; or heteroaryl containing 1-6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5-10 ring-constituting atoms, which is optionally substituted by substituent B shown below, the right bond is bonded to carbonyl, and the left bond is bonded to substituent W, and

wherein substituent B is

a halogen atom; a hydroxyl group; cyano; C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group or amino; C 1 -C 6 alkoxy optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; amino optionally mono- or di-substituted by C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; aminocarbonyl wherein the amino moiety is optionally mono- or di-substituted by C 1 -C 6 alkyl or C 3 C 6 cycloalkyl; or carbonyl which is substituted by a nonaromatic heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 3-7 ring-constituting atoms and optionally substituted by a halogen atom, a hydroxyl group, oxo, dioxo, C 1 -C 6 alkyl or C 1 -C 6 alkoxy,

or a pharmacologically acceptable salt thereof.

4. The amide derivative according to claim 1 , wherein A is phenylene or 6-membered heteroarylene, or a pharmacologically acceptable salt thereof.

5. The amide derivative according to claim 1 , wherein W is a bond, or a pharmacologically acceptable salt thereof.

6. The amide derivative according to claim 1 , wherein Z 2 and Z 3 are carbon atoms, or a pharmacologically acceptable salt thereof.

7. The amide derivative according to claim 1 , wherein R 1 is C 1 -C 6 alkyl optionally substituted by a halogen atom; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group or amino,

R 2 is C 1 -C 6 alkyl optionally substituted by a halogen atom; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group or amino, and

R 3 is a hydrogen atom; a halogen atom; C 1 -C 6 alkyl optionally substituted by a halogen atom; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group or amino, or a pharmacologically acceptable salt thereof.

8. The amide derivative according to claim 1 , wherein R 4a ,R 4b and R 4c are hydrogen atoms, or a pharmacologically acceptable salt thereof.

9. [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl][4-(1,1-dioxo-1λ 6 -isothiazolidin-2-yl)-2-fluorophenyl]methanone,

[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(1,1-dioxo-1λ 6 -isothiazolidin-2-yl)-2-methylpyridin-3-yl]methanone,

1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}imidazolidin-2-one, or

1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-3,5-dimethylimidazolidine-2,4-dione.

10. A pharmaceutical composition comprising the amide derivative according to claim 1 , or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable additive.

11. A method of suppressing MMP-9 production in a mammal, comprising administering an effective amount of the amide derivative according to claim 1 , or a pharmacologically acceptable salt thereof to the mammal, thereby suppressing MMP-9 production in the mammal.

12. A method of treating osteoarthritis, comprising administering an effective amount of the amide derivative according to claim 1 , or a pharmacologically acceptable salt thereof to the mammal, thereby treating osteoarthritis in the mammal.

13. A method of treating an autoimmune disease in a mammal, wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis or systemic lupus erythematosus, comprising administering an effective amount of the amide derivative according to claim 1 , or a pharmacologically acceptable salt thereof to the mammal, thereby treating the autoimmune disease in the mammal.

14. A method of treating an inflammatory bowel disease in a mammal, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis, comprising administering an effective amount of the amide derivative according to claim 1 , or a pharmacologically acceptable salt thereof to the mammal, thereby treating the inflammatory bowel disease in the mammal.