Specific nad(p)h oxidase inhibitor

1 . An agent for inhibiting an excessive effect of NAD(P)H oxidase, which comprises a compound that does not substantially inhibit the effect of leukocyte NADPH oxidase but inhibits the effect of NAD(P)H oxidase in a tissue other than leukocyte.

2 . The agent of claim 1 , wherein the tissue other than leukocyte is a tissue of a vascular cell, the heart, the kidney, the retina, the microglia or a tumor cell.

3 . The agent of claim 1 , wherein the excessive effect of NAD(P)H oxidase is caused by diabetes, hypertension, hyperlipidemia, obesity, smoking, heart failure, cardiac hypertrophy, ischemic heart diseases, angioplasty or ischemia-reperfusion in organ transplantation.

4 . The agent of claim 1 , wherein the excessive effect of NAD(P)H oxidase is caused by cancer or dementia.

5 . The agent of claim 1 , wherein the excessive effect of NAD(P)H oxidase is caused by intake of chemicals.

6 . The agent of any one of claims 1 to 5 , wherein the compound that does not substantially affect leukocyte NADPH oxidase but inhibits an excessive effect of NAD(P)H oxidase in a tissue other than leukocyte is a bicyclic pyridazine compound represented by the following formulas (I) to (VIII) or a pharmacologically acceptable salt thereof:

wherein A is C 3 -C 6 alkyl, C 5 -C 7 cycloalkyl, or phenyl, thienyl, furyl, thiazolyl, phenoxy, C 7 -C 9 phenylalkyl, phenylthio, nitrogen-containing saturated ring group, pyridyl or imidazolyl, each optionally having one or more substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and halogen,

B is —NH—D

[D is

wherein R 1 is hydrogen or C 1 -C 4 alkyl, X is halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and k is an integer of 0 to 3, when k is an integer of 2 or more, multiple Xs may be the same or different,

wherein R 2 is hydrogen or C 1 -C 4 alkyl, Y is C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and m is an integer of 0 to 6, when m is 2 or more, multiple Ys may be the same or different, and any two Ys may be joined to form optionally branched C 1 -C 6 alkylene,

wherein ring H is C 5 -C 7 cycloalkyl, and Y and m are as defined above,

—CHR 3 R 4

wherein R 3 is C 1 -C 5 alkyl, and R 4 is C 5 -C 8 cycloalkyl or thienyl,

or C 3 -C 8 alkyl]

or

wherein Z is C 1 -C 4 alkyl or phenyl, and n is an integer of 0 to 2, when n is 2, these Zs may be the same or different, and

Q is a benzene ring, a furan ring or a thiophene ring optionally substituted by C 1 -C 4 alkyl,

wherein R 5 and R 6 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, cyano, nitro, amino, trifluoromethyl or carboxyl, and X′ is —COOR 7 (R 7 is hydrogen or optionally substituted C 1 -C 6 alkyl), —CONH 2 , —CN, —COR 8 (R 8 is optionally substituted C 1 -C 6 alkyl or optionally substituted aryl), —NH 2 ,

—NO 2 or —OR 7 (R 7 is as defined above),

wherein R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, cyano, nitro, amino, trifluoromethyl or carboxyl,

wherein R 11 and R 12 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, cyano, nitro, amino, trifluoromethyl or carboxyl, and X″ is —OR 13 (R 13 is hydrogen, C 1 -C 6 alkyl or aryl) or —NR 14 R 15 (R 14 and R 15 are each independently hydrogen, C 1 -C 6 alkyl or aryl,

wherein R 16 and R 17 are each independently hydrogen, C 1 -C 6 alkyl, alkoxy, halogen, cyano, nitro, amino, trifluoromethyl or carboxyl, R 18 and R 19 are each independently hydrogen or C 1 -C 6 alkyl, and Y′ is oxygen or sulfur.

7 . A pharmaceutical composition for the diseases caused by an excessive effect of NAD(P)H oxidase, which comprises the agent of claim 1 as an active ingredient.

8 . The pharmaceutical composition of claim 7 , which is administered simultaneously with a hypolipidemic agent, an antihypertensive agent, a hypoglycemic agent, a vasodilator, an antiplatelet agent, an anticoagulant, a brain protective agent, an anticancer agent, a diuretic agent, a cardiotonic agent, an analgesic agent, an antiedemic agent, a thrombolytic agent, an immunosuppressant, a steroid, a vitamin or an antioxidant, or administered separately therefrom, or administered sequentially therewith.

9 . The agent of claim 2 , wherein the excessive effect of NAD(P)H oxidase is caused by diabetes, hypertension, hyperlipidemia, obesity, smoking, heart failure, cardiac hypertrophy, ischemic heart diseases, angioplasty or ischemia-reperfusion in organ transplantation.

10 . The agent of claim 2 , wherein the excessive effect of NAD(P)H oxidase is caused by cancer or dementia.

11 . The agent of claim 2 , wherein the excessive effect of NAD(P)H oxidase is caused by intake of chemicals.

12 . The agent of any one of claims 9 to 11 , wherein the compound that does not substantially affect leukocyte NADPH oxidase but inhibits an excessive effect of NAD(P)H oxidase in a tissue other than leukocyte is a bicyclic pyridazine compound represented by the following formulas (I) to (VII) or a pharmacologically acceptable salt thereof:

wherein A is C 3 -C 6 alkyl, C 5 -C 7 cycloalkyl, or phenyl, thienyl, furyl, thiazolyl, phenoxy, C 7 -C 9 phenylalkyl, phenylthio, nitrogen-containing saturated ring group, pyridyl or imidazolyl, each optionally having one or more substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and halogen,

B is —NH—D

[D is

wherein R 1 is hydrogen or C 1 -C 4 alkyl, X is halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and k is an integer of 0 to 3, when k is an integer of 2 or more, multiple Xs may be the same or different,

wherein R 2 is hydrogen or C 1 -C 4 alkyl, Y is C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and m is an integer of 0 to 6, when m is 2 or more, multiple Ys may be the same or different, and any two Ys may be joined to form optionally branched C 1 -C 6 alkylene,

wherein ring H is C 5 -C 7 cycloalkyl, and Y and m are as defined above,

—CHR 3 R 4

wherein R 3 is C 1 -C 5 alkyl, and R 4 is C 5 -C 8 cycloalkyl or thienyl,

or C 3 -C 8 alkyl]

or

wherein Z is C 1 -C 4 alkyl or phenyl, and n is an integer of 0 to 2, when n is 2, these Zs may be the same or different, and

Q is a benzene ring, a furan ring or a thiophene ring optionally substituted by C 1 -C 4 alkyl,

wherein R 5 and R 6 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, cyano, nitro, amino, trifluoromethyl or carboxyl, and X′ is —COOR 7 (R 7 is hydrogen or optionally substituted C 1 -C 6 alkyl), —CONH 2 , —CN, —COR 8 (R 8 is optionally substituted C 1 -C 6 alkyl or optionally substituted aryl), —NH 2 ,

—NO 2 or —OR 7 (R 7 is as defined above),

wherein R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, cyano, nitro, amino, trifluoromethyl or carboxyl,

wherein R 11 and R 12 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, cyano, nitro, amino, trifluoromethyl or carboxyl, and X′ is —OR 13 (R 13 is hydrogen, C 1 -C 6 alkyl or aryl) or —NR 14 R 15 (R 14 and R 15 are each independently hydrogen, C 1 -C 6 alkyl or aryl,

wherein R 16 and R 17 are each independently hydrogen, C 1 -C 6 alkyl, alkoxy, halogen, cyano, nitro, amino, trifluoromethyl or carboxyl, R 18 and R 9 are each independently hydrogen or C 1 -C 6 alkyl, and Y′ is oxygen or sulfur.

13 . A pharmaceutical composition for the diseases caused by an excessive effect of NAD(P)H oxidase, which comprises the agent of claim 6 as an active ingredient.

14 . The pharmaceutical composition of claim 13 , which is administered simultaneously with a hypolipidemic agent, an antihypertensive agent, a hypoglycemic agent, a vasodilator, an antiplatelet agent, an anticoagulant, a brain protective agent, an anticancer agent, a diuretic agent, a cardiotonic agent, an analgesic agent, an antiedemic agent, a thrombolytic agent, an immunosuppressant, a steroid, a vitamin or an antioxidant, or administered separately therefrom, or administered sequentially therewith.