Functionalized phenolic esters and amides and polymers therefrom

• US 8,372,882 B2
• Filed: 12/07/2010
• Issued: 02/12/2013
• Est. Priority Date: 01/28/2005
• Status: Active Grant

• Current Assignee: Bezwada Biomedical, LLC
• Original Assignee: Bezwada Biomedical, LLC
• Inventors: Bezwada, Rao S.
• Primary Examiner(s): DICKINSON, PAUL W
• Application Number:
  US12/962,195
• Publication Number:
  US 20110130448A1
• Time in Patent Office: 798 Days
• Field of Search: None
• US Class Current: 514/506
• 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, salicyclic 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
  • —CO CH₂O (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 having the formula comprising:

AR—

O—

Y—

R′

wherein (a) AR—

O—

is a biologically active phenolic moiety selected from the group consisting of isopimpinellin, isoflavones and resveratrol, substituted with one or more functional groups selected from the group consisting of alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid, —

NO₂, —

NH₂, NHCOCH₃, and —

NH—

Y—

R′

, and (b) AR represents an aromatic moiety comprising 1 to 3 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)

—

COCH₂OCH₂ CH₂O—

(dioxanone ester moiety)

—

COCH₂CH₂CH₂CH₂CH₂O—

(caprolactone ester moiety)

—

CO(CH₂)_mO—

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

—

COCH₂O(CH₂CH₂O)_n—

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

the carbonyl end of Y is attached to the O—

of said biologically active phenolic moiety to form an ester linkage; and

R′

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

3. A composition comprising two or more of the compounds according to claim 1.

2. A compound having the formula comprising:

AR—

O—

Y—

R′

wherein (a) AR—

O—

is a biologically active phenolic moiety selected from the group consisting of phenols, naphthols, flavonoids, isoflavonoids, coumarins, chromones, chalcones, cinnamic acids, benzoic acids, indoles, acetophenones, benzophenones, alkaloids, catechins, catechols, aminoalcohols, aminosalicylic acids, hydrocinnamic acids, phenolic acids, resorcinol, and hydroquinone, substituted with one or more functional groups selected from the group consisting of alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid, —

NO₂, —

NH₂, NHCOCH₃, and —

NH—

Y—

R′

, and (b) AR represents an aromatic moiety comprising 1 to 3 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)

—

COCH₂OCH₂ CH₂O—

(dioxanone ester moiety)

—

COCH₂CH₂CH₂CH₂CH₂O—

(caprolactone ester moiety)

—

CO(CH₂)_mO—

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

—

COCH₂O(CH₂CH₂O)_n—

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

the carbonyl end of Y is attached to the O—

of said biologically active phenolic moiety to form an ester linkage; and

R′

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

4. A composition comprising two or more of the compounds according to claim 2.

5. A compound having the formula:

AR—

O—

Y—

R′

wherein,

(a) AR—

O—

is selected from the group consisting of anthocyanidins, anthocyanins, coumarins, chromones, chalcones, cinnamic acids, catechins, epicatechin, epicatechin gallate, epigallocatechin gallate, hydroxyethylrutosides (HER), hesperidin, leucoanthocyanins, polyphenols, proanthocyanidins, procyanidolic oligomers (PCO), quercetin, quercetrin, resveratrol, rutin, rutinosides;

glucosides thereof and β

-glycosides thereof;

comprising 1 to 3 substituted or unsubstituted aryl rings that are directly bonded to each other, fused together, or joined through a linking group, and being a residue of said phenolic moiety with at least two active sites for polymerization; and

(b) the aryl portion of AR—

O—

comprises one or more functional groups R selected from the group consisting of alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid, —

NO₂, —

NH₂, NHCOCH₃, —

NH—

Y—

R′

, and

Y represents a member selected from the group consisting of;

—

CO(CH₂)_mO—

where m is an integer between 1-24 inclusive,

—

COCH(CH₃)O—

(lactic ester moiety),

—

COCH₂OCH₂CH₂O—

(dioxanone ester moiety),

—

COCH₂O(CH₂CH₂O)_n—

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

is attached via its carbonyl end to the O—

of said biologically active phenolic moiety to form an ester linkage;

R′

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

R is attached directly or through an aliphatic chain to the aryl ring of the AR-O moiety.

6. The compound of claim 5, wherein m is 1 and Y is —

COCH₂O—

(glycolic ester moiety).

7. The compound of claim 5, wherein m is 5 and Y is COCH₂CH₂CH₂CH₂CH₂O—

(caprolactone ester moiety).

8. The compound of claim 5 wherein AR is a substituted diphenolic residue selected from the group consisting of chromones, flavones, flavanones and isoflavones.

9. A method for delivering a therapeutic polymer to a patient in need of antioxidant therapy comprising administrating to the patient and antioxidant composition comprising an effective amount of the compound of claim 5.

10. A method for treating a patient in need of antimicrobial therapy comprising administering to the patient an antimicrobial composition comprising an effective amount of the compound of claim 5, a pharmaceutically acceptable excipient, and, optionally, further comprising an antimicrobial agent, wherein said biologically active phenolic moiety has antimicrobial properties.

11. A method for providing nutritional supplementation in a patient in need thereof comprising administering to the patient a nutrition supplement comprising the compound of claim 5, a nutritionally acceptable excipient, and optionally, vitamins.

12. A compound having the formula:

AR—

O—

X—

R′

wherein,

(a) AR—

O—

is a phenolic residue selected from the group consisting of;

anthocyanidins, anthocyanins, coumarins, chromones, chalcones, cinnamic acids, catechins, epicatechin, epicatechin gallate, epigallocatechin gallate, hydroxyethylrutosides (HER), hesperidin, leucoanthocyanins, polyphenols, proanthocyanidins, procyanidolic oligomers (PCO), quercetin, quercetrin, reservetrol, rutin, rutinosidesand, glucosides thereof and β

-glycosides thereof,

(b) the aryl ring of AR-O comprises one or more functional groups R attached to said aryl ring directly or via an aliphatic chain, wherein R is selected from a group consisting of H, alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid, —

NO₂, —

NH₂, NHCOCH₃, and —

NHCOCH₂OH;

(c) 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)_z CH₂COO—

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

and the methylene end of X is attached to said phenolic residue; and

R′

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

13. The compound of claim 12, wherein AR is a substituted diphenolic residue selected from the group consisting of chromones, flavones, flavanones and isoflavones.

14. The compound of claim 12, wherein X is —

CH₂COO—

(glycolic acid moiety).

15. The compound of claim 12, wherein X is —

CH₂CH₂CH₂CH₂CH₂COO—

(caprolactone moiety).

16. A method for delivering a therapeutic polymer to a patient in need of antioxidant therapy comprising administering to the patient an antioxidant composition comprising an effective amount of the compound of claim 13.