6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives, addition salts thereof, and processes for the preparation of both

• US 6,348,461 B1
• Filed: 03/01/2000
• Issued: 02/19/2002
• Est. Priority Date: 09/01/1997
• Status: Expired due to Fees

• Current Assignee: Kyorin Pharmaceutical Company Limited (Kyorin Holdings Incorporated)
• Original Assignee: Kyorin Pharmaceutical Company Limited (Kyorin Holdings Incorporated)
• Inventors: Takadoi, Masanori, Ando, Naoki, Uda, Junichiro, Uchiki, Hideharu, Shiga, Futoshi, Takano, Yasuo, Anraku, Tsuyoshi, Asano, Jun, Fukuchi, Kazunori
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): LIU, HONG
• Application Number:
  US09/485,716
• Time in Patent Office: 720 Days
• Field of Search: 544/354, 544/119, 544/333, 514/249, 514/235.2, 514/232.5
• US Class Current: 514/232.5
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 241/44 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The present invention provides 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compounds and their addition salts, and processes for preparing them, which have antagonism against excitatory amino acid receptors, in particular, an AMPA receptor. The 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compounds and their addition salts of the present invention are represented by formula (1)

wherein Q, R, R¹ and R² are as described in the specification.

Claims

1. A 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compound represented by formula (1-a)

wherein, L denotes formula (4)

(wherein V denotes a single bond, a lower alkylene group or a lower alkenylene group, T denotes a phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydroxyl group, a thiol group, a substituted or unsubstituted amino group, a lower alkoxycarbonyl group, a carboxyl group, an aldehyde group, formula (4-a)

or formula (4-b)

(wherein U denotes an oxygen atom or sulfur atom, X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R³ denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group), or formula (4-c)

(wherein X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R⁴ and R⁵ are identical or different, and each independently denote an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group), ring B denotes a saturated or unsaturated heterocycle and its condensed ring (each of which may have one or more substituents on the heterocycle or its condensed ring) and which may additionally contain one or two oxygen, nitrogen or sulfur atoms, and m denotes 0 or 1);

A denotes a single bond, a lower alkylene group or a lower alkenylene group,

R¹ denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle or its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R² denotes a hydroxyl group, a lower alkoxy group, or formula (6)

 

(wherein R⁸ and R⁹ are identical or different and each independently denote an aralkyl group, a phenyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, or R⁸ and R⁹ may form a ring (wherein said ring may additionally contain one or two heteroatoms) together with a nitrogen atom, or either of R⁸ and R⁹ denotes a hydrogen atom while the other denotes a phenyloxy group or an aralkyloxy group (each of which may have one or more substituents on the aromatic ring), a hydroxyl group or a lower alkoxy group), and their addition salts.

5. The 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compound of claim 1 represented by formula (9)

wherein, V denotes a single bond, a lower alkylene group or a lower alkenylene group, T denotes a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on aromatic ring or heterocycle), a hydroxyl group, a thiol group, a substituted or unsubstituted amino group, a lower alkoxycarbonyl group, a carboxyl group or an aldehyde group, formula (4-a),

or formula (4-b)

(wherein U denotes an oxygen atom or sulfur atom, X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R³ denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group), or formula (4-c)

(wherein X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on aromatic ring or heterocycle), a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R⁴ and R⁵ are identical or different and each independently denote an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl groups which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl groups);

A denotes a single bond, a lower alkylene group or a lower alkenylene group,

R denotes a nitro group, a trifluoromethyl group, a substituted or unsubstituted amino group, or formula (7)

 

(wherein R¹⁰ and R¹¹ are identical or different and each independently denote an aralkyl group, a phenyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, or R¹⁰ and R¹¹ may form a ring (wherein said ring may additionally contain one or two heteroatoms) together with a nitrogen atom, and n denotes 1 to

     2),

R¹ denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group,

R² denotes a hydroxyl group, a lower alkoxy group, or formula (6)

 

(wherein R⁸ and R⁹ are identical or different and each independently denote an aralkyl group, a phenyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, or R⁸ and R⁹ may form a ring (wherein said ring may additionally contain one or two heteroatoms) together with a nitrogen atom, or either of R⁸ and R⁹ denotes a hydrogen atom while the other denotes a phenyloxy group or an aralkyloxy group (each of which may have one or more substituents on the aromatic ring), a hydroxyl group or a lower alkoxy group), and their addition salts.

6. The 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compound of claim 5 represented by formula (9)

wherein V denotes a single bond or a lower alkylene group,

A denotes a single bond or a lower alkylene group,

R denotes a nitro group, a trifluoromethyl group or a substituted or unsubstituted amino group,

R¹ denotes a hydrogen atom, and

R² denotes a hydroxyl group or a lower alkoxy group, and their addition salts.

7. The 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compound of claim 1, wherein the compound is 7-(3-(((4-carboxyphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-3,4-dihydro-3-oxo-6-trifluoromethylquinoxaline-2-carboxylic acid, and its addition salt.

8. The 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compound of claim 1, wherein the compound is 7-(4-(((4-carboxyphenyl)aminocarbonylamino)methyl)imidazole-1-yl)-3,4-dihydro-3-oxo-6-trifluoromethylquinoxaline-2-carboxylic acid, and its addition salt.

9. The 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compound of claim 1, wherein the compound is 7-(4-((N-(4-carboxyphenyl)carbamoyloxy)methyl)imidazole-1-yl)-3,4-dihydro-3-oxo-6-trifluoromethylquinoxaline-2-carboxylic acid, and its addition salt.

10. The 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compound of claim 1, wherein the compound is 7-(4-((N-(4-carboxyphenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid, and its addition salt.

2. A 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compound represented by formula (1-b)

wherein, L denotes formula (4)

(wherein V denotes a single bond, a lower alkylene group or a lower alkenylene group, T denotes a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydroxyl group, a thiol group, a substituted or unsubstituted amino group, a lower alkoxycarbonyl group, a carboxyl group, an aldehyde group, formula (4-a)

formula (4-b)

(wherein U denotes an oxygen atom or sulfur atom, X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R³ denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group), or formula (4-c)

(wherein X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R⁴ and R⁵ are identical or different and each independently denote an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group), ring B denotes a saturated or unsaturated heterocycle and its condensed ring (each of which may have one or more substituents on the heterocycle or its condensed ring) which may additionally contain one or two oxygen, nitrogen or sulfur atoms, and m denotes 0 or 1);

A denotes a single bond, a lower alkylene group or a lower alkenylene group,

R denotes a nitro group, a trifluoromethyl group, a substituted or unsubstituted amino group, or formula (7)

 

(wherein R¹⁰ and R¹¹ are identical or different and each independently denote an aralkyl group, a phenyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, or R¹⁰ and R¹¹ may form a ring (wherein said ring may additionally contain one or two heteroatoms) together with a nitrogen atom, and n denotes 1 to

     2),

R¹ denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R² denotes a hydroxyl group, a lower alkoxy group, formula (6)

 

(wherein R⁸ and R⁹ are identical or different and each independently denote an aralkyl group, a phenyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, or R⁸ and R⁹ may form a ring (wherein said ring may additionally contain one or two heteroatoms) together with a nitrogen atom, or either of R⁸ and R⁹ denotes a hydrogen atom while the other denotes a phenyloxy group or an aralkyloxy group (each of which may have one or more substituents on the aromatic ring), a hydroxyl group or a lower alkoxy group), and their addition salts.

3. A 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compound represented by formula (8)

wherein, V denotes a single bond, a lower alkylene group or a lower alkenylene group, T denotes a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydroxyl group, a thiol group, a substituted or unsubstituted amino group, a lower alkoxycarbonyl group, a carboxyl group or an aldehyde group, formula (4-a)

or formula (4-b)

(wherein U denotes an oxygen atom or sulfur atom, X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R³ denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group), or formula (4-c)

(wherein X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R⁴ and R⁵ are identical or different and each independently denote an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic rings or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group);

A denotes a single bond, a lower alkylene group or a lower alkenylene group,

R denotes a nitro group, a trifluoromethyl group, a substituted or unsubstituted amino group, or formula (7)

 

(wherein R¹⁰ and R¹¹ are identical or different and each independently denote an aralkyl group, a phenyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, or R¹⁰ and R¹¹ may form a ring (wherein said ring may additionally contain one or two heteroatoms) together with a nitrogen atom, and n denotes 1 to

     2),

Y denotes a nitrogen atom or ═

CH—

,

R¹ denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group,

R² denotes a hydroxyl group, a lower alkoxy group, or formula (6)

 

(wherein R⁸ and R⁹ are identical or different and each independently denote an aralkyl group, a phenyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, or R⁸ and R⁹ may form a ring (wherein said ring may additionally contain one or two heteroatoms) together with a nitrogen atom, or either of R⁸ and R⁹ denotes a hydrogen atom while the other denotes a phenyloxy group or an aralkyloxy group (each of which may have one or more substituents on the aromatic ring), a hydroxyl group or a lower alkoxy group), and their addition salts.

4. The 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compound of claim 3 represented by formula (8)

wherein

V denotes a single bond or a lower alkylene group,

A denotes a single bond or a lower alkylene group,

Y denotes a nitrogen atom or ═ CH—

,

R denotes a nitro group, a trifluoromethyl group or a substituted or unsubstituted amino group,

R¹ denotes a hydrogen atom, and

R² denotes a hydroxyl group or a lower alkoxy group, and their addition salts.

11. A composition comprising one or more 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives represented by formula (1-a)

wherein, L denotes a formula (4)

(wherein V denotes a single bond, a lower alkylene group or a lower alkenylene group, T denotes a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydroxyl group, a thiol group, a substituted or unsubstituted amino group, a lower alkoxycarbonyl group, a carboxyl group or an aldehyde group, formula (4-a)

or formula (4-b)

(wherein U denotes an oxygen atom or sulfur atom, X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R³ denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group), or formula (4-c)

(wherein X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R⁴ and R⁵ are identical or different and each independently denote an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group), ring B denotes a saturated or unsaturated heterocycle and its condensed ring (each of which may have one or more substituents on the heterocycle or condensed ring) which may additionally contain one or two oxygen, nitrogen or sulfur atoms, and m denotes 0 or 1);

A denotes a single bond, a lower alkylene group or a lower alkenylene group,

R¹ denotes an aralkyl group, a phenyl group, a naphthyl group, 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and

R² denotes a hydroxyl group, a lower alkoxy group or formula (6)

 

(wherein R⁸ and R⁹ are identical or different and each independently denote an aralkyl group, a phenyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, or R⁸ and R⁹ may form a ring (wherein said ring may additionally contain one or two heteroatoms) together with a nitrogen atom, or either of R⁸ and R⁹ denotes a hydrogen atom while the other denotes a phenyloxy group or an aralkyloxy group (each of which may have one or more substituents on the aromatic ring), a hydroxyl group or a lower alkoxy group), and their addition salts as effective ingredients.

12. A composition comprising one or more 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives represented by formula (1-b)

wherein, L denotes a formula (4)

(wherein V denotes a single bond, a lower alkylene group or lower alkenylene group, T denotes a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydroxyl group, a thiol group, a substituted or unsubstituted amino group, a lower alkoxycarbonyl group, a carboxyl group or an aldehyde group, formula (4-a)

or formula (4-b)

(wherein U denotes an oxygen atom or sulfur atom, X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R³ denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group), or formula (4-c)

(wherein X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and R⁴ and R⁵ are identical or different and each independently denote an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group), ring B denotes a saturated or unsaturated heterocycle and its condensed ring (each of which may have one or more substituents on the heterocycle or its condensed ring) which may additionally contain one or two oxygen, nitrogen or sulfur atoms, and m denotes 0 or 1);

A denotes a single bond, a lower alkylene group or a lower alkenylene group,

R denotes a nitro group, a trifluoromethyl group, a substituted or unsubstituted amino group, or formula (7)

 

(wherein R¹⁰ and R¹¹ are identical or different and each independently denote an aralkyl group, a phenyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, or R¹⁰ and R¹¹ may form a ring (wherein said ring may additionally contain one or two heteroatoms) together with a nitrogen atom, and n denotes 1 to

     2),

R¹ denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, and

R² denotes a hydroxyl group, a lower alkoxy group, or formula (6)

 

(wherein R⁸ and R⁹ are identical or different and each independently denote an aralkyl group, a phenyl group, a 5- or 6-membered heterocycle and its condensed ring (each of which may have one or more substituents on the aromatic ring or heterocycle), a hydrogen atom, a lower alkyl group which may be unsubstituted or substituted with at least one halogen atom or a cycloalkyl group, or R⁸ and R⁹ may form a ring (wherein said ring may additionally contain one or two heteroatoms) together with a nitrogen atom, or either of R⁸ and R⁹ denotes a hydrogen atom while the other denotes a phenyloxy group or an aralkyloxy group (each of which may have one or more substituents on the aromatic ring), a hydroxyl group or a lower alkoxy group), and their addition salts as effective ingredients.