3-(4-aminophenyl)-2-furancarboxylic acid derivative and pharmaceutically acceptable salt thereof

1. A compound represented by Formula (II) or a pharmaceutically acceptable salt thereof:

wherein A is one member selected from the group consisting of groups represented by Formulae (a) to (d) below:

wherein R 12a , R 12b , and R 12c are the same or different, and independently represent:

1: a hydrogen atom,

2: a halogen atom,

3: a C 1-4 alkyl group, which is optionally substituted with 1 to 3 fluorine atoms,

4: a C 1-4 alkoxy group, which is optionally substituted with 1 to 3 fluorine atoms, or

5: a C 1-4 alkylcarbonyl group, which is optionally substituted with C 1-4 alkoxy;

R 12d , R 12e , and R 12f are the same or different, and independently represent:

1: a hydrogen atom,

2: a halogen atom, or

3: C 1-4 alkyl; and

R 22 is a cyano group or a nitro group.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a methylphenyl group.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a ethylpheny group.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a 4-(2 propyl)phenyl group.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a 4-(1,1,1-trimrthylmethyl)phenyl group.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 22 is a cyano group.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 22 is a nitro group.

8. The compound according to claim 1 selected from a compound group below, or a pharmaceutically acceptable salt thereof, the compound group consisting of:

3-{4-[((1S)-1-phenylethyl)amino]phenyl}-2-furancarboxylic acid-2-(4-hydroxy-3-nitrobenzoyl)hydrazide,

3-(4-{[(1S)-1-(3-methylphenyl)ethyl]amino}phenyl)-2-furancarboxylic acid-2-(4-hydrox)-3-nitrobenzoyl)hydrazide,

3-(4-{[(1S)-1-(4-ethylphenyl)ethyl]amino}phenyl)-2-furancarboxylic acid-2-(4-hydroxy)-3-nitrobenzoyl)hydrazide,

3-(4-{[(1S)-1-(4-chlorophenyl)ethyl]amino}phenyl)-2-furancarboxylic acid-2-(4-hydroxy-3-nitrobenzoyl)hydrazide,

3-(4{[(1S)-1-(3,4-dimethylphenyl)ethyl ]amino}phenyl)-2-furancarboxylic acid-2-(4-hydroxy)-3-nitrobenzoyl)hydrazide,

3-(4{[(1S)-1-cyclohexylethyl]amino}phenyl)-2-furancarboxylic acid-2-(4-hydroxy-3-nitrobenzoyl)hydrazide,

3-(4-{[(1S)-1-(4-chloro-3-methylphenyl)ethyl]amino}phenyl)-2-furancarboxylic acid-2-(4-hydroxy-3-nitrobenzoyl)hydrazide,

3-(4-{[(1S)-1-(4-chloro-2-fluorophenyl)ethyl]amino}phenyl)-2-furancarboxylic acid-2-(4-hydroxy-3-nitrobenzoyl)hydrazide,

3-(4-{[(1S)-1-(4-fluorophenyl)ethyl]amino}phenyl)-2-furancarboxylic acid-2-(4-hydroxy-3-nitrobenzoyl)hydrazide, and

3-(4-{[(1S)-1-(4-methylphenyl)ethyl]amino}phenyl)-2-furancarboxylic acid-2-(4-hydroxy-3-nitrobenzoyl)hydrazide.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, the compound is

3-(4{[(1S)-1-(4-methylphenyl)ethyl]amino}phenyl)-2-furancarboxylic acid-2-(4-hydroxy-3-nitrobenzoyl)hydrazide.

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 22 is a nitro group.

11. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, the compound is

3-(4{[(1S)-1-(3,4-dimethylphenyl)ethyl]amino}phenyl)-2-furancarboxylic acid-2-(4-hydroxy-3-nitrobenzoyl)hydrazide.

13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, the compound is

3-(4-{[(1S)-1-(4-fluorophenyl)ethyl]amino }phenyl)-2-furancarboxylic acid-2-(4- hydroxy-3-nitrobenzoyl)hydrazide.

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is represented by Formula (a) below:

15. The compound according to claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 12a ,R 12b , and R 12c are the same or different, and independently represent a hydrogen atom or a C 1-4 alkyl optionally substituted with 1 to 3 fluorine atoms.

16. The compound according to claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 12a , R 12b , and R 12c are the same or different, and independently represent a hydrogen atom, a methyl, an ethyl, a 2-propyl, or a 1,1,1-trimethylmethyl.

17. A compound represented by Formula (III) or a pharmaceutically acceptable salt thereof:

wherein R 13a , R 13b , and R 13c are the same or different, and independently represent:

1: a hydrogen atom,

2: a halogen atom,

3: a C 1-4 alkyl group, which is optionally substituted with 1 to 3 fluorine atoms,

4: a C 1-4 alkoxy group, which is optionally substituted with 1 to 3 fluorine atoms, or

5: a C 1-4 alkylcarbonyl group, which is optionally substituted with C 1-4 alkoxy.

18. A method for treating a symptom and disease selected from the group consisting of hyperglycemia, abnormal glucose tolerance, insulin resistance syndrome, type I diabetes, type II diabetes, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, arteriosclerosis, glucagonoma, acute pancreatitis, cardiovascular disorders, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, diabetes caused by obesity, metabolic syndrome, and diabetic complications; the method comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient into a patient in need thereof.

19. A method for treating a symptom and disease selected from the group consisting of hyperglycemia, abnormal glucose tolerance, insulin resistance syndrome, type I diabetes, type II diabetes, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, arteriosclerosis, glucagonoma, acute pancreatitis, cardiovascular disorders, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, diabetes caused by obesity, metabolic syndrome, and diabetic complications; the method comprising administering the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and one drug selected from the drug group (A) below into a mammal in need thereof;

the drug group (A) consisting of insulin preparations, insulin resistance improving agents, α-glucosidase inhibitors, biguanides, insulin secretagogues, GLP-1, GLP-1 analogs, GLP-1 secretagogues, protein tyrosine phosphatase inhibitors, β3-agonists, DPPIV inhibitors, amyrin agonists, gluconeogenesis inhibitors, SGLT (sodium-glucose cotransporter) inhibitors, 11β-HSD1 inhibitors, adiponectin or adiponectin receptor agonists, leptin resistance improving drugs, somatostatin receptor agonists, AMPK activators, aldose reductase inhibitors, neurotrophic factors, PKC inhibitors, AGE inhibitors, active oxygen-eliminating agents, cerebral vasodilators, HMG-CoA reductase inhibitors, squalene synthetase inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, angiotensin-converting enzyme inhibitors, angiotensin II antagonists, calcium antagonists, ACE/NEP inhibitors, β-blockers, α-blockers, αβ-blockers, renin inhibitors, aldosterone receptor antagonists, central anti-obesity drugs, pancreatic lipase inhibitors, peptide appetite suppressants, cholecystokinin agonists, xanthine derivatives, thiazide preparations, anti-aldosterone preparations, carbonic anhydrase inhibitors, chlorobenzene sulfonamide preparations, azosemido, isosorbide, ethacrynic acid, piretanide, bumetanide, and furosemide.

20. A method for producing a compound represented by Formula (II) or a pharmaceutically acceptable salt thereof:

wherein A and R 22 are as defined in claim 1

the method comprising the step of reacting a compound represented by Formula (IV):

wherein R 14 has the same meaning as the group

 of formula (II) of claim 1 , Y is a group: —COOR 9 or a group: —CONHNH 2 , and R 9 is a hydrogen atom or a C 1-6 alkyl group, with a compound represented by Formula (K):

wherein R 22 is as defined above, and R 8 is a hydrogen atom, a C 1-4 alkyl group, a C 1-4 alkoxy C 1-4 alkyl group, a C 6-10 aryl group, a C 7-14 aralkyl group, or a C 1-4 alkylcarbonyl group; and, as necessary, converting the reaction product to a pharmaceutically acceptable salt.

21. The method according to claim 20 , wherein Y is a group: —CONHNH 2 .

22. The method according to claim 20 wherein Y is a group: —COOR 9 , and a compound obtained by hydrazidation of the compound represented by Formula (IV) is reacted with the compound represented by Formula (K).

23. The method according to claim 21 , further comprises the following steps 1 to 4 below, wherein the compound represented by Formula (IV) wherein Y is a group: —CONHNH 2 is obtained by the reaction of step 4:

Step 1: reacting a compound represented by Formula (A):)

wherein R 3 is a halogen atom or a group: —N(R 14 )(R 5 )R 5 is a hydrogen atom, and R 14 is as defined above, with a compound represented by Formula (B):

HCOOR 6   (B)

wherein R 6 is a C 1-6 alkyl group, in the presence of a base, followed by a reaction in an alcohol solvent: R 4 OH, wherein R 4 is a C 1-6 alkyl group, in the presence of an acid;

Step 2: reacting the compound obtained by the reaction of step 1 and represented by Formula (C):

wherein R 3 and R 4 are as defined above, with a compound represented by Formula (E):

X 1 —CH 2 COOR 7   (E)

wherein X 1 is a halogen atom, and

R 7 is

1: a C 1-6 alkyl group,

2: a C 7-14 aralkyl group, which is optionally substituted with the same or different 1 to 3 groups selected from the group consisting of:

(a) halogen,

(b) methyl,

(c) methoxy, and

(e) nitro, or

3: a C 6-10 arylcarbonyl C 1-4 alkyl group, which is substituted with the same or different 1 to 3 groups selected from the group consisting of:

(a) halogen,

(b) methyl, and

(c) methoxy,

in the presence of a base;

Step 3: reacting the compound obtained by the reaction of step 2 and represented by Formula (F):

wherein R 3 , R 4 , and R 7 are as defined above, in the presence of an acid; and

Step 4: reacting the compound obtained by the reaction of step 3 and represented by Formula (G):

wherein R 3 and R 7 are as defined above, with

(1) hydrazine monohydrate after a coupling reaction with a compound represented by Formula (H) below, when R 3 is a halogen atom:

R 14 NH 2   (H)

wherein R 14 is as defined above, or with

(2) hydrazine monohydrate, when R 3 is a group: —NH(R 14 ).

24. A compound represented by Formula (IV) below or a pharmaceutically acceptable salt thereof:

wherein R 14

has the same meaning as the group

of formula (II) of claim 1

Y is a group: —COOR 9 or a group: —CONHNH 2 ; and

R 9 is a hydrogen atom or a C 1-6 alkyl group.