FUNCTIONALIZED PHENOLIC COMPOUNDS AND POLYMERS THEREFROM

• US 20090170927A1
• Filed: 10/16/2006
• Published: 07/02/2009
• Est. Priority Date: 10/21/2005
• Status: Active Grant

• Current Assignee: Bezwada Biomedical, LLC
• Original Assignee: Bezwada Biomedical, LLC
• Inventors: Bezwada, Rao S.
• Granted Patent: US 8,318,973 B2
• Time in Patent Office: Days
• US Class Current: 514/455
• CPC Class Codes: A23L 29/288 Synthetic resins, e.g. polyvinylpyrrolidone
• 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 2800/522 Antioxidants; Radical scavengers
• CPC Class Codes: A61K 8/37 Esters of carboxylic acids
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 31/04 Macromolecular materials
• CPC Class Codes: A61L 31/10 Macromolecular materials
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin
• CPC Class Codes: A61Q 19/08 Anti-ageing preparations
• CPC Class Codes: C07C 205/37 the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 217/84 the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 233/18 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/25 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 65/21 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 65/24 polycyclic
• CPC Class Codes: C07C 69/712 the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 69/732 : of unsaturated hydroxy carboxylic acids
• CPC Class Codes: C07C 69/734 : Ethers
• CPC Class Codes: C07C 69/92 : with etherified hydroxyl groups
• CPC Class Codes: C07D 311/12 : substituted in position 3 and unsubstituted in position 7
• CPC Class Codes: C07D 311/16 : substituted in position 7
• CPC Class Codes: C07D 311/36 : not hydrogenated in the hetero ring, e.g. isoflavones
• CPC Class Codes: C07D 493/04 : Ortho-condensed systems
• CPC Class Codes: C08G 63/66 : Polyesters containing oxygen in the form of ether groups C08G63/42, C08G63/58 take precedence
• CPC Class Codes: C08G 69/40 : Polyamides containing oxygen in the form of ether groups C08G69/12, C08G69/32 take precedence
• CPC Class Codes: C08G 69/44 : Polyester-amides
• CPC Class Codes: C08L 67/04 : Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

Abstract

The present invention relates to compounds of formula I, which are functionalized phenolic compounds, and polymers formed from the same.

Ar—[O—(X)_p—R′]_q  I

Polymers formed from the functionalized phenolics are expected to have controllable degradation profiles, enabling them to release an active component over a desired time range. The polymers are also expected to be useful in a variety of medical applications.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

Ar—

[O—

(X)_p—

R′

]_q 

 

I

wherein;

Ar—

(O)_q is a phenolic residue;

X is independently at each occurrence selected from;

—

CH₂COO—

;

—

CH(CH₃)COO—

;

—

CH₂CH₂OCH₂COO—

;

—

CH₂CH₂CH₂CH₂CH₂COO—

;

—

(CH₂)_yCOO—

; and

, —

(CH₂CH₂O)_zCH₂COO—

, where y is independently selected from 2,3,4 and 6-24 and z is independently selected from 2-24;

R′

is selected from H, benzyl, and C_1-6 alkyl;

p is independently selected from 0, 1, 2, 3, and 4; and

,

q is selected from 1-10;

provided that at least one X is present; and

,

further provided that when X is solely —

CH₂COO—

or —

CH(CH₃)COO—

or —

CH₂CH₂CH₂CH₂CH₂COO— and

q is 1 or 2, then p is ≧

2.

2. A compound according to claim 1, wherein

X is selected from:

—

CH₂COO—

;

—

CH(CH₃)COO—

;

—

CH₂CH₂OCH₂COO—

; and

,

—

CH₂CH₂CH₂CH₂CH₂COO—

;

p is 2; and

,

q is selected from 1 and 2;

3. A compound according to claim 1, wherein

y is independently selected from 2, 3, and 4;

z is independently selected from 2, 3, and 4;

p is independently selected from 1, 2, and 3; and

,

q is selected from 1, 2, and 3.

4. A compound according to claim 2, wherein Ar—

(O)_q corresponds to the residue of a phenolic compound selected from;

phenols, naphthols, hydroxy-benzoic acids, indoles, acetophenones, benzophenones, drugs containing phenolic groups, and natural products containing phenolic groups.

5. A compound according to claim 4, wherein Ar—

(O)_q corresponds to the residue of a natural product containing phenolic groups selected from;

cinnamic acids, capsaicin, coumarins, furanocoumarins, alkaloids, catechins, chromones, chalcones, daidzein, 2,5-dihydroxybenzoic acid, flavonoids or bioflavonoids, isoflavones, resveratrol, sinapic acid, vanillic acid, and vanillin.

6. A compound according to claim 5, wherein Ar—

(O)_q corresponds to the residue of a phenolic compound selected from;

4-hydroxycinnamic acid, caffeic acid, chlorogenic acid, ferulic acid, capsaicin, 4-hydroxycoumarin, psoralen, bergapten, bergaptol, xanthotoxin, isopimpinellin, 4,5′

,8-trimethylenepsoralen, daidzein, 2,5-dihydroxybenzoic acid, resveratrol, sinapic acid, vanillic acid, and vanillin.

7. A compound according to claim 4, wherein Ar—

(O)_q corresponds to the residue of a phenolic compound selected from;

hydroxy-phenyl, resorcinol, catechol, 1,4-dihydroxy-phenyl, tri-hydroxy-phenyls, hydroxy-naphthyl, dihydroxy-naphthyl, tri-hydroxy-naphthyl, and tetra-hydroxy-napthyl, chromones, chalcones, hydroxy-benzoic acid, dihydroxy-benzoic acid, indoles, acetophenones, benzophenones, catechins, hydroquinone, naproxen, paracetanol, acetaminophen, and acetylsalicylic acid.

8. A compound according to claim 2, wherein:

Ar is a substituted or unsubstituted aryl ring consisting of 1-6 phenyl rings.

9. A compound according to claim 8, wherein:

Ar is a substituted or unsubstituted aryl ring consisting of 1-3 phenyl rings.

10. A compound according to claim 9, wherein:

each Ar ring is independently substituted with 1, 2, or 3 R groups

R is independently selected from H, ═

O, O-glycosides, —

(CH₂)_0-2—

OR^a, —

(CH₂)_0-2—

C₆H₅, —

(CH₂)_0-2—

CHO, Cl, F, Br, I, —

(CH₂)_0-2—

OC(O)—

R^a, —

(CH₂)_0-2—

CO₂—

R^a, —

(C(CH₃))_0-2—

CO₂—

R^a, —

(CH₂)_0-2—

CO₂—

(CH₂)_1-2—

CO₂—

R^a, —

(C(CH₃))_0-2—

CO₂—

(CH₂)_1-2—

CO₂—

R^a, —

(CH₂)_0-2—

CO—

R^a, —

O(CH₂)_0-2—

C₆H₅, —

O(CH₂)_1-2—

CO₂—

R^a, —

O(C(CH₃))_1-2—

CO₂—

R^a, —

O(CH₂)_1-2—

CO—

R^a, —

CO₂(CH₂)_1-2—

CO₂—

R^a, —

CO₂(C(CH₃))_1-2—

CO₂—

R^a, —

(CH₂)_0-2—

NO₂, —

(CH₂)_0-2—

NR^aR^a, —

(CH₂)_0-2—

NR^aCOR^a, —

(CH₂)_0-2—

NR^aC(O)(CH₂)_1-2OR^a, —

C₆H₅, —

C₆H₅OR^a, and —

C₆H₅—

CH═

CHCO₂R^a; and

,

R^a is independently selected from H and C_1-6 alkyl.

11. A compound according to claim 2, wherein:

Ar is selected from;

each Ar is substituted with 1-2 R;

R is independently selected from H, ═

O, —

(CH₂)_0-2—

OR^a, —

(CH₂)_0-2—

C₆H₅, —

(CH₂)_0-2—

CHO, Cl, F, Br, I, —

(CH₂)_0-2—

OC(O)—

R^a, —

(CH₂)_0-2—

CO₂—

R^a, —

(C(CH₃))_0-2—

CO₂—

R^a, —

(CH₂)_0-2—

CO₂—

(CH₂)_1-2—

CO₂—

R^a, —

(C(CH₃))_0-2—

CO₂—

(CH₂)_1-2—

CO₂—

R^a, —

(CH₂)_0-2—

CO—

R^a, —

O(CH₂)_0-2—

C₆H₅, —

O(CH₂)_1-2—

CO₂—

R^a, —

O(C(CH₃))_1-2—

CO₂—

R^a, —

O(CH₂)_1-2—

CO—

R^a, —

CO₂(CH₂)_1-2—

CO₂—

R^a, —

CO₂(C(CH₃))_1-2—

CO₂—

R^a, —

(CH₂)_0-2—

NO₂, —

(CH₂)_0-2—

NR^aR^a, —

(CH₂)_0-2—

NR^aCOR^a, —

(CH₂)_0-2—

NR^aC(O)(CH₂)_1-2OR^a, —

C₆H₅, —

C₆H₅OR^a, and —

C₆H₅—

CH═

CHCO₂R^a; and

,

R^a is independently selected from H and C_1-4 alkyl.

12. A composition, comprising:

at least two different compounds of claim 2.

13. A solvent for a drug, comprising:

at least one compound of claim 2.

14. A nutritional composition, comprising at least one compound of claim 2.

15. The nutritional composition of claim 14, wherein the phenolic residue in the compound of formula I was derived from a compound that is a nutritional supplement or a food intermediary.

16. A cosmetic composition, comprising at least one compound of claim 2 and a cosmetic ingredient.

17. A pharmaceutical composition, comprising at least one compound of claim 2 and a pharmaceutically acceptable excipient.

18. The composition of claim 17, wherein the composition is suitable for administration via a route selected from oral, enteral, parenteral, topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, and vaginal.

19. The composition of claim 17, wherein the phenolic residue in the compound of formula I was derived from a cancer preventing phenolic

20. The composition of claim 21, further comprising:

an anti-cancer agent.

21. The composition of claim 17, wherein the phenolic residue in the compound of formula I was derived from a phenolic with antimicrobial properties.

22. The composition of claim 21, further comprising:

an antimicrobial agent.

23. The composition of claim 17, wherein the phenolic residue in the compound of formula I was derived from a phenolic with anti-inflammatory properties.

24. The composition of claim 23, further comprising:

anti-inflammatory agent.

25. The composition of claim 17, wherein the phenolic residue in the compound of formula I was derived from a phenolic with pain-reducing properties.

26. The composition of claim 25, further comprising:

a pain reducing agent.

27. The composition of claim 17, wherein the phenolic residue in the compound of formula I was derived from a phenolic with antioxidant properties.

28. The composition of claim 27, further comprising:

an antioxidant agent.

29. A polymer, comprising:

a functionalized phenolic of formula I;

Ar—

[O—

(X)_p—

R′

]_q 

 

I

wherein;

Ar—

(O)_q is a phenolic residue;

X is independently at each occurrence selected from;

—

CH₂COO—

;

—

CH(CH₃)COO—

;

—

CH₂CH₂OCH₂COO—

;

—

CH₂CH₂CH₂CH₂CH₂COO—

;

—

(CH₂)_yCOO—

; and

, —

(CH₂CH₂O)_zCH₂COO—

, where y is independently selected from 2, 3, 4 and 6-24 and z is independently selected from 2-24;

R′

is selected from H, benzyl, and C_1-6 alkyl;

p is independently selected from 0, 1, 2, 3, and 4; and

,

q is selected from 1-10;

provided that at least one X is present; and

,

further provided that when Ar—

[O]_q is hydroxy benzene, then (X)_p is other than —

CH₂COO—

or —

CH₂CH₂CH₂CH₂CH₂COO—

.

30. A polymer of claim 29, wherein

X is selected from:

—

CH₂COO—

;

—

CH(CH₃)COO—

;

—

CH₂CH₂OCH₂COO—

; and

,

—

CH₂CH₂CH₂CH₂CH₂COO—

;

p is 2; and

,

q is selected from 1 and 2;

31. The polymer of claim 30, wherein the functionalized phenolic comprises:

at least two active sites for polymerization, which are independently selected from;

two hydroxyl groups, a hydroxyl group and a carboxylic acid, a hydroxyl group and an amine group, a carboxylic acid group and an amino group; and

two carboxylic acid groups.

32. The polymer of claim 31, wherein the functionalized phenolic is reacted with a compound selected from a dicarboxylic acid, a dialcohol, a diisocyanate, an amino-alcohol, a hydroxycarboxylic acid, and a diamine to form a polymer selected from a polyester, polyurethane, polyesteramide, polyamide, and polyanhydride.

33. The polymer of claim 30, wherein the polymer, further comprises:

a second functionalized phenolic.

34. The polymer of claim 30, wherein the polymer is further polymerized with a lactone monomer.

35. The polymer of claim 34, wherein the lactone monomer is selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, and p-dioxanone.

36. An implantable medical device, comprising:

a polymer of claim 30.

37. The implantable medical device of claim 36, wherein the polymer has been further polymerized with a lactone monomer selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, and p-dioxanone.

38. The implantable medical device of claim 36, wherein the device is a stent.

39. The implantable medical device of claim 38, wherein the polymer has been further polymerized with a lactone monomer selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, and p-dioxanone.

40. The implantable medical device of claim 36, wherein the device is a scaffold for tissue engineer, comprising:

a porous structure for the attachment and proliferation of cells.

41. The implantable medical device of claim 40, wherein the polymer has been further polymerized with a lactone monomer selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, and p-dioxanone.

42. A coating for a stent, comprising:

a polymer of claim 30.

43. The stent coating of claim 42, wherein the polymer has been further polymerized with a lactone monomer selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, and p-dioxanone.

44. A drug delivery system, comprising:

a polymer of claim 30 physically admixed with a biologically or pharmacologically active agent.

45. The drug delivery system of claim 44, wherein the biologically or pharmacologically active agent is physically embedded or dispersed into the polymer and the polymer is in the form of a polymeric matrix.

46. The drug delivery system of claim 44, wherein the polymer has been further polymerized with a lactone monomer selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, and p-dioxanone.

47. A polymer blend, comprising:

two different polymers of claim 30.

48. A nutritional composition, comprising at least one polymer of claim 30.

49. The nutritional composition of claim 48, wherein the phenolic residue in the polymer was derived from a compound that is a nutritional supplement or a food intermediary.

50. A cosmetic composition, comprising at least one polymer of claim 30 and a cosmetic ingredient.

51. A pharmaceutical composition, comprising at least one polymer of claim 30 and a pharmaceutically acceptable excipient.

52. The composition of claim 51, wherein the composition is suitable for administration via a route selected from oral, enteral, parenteral, topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, and vaginal.

53. The composition of claim 51, wherein the phenolic residue in the polymer was derived from a cancer preventing phenolic

54. The composition of claim 53, further comprising:

an anti-cancer agent.

55. The composition of claim 51, wherein the phenolic residue in the polymer was derived from a phenolic with antimicrobial properties.

56. The composition of claim 55, further comprising:

an antimicrobial agent.

57. The composition of claim 51, wherein the phenolic residue in the polymer was derived from a phenolic with anti-inflammatory properties.

58. The composition of claim 57, further comprising:

anti-inflammatory agent.

59. The composition of claim 51, wherein the phenolic residue in the polymer was derived from a phenolic with pain-reducing properties.

60. The composition of claim 59, further comprising:

a pain reducing agent.

61. The composition of claim 51, wherein the phenolic residue in the polymer was derived from a phenolic with antioxidant properties.

62. The composition of claim 61, further comprising:

an antioxidant agent.