US 20090170927A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2009/0170927 A1 Bezwada (43) Pub. Date: Jul. 2, 2009 (54) FUNCTIONALIZED PHENOLIC Related U.S. Application Data COMPOUNDS AND POLYMERS (60) Provisional application No. 60/728,823, filed on Oct. THEREFROM 21, 2005. Publication Classification (75) Inventor: Rao S. Bezwada, Hillsborough, NJ (US) (51) Int. Cl. A61 K. 3 1/35 (2006.01) C07D 3II/04 (2006.01) Correspondence Address: C07D 493/04 (2006.01) FELDMANGALE, P.A. A61 K. 3 1/352 (2006.01) 1700 Market Street, Suite # 3130 A6IP 35/06) (2006.01) Philadelphia, PA 19103 (US) A6.1 F 2/06 (2006.01) (52) U.S. Cl. ......... 514/455; 549/403; 549/387: 514/456; 528/125; 528/208: 528/190: 525/397: 514/772.3: (73) Assignee: BEZWADA BIOMEDICAL, 424/486; 523/113; 623/1.42 LLC, Hillsborough, NJ (US) (57) ABSTRACT The present invention relates to compounds of formula I, (21) Appl. No.: 12/089,101 which are functionalized phenolic compounds, and polymers formed from the same. (22) PCT Filed: Oct. 16, 2006 Polymers formed from the functionalized phenolics are (86) PCT No.: PCT/US2006/060002 expected to have controllable degradation profiles, enabling them to release an active component over a desired time § 371 (c)(1), range. The polymers are also expected to be useful in a variety (2), (4) Date: Aug. 18, 2008 of medical applications. US 2009/0170927 A1 Jul. 2, 2009 FUNCTIONALIZED PHENOLIC [0007] Other features of the present invention will be COMPOUNDS AND POLYMERS pointed out in the following description and claims. THEREFROM DETAILED DESCRIPTION OF THE PRESENT FIELD OF THE INVENTION INVENTION [0008] The present invention provides novel functionalized [0001] The present invention relates to the discovery of phenolic compounds and absorbable polymers derived from functionalized phenolic compounds and polymers derived them. The present invention is designed to extend the useful therefrom, which can have controllable degradation profiles. ness of phenolic compounds while retaining their inherent biological properties. The phenolic compounds are function BACKGROUND OF THE INVENTION alized with safe and biocompatible molecules (e.g., glycolic acid, lactic acid, caprolactone, and dioxanone). The novel [0002] There are a vast number of known phenolic com functionalized phenolic compounds of the present invention pounds orphenolics (e.g., flavonoids) with a variety of known are expected to have controllable hydrolysis profiles, beneficial uses. Phenolic and polyphenolic compounds are improved bioavailability, improved efficacy, and enhanced found widely in nature: in cereals, legumes, nuts, oilseeds, functionality. plant oils, fruits, vegetables, tea, coffee, cocoa, beer, wine, [0009] Some of the functionalized phenolic compounds of herbal products, such as Echinacea, ginseng, gingko biloba, the present invention can be monomers from which polymers St. John’s wort, Valerian, hawthorne, ginger, licorice, milk can be made that are useful for medical applications. For thistle, goldenseal, devil’s claw, black cohosh, saw palmetto, example, a phenolic compound can be functionalized to form and kavakava, for example. These substances are essential for functionalized monomers that can then be polymerized to growth and reproduction of plants and serve as antifeedants form absorbable polymers (e.g., polyesters, polyamides, and antipathogens, among other purposes. Phenolic com polyester amides, polyurethanes, and polyanhydrides). It can pounds can also aid in the maintenance of food, fresh flavor, be advantageous for the monomers that are to be polymerized taste, color, and prevention of oxidation deterioration. Many to have at least two active sites (e.g., 2 or 3) for polymeriza phenolic compounds are attracting the attention of food and tion. These active sites include hydroxyl, amino, and car medical scientists because of their antioxidative, anti-inflam boxylic acid groups (e.g., two hydroxyl groups, a hydroxyl matory, antimutagenic, and anticarcinogenic properties, and group and a carboxylic acid, a hydroxyl group and an amine their capacity to modulate key cellular enzyme function. Phe group, a carboxylic acid group and an amino group, and two nolics pigment plant products and function as antibiotics, carboxylic acid groups). The functionalized phenolic com natural pesticides, signal substances for the establishment of pounds with at least two active sites can also be copolymer symbiosis with rhizobia, attractants for pollinators, protective ized with selected difunctional molecules (e.g., dicarboxylic agents against ultraviolet light, insulating materials to make acids, dialcohols, diisocyanates, amino-alcohols, hydroxy cell walls impermeable to gas and water, and as structural carboxylic acids, and diamines) based on the starting func materials to give plants stability. The members of this class tionalized phenolic to form absorbable polymers. The poly have many valuable uses in the fields of nutrition, nutriceuti mers (and copolymers) of the present invention can also be cals, pharmaceuticals, medicine, agriculture, chemistry, and further reacted/polymerized to form additional useful poly in other fields of technology. mers of the present invention. [0003] Unfortunately, phenolic compounds generally can [0010] The definitions and examples provided in this appli be difficult to dissolve in water or the human body and can cation are not intended to be limiting, unless specifically also be very difficult to polymerize in the phenolic state. Due stated. to the availability and numerous uses of phenolics, it is desir [0011] Phenolic compound (also called phenolics) as used able to enhance their native value by, for example, providing herein are defined substances that have at least one phenyl compounds or combinations of compounds with a specific ring that is substituted with at least on hydroxyl group (e.g., controlled degradation profile or range enabling controlled hydroxy-phenyl). [0012] Phenolic residue means the portion of the phenolic release of the phenolic over an extended, controllable time compound remaining after removing a H from at least one range. hydroxyl group. [0013] Ar, as used herein, is an aromatic moiety that typi SUMMARY OF INVENTION cally has 1, 2, 3, 4, 5, or 6 aromatic rings (e.g., phenyl) and bear one or more hydroxyl substituents (e.g., 1, 2, 3, 4, 5, 6, 7, [0004] The present invention provides novel functionalized 8, 9, 10, 11, 12, 13, 4, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and phenolic compounds, which are hydrolysable and can be 25) on at least one of the aromatic rings. Additional examples useful for medical applications (e.g., drug delivery and sol of the number of aromatic groups present in the phenolic vent for dissolving drugs). include (a) 1, 2, and 3 and (b) 1 and 2. Additional examples of [0005] The present invention also provides novel, absorb the number of hydroxyl groups present on the phenolic able polymers and co-polymers (e.g., polyesters, polyamides, include (a) 1, 2, 3, 4, and 5 and (b) 1 and 2. From one to all of polyester amides, polyurethanes, and polyanhydrides) the hydroxyl groups present on the phenolic compound may derived from functionalized phenolic compounds. These be functionalized. Phenolics are typically bioactive sub polymers are expected to have controllable degradation pro stances occurring widely in food plants that are eaten regu files. larly by substantial numbers of animals and people and have [0006] The present invention also provides novel medical been found to be safe compounds. devices comprising functionalized phenolic compounds or [0014] The aromatic rings of the Ar group can be fused polymers derived from functionalized phenolic compounds. together (e.g., naphthyl), bonded together (e.g., bi-phenyl), or US 2009/0170927 A1 Jul. 2, 2009 linked together via a linking group. Typical linking groups [0017| Examples of substituent R include H, -O, O-gly include, O, S(O)o.2, NH (or a substituted amine, e.g., Cl-g cosides, –(CH2)o 2–OR*, -(CH2)o 2–CaFis, -(CH2)o. alkyl, phenyl, or benzyl), C1-6 alkylene, or a C1-6 alkylene 2–CHO, CI, F, Br, I, -(CH2)o 2–OC(O)—R“, -(CH2)o. wherein one or two of the alkylene carbon atoms is replaced 2–CO2–R*, -(C(CH3))o 2–CO2–R*, -(CH2)o 2– by one or two of the previously noted heteroatoms. The aro CO2–(CH2), 2–CO2–R“, -(C(CH3))o 2–CO2–(CH2) matic rings of the Ar group can also be fused to heteroaryl 1-2–CO2–R*, (CH2)o 2–CO-R*, O(CH2)o 2– rings and/or non-aromatic rings. Examples of heteroaryl CaFis, -O(CH3)1-2–CO2–R“, -O(C(CH3)), 2–CO2– rings include 5-6 membered rings consisting of carbon atoms R“, -O(CH2), 2–CO-R“, -CO2(CH2), 2–CO2–R*, and 0-4 heteroatoms selected from O, N, and S(O)o 2. —CO2(C(CH3)), 2–CO2–R*, -(CH2)6-2–NO2. –(CH2) Examples of non-aromatic rings include 5-6 membered car o 2–NR"R", -(CH2), 2–NR"COR*, *-(CH2), 2–NR"C bocyclic or heterocyclic rings consisting of carbon atoms and (O)(CH2), 20R*, -CoIHs, -CoIHsOR*, and –CaFis– 0-3 heteroatoms selected from O, N, and S(O)o 2. The non CH=CHCO.R.". aromatic rings can consist of 0–2 ring double bonds as well as [0018] Examples of Rº include H and C1-c alkyl; 0-2 carbonyl groups attached to the ring. Examples of non [0019] As described herein, the functionalized phenolic aromatic rings include pyran and pyran-one. The non-aro compounds and polymers of the present invention are matic rings can also be substituted by 1-2 carbonyl groups, in expected to be useful in medical applications/medical addition to other substituents defined elsewhere. When more devices. Medical application/medical devices, as used herein, than one aromatic ring is present (e.g., two phenyl rings), then encompass medical and biomedical applications and include they can be separated by a heteroaryl or non-aromatic ring as all types of applications involved in the practice of medicine described above.