FUNCTIONALIZED DIPHENOLICS AND ABSORBABLE POLYMERS THEREFROM

• US 20070135355A1
• Filed: 12/08/2006
• Published: 06/14/2007
• Est. Priority Date: 12/09/2005
• Status: Active Grant

• Current Assignee: Bezwada Biomedical, LLC
• Original Assignee: Bezwada Biomedical, LLC
• Inventors: Bezwada, Rao
• Granted Patent: US 7,935,843 B2
• Time in Patent Office: Days
• US Class Current: 434/350
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

Abstract

The present invention relates to dephenolic compounds, an example of which is shown below, which are functionalized, and polymers formed from the same. Polymers formed from the functionalized diphenolics 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 functionalized diphenolic compound selected from:

wherein;

Amino Acid is independently a phenol-containing amino acid;

X is independently selected from;

—

CH₂COO—

;

—

CH(CH₃)COO—

;

—

CH₂CH₂OCH₂COO—

;

—

CH₂CH₂CH₂CH₂CH₂COO—

;

—

(CH₂)_yCOO—

; and

, —

(CH₂CH₂O)_zCH₂COO—

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

Y is independently selected from;

—

COCH₂O—

;

—

COCH(CH₃)O—

;

—

COCH₂OCH₂CH₂O—

;

—

COCH₂CH₂CH₂CH₂CH₂O—

;

—

CO(CH₂)_mO—

; and

, —

COCH₂O(CH₂CH₂O)_n—

, where m is selected from 2-4 and 6-24 and n is selected from 2-24;

R′

is independently selected from hydrogen, benzyl, and C_1-6 alkyl; and

,

a, b, and c, are independently selected from 0-4, provided that a+b+c total from 1-6.

2. A compound according to claim 1, wherein:

Amino Acid is independently selected from;

tyrosine;

3-aminotyrosine;

3-chlorotyrosine;

3,5-dibromotyrosine;

3,5-diiodotyrosine;

3-iodotyrosine;

3-nitrotyrosine;

2-tyrosine;

3-tyrosine;

thyronine;

homotyrosine;

5-hydroxytryptophan;

3,4-dihydroxyphenylalanine;

4-hydroxyphenylglycine;

3-aminosalicylic acid;

4-aminosalicylic acid; and

5-aminosalicylic acid.

3. A compound according to claim 2, wherein:

each Amino Acid is tyrosine.

4. A functionalized diphenolic compound of formula I, II, or III:

R₁ is a bond or is selected from OCH₂, OCH₂CO₂CH₂, CO₂CH₂CO₂CH₂, CH₂CHR_1a, CH₂CHR_1aCO₂CH₂, CH₂CHR_1aCO₂CH₂CO₂CH₂, CH═

CH or (CH₂)_d;

R_1a is selected from H and NC(O)R′

;

X is independently selected from;

—

CH₂COO—

;

—

CH(CH₃)COO—

;

—

CH₂CH₂OCH₂COO—

;

—

CH₂CH₂CH₂CH₂CH₂COO—

;

—

(CH₂)_yCOO—

; and

, —

(CH₂CH₂O)_zCH₂COO—

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

Y is independently selected from;

—

COCH₂O—

;

—

COCH(CH₃)O—

;

—

COCH₂OCH₂CH₂O—

;

—

COCH₂CH₂CH₂CH₂CH₂O—

;

—

CO(CH₂)_mO—

; and

, —

COCH₂O(CH₂CH₂O)_n—

, where m is selected from 2-4 and 6-24 and n is selected from 2-24;

R′

is independently selected from hydrogen, benzyl, and C_1-6 alkyl;

a, b, and c, are independently selected from 0-4, provided that a+b+c total from 1-6;

d is selected from 1-8; and

,

e is selected from 0, 1, and 2.

5. A compound according to claim 4, wherein the compound is of formula Ia, IIa, or IIIa:

6. A compound according to claim 5, wherein:

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

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

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

n is independently selected from 2, 3, and 4.

7. A compound according to claim 5, wherein:

X is independently selected from;

—

CH₂COO—

;

—

CH(CH₃)COO—

;

—

CH₂CH₂OCH₂COO—

; and

,

—

CH₂CH₂CH₂CH₂CH₂COO—

;

Y is independently selected from;

—

COCH₂O—

;

—

COCH(CH₃)O—

;

—

COCH₂OCH₂CH₂O—

;

—

COCH₂CH₂CH₂CH₂CH₂O—

;

a, b, and c, are independently selected from 0-2, provided that a+b+c total from 2-4; and

,

d is selected from 1, 2, 3, and 4.

8. A compound according to claim 7, wherein:

R′

is independently selected from hydrogen, benzyl, and C_1-4 alkyl;

a, b, and c, are independently selected from 0-2, provided that a+b+c total from 2-3; and

,

d is selected from 1, 2, and 3.

9. A compound according to claim 8, wherein:

R′

is independently selected from hydrogen, benzyl, and CH₃;

a, b, and c, are independently selected from 0-1, provided that a+b+c total from 2-3; and

,

d is selected from 1 and 2.

10. A compound according to claim 5, wherein:

X is —

CH₂COO—

;

Y is —

COCH₂O—

;

R′

is independently selected from hydrogen, benzyl, and C_1-4 alkyl;

a, b, and c, are independently selected from 0-2, provided that a+b+c total from 2-4; and

,

d is selected from 1, 2, 3, and 4.

11. A compound according to claim 10, wherein:

R′

is independently selected from hydrogen, benzyl, and CH₃; and

,

a, b, and c, are independently selected from 0-1, provided that a+b+c total from 2-3; and

,

d is selected from 1 and 2.

12. A compound according to claim 4, wherein the compound is selected from:

13. A composition, comprising:

two or more different compounds of claim 4.

14. A solvent for a drug, comprising:

at least one compound of claim 4.

15. A nutritional composition, comprising at least one compound of claim 4.

16. A cosmetic composition, comprising at least one compound of claim 4 and a cosmetic ingredient.

17. A pharmaceutical composition, comprising at least one compound of claim 4 and a pharmaceutically acceptable excipient.

18. A polymer, comprising:

a functionalized diphenolic compound of formula I, II, or III;

III

wherein;

R₁ is a bond or is selected from OCH₂, OCH₂CO₂CH₂, CO₂CH₂CO₂CH₂, CH₂CHR_1a, CH₂CHR_1aCO₂CH₂, CH₂CHR_1aCO₂CH₂CO₂CH₂, CH═

CH or (CH₂)_d;

R_1a is selected from H and NR′

R′

;

X is independently selected from;

—

CH₂COO—

;

—

CH(CH₃)COO—

;

—

CH₂CH₂OCH₂COO—

;

—

CH₂CH₂CH₂CH₂CH₂COO—

;

—

(CH₂)_yCOO—

; and

, —

(CH₂CH₂O)_zCH₂COO—

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

Y is independently selected from;

—

COCH₂O—

;

—

COCH(CH₃)O—

;

—

COCH₂OCH₂CH₂O—

;

—

COCH₂CH₂CH₂CH₂CH₂O—

;

—

CO(CH₂)_mO—

; and

, —

COCH₂O(CH₂CH₂O)_n—

, where m is selected from 2-4 and 6-24 and n is selected from 2-24;

R′

is independently selected from hydrogen, benzyl, and C_1-6 alkyl;

a, b, and c, are independently selected from 0-4, provided that a+b+c total from 1-6;

d is selected from 1-8; and

,

e is selected from 0, 1, and 2.

19. The polymer of claim 18, wherein the functionalized diphenolic compound is of formula Ia, IIa, or IIIa:

20. The polymer of claim 19, wherein:

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

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

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

n is independently selected from 2, 3, and 4.

21. The polymer of claim 19, wherein:

X is independently selected from;

—

CH₂COO—

;

—

CH(CH₃)COO—

;

+P2

—

CH₂CH₂OCH₂COO—

; and

,

—

CH₂CH₂CH₂CH₂CH₂COO—

;

Y is independently selected from;

—

COCH₂O—

;

—

COCH(CH₃)O—

;

—

COCH₂OCH₂CH₂O—

;

—

COCH₂CH₂CH₂CH₂CH₂O—

;

a, b, and c, are independently selected from 0-2, provided that a+b+c total from 2-4; and

,

d is selected from 1, 2, 3, and 4.

22. The polymer of claim 21, wherein:

R′

is independently selected from hydrogen, benzyl, and C_1-4 alkyl;

a, b, and c, are independently selected from 0-2, provided that a+b+c total from 2-3; and

,

d is selected from 1, 2, and 3.

23. The polymer of claim 22, wherein:

R′

is independently selected from hydrogen, benzyl, and CH₃;

a, b, and c, are independently selected from 0-1, provided that a+b+c total from 2-3; and

,

d is selected from 1 and 2.

24. The polymer of claim 19, wherein:

X is —

CH₂COO—

;

Y is —

COCH₂O—

;

R′

is independently selected from hydrogen, benzyl, and C_1-4 alkyl;

a, b, and c, are independently selected from 0-2, provided that a+b+c total from 2-4; and

,

d is selected from 1, 2, 3, and 4.

25. The polymer of claim 24, wherein:

R′

is independently selected from hydrogen, benzyl, and CH₃; and

,

a, b, and c, are independently selected from 0-1, provided that a+b+c total from 2-3; and

,

d is selected from 1 and 2.

26. The polymer of claim 19, wherein the functionalized diphenolic 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.

27. The polymer of claim 26, wherein the polymer, further comprises:

a second functionalized diphenolic.

28. The polymer of claim 26, wherein the polymer is further polymerized with a lactone monomer.

29. The polymer of claim 28, wherein the lactone monomer is selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, and p-dioxanone.

30. An implantable medical device, comprising:

a polymer of claim 26.

31. The implantable medical device of claim 30, wherein the polymer has been further polymerized with a lactone monomer selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, and p-dioxanone.

32. The implantable medical device of claim 30, wherein the device is a stent.

33. The implantable medical device of claim 32, wherein the polymer has been further polymerized with a lactone monomer selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, and p-dioxanone.

34. The implantable medical device of claim 30, wherein the device is a scaffold for tissue engineer, comprising:

a porous structure for the attachment and proliferation of cells.

35. The implantable medical device of claim 34, wherein the polymer has been further polymerized with a lactone monomer selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, and p-dioxanone.

36. A coating for a stent, comprising:

a polymer of claim 26.

37. The stent coating 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. A drug delivery system, comprising:

a polymer of claim 26 physically admixed with a biologically or pharmacologically active agent.

39. The drug delivery system of claim 38, 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.

40. The drug delivery system of claim 39, wherein the polymer has been further polymerized with a lactone monomer selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, and p-dioxanone.