Benzene compounds

• US 20070105899A1
• Filed: 10/13/2006
• Published: 05/10/2007
• Est. Priority Date: 04/16/2004
• Status: Active Grant

• Current Assignee: Ajinomoto Co., Inc.
• Original Assignee: Ajinomoto Co., Inc.
• Inventors: Nakanishi, Eiji, Kondo, Nobuo, Tanaka, Hideyuki, Hatanaka, Toshihiro, Masuzawa, Yoko, Nihei, Yukio, SUZUKI, Nobuyasu, Yasa, Noriko, Ichinose, Hidehiro
• Granted Patent: US 7,402,696 B2
• Time in Patent Office: Days
• US Class Current: 514/312
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/402 1-aryl substituted, e.g. piretanide
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/455 Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/501 : not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/502 : ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/5377 : not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/551 : having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61P 1/16 : for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 : of the kidneys
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07C 233/66 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 2601/02 : with a three-membered ring
• CPC Class Codes: C07C 2601/04 : with a four-membered ring
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2603/24 : Anthracenes; Hydrogenated anthracenes
• CPC Class Codes: C07C 275/30 : being further substituted by halogen atoms, or by nitro or nitroso groups
• CPC Class Codes: C07C 311/16 : having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07C 311/21 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/51 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07D 207/452 : with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 209/48 : with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 215/48 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 235/18 : with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 271/06 : 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 277/28 : Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 277/30 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07F 9/65318 : having the two nitrogen atoms in positions 1 and 3

Abstract

The present invention provides novel benzene compounds presented by the following formulas, and analogs thereof, that exert an ACC activity-inhibiting effect that is effective in the treatment of obesity, hyperlipemia, fatty liver, hyperglycemia, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, and diabetic macroangiopathy, hypertension, arteriosclerosis), hypertension, and arteriosclerosis.

Claims

1. A compound of formula (I-I), a pharmaceutically acceptable salt thereof, or a solvate thereof:

2. A method for preventing and/or treating hyperlipemia, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.

3. A method for preventing and/or treating fatty liver, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.

4. A method for preventing and/or treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.

5. A method for preventing and/or treating, impaired glucose tolerance or diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1, a pharmaceutically acceptable salt thereof or a solvate thereof.

6. A method for preventing and/or treating diabetic complications, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof;

wherein said diabetic complications represent diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, or arteriosclerosis.

7. A method for preventing and/or treating hypertension or arteriosclerosis, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.

8. A method for preventing and/or treating obesity, hyperlipemia, fatty liver, impaired glucose tolerance, diabetes, diabetic complications, hypertension, arteriosclerosis, or hyperglycemia, comprising administering to a subject in need thereof an effective amount of i) a compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, and ii) any one or two of drugs which is selected from the group consisting of insulin, sulfonylurea agents, α

-glucosidase inhibitors, biguanide agents, PPAR-γ

agonists, PPAR-γ

antagonists, PPAR-α

agonists, SGLT inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, aldose reductase inhibitors, anti-diabetic neuropathy drugs, HMG-CoA reductase inhibitors, antioxidants, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, beta blockers, α

1 blockers, diuretics, anti-obesity drugs, and low energy foods;

wherein said diabetic complications represent diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, or arteriosclerosis.

9. A pharmaceutical composition comprising i) a compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, and ii) a pharmaceutical acceptable carrier.

10. A pharmaceutical composition comprising i) a compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, and ii) any one or two of drugs which is selected from the group consisting of insulin, sulfonylurea agents, α

-glucosidase inhibitors, biguanide agents, PPAR-γ

agonists, PPAR-γ

antagonists, PPAR-α

agonists, SGLT inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, aldose reductase inhibitors, anti-diabetic neuropathy drugs, HMG-CoA reductase inhibitors, antioxidants, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, beta blockers, α

1 blockers, diuretics, anti-obesity drugs, and low energy foods.

15. A method for preventing and/or treating impaired glucose tolerance or diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.

11. A compound of formula (I-II), a pharmaceutically acceptable salt thereof, or a solvate thereof:

12. A method for preventing and/or treating hyperlipemia, comprising administering to a subject in need thereof an effective amount of a compound according to claim 11, a pharmaceutically acceptable salt thereof, or a solvate thereof.

13. A method for preventing and/or treating fatty liver, comprising administering to a subject in need thereof an effective amount of a compound according to claim 11, a pharmaceutically acceptable salt thereof, or a solvate thereof.

14. A method for, preventing and/or treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a compound according to claim 11, a pharmaceutically acceptable salt thereof;

or a solvate thereof.

16. A method for preventing and/or treating diabetic complications, comprising administering to a subject in need thereof an effective amount of a compound according to claim 11, a pharmaceutically acceptable salt thereof, or a solvate thereof;

wherein said diabetic complications represent diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, or arteriosclerosis.

17. A method for preventing and/or treating hypertension or arteriosclerosis, comprising administering to a subject in need thereof an effective amount of a compound according to claim 11, a pharmaceutically acceptable salt thereof, or a solvate thereof.

18. A method for preventing and/or treating obesity, hyperlipemia, fatty liver, impaired glucose tolerance, diabetes, diabetic complications, hypertension, arteriosclerosis, or hyperglycemia, comprising administering to a subject in need thereof an effective amount of i) a compound according to claim 11, a pharmaceutically acceptable salt thereof, or a solvate thereof, and ii) any one or two of drugs which is selected from the group consisting of insulin, sulfonylurea agents, α

-glucosidase inhibitors, biguanide agents, PPAR-γ

agonists, PPAR-γ

antagonists, PPAR-α

agonists, SGLT inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, aldose reductase inhibitors, anti-diabetic neuropathy drugs, HMG-CoA reductase inhibitors, antioxidants, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, beta blockers, α

1 blockers, diuretics, anti-obesity drugs, and low energy foods;

wherein said diabetic complications represent diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, or arteriosclerosis.

19. A pharmaceutical composition comprising i) a compound according to claim 11, a pharmaceutically acceptable salt thereof, or a solvate thereof, and ii) a pharmaceutical acceptable carrier.

20. A pharmaceutical composition comprising i) a compound according to claim 11, a pharmaceutically acceptable salt thereof, or a solvate thereof, and ii) any one or two of drugs which is selected from the group consisting of insulin, sulfonylurea agents, α

-glucosidase inhibitors, biguanide agents, PPAR-γ

agonists, PPAR-γ

antagonists, PPAR-α

agonists, SGLT inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, aldose reductase inhibitors, anti-diabetic neuropathy drugs, HMG-CoA reductase inhibitors, antioxidants, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, beta blockers, α

1 blockers, diuretics, anti-obesity drugs, and low energy foods.

21. A compound of formula (1A-III), (1B-III), (1C-III), or (1D-III), a pharmaceutically acceptable salt thereof, or a solvate thereof:

22. A method for preventing and/or treating hyperlipemia, comprising administering to a subject in need thereof an effective amount of a compound according to claim 21, a pharmaceutically acceptable salt thereof, or a solvate thereof.

23. A method for preventing and/or treating fatty liver, comprising administering to a subject in need thereof an effective amount of a compound according to claim 21, a pharmaceutically acceptable salt thereof or a solvate thereof.

24. A method for preventing and/or treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a compound according to claim 21, a pharmaceutically acceptable salt thereof or a solvate thereof.

25. A method for preventing and/or treating impaired glucose tolerance or diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to claim 21, a pharmaceutically acceptable salt thereof or a solvate thereof.

26. A method for preventing and/or treating diabetic complications, comprising administering to a subject in need thereof an effective amount of a compound according to claim 21, a pharmaceutically acceptable salt thereof, or a solvate thereof;

wherein said diabetic complications represent diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, or arteriosclerosis.

27. A method for preventing and/or, treating hypertension or arteriosclerosis, comprising administering to a subject in need thereof an effective amount of a compound according to claim 21, a pharmaceutically acceptable salt thereof, or a solvate thereof.

28. A method for preventing and/or treating obesity, hyperlipemia, fatty liver, impaired glucose tolerance, diabetes, diabetic complications, hypertension, arteriosclerosis, or hyperglycemia, comprising administering to a subject in need thereof an effective amount of i) a compound according to claim 21, a pharmaceutically acceptable salt thereof, or a solvate thereof, and ii) any one or two of drugs which is selected from the group consisting of insulin, sulfonylurea agents, α

-glucosidase inhibitors, biguanide agents, PPAR-γ

agonists, PPAR-γ

antagonists, PPAR-α

agonists, SGLT inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, aldose reductase inhibitors, anti-diabetic neuropathy drugs, HMG-CoA reductase inhibitors, antioxidants, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, beta blockers, α

1 blockers, diuretics, anti-obesity drugs, and low energy foods;

wherein said diabetic complications represent diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, or arteriosclerosis.

29. A pharmaceutical composition comprising i) a compound according to claim 21, a pharmaceutically acceptable salt thereof, or a solvate thereof, and ii) a pharmaceutical acceptable carrier.

30. A pharmaceutical composition comprising i) a compound according to claim 21, a pharmaceutically acceptable salt thereof, or a solvate thereof, and ii) any one or two of drugs which is selected from the group consisting, of insulin, sulfonylurea agents, α

-glucosidase inhibitors, biguanide agents, PPAR-γ

agonists, PPAR-γ

antagonists, PPAR-α

agonists, SGLT inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, aldose reductase inhibitors, anti-diabetic neuropathy drugs, HMG-CoA reductase inhibitors, antioxidants, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, beta blockers, α

1 blockers, diuretics, anti-obesity drugs, and low energy foods.

31. A compound of formula (1A-IV), a pharmaceutically acceptable salt thereof, or a solvate thereof:

32. A method for preventing and/or treating hyperlipemia, comprising administering to a subject in need thereof an effective amount of a compound according to claim 31, a pharmaceutically acceptable salt thereof, or a solvate thereof.

33. A method for preventing and/or treating fatty liver, comprising administering to a subject in need thereof an effective amount of a compound according to claim 31, a pharmaceutically acceptable salt thereof, or a solvate thereof.

34. A method for preventing and/or treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a compound according to claim 31, a pharmaceutically acceptable salt thereof, or a solvate thereof.

35. A method for preventing and/or treating impaired glucose tolerance or diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to claim 31, a pharmaceutically acceptable salt thereof, or a solvate thereof.

36. A method for preventing and/or treating diabetic complications, comprising administering to a subject in need thereof an effective amount of a compound according to claim 31, a pharmaceutically acceptable salt thereof, or a solvate thereof,

wherein said diabetic complications represent diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, or arteriosclerosis.

37. A method for preventing and/or treating hypertension or arteriosclerosis, comprising administering to a subject in need thereof an effective amount of a compound according to claim 31, a pharmaceutically acceptable salt thereof, or a solvate thereof.

38. A method for preventing and/or treating obesity, hyperlipemia, fatty liver, impaired glucose tolerance, diabetes, diabetic complications, hypertension, arteriosclerosis, or hyperglycemia, comprising administering to a subject in need thereof an effective amount of i) a compound according to claim 31, a pharmaceutically acceptable salt thereof, or a solvate thereof, and ii) any one or two of drugs which is selected from the group consisting of insulin, sulfonylurea agents, α

-glucosidase inhibitors, biguanide agents, PPAR-γ

agonists, PPAR-γ

antagonists, PPAR-α

agonists, SGLT inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, aldose reductase inhibitors, anti-diabetic neuropathy drugs, HMG-CoA reductase inhibitors, antioxidants, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, beta blockers, α

1 blockers, diuretics, anti-obesity drugs, and low energy foods;

wherein said diabetic complications represent diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, or arteriosclerosis.

39. A pharmaceutical composition comprising i) a compound according to claim 31, a pharmaceutically acceptable salt thereof, or a solvate thereof;

and ii) a pharmaceutical acceptable carrier.

40. A pharmaceutical composition comprising a combination of i) a compound according to claim 31, a pharmaceutically acceptable salt thereof, or a solvate thereof, and ii) any one or two of drugs which is selected from the group consisting of insulin, sulfonylurea agents, α

-glucosidase inhibitors, biguanide agents, PPAR-γ

agonists, PPAR-γ

antagonists, PPAR-α

agonists, SGLT inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, aldose reductase inhibitors, anti-diabetic neuropathy drugs, HMG-CoA reductase inhibitors, antioxidants, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, beta blockers, α

1 blockers, diuretics, anti-obesity drugs, and low energy foods.