Functionalized phenolic esters and amides and polymers therefrom

• US 20060173065A1
• Filed: 09/06/2005
• Published: 08/03/2006
• Est. Priority Date: 01/28/2005
• Status: Active Grant

• Current Assignee: Bezwada Biomedical, LLC
• Original Assignee: Bezwada Biomedical, LLC
• Inventors: Bezwada, Rao S.
• Granted Patent: US 7,858,077 B2
• Time in Patent Office: Days
• US Class Current: 514/419
• 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 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: C07C 69/734 Ethers
• CPC Class Codes: C07C 69/92 with etherified hydroxyl groups

Abstract

The present invention relates to a compound of the formula:
R-AR—O—Y—R′

• • Wherein R represents one or more members selected from H, alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid, —NO₂, —NH₂, —NHCOCH₃, and —NH—Y—R′, which is attached directly to AR or attached through an aliphatic chain. The carboxylic acid moiety in R includes but is not limited to the following carboxylic acids: benzoic acids, cinnamic acids, ferulic acid, caffeic acid, syringic acid, salicylic acid, vanillic acid, phenylacetic acids, phenylpropionic acids, and sinapinic acid. -AR—O— is a biologically active phenolic moiety comprising 1 to 6 substituted or unsubstituted aryl rings that are directly bonded to each other, fused together, or joined through a linking group. Y represents a member selected from:
  • —COCH₂O— (glycolic ester moiety)
  • —COCH(CH₃)O— (lactic ester moiety)
  • —COCH₂OCH₂CH₂O— (dioxanone ester moiety)
  • —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety)
  • —CO(CH₂)_mO— where m is an integer between 2-4 and 6-24 inclusive
  • —COCH₂O(CH₂CH₂O)_n— where n is an integer between 2 and 24, inclusive; and R′ is either hydrogen or a benzyl or an alkyl group, the alkyl group being either straight-chained or branched. The resultant functionalized phenolic compounds, used singly or in combinations, and their polymers have controllable degradation profiles, releasing the active component over a desired time range. The polymers are useful for biomaterials and biomedical devices, wherein said biologically active phenolic moiety is a residue of a phenolic compound.

Claims

1. A compound of the formula:

R-AR—

O—

Y—

R′

Wherein R represents one or more members selected from the group consisting of H, alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid, —

NO₂, —

NH₂, —

NHCOCH₃, and —

NH—

Y—

R′

, which is attached directly to AR or attached through an aliphatic chain;

-AR—

O—

is a biologically active phenolic moiety comprising 1 to 6 substituted or unsubstituted aryl rings that are directly bonded to each other, fused together, or joined through a linking group;

Y represents a member selected from the group consisting of;

—

COCH₂O—

(glycolic ester moiety)

—

COCH(CH₃)O—

(lactic ester moiety)

—

COCH₂OCH₂CH₂O—

(dioxanone ester moiety)

—

COCH₂CH₂CH₂CH₂CH₂O—

(caprolactone ester moiety)

—

CO(CH₂)_mO—

where m is an integer between 2-4 and 6-24 inclusive

—

COCH₂O(CH₂CH₂O)_n—

where n is an integer between 2 and 24, inclusive; and

R′

is either hydrogen or a benzyl or an alkyl group, the alkyl group being either straight-chained or branched.

2. A compound according to claim 1 wherein said biologically active phenolic moiety is the residue of a biologically active phenolic compound selected from the group consisting of phenols, thiophenols, naphthols, flavonoids, isoflavonoids, coumarins, chromones, chalcones, cinnamic acids, simple benzoic acids, indoles, acetophenones, benzophenones, alkaloids, catechins, catechols, aminoalcohols, aminosalicylic acids, hydrocinnamic acids, phenolic acids, resorcinol, hydroquinone, drugs containing phenolic groups, natural products containing phenolic groups, amino acids containing phenolic groups, and drugs containing naphthols.

3. A compound according to claim 1 wherein Y is selected from the group consisting of:

—

COCH₂O—

(glycolic ester moiety)

—

COCH(CH₃)O—

(lactic ester moiety)

—

COCH₂OCH₂CH₂O—

(dioxanone ester moiety)

—

COCH₂CH₂CH₂CH₂CH₂O—

(caprolactone ester moiety)

4. A composition comprising one or more species according to claim 1 in combination with one or more compounds of the formula:

R-AR—

O—

X—

R′

Wherein R represents one or more members selected from the group consisting of H, alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid, —

NO₂, —

NH₂, —

NHCOCH₃, and —

NHCOCH₂OH, which is attached directly to AR;

-AR—

O—

is a biologically active phenolic moiety comprising 1 to 6 substituted or unsubstituted aryl rings that are directly bonded to each other, fused together, or joined through a linking group;

X represents a member selected from the group consisting of;

—

CH₂COO—

(glycolic acid moiety)

—

CH(CH₃)COO—

(lactic acid moiety)

—

CH₂CH₂OCH₂COO—

(dioxanone moiety)

—

CH₂CH₂CH₂CH₂CH₂COO—

(caprolactone moiety)

—

(CH₂)_yCOO—

where y is one of the numbers 2, 3, 4 and 6-24 inclusive

—

(CH₂CH₂O)_zCH₂COO—

where z is an integer between 2 and 24, inclusive; and

R′

is either hydrogen or a benzyl or an alkyl group, the alkyl group being either straight-chained or branched;

wherein the biologically active phenolic moiety is a residue of a compound selected from the group consisting of phenols, naphthols, flavonoids, isoflavonoids, coumarins, chromones, chalcones, cinnamic acids, simple benzoic acids, indoles, acetophenones, benzophenones, alkaloids, catechins, catechols, hydrocinnamic acids, phenolic acids,

resorcinol, hydroquinone, drugs containing phenolic groups, natural products containing phenolic groups, amino acids containing phenolic groups, and drugs containing naphthols.

5. A composition comprising two or more different species of the compound according to claim 1.

6. A composition comprising two or more different species of the compound according to claim 2.

7. A composition comprising two or more different species of the compound according to claim 3.

8. A cancer prevention composition comprising an effective amount of at least one compound of claim 1, wherein said biologically active phenolic moiety is a residue of a cancer-preventing phenolic compound, a pharmaceutically acceptable excipient, and, optionally, further comprising an anti-cancer agent.

9. An anti-inflammatory composition comprising an effective amount of at least one compound of claim 1 wherein said biologically active phenolic moiety is a residue of a phenolic compound having anti-inflammatory properties, a pharmaceutically acceptable excipient, and, optionally, further comprising an anti-inflammatory agent.

10. A pain-reducing composition comprising an effective amount of at least one compound of claim 1 wherein said biologically active phenolic moiety is a residue of a phenolic compound having pain-reducing properties, a pharmaceutically acceptable excipient, and, optionally, further comprising a pain-reducing agent.

11. A biologically active composition comprising an effective amount of at least one compound of claim 1 and a pharmaceutically acceptable excipient wherein said composition is in a form suitable for oral, enteral, parenteral, topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, or vaginal administration.

12. A cosmetic composition comprising an effective amount of at least one compound of claim 1 and one or more cosmetic ingredients.

13. An antimicrobial composition comprising an effective amount of at least one compound of claim 1 wherein said biologically active phenolic moiety is a residue of a phenolic compound with antimicrobial properties, a pharmaceutically acceptable excipient, and, optionally, further comprising an antimicrobial agent.

14. A pharmaceutical composition comprising an effective amount of at least one compound of claim 1 and a pharmaceutically acceptable excipient.

15. A composition comprising at least one compound of claim 1, wherein said composition is suitable for use as a solvent for drugs.

16. A composition comprising an effective amount of at least one compound of claim 1 and a pharmaceutically acceptable excipient, wherein said biologically active phenolic moiety is a residue of a nutrition supplement or a food intermediary phenolic compound.

17. An antioxidant composition comprising an effective amount of at least one compound of claim 1, wherein said biologically active phenolic moiety is a residue of a phenolic compound with antioxidant properties, a pharmaceutically acceptable excipient, and, optionally, further comprising an antioxidant.

18. A polymer comprising at least one compound of claim 1, wherein said biologically active phenolic moiety is a residue of a phenolic compound with at least two active sites for polymerization.

19. The polymer of claim 18, wherein said two active sites for polymerization are independently selected from the group consisting of two hydroxyl groups, a hydroxyl group and a carboxylic acid, and a hydroxyl group and an amine group.

20. The polymer of claim 18, wherein said two active sites are two hydroxyl groups and said compound is reacted with a dicarboxylic acid to form a polyester.

21. The polymer of claim 18, wherein said two active sites are a hydroxyl group and an amine group and said compound is reacted with a dicarboxylic acid to form a polyesteramide.

22. The polymer of claim 18, wherein said two active sites are a hydroxyl group and a carboxylic acid and said compound is reacted with a hydroxycarboxylic acid to form a polyester.

23. A polymer comprising at least one compound of claim 1 and at least one compound of the formula:

R-AR—

O—

X—

R′

Wherein R represents one or more members selected from the group consisting of H, alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid, —

NO₂, —

NH₂, —

NHCOCH₃, and —

NHCOCH₂OH, which is attached directly to AR;

-AR—

O—

is a biologically active phenolic moiety comprising 1 to 6 substituted or unsubstituted aryl rings that are directly bonded to each other, fused together, or joined through a linking group;

X represents a member selected from the group consisting of;

—

CH₂COO—

(glycolic acid moiety)

—

CH(CH₃)COO—

(lactic acid moiety)

—

CH₂CH₂OCH₂COO—

(dioxanone moiety)

—

CH₂CH₂CH₂CH₂CH₂COO—

(caprolactone moiety)

—

(CH₂)COO—

where y is one of the numbers 2, 3, 4 and 6-24 inclusive

—

(CH₂CH₂O)_zCH₂COO—

where z is an integer between 2 and 24, inclusive; and

R′

is either hydrogen or a benzyl or an alkyl group, the alkyl group being either straight-chained or branched;

wherein said biologically active phenolic moiety is a residue of a phenolic compound selected from the group consisting of phenols, naphthols, flavonoids, isoflavonoids, coumarins, chromones, chalcones, cinnamic acids, simple benzoic acids, indoles, acetophenones, benzophenones, alkaloids, catechins, catechols, hydrocinnamic acids, phenolic acids, resorcinol, hydroquinone, drugs containing phenolic groups, natural products containing phenolic groups, amino acids containing phenolic groups, and drugs containing naphthols.

24. A polymeric blend comprising at least one polymer of claim 23 combined with at least one polymer formed from a compound of the formula:

R-AR—

O—

X—

R′

Wherein R represents one or more members selected from the group consisting of H, alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid, —

NO₂, —

NH₂, —

NHCOCH₃, and —

NHCOCH₂OH, which is attached directly to AR;

-AR—

O—

is a biologically active phenolic moiety comprising 1 to 6 substituted or unsubstituted aryl rings that are directly bonded to each other, fused together, or joined through a linking group;

X represents a member selected from the group consisting of;

—

CH₂COO—

(glycolic acid moiety)

—

CH(CH₃)COO—

(lactic acid moiety)

—

CH₂CH₂OCH₂COO—

(dioxanone moiety)

—

CH₂CH₂CH₂CH₂CH₂COO—

(caprolactone moiety)

—

(CH₂)_yCOO—

where y is one of the numbers 2, 3, 4 and 6-24 inclusive

—

(CH₂CH₂O)_zCH₂COO—

where z is an integer between 2 and 24, inclusive; and

R′

is either hydrogen or a benzyl or an alkyl group, the alkyl group being either straight-chained or branched;

wherein said biologically active phenolic moiety is a residue of a phenolic compound selected from the group consisting of phenols, naphthols, flavonoids, isoflavonoids, coumarins, chromones, chalcones, cinnamic acids, simple benzoic acids, indoles, acetophenones, benzophenones, alkaloids, catechins, catechols, hydrocinnamic acids, phenolic acids, resorcinol, hydroquinone, drugs containing phenolic groups, natural products containing phenolic groups, amino acids containing phenolic groups, and drugs containing naphthols.

25. A cancer prevention composition comprising an effective amount of at least one polymer of claim 18, wherein said biologically active phenolic moiety is a residue of a cancer-preventing phenolic compound, a pharmaceutically acceptable excipient, and, optionally, further comprising an anti-cancer agent.

26. An anti-inflammatory composition comprising an effective amount of at least one compound of claim 18, wherein said biologically active phenolic moiety is a residue of a phenolic compound having anti-inflammatory properties, a pharmaceutically acceptable excipient, and, optionally, further comprising an anti-inflammatory agent.

27. A pain-reducing composition comprising an effective amount of at least one polymer of claim 18, wherein said biologically active phenolic moiety is a residue of a phenolic compound having pain-reducing properties, a pharmaceutically acceptable excipient, and, optionally, further comprising a pain-reducing agent.

28. A biologically active composition comprising an effective amount of at least one polymer of claim 18 and a pharmaceutically acceptable excipient, wherein said composition is in a form suitable for oral, enteral, parenteral, topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, or vaginal administration.

29. An article comprising a metal or polymeric substrate and having thereon a coating, wherein said coating comprises at least one polymer according to claim 18.

30. The article of claim 29, wherein said article is an implantable biomedical device.

31. An implantable biomedical device comprising the polymer according to claim 18.

32. A cosmetic composition comprising an effective amount of at least one polymer of claim 18 and one or more cosmetic ingredients.

33. An antimicrobial composition comprising an effective amount of at least one polymer of claim 18, wherein said biologically active phenolic moiety is a residue of a phenolic compound with antimicrobial properties, a pharmaceutically acceptable excipient, and, optionally, further comprising an antimicrobial agent.

34. A pharmaceutical composition comprising an effective amount of at least one compound of claim 18 and a pharmaceutically acceptable excipient.

35. A biodegradable chewing gum composition comprising at least one polymer of claim 18.

36. A composition comprising at an effective amount of at least one polymer of claim 18 and a pharmaceutically acceptable excipient, wherein said biological active phenolic moiety is a nutrition supplement or a food intermediary phenolic compound.

37. An antioxidant composition comprising an effective amount of at least one compound of claim 18, wherein said biologically active phenolic moiety is a residue of a phenolic compound with antioxidant properties, a pharmaceutically acceptable excipient, and, optionally, further comprising an antioxidant.

38. The composition comprising at least one polymer of claim 18 that is further reacted to form reactive end groups.

39. The composition of claim 38, wherein each reactive end group is independently selected from the group consisting of isocyanates, epoxides, and acrylates.

40. The composition comprising at least one polymer according to claim 18, which is further polymerized with at least one lactone monomer selected from the group consisting of glycolide, lactide, p-dioxanone, trimethylene carbonate and caprolactone.

41. An implantable biomedical device comprising the composition according to claim 40.

42. A biodegradable chewing gum composition comprising at least one polymer of claim 40.

43. A cancer prevention composition comprising an effective amount of at least one polymer of claim 23, wherein said biologically active phenolic moiety is a residue of a cancer-preventing phenolic compound, a pharmaceutically acceptable excipient, and, optionally, further comprising an anti-cancer agent.

44. An anti-inflammatory composition comprising an effective amount of at least one compound of claim 23, wherein said biologically active phenolic moiety is a residue of a phenolic compound having anti-inflammatory properties, a pharmaceutically acceptable excipient, and, optionally, further comprising an anti-inflammatory agent.

45. A pain-reducing composition comprising an effective amount of at least one polymer of claim 23, wherein said biologically active phenolic moiety is a residue of a phenolic compound having pain-reducing properties, a pharmaceutically acceptable excipient, and, optionally, further comprising a pain-reducing agent.

46. A biologically active composition comprising an effective amount of at least one polymer of claim 23 and a pharmaceutically acceptable excipient, wherein said composition is in a form suitable for oral, enteral, parenteral, topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, or vaginal administration.

47. An article comprising a metal or polymeric substrate and having thereon a coating, wherein said coating comprises at least one polymer according to claim 23.

48. The article of claim 47, wherein said article is an implantable medical device.

49. An implantable biomedical device comprising the polymer according to claim 23.

50. A cosmetic composition comprising an effective amount of at least one polymer of claim 23 and one or more cosmetic ingredients.

51. An antimicrobial composition comprising an effective amount of at least one compound of claim 23, wherein said biologically active phenolic moiety is a residue of a phenolic compound with antimicrobial properties, a pharmaceutically acceptable excipient, and, optionally, further comprising an antimicrobial agent.

52. A pharmaceutical composition comprising an effective amount of at least one polymer of claim 23 and a pharmaceutically acceptable excipient.

53. A biodegradable chewing gum composition comprising an effective amount of at least one polymer of claim 23.

54. A composition comprising an effective amount of at least one polymer of claim 23 and a pharmaceutically acceptable excipient, wherein said biologically active phenolic moiety is a nutrition supplement or a food intermediary phenolic compound.

55. An antioxidant composition comprising an effective amount of at least one compound of claim 23, wherein said biologically active phenolic moiety is a residue of a phenolic compound with antioxidant properties, a pharmaceutically acceptable excipient, and, optionally, further comprising an antioxidant.

56. The composition comprising at least one polymer of claim 23 that is further reacted to form reactive end groups.

57. The composition of claim 56, wherein each reactive end group is independently selected from the group consisting of isocyanates, epoxides, and acrylates.

58. The composition comprising at least one polymer according to claim 23, which is further polymerized with at least one lactone monomer selected from the group consisting of glycolide, lactide, p-dioxanone, trimethylene carbonate and caprolactone.

59. An implantable biomedical device comprising the polymer according to claim 58.

60. A biodegradable chewing gum composition comprising an effective amount of at least one polymer of claim 58.

61. A cancer-preventing composition comprising an effective amount of at least one polymeric blend of claim 24, wherein said biologically active phenolic moiety is a residue of a cancer-preventing phenolic compound, a pharmaceutically acceptable excipient, and, optionally, further comprising an anti-cancer agent.

62. An anti-inflammatory composition comprising an effective amount of at least one polymeric blend of claim 24, wherein said biologically active phenolic moiety is a residue of a phenolic compound having anti-inflammatory properties, a pharmaceutically acceptable excipient, and, optionally, further comprising an anti-inflammatory agent.

63. A pain-reducing composition comprising an effective amount of at least one polymeric blend of claim 24, wherein said biologically active phenolic moiety is a residue of a phenolic compound having pain-reducing properties, a pharmaceutically acceptable excipient, and, optionally, further comprising a pain-reducing agent.

64. A biologically active composition comprising an effective amount of at least one polymer of claim 24 and a pharmaceutically acceptable excipient, wherein said composition is in a form suitable for oral, enteral, parenteral, topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, or vaginal administration.

65. An article comprising a metal or polymeric substrate and having thereon a coating, wherein said coating comprises at least one polymeric blend according to claim 24.

66. The article of claim 65, wherein said article is an implantable medical device.

67. An implantable medical device comprising the polymeric blend according to claim 24.

68. A cosmetic composition comprising an effective amount of at least one polymeric blend of claim 24 and one or more cosmetic ingredients.

69. An antimicrobial composition comprising an effective amount of at least one polymeric blend of claim 24, wherein said biologically active phenolic moiety is a residue of a phenolic compound with antimicrobial properties, a pharmaceutically acceptable excipient, and, optionally, further comprising an antimicrobial agent.

70. A pharmaceutical composition comprising an effective amount of at least one polymeric blend of claim 24 and a pharmaceutically acceptable excipient.

71. A biodegradable chewing gum composition comprising an effective amount of at least one polymeric blend of claim 24.

72. A composition comprising an effective amount of at least one polymeric blend of claim 24 and a pharmaceutically acceptable excipient, wherein said biologically active phenolic moiety is a nutrition supplement or a food intermediary phenolic compound.

73. An antioxidant composition comprising an effective amount of at least one polymeric blend of claim 24, wherein said biologically active phenolic moiety is derived from a phenolic compound with antioxidant properties, a pharmaceutically acceptable excipient, and, optionally, further comprising an antimicrobial agent.

74. A composition comprising at least one polymeric blend of claim 24 that is further reacted to form reactive end groups.

75. The composition of claim 74, wherein each reactive end group is independently selected from the group consisting of isocyanates, epoxides, and acrylates.

76. The composition comprising at least one polymeric blend according to claim 24 which is further polymerized with at least one lactone monomer selected from the group consisting of glycolide, lactide, p-dioxanone, trimethylene carbonate and caprolactone.

77. An implantable medical device comprising the polymeric blend according to claim 76.

78. A biodegradable chewing gum composition comprising an effective amount of at least one polymeric blend of claim 76.

79. A controlled release method for the treatment or prophylaxis of a cancerous disease which comprises administering to a subject in need thereof a controlled release dosage form comprising a therapeutically effective amount of at least one compound of claim 1.

80. A controlled release method for the reduction of pain which comprises administering to a subject in need thereof a controlled release dosage form comprising a therapeutically effective amount of at least one compound of claim 1.

81. A controlled release method for the treatment of inflammation which comprises administering to a subject in need thereof a controlled release dosage form comprising a therapeutically effective amount of at least one compound of claim 1.