FUNCTIONALIZED PHENOLIC ESTERS AND AMIDES AND POLYMERS THEREFROM

• US 20110130448A1
• Filed: 12/07/2010
• Published: 06/02/2011
• 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 8,372,882 B2
• Time in Patent Office: Days
• US Class Current: 514/456
• 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
  • —COCH₂—O—(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′

AR—

O—

is a biologically active phenolic moiety selected from the group consisting of isopimpinellin, isoflavones, resveratrol, and bioflavonoids substituted with (a) a functional group selected from the group consisting of alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid, —

NO₂, —

NH₂, NHCOCH₃, —

NH—

Y—

R′

, and a combination thereof, and (b) AR representing 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)

—

COCH₂OCH₂CH₂O—

(dioxanone ester moiety)

—

COCH₂CH₂CH₂CH₂CH₂O—

(caprolactone ester moiety)

—

CO(CH₂)_mO—

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

—

COCH₂—

O—

(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 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.

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

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

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

82. The polymer of claim 18, wherein said phenolic moiety is an isoflavone or an isopimpinellin or a combination thereof.

83. The polymer according to claim 82, wherein the isoflavone is selected from the group consisting of:

biochanin A, daidzein, formononetin, genistein, glycitein, orobol, pratensein, prunetin, and santal, and glucosides or β

-glycosides thereof or a combination thereof.

84. The polymer of claim 83, wherein the isoflavone is selected from the group consisting of daidzein, equol, and gycitein or a combination thereof.

85. The polymer of claim 18, wherein said phenolic moiety is resveratrol.

3-4. -4. (canceled)

8-17. -17. (canceled)

19. The polymer of claim 19, 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 19, 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 19, 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 19, 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.

23-81. -81. (canceled)

86. A monomeric unit having the formula:

AR—

O—

Y—

R′

(a) AR—

O—

is selected from a group consisting of;

anthocyanidins, anthocyanins, bioflavanones, biflavans, bioflavones, bioflavanols, 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; and

glucosides or 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;

(b) and the aryl portion of AR—

O—

comprise the functional group R selected from the group consisting of alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid, —

NO₂, —

NH₂, NHCOCH₃, —

NH—

Y—

R′

, and a combination thereof, 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),

—

COCH₂—

O—

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

R is attached directly or through an aliphatic chain to the aryl ring of the AR—

O.

87. The polymer of claim 86, wherein m is 1 and Y is —

COCH₂O—

(glycolic ester moiety).

88. The polymer of claim 86, wherein m is 5 and Y is COCH₂CH₂CH₂CH₂CH₂O—

(caprolactone ester moiety).

89. The polymer of claim 86 wherein AR is a substituted diphenolic residue selected from the group consisting of chromones;

flavones;

flavanones and isoflavones.

90. 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 86.

91. 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 86, a pharmaceutically acceptable excipient, and, optionally, further comprising an antimicrobial agent, wherein said biologically active phenolic moiety has antimicrobial properties.

92. 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 86, a nutritionally acceptable excipient, and optionally, vitamins.

93. A monomeric unit having the formula:

AR—

O—

X—

R′

(a) -AR—

O—

is a bioflavanoid or a phenolic residue thereof selected from the group consisting of;

anthocyanidins, anthocyanins, bioflavanones, biflavans, bioflavones, bioflavanols, 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; and

glucosides or β

-glycosides thereof,

(b) the aryl ring of AR—

O comprise the functional group 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, or combinations thereof;

(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)_zCH₂COO—

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

and the methylene end of X is attached to said bioflavonoid; and

R′

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

94. The polymer of claim 93, wherein AR is a substituted diphenolic residue selected from the group consisting of chromones;

flavones;

flavanones and isoflavones.

95. The polymer of claim 93, wherein m is 1 and Y is —

COCH₂O—

(glycolic ester moiety).

96. The polymer of claim 93, wherein m is 5 and Y is COCH₂CH₂CH₂CH₂CH₂O—

(caprolactone ester moiety).

97. 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 94.