Furan or thiopene derivative and medicinal use thereof

• US 20060100261A1
• Filed: 09/04/2003
• Published: 05/11/2006
• Est. Priority Date: 09/06/2002
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Fukatsu, Kohji, Sasaki, Shigekazu, Sakamoto, Junichi, Hamamura, Kazumasa, Amano, Yuichiro
• Granted Patent: US 7,553,867 B2
• Time in Patent Office: Days
• US Class Current: 514/408
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• 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: C07D 307/38 : with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 307/42 : Singly bound oxygen atoms
• CPC Class Codes: C07D 307/54 : 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 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/79 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides a compound represented by the formula (I):
[wherein R is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, p is 0, 1 or 2, and when p is 2, each R may be the same or different, R¹ is a hydrogen atom or an optionally substituted hydrocarbon group, R² is an optionally substituted aromatic group, Ring A is an optionally substituted monocyclic aromatic ring or optionally substituted bicyclic aromatic fused ring, X¹ is an oxygen atom or a sulfur atom, X² is a bond, an oxygen atom or —S(O)_n— (wherein n is 0, 1 or 2), Y is a bond, an oxygen atom, —S(O)_m—, —C(═O)—N(R³)— or —N(R³)—C(═O)— (R³ is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and m is 0, 1 or 2), M¹, M² and M³ may be the same or different and are each independently a bond or an optionally substituted divalent aliphatic hydrocarbon group, and M⁴ is an optionally substituted divalent aliphatic hydrocarbon group] or a salt thereof, which is useful as a prophylactic and/or therapeutic agent for lipid metabolism abnormality, arteriosclerotic disease and sequelae thereof, diabetes mellitus and the like.

Claims

1. A compound represented by the formula (i):

2. The compound according to the claim 1, wherein R is an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted cycloalkyl or an optionally substituted aryl.

3. The compound according to the claim 1, wherein p is 1.

4. The compound according to the claim 1, wherein R¹ is a hydrogen atom.

5. The compound according to the claim 1, wherein R² is an optionally substituted phenyl.

6. The compound according to the claim 1, wherein Ring A is an optionally substituted monocyclic aromatic ring.

7. The compound according to the claim 6, wherein the monocyclic aromatic ring is a monocyclic aromatic heterocycle.

8. The compound according to the claim 6, wherein the monocyclic aromatic ring is a benzene ring or a thiazole ring.

9. The compound according to the claim 1, wherein the formula:

10. The compound according to the claim 1, wherein X¹ is an oxygen atom.

11. The compound according to the claim 1, wherein X² is a bond, an oxygen atom or a sulfur atom.

12. The compound according to the claim 1, wherein Y is an oxygen atom or a sulfur atom.

13. The compound according to the claim 1, wherein Y is —

C(═

O)—

N(R³)—

, wherein R³ is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and the carbon atom is bonded to M₁, and the nitrogen atom to M².

14. The compound according to the claim 13, wherein R³ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted cycloalkyl or an optionally substituted aryl.

15. The compound according to the claim 1, wherein M¹ is an alkylene having 3 or more carbon atoms.

16. The compound according to the claim 1, wherein M¹, M² and M³ may be the same or different and are each independently a bond, an alkylene, an alkenylene or an alkynylene, and M⁴ is an alkylene, an alkenylene or an alkynylene.

17. The compound according to the claim 1, wherein X² is an oxygen atom or —

S(O)_n—

, wherein n is 0, 1 or 2 and M³ is an optionally substituted divalent aliphatic hydrocarbon group.

18. The compound according to the claim 1, wherein the formula (I) is

19. The compound according to the claim 18, wherein the formula (I′

) is

20. The compound according to the claim 19, wherein X¹ is an oxygen atom, X² is an oxygen atom or —

S(O)_n—

wherein n is 0, 1 or 2, Y is an oxygen atom, M¹ is an optionally substituted C_1-3 alkylene, M² is a bond, M³ is a bond or an optionally substituted methylene, and M⁴ is an optionally substituted methylene.

21. The compound according to the claim 20, wherein M¹ and M³ may be the same or different and are each independently an optionally substituted methylene.

22. The compound according to the claim 19, wherein X¹ is an oxygen atom, X² is a bond, Y is an oxygen atom, M¹ is an optionally substituted n-propylene, M² and M³ are a bond, and M⁴ is an optionally substituted methylene.

23. The compound according to the claim 18, wherein Ring A is an optionally substituted monocyclic aromatic heterocycle.

24. The compound according to the claim 18, wherein Ring A is an optionally substituted thiazole ring or an optionally substituted oxazole ring, X¹ is an oxygen atom, X² is a bond, Y is an oxygen atom or —

S(O)_n—

, wherein n is 0, 1 or 2+, M¹ is an optionally substituted C_1-3 alkylene, M² and M³ are a bond, and M⁴ is an optionally substituted methylene.

25. The compound according to the claim 18, wherein Ring A is an optionally substituted thiazole ring, X¹ is an oxygen atom, X² is a bond, Y is —

S—

, M¹ is an optionally substituted methylene or an optionally substituted n-propylene, M² and M³ are a bond, and M⁴ is an optionally substituted methylene.

26. The compound according to the claim 18, wherein the formula (I′

) is

27. The compound according to the claim 1, wherein R is an optionally substituted alkyl, aryl or cycloalkyl group, p is 0 or 1, R¹ is a hydrogen atom, R² is an optionally substituted phenyl group, Ring A is an optionally substituted benzene ring or an optionally substituted thiazole ring, X¹ is an oxygen atom, X² is a bond or an oxygen atom, Y is an oxygen atom or —

C(═

O)—

N(R³)—

wherein R³ is a hydrogen atom, alkyl or aralkyl, and the carbon atom is bonded to M¹, and the nitrogen atom to M², M¹, M² and M³ may be the same or different and are each independently a bond or alkylene, and M⁴ is alkylene.

28. The compound according to the claim 1, wherein R is an optionally substituted alkyl, aryl or cycloalkyl group, p is 0 or 1, R¹ is a hydrogen atom, R² is an optionally substituted phenyl group, Ring A is an optionally substituted benzene ring or an optionally substituted thiazole ring, X¹ is an oxygen atom, x is a bond or —

S(O)_n—

wherein n is 0, 1 or 2, Y is an oxygen atom or —

C(═

O)—

N(R³)—

wherein R³ is a hydrogen atom, alkyl or aralkyl, and the carbon atom is bonded to M¹, and the nitrogen atom to M², M¹, M² and M³ may be the same or different and are each independently a bond or alkylene, and M⁴ is alkylene.

29. A prodrug of the compound according to the claim 1.

30. A pharmaceutical medicine composition comprising the compound according to the claim 1 or a prodrug thereof and a pharmaceutically acceptable carrier, excipient, or diluent.

31. An agent of regulating nuclear receptor PPAR comprising the compound according to the claim 1 or a prodrug thereof.

32. A prophylactic or therapeutic agent for nuclear receptor PPAR-related diseases comprising the compound according to the claim 1 or a prodrug thereof.

33. The prophylactic or therapeutic agent according to the claim 32, wherein the nuclear receptor PPAR-related diseases are lipid metabolism abnormality or sequelae thereof, arteriosclerotic disease or sequelae thereof, diabetes mellitus, or impaired glucose tolerance.

34. The medicine according to the claim 30, which is an agent of raising high-density lipoprotein cholesterol, an agent of lowering triglyceride, an agent of lowering low-density lipoprotein cholesterol or an agent of suppressing progress of arteriosclerotic plaque.

35. An agent of regulating GPR40 receptor function comprising the compound according to the claim 1 or a prodrug thereof.

36. The agent according to the claim 35, which is an agent of regulating insulin secretion, an agent of lowering blood glucose or an agent of protecting pancreatic β

cell.

37. The agent according to the claim 35, which is a prophylactic or therapeutic agent for diabetes mellitus, glucose intolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, sexual dysfunction, cutaneous diseases, arthropathy, osteopenia, arteriosclerosis, thrombotic diseases, dyspepsia, memory and learning disorders, obesity, hypoglycaemia, hypertension, edema, insulin resistant syndrome, unstable diabetes mellitus, lipoatrophy, insulin allergy, insulinoma, lipotoxicity or cancer.

38. A method of regulating nuclear receptor PPAR, which comprises administering to a mammal an effective amount of the compound according to the claim 1 or a prodrug thereof.

39. A method of preventing or treating nuclear receptor PPAR-related disease, which comprises administering to a mammal an effective amount of the compound according to the claim 1 or a prodrug thereof.

40. The method according to the claim 39, wherein the nuclear receptor PPAR-related diseases is lipid metabolism abnormality or sequelae thereof, arteriosclerotic disease or sequelae thereof, diabetes mellitus, or impaired glucose tolerance.

41. A method of raising high-density lipoprotein cholesterol, lowering triglyceride, lowering low-density lipoprotein cholesterol or suppressing progress of arteriosclerotic plaque, which comprises administering to a mammal an effective amount of the compound according to the claim 1 or a prodrug thereof.

42. A method of regulating GPR40 receptor function, which comprises administering to a mammal an effective amount of the compound according to the claim 1 or a prodrug thereof.

43. A method of regulating insulin secretion, lowering blood glucose or protecting pancreatic β

cell, which comprises administering to a mammal an effective amount of the compound according to the claim 1 or a prodrug thereof.

44. A method of preventing or treating diabetes mellitus, glucose intolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, sexual dysfunction, cutaneous diseases, arthropathy, osteopenia, arteriosclerosis, thrombotic diseases, dyspepsia, memory and learning disorders, obesity, hypoglycaemia, hypertension, edema, insulin resistant syndrome, unstable diabetes mellitus, lipoatrophy, insulin allergy, insulinoma, lipotoxicity or cancer, which comprises administering to a mammal an effective amount of the compound according to the claim 1 or a prodrug thereof.

45-51. -51. (canceled)