Peroxisome proliferator activated receptor ligands and process for producing the same

• US 20050014819A1
• Filed: 10/11/2002
• Published: 01/20/2005
• Est. Priority Date: 10/11/2001
• Status: Active Grant

• Current Assignee: Kaneka Corporation
• Original Assignee: Kaneka Corporation
• Inventors: Kitahara, Mikio, Mimaki, Yoshihiro, Kitamura, Shiro, Ueda, Yasuyoshi, Sashida, Yutaka, Kuroda, Minpei, Mae, Tatsumasa, Tsukagawa, Misuzu, Nakagawa, Kaku
• Granted Patent: US 7,524,975 B2
• Time in Patent Office: Days
• US Class Current: 514/457
• CPC Class Codes: A23K 20/111 Aromatic compounds
• CPC Class Codes: A23K 20/121 containing oxygen or sulfur as hetero atom
• CPC Class Codes: A23K 50/00 Feeding-stuffs specially adapted for particular animals
• CPC Class Codes: A23K 50/40 for carnivorous animals, e.g. cats or dogs
• CPC Class Codes: A23L 33/10 using additives addition of substantially indigestible substances A23L33/21
• CPC Class Codes: A23L 33/105 Plant extracts, their artificial duplicates or their derivatives
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/37 Coumarins, e.g. psoralen
• CPC Class Codes: A61K 36/484 Glycyrrhiza (licorice)
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• 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 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 311/06 : with oxygen or sulfur atoms directly attached in position 2

Abstract

The present invention easily and efficiently provides a peroxisome proliferator-activated receptor ligand, and a composition for amelioration of insulin resistance or for prevention and/or amelioration of the insulin resistance syndrome containing the same, as an active ingredient. The present invention relates to a peroxisome proliferator-activated receptor ligand which comprises a prenylflavonoid, a chalcone derivative exclusive of prenyl flavonoids, a flavonol derivative exclusive of prenylflavonoids, and a salt, a glycoside and/or an esterified substance thereof acceptable as a pharmaceutical preparation or a food or a beverage; a composition containing the above ligand; a plant-derived extract containing the above ligand; and a process for producing the above extract.

Claims

1. A peroxisome proliferator-activated receptor ligand

which comprises at least one species selected from the group consisting of a prenylflavonoid and a salt, a glycoside and an esterified substance thereof acceptable as a pharmaceutical preparation or a food or a beverage.

2. The peroxisome proliferator-activated receptor ligand according to claim 1,

wherein the prenylflavonoid is at least one species selected from the group consisting of a 3-arylcoumarin derivative, an isoflav-3-ene derivative, an isoflavan derivative, an isoflavanone derivative, an isoflavone derivative, a flavonol derivative, a flavanone derivative, a chalcone derivative and a dibenzoylmethane derivative.

3. The peroxisome proliferator-activated receptor ligand according to claim 1,

wherein the prenylflavonoid comprises a 3-arylcoumarin derivative represented by the general formula (1):

 

in the formula, at least one of R1 to R7 represents a prenyl group or a structure wherein adjacent 2 R groups form a 6-membered ring comprising —

CH═

CHC(CH₃)₂O—

, and other R groups represent H, OH or OCH₃.

4. The peroxisome proliferator-activated receptor ligand according to claim 3,

wherein the 3-arylcoumarin derivative represented by the general formula (1) is glycycoumarin or glycyrin.

5. The peroxisome proliferator-activated receptor ligand according to claim 1,

wherein the prenylflavonoid comprises an isoflav-3-ene derivative represented by the general formula (2):

 

n the formula, at least one of R1 to R7 represents a prenyl group or a structure wherein adjacent 2 R groups form a 6-membered ring comprising —

CH═

CHC(CH₃)₂O—

, and other R groups represent H, OH or OCH₃.

6. The peroxisome proliferator-activated receptor ligand according to claim 5,

wherein the isoflav-3-ene derivative represented by the general formula (2) is dehydroglyasperin D, dehydroglyasperin C or glabrene.

7. The peroxisome proliferator-activated receptor ligand according to claim 1,

wherein the prenylflavonoid comprises an isoflavan derivative represented by the general formula (3):

 

in the formula, at least one of R1 to R7 represents a prenyl group or a structure wherein adjacent 2 R groups form a 6-membered ring comprising —

CH═

CHC(CH₃)₂O—

, and other R groups represent H, OH or OCH₃.

8. The peroxisome proliferator-activated receptor ligand according to claim 7,

wherein the isoflavan derivative represented by the general formula (3) is glyasperin D, glabridin, hispaglabridin B, 4′

-O-methylglabridin or 3′

-hydroxy-4′

-O-methylglabridin.

9. The peroxisome proliferator-activated receptor ligand according to claim 1,

wherein the prenylflavonoid comprises an isoflavanone derivative represented by the general formula (4):

 

in the formula, at least one of R1 to R8 represents a prenyl group or a structure wherein adjacent 2 R groups form a 6-membered ring comprising —

CH═

CHC(CH₃)₂O—

, and other R groups represent H, OH or OCH₃.

10. The peroxisome proliferator-activated receptor ligand according to claim 9,

wherein the isoflavanone derivative represented by the general formula (4) is glyasperin B or glycyrrhisoflavanone.

11. The peroxisome proliferator-activated receptor ligand according to claim 1,

wherein the prenylflavonoid comprises an isoflavone derivative represented by the general formula (5):

 

in the formula, at least one of R1 to R9 represents a prenyl group or a structure wherein adjacent 2 R groups form a 6-membered ring comprising —

CH═

CHC(CH₃)₂O—

, and other R groups represent H, OH or OCH₃.

12. The peroxisome proliferator-activated receptor ligand according to claim 11,

wherein the isoflavone derivative represented by the general formula (5) is glyurallin B, lupiwighteone, semilicoisoflavone B or glycyrrhisoflavone.

13. The peroxisome proliferator-activated receptor ligand according to claim 1,

wherein the prenylflavonoid comprises a flavonol derivative represented by the general formula (6):

 

in the formula, R1 is OH or OCH₃, at least one of R2 to R9 represents a prenyl group or a structure wherein adjacent 2 R groups form a 6-membered ring comprising —

CH═

CHC(CH₃)₂O—

, and other R groups represent H, OH or OCH₃.

14. The peroxisome proliferator-activated receptor ligand according to claim 13,

wherein the flavonol derivative represented by the general formula (6) is isolicoflavono licoflavonol or topazolin.

15. The peroxisome proliferator-activated receptor ligand according to claim 1, wherein the prenylflavonoid comprises a flavanone derivative represented by the general formula (7):

16. The peroxisome proliferator-activated receptor ligand according to claim 15,

wherein the flavanone derivative represented by the general formula (7) is glabrol.

17. The peroxisome proliferator-activated receptor ligand according to claim 1,

wherein the prenylflavonoid comprises a chalcone derivative represented by the general formula (8):

 

in the formula, at least one of R1 to R9 represents a prenyl group or a structure wherein adjacent 2 R groups form a 6-membered ring comprising —

CH═

CHC(CH₃)₂O—

, and other R groups represent H, OH or OCH₃.

18. The peroxisome proliferator-activated receptor ligand according to claim 17,

wherein the chalcone derivative represented by the general formula (8) is licochalcone C.

19. The peroxisome proliferator-activated receptor ligand according to claim 1,

wherein the prenylflavonoid comprises a dibenzoylmethane derivative represented by the general formula (9):

 

in the formula, at least one of R1 to R7 represents a prenyl group or a structure wherein adjacent 2 R groups form a 6-membered ring comprising —

CH═

CHC(CH₃)₂O—

, and other R groups represent H, OH or OCH₃.

20. The peroxisome proliferator-activated receptor ligand according to claim 19,

wherein the dibenzoylmethane derivative represented by the general formula (9) is glycyrdione A or glycyrdione C.

25. The peroxisome proliferator-activated receptor ligand according to claim 1,

wherein the peroxisome proliferator-activated receptor is a peroxisome proliferator-activated receptor γ

.

27. A plant-derived extract

which comprises the peroxisome proliferator-activated receptor ligand according to claim 1.

28. The extract according to claim 27,

which is extracted with an organic solvent.

29. The extract according to claim 27

which comprises not less than 5% by weight of a peroxisome proliferator-activated receptor ligand on a dry weight basis.

30. The extract according to claim 27,

which comprises at least one species selected from the group consisting of glycycoumarin, glycyrin, dehydroglyasperin C, dehydroglyasperin D, glyasperin B and glyasperin D in an amount of not less than 0.5% by weight on a dry weight basis.

31. The extract according to claim 27,

dehydroglyasperin D,

glyasperin B and glyasperin D, respectively, in an amount of not less than 0.5% by weight on a dry weight basis.

32. The extract according to claim 27,

which comprises at least one species selected from the group consisting of glycyrrhisoflavanone, glycyrrhisoflavone, glyurallin B, semilicoisoflavone B and isoliquiritigenin in an amount of not less than 0.01% by weight on a dry weight basis.

33. The extract according to claim 27,

which comprises glycyrrhisoflavanone, glycyrrhisoflavone, glyurallin B, semilicoisoflavone B and isoliquiritigenin respectively in an amount of not less than 0.01% by weight on a dry weight basis.

34. The extract according to claim 27,

which comprises at least one species selected from the group consisting of glabrene, glabridin, glabrol, 3′

-hydroxy-4′

-O-methylglabridin, 4′

-O-methylglabridin and hispaglabridin B in an amount of not less than 0.5% by weight on a dry weight basis.

35. The extract according to claim 27,

which comprises glabrene, glabridin, glabrol, 3′

-hydroxy-4′

-O-methylglabridin, 4′

-O-methylglabridin and hispaglabridin B respectively in an amount of not less than 0.5% by weight on a dry weight basis.

36. The extract according to claim 27,

which comprises at least one species selected from the group consisting of licochalcone A, licochalcone B, licochalcone C, glycyrdione A and glycyrdione C in an amount of not less than 0.5% by weight on a dry weight basis.

37. The extract according to claim 27,

which comprises licochalcone A, licochalcone B, licochalcone C, glycyrdione A and glycyrdione C respectively in an amount of not less than 0.5% by weight on a dry weight basis.

38. The extract according to claim 27,

wherein the content of glycyrrhizin is 0.001 to 0.5% by weight on a dry weight basis.

39. The extract according to claim 27,

which is derived from licorice.

40. The extract according to claim 39,

wherein the licorice is at least one species selected from the group consisting of Glycyrrhiza uralensis, Glycyrrhiza glabra, Glycyrrhiza inflata and Glycyrrhiza echinata.

41. The extract according to claim 39,

wherein the licorice is Glycyrrhiza uralensis.

42. The extract according to claim 39,

wherein the licorice is Glycyrrhiza glabra.

43. The extract according to claim 39,

wherein the licorice is Glycyrrhiza inflata.

48. A composition for amelioration of insulin resistance or for prevention and/or amelioration of the insulin resistance syndrome

which comprises, as an active ingredient, the peroxisome proliferator-activated receptor ligand according to claim 1.

49. The composition according to claim 48,

wherein the insulin resistance syndrome is at least one symptom or disease selected from the group consisting of hyperinsulinemia, diabetes mellitus, dyslipidemia, obesity, hypertension and arteriosclerosis.

50. The composition according to claim 49,

wherein the symptom or disease is diabetes mellitus.

51. A composition for prevention and/or amelioration of inflammations or cancers

which comprises, as an active ingredient, the peroxisome proliferator-activated receptor ligand according to claim 1.

52. A composition for amelioration of insulin resistance or for prevention and/or amelioration of the insulin resistance syndrome

which comprises, as an active ingredient, a prenylflavonoid having an ability to

which comprises, as an active ingredient, a prenylflavonoid having an ability to bind to a ligand-binding region of a peroxisome proliferator-activated receptor

and which further comprises the extract according to claim 27 as the prenylflavonoid having an ability to bind to a ligand-binding region of a peroxisome proliferator-activated receptor or as a peroxisome proliferator-activated receptor ligand.

57. A composition for amelioration of insulin resistance or for prevention and/or amelioration of the insulin resistance syndrome

which comprises, as an active ingredient, a prenylflavonoid having an ability to bind to a ligand-binding region of a peroxisome proliferator-activated receptor, which is in the form of a tablet, a capsule, granules or powders

and which further comprises 0.1 to 1000 mg of the extract according to claim 27 per tablet.

58. A process for producing the extract according to claim 39

which comprises extracting the extract from licorice having the ratio of the skin

59. The process according to claim 58,

wherein the licorice is in the form of a cut product or periderm thereof.

60. The process according to claim 58,

wherein the licorice is in the form of a cut product.

61. The process for producing the extract according to claim 39,

wherein the extraction from licorice is carried out with a fatty acid ester.

62. The process according to claim 61,

wherein the fatty acid ester is ethyl acetate.

63. A process for producing the extract according claim 39,

which comprises extracting the extract from licorice with a water-soluble organic solvent.

64. The process according to claim 63,

wherein the water-soluble organic solvent is a monohydric alcohol having 1 to 4 carbon atoms, acetone or a mixture thereof.

65. The process according to claim 63,

wherein the water-soluble organic solvent is ethanol, acetone or a mixture thereof.

66. The process according to claim 63,

wherein the water-soluble organic solvent is ethanol.

67. A process for producing the extract according to claim 39

which comprises extracting from licorice with an organic solvent having a water content of 30% by volume or less.

68. The process according to claim 58,

which further comprises purifying by adsorption treatment and/or fractionation after extraction.

69. The process according to claim 58,

wherein an extraction from licorice and/or a subsequent procedure is carried out under a deoxidized atmosphere.

21. A peroxisome proliferator-activated receptor ligand

which comprises at least one species selected from the group consisting of a chalcone derivative exclusive of prenylflavonoids, and a salt, a glycoside and an esterified substance thereof acceptable as a pharmaceutical preparation or a food or a beverage.

22. The peroxisome proliferator-activated receptor ligand according to claim 21,

wherein the chalcone derivative exclusive of prenyl flavonoids is echinatin, isoliquiritigenin, licochalcone A or licochalcone B.

23. A peroxisome proliferator-activated receptor ligand

which comprises at least one species selected from the group consisting of a flavonol derivative exclusive of prenylflavonoids, and a salt, a glycoside and an esterified substance thereof acceptable as a pharmaceutical preparation or a food or a beverage.

24. The peroxisome proliferator-activated receptor ligand according to claim 23,

wherein the flavonol derivative exclusive of prenyl flavonoids is kaempferol 3-O-methylester.

26. A compound represented by the formula:

44. A composition for amelioration of insulin resistance or for prevention and/or amelioration of the insulin resistance syndrome

which comprises, as an active ingredient, a prenylflavonoid having an ability to bind to a ligand-binding region of a peroxisome proliferator-activated receptor.

45. The composition according to claim 44, wherein the insulin resistance syndrome is at least one symptom or disease selected from the group consisting of hyperinsulinemia, diabetes mellitus, dyslipidemia, obesity, hypertension and arteriosclerosis.

46. The composition according to claim 45,

wherein the symptom or disease is diabetes mellitus.

53. The composition according to claim 44 which is used as a food or a beverage.

54. The composition according to claim 44

which is used as a pharmaceutical preparation.

55. The composition according to claim 44

which is used for a domestic animal or a pet.

56. The composition according to claim 44,

which is in the form of a tablet, a capsule, granules or powders.

47. A composition for prevention and/or amelioration of inflammations or cancers

which comprises, as an active ingredient, a prenylflavonoid having an ability to bind to a ligand-binding region of a peroxisome proliferator-activated receptor.