(12) United States Patent (10) Patent No.: US 8,062,653 B2 Bezwada (45) Date of Patent: Nov

US008062653B2

(12) United States Patent (10) Patent No.: US 8,062,653 B2 BeZWada (45) Date of Patent: Nov. 22, 2011

(54) CONTROLLED RELEASE OF NITRICOXIDE 7,629,368 B2 12/2009 Del Soldato et al. AND DRUGS FROM FUNCTIONALIZED 292 s R: $33.9 ES tal MACROMERS AND OLGOMERS 7,858,6654 - B2 12/2010 OnginiSOCO et al. a 7,883,714 B2 2/2011 Earl et al. (75) Inventor: Rao S. Bezwada, Whitehouse Station, 2002fOO28845 A1 3/2002 Ekwuribe et al. NJ (US) 2002.0143047 A1* 10, 2002 Galer et al...... 514,420 2008/0175881 A1* 7/2008 Ippolitietal...... 424/423 (73) Assignee: Bezwada Biomedical, LLC, 2008/028817.6 A1 11/2008 Tam et al. Hillborough, NJ (US) 2009/0076174 A1 3, 2009 Bezwada 2l, 2009/0092676 A1* 4/2009 Richard et al...... 424,501 (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 CN 101.053662 * 10/2007 U.S.C. 154(b) by 175 days. CN 101.053662 A 10, 2007 WO O1-30334 A2 5, 2001 (21) Appl. No.: 12/508,854 WO 2004-004648 A2 1, 2004 WO WO 2005/05.3685 A1 * 6/2005 WO WO 2007/O25632 A1 * 3, 2007 (22) Filed: Jul. 24, 2009 WO WO 2007/090793 A1 * 8, 2007 WO WO 2008/071421 A1 * 6, 2008 (65) Prior Publication Data k cited. by examiner US 2010/0209469 A1 Aug. 19, 2010 Primary Examiner — Blessing Fubara Related U.S. Application Data (74) Attorney, Agent, or Firm — Moser Taboada (60) Pygal application No. 61/153,349, filed on Feb. (57) ABSTRACT s The present invention provides NO and, optionally, drug (51) Int. Cl. releasing macromers and oligomers wherein the drug mol A6F 2/00 (2006.01) ecule and NO releasing moiety are linked an absorbable mac A63/74 (2006.01) romer or oligomeric chain susceptible to hydrolytic degrada A6 IK3I/21 (2006.01) tion and wherein the macromer or oligomer comprises of (52) U.S. Cl...... 424/423; 424/78.08: 514/509 repeat units derived from Safe and biocompatible molecules (58) Field of Classification Search ...... 424/423, such as glycolic acid, lactic acid, caprolactone and p-diox 424/78.08: 514/509; 525/450, 415 anone. Furthermore, the present invention relates to con See application file for complete search history. trolled release of nitric oxide (NO) and/or drug molecule from a NO and drug releasing macromer or oligomer. More (56) References Cited over, the present invention also relates to medical devices, medical device coatings and therapeutic formulations com U.S. PATENT DOCUMENTS prising of nitric oxide and drug releasing macromers and 7,199,258 B2 4/2007 Del Soldato et al. oligomers of the present invention. 7,279, 176 B1 * 10/2007 West et al...... 424/426 7,442,826 B2 10/2008 Rivolta et al. 17 Claims, No Drawings US 8,062,653 B2 1. 2 CONTROLLED RELEASE OF NITRC OXDE Medical research is rapidly discovering therapeutic appli AND DRUGS FROM FUNCTIONALIZED cations for NO including the fields of vascular surgery and MACROMERS AND OLGOMERS interventional cardiology. For example, Stents and DES car diovascular stents have been used clinically for treatment of This Application claims the priority of U.S. Ser. No. 5 occluded cardiac arteries for over fifteen years and their use 61/153,349, filed 18 Feb. 2009. has resulted in substantial clinical benefit for cardiac patients. However, a significant problem with bare-metal stents in FIELD OF THE INVENTION clinical usage is restenosis of the artery, leading to recurrence of the primary cardiac symptoms and effects. Localized NO The present invention relates to NO and, optionally, drug 10 release appears to address Some of the root causes of the molecule releasing macromers and oligomers wherein the restenosis including: 1) the fibrinogen binding-platelet adhe drug molecule and NO releasing moiety are linked a hydro sion-release of platelet derived growth factor cycle and 2) lytically degradable macromer or oligomeric chain compris inflammation and associated release of growth factors. NO ing of repeat units derived from safe and biocompatible mol release also addresses associated problems with undesired ecules such as glycolic acid, lactic acid, caprolactone and 15 smooth muscle cell growth (Raulli et al. WO2007/053578 p-dioxanone. The present invention also relates to controlled A2), and provides a long-term biocompatible solution to the release of NO and, optionally drug molecule from macromers presence of the stent by stimulating rapid endothelialization and oligomers of the present invention. Furthermore, the of the stent itself. Stent endothelialization results in a natural present invention relates to medical devices, medical device cell coating for the stent that essentially seeks to make the coatings and therapeutic formulations comprising nitric stent surface invisible to the blood and its components. oxide and drug releasing macromers and oligomers of the Delayed endothelialization has been linked of late in stent present invention. thrombosis, a potentially fatal event. Thus, the use of nitric The present invention relates to NO and, optionally, drug oxide eluting stent coatings has many advantages over anti molecule releasing macromers and oligomers wherein the proliferatives drugs, especially at the very early stages in the drug molecule and NO releasing moiety are linked to a hydro 25 stent placement pathophysiology. One of the key benefits of lytically degradable macromer or oligomeric chain compris NO is the stimulation of endothelialization which is a primary ing of repeat units derived from safe and biocompatible mol measure of healing. Thus, rapid division of endothelial cells ecules such as glycolic acid, lactic acid, caprolactone and and their rapid colonization of the stent material may be an p-dioxanone. The present invention also relates to controlled ultimate safety feature in DES development. Hence, there release of NO and drug molecule from macromers and oligo 30 exists a need for better technology addressing the release of mers of the present invention. Furthermore, the present inven NO and, optionally, additional drugs in drug-eluting stents. tion relates to medical devices, medical device coatings and Researchers have sought various ways to deliver NO to therapeutic formulations comprising nitric oxide and drug damaged tissue and to tissues and organs at risk of injury. One releasing macromers and oligomers of the present invention. approach for providing a therapeutic level of NO at an injury Nitric oxide (referred to herein as “NO”) is a vital biologi 35 site is to increase systemic NO levels prophylactically. This cal molecule. It plays a significant role in diverse biological can be accomplished by Stimulating endogenous NO produc processes such as host defense, cardiovascular regulation, tion or using exogenous NO sources. Methods to regulate signal transduction, neurotransmission and woundhealing. In endogenous NO release have primarily focused on activation addition to helping body cells to communicate with each of synthetic pathways using excess amounts of NO precursors other by transmitting signals throughout the entire body, NO 40 like L-arginine, or increasing expression of nitric oxide Syn assists the immune system at fighting offbacteria and defend thase (NOS) using gene therapy. U.S. Pat. Nos. 5.945,452, ing against tumors. Furthermore, it helps reduce inflamma 5,891.459 and 5,428,070 describe sustained NO elevation tion and regulate blood pressure by dilating arteries. More using orally administrated L-arginine and/or L-lysine. How over, NO assist in gastric motility and alleviating erectile ever, these methods have not been proven effective in pre dysfunction. 45 venting restenosis. Regulating endogenously expressed NO NO is a well known inhibitor of platelet adhesion and using gene therapy techniques remains highly experimental activation. Continuous release of NO from surface of endot and has not yet proven safe and effective. U.S. Pat. Nos. helial cells effectively prevents the adhesion/activation of 5,268,465, 5,468,630 and 5,658,565, describe various gene platelets on normal blood vessel walls. Furthermore, NO is therapy approaches. also a potent inhibitor of smooth muscle cell proliferation, 50 Exogenous NO sources Such as pure NO gas are highly and agents that release or generate NO locally have been toxic, short-lived and relatively insoluble in physiological proposed as Systematic drugs to prevent and/or treat resteno fluids. Consequently, systemic exogenous NO delivery is sis and thrombus formation when delivered to treatment sites generally accomplished using organic nitrate pro-drugs such inside an individual that have come in contact with medical as nitroglycerin tablets, intravenous Suspensions, sprays and devices such as cardiovascular drug-eluting stents, diagnostic 55 transdermal patches. The human body rapidly converts nitro catheters, guide wires, guide catheters, PTCA balloon cath glycerin into NO; however, enzyme levels and co-factors eters (for percutaneous transluminal coronary angioplasty) in required to activate the pro-drug are rapidly depleted, result blood vessels, in-dwelling sheaths (venous and arterial), ing in drug tolerance. Moreover, systemic NO administration intraaortic balloon pump catheters, intravascular sensors, can have devastating side effects including hypotension and extracorporeal blood loop circuits, intravenous grafts/shunts 60 free radical cell damage. Therefore, using organic nitrate and adhesion prevention barriers including meshes. Further pro-drugs to maintain systemic anti-restenotic therapeutic more, NO released from wound resident cells also play an blood levels is not currently possible. important role in unique cell signaling pathways and the Ideally, NO should be delivered in a controlled manner re-establishment of the microcirculation as newly vascular specifically to those tissues and organs that have been injured ized tissue is formed. Moreover, NO is anti-inflammatory, 65 or are at risk of injury. Furthermore, topical NO delivery may which would be of value for in dwelling urethral or TPN also be a crucial component of a new generation of wound catheters. dressings, since few controlled release drugs are currently US 8,062,653 B2 3 4 available. Therefore, considerable attention has been focused tions thereof and their blends with absorbable and non-ab on localized, or site specific, NO delivery to ameliorate the Sorbable polymers for applications in medical devices and disadvantages associated with systemic prophylaxis. medical device coatings. Moreover, the Nicoletta disclosure Implantable medical devices and/or local gene therapy tech also does not teach art by which the rate of release of NO can niques including medical devices coated with NO-releasing be controlled. compounds, or vectors that deliver NOS genes to target cells, There are a number of delivery methods of nitric oxide have been evaluated. Like their systemic counterparts, gene through a polymer including use of Small molecule N-diaz therapy techniques for the localized NO delivery have not eniumdiolates from a pore matrix (WO 2007/053578, Raulli been proven safe and effective. There are still significant et al), use of N-diazeniumdiolate polymers (U.S. Pat. Nos. technical hurdles and safety concerns that must be overcome 10 5,405,919 and 5,525,357 Keefer et al., U.S. Pat. No. 6,703, before site-specific NOS gene delivery will become a reality. 046 Fitzhugh et al), nitrosothiols (U.S. Pat. No. 6,673,891 However, significant progress has been made in the field of Stamler et al.) and nitroprusside (U.S. Pat. No. 6,656,217 localized exogenous NO application. To be effective at pre Herzog et al.). However, N-diazeniumdiolate small mol venting restenosis, an inhibitory therapeutic Such as NO must ecules and polymers have the potential to form carcinogenic be administered at a controlled rate for a sustained period at 15 nitrosamines (WO 2007/053578, Raulietal). The nitrosothi therapeutic levels. Consequently, any NO-releasing medical ols have been shown to be unstable and labile to standard device that releases NO at a controlled rate and is used to treat sterilization methods, and nitroprusside is difficult to steril restenosis must be Suitable for implantation. An ideal candi ize. Both nitrosothiols and nitroprusside require metabolism date device is the drug eluting vascular stent. Therefore, a to release NO and are subject to tolerance formation. Arnold stent that safely provides therapeutically effective amounts of et al. have previously reported C-diazeniumdiolate polymers NO and a drug molecule at a controlled rate to a precise (U.S. Pat. No. 7,105,502; US Pat. Application 2005/ location simultaneously would represent a significant 0203069). C-daizemiumdiolate polymers were also reported advance in restenosis treatment and prevention. by Kalivretenos et al. (WO 2007/053578). Chen et al (US Various compounds have been used to deliver NO thera Patent Application 2008/0220048) reported NO releasing peutically. Nitric oxide-releasing compounds Suitable for in 25 biodegradable polymers derived from 1.4 oxazepan-7-one vivo applications have been developed by a number of inves Suitable for use as medical devices and coatings for medical tigators. As early as 1960 it was demonstrated that nitric oxide devices. Raulli et al (WO 2007/053578) described multi gas could be reacted with amines to form NO-releasing phasic nitric oxide and anti-proliferative drug eluting poly anions having the following general formula 1 R RN N mer coatings for medical devices wherein the NO is released (O)NO wherein Rand Rare ethyl. Salts of these compounds 30 by a NO donor selected from a group consisting of C-diaz could spontaneously decompose and release NO in solution. eniumdiolates, O-diazenium diolates, N-diazenium diolates, (Chen et al. US 2008/0220048A1). nitrosothiols, organic nitrates and nitrites, nitroprusside and Nitric oxide-releasing compounds with sufficient stability other iron nitrosyl compounds, ruthenium/NO or other metal/ at body temperatures to be useful as therapeutics were ulti NO complexes, heterocyclic N-oxides, messianic hetero mately developed by Keefer et al. as described in U.S. Pat. 35 cycles, C-nitroso compounds, oximes, N-hydroxyguanidines Nos. 4,954,526, 5,039,705, 5,155,137, 5,212.204, 5,250,550, and N-hydroxyureas, and other nitric oxide releasing com 5,366,997, 5,405,919, 5,525,357 and 5,650,447 and by Hra pounds. However, all these NO donors do not provideus with bie et al., J. Org. Chem. 1993, 58:1472-1476, all of which are a controlled release of NO. herein incorporated by reference. Polymers containing groups capable of delivering NO, for Briefly, Hrabie et al. describes NO-releasing intramolecu 40 example polymers containing diazeniumdiolate groups lar salts (Zwitterions) having the general formula 2 RNIN(O) (NONOate groups), have been used to coat medical devices. NO(CH)NHR'. Furthermore, the use of NONOates for the release of nitric The N(O)NOI (abbreviated hereinafter as NONO) con oxide to specifically treat tissue that has been injured or is at taining compounds release NO via a first-order reaction that risk of injury during sepsis or shock has been described in at is predictable and easily quantified. This is in sharp contrast to 45 least Saavedra et al. U.S. Pat. No. 5,814,656, the disclosure of other known NO-releasing compounds such as the S-nitro which is incorporated herein by reference. Insoluble poly Sothiol series as described in U.S. Pat. Nos. 5,380,758, 5,574, meric NONOates have also been generally described in Smith 068 and 5,583,101. Stable NO-releasing compounds have et al. U.S. Pat. No. 5,519,020, the disclosure of which is also been coupled to amine containing polymers. U.S. Pat. No. incorporated herein by reference. These polymers were used 5,405,919 describes biologically acceptable polymers that 50 to deliver NO to specific tissues, and results have shown that may be coupled to NO-releasing groups including polyole controlled release of NO to a specific site greatly reduced the fins, such as polystyrene, polypropylene, polyethylene, poly inflammation and accelerates the healing process at that site. tetrafluoroethylene and polyvinylidene, and polyethylen However, decomposition products of NONOates under oxy imine, polyesters, polyethers, polyurethanes and the like. genated conditions can include nitrosamines. Some of which Medical devices, such as arterial stents, composed of these 55 may be carcinogenic. In addition, NONOates generally polymers represent a potential means for the site-specific release NO radical, which is rapidly consumed by hemoglo delivery of NO. bin and can be toxic in individuals with arteriosclerosis. Fur Nitric oxide-donor compounds and compositions compris thermore, the elasticity of known NO-delivering polymers is ing them can be useful for treating cardiovascular disorders, generally inadequate, making it difficult to coat medical gastrointestinal disorders, hepatic disorders and for inhibiting 60 devices with the polymer and deliver NO with the coated platelet adhesion were developed by Nicoletta et al. (WO device under physiological conditions. Protein based poly Patent No. 2008/095841 A2). However, the Nicoletta disclo mers have a high solubility in blood, which results in short Sure does not relate to and also does not provide macromers lifetimes. Finally, many NO-delivering polymers cannot be and oligomers that release nitric oxide and, optionally, drug sterilized without loss of NO from the polymer and amounts molecule. Furthermore, the Nicoletta disclosure does not 65 of NO delivered are limiting. relate to and also does not provide compositions comprising There are many shortcomings associated with present NO and drug releasing macromers and oligomers, combina methods of delivering NO to treatment sites. NO itself is too US 8,062,653 B2 5 6 reactive to be used without some means of stabilizing the ones wherein the degradable linker comprises of repeat units molecule until it reaches the treatment site. Thus, NO is derived from glycolic acid and p-dioxanone. generally delivered to treatment sites in an individual by Abiologically active Substance in the context of the present means of polymers and small molecules which release NO. invention is a Substance that can act on a cell, virus, organ or However, these polymers and Small molecules typically 5 organism, including but not limited to drugs (i.e. pharmaceu release NO rapidly. As a result, they have short shelf lives and ticals) to create a change in the functioning of the cell, virus, rapidly lose their ability to deliver NO under physiological organ or organism. In certain embodiments of the invention, conditions. For example, the lifetime of S-nitroso-D.L-peni the biologically active Substances are organic molecules hav cillamine and S-nitrosocysteine in physiological solution is ing molecular weight of about 600 or less, or to polymeric no more than about an hour. As a result of the rapid rate of NO 10 species such as proteins, nucleic acids, and the like. A bio release by these compositions, it is difficult to deliver suffi logically active Substance can be a Substance used in therapy cient quantities of NO to a treatment site for extended periods of an animal, preferably a human. For use in the invention, a of time or to control the amount of NO delivered. biologically active Substance bears, or has a functional Although, work has been carried out in the past to develop homolog that bears, one or more hydroxyl, amino or carboxy NO donors and NO donor drug molecules including NO 15 lic acid substituents, including functional derivatives such as donor aspirin (US Patent Publication No. 2008/0288.176), the esters, amides, methyl ethers, glycosides and other deriva work suffers from the following disadvantages (a) the rate of tives that are apparent to those skilled in the art. release of nitric oxide and drug molecule cannot be controlled In certain embodiments, a biologically active Substance (b) Some of the NO donors reported so far release toxic and has one or more aromatic rings. Phenol(hydroxybenzene) is carcinogenic nitrosamines upon decomposition under oxy the simplest example of a phenolic compound, but most phe genated conditions (c) Some of the NO donors release NO nolics have two or more hydroxyl groups and are bioactive radical, which is rapidly consumed by hemoglobin and is Substances occurring widely in food plants that are eaten toxic to individuals with arteriosclerosis and (c) NO donors regularly by Substantial numbers of animals and people and reported in the literature have short lives and they rapidly lose have been found to be safe compounds. Included in the defi their ability to deliver NO under physiological conditions. In 25 nition of biologically active phenolics are poly-phenols hav light of the above drawbacks, therefore, there is a need for ing complex Substitution patterns and compounds having new molecules and compositions capable of delivering NO condensed rings and drug to treatment sites in a controlled manner and which Biologically active Substances are well known (e.g., aspi can overcome the aforementioned shortcomings. rin and capsaicin) and have been beneficially administered to The present invention overcomes the aforementioned chal 30 patients in need thereof for more than a century. One problem lenges by providing NO and drug releasing macromers and that has been associated with many biologically active Sub oligomers wherein the rate, extent and site of release of NO stances is that they can be difficult to dissolve in water or the and the drug molecule can be controlled independently of human body and can also be very difficult to polymerize. Due each other. NO and drug releasing macromers and oligomers to the availability and numerous uses of biologically active of the present invention have highly controllable hydrolysis 35 substances, it is desirable to enhance their native value by, for profiles, increased solubility, improved bioavailability, example, providing compounds or combinations of com improved efficacy and enhanced functionality. The controlled pounds with a specific controlled degradation profile or range release profiles represent slow, moderate and/or rapid release enabling controlled release of the biologically active sub of drug and nitric oxide. This release may be targeted to one stance over an extended, controllable time range. or more specific organs or parts of the body. The hydrolytic 40 Although, work has been carried out in the past to develop degradation of some specific NO and drug releasing mac NO donors and NO donor drug molecules including NO romers and oligomers of the present invention typically donor aspirin (US Patent Publication No. 2008/0288.176), the releases drug molecule as such with no change in native work suffers from the following disadvantages (a) the rate of chemical structure and efficacy. This invention provides release of nitric oxide and drug molecule cannot be controlled greater control of the bioavailability of the drug and nitric 45 (b) Some of the NO donors reported so far release toxic and oxide while retaining the inherent biological properties of carcinogenic nitrosamines upon decomposition under oxy both. genated conditions (c) Some of the NO donors release NO NO and drug releasing macromers and oligomers of the radical, which is rapidly consumed by hemoglobin and is present invention comprise of a drug molecule and a NO toxic to individuals with arteriosclerosis and (d) NO donors releasing moiety linked to each other via a hydrolytically 50 reported in the literature have short lives and they rapidly lose degradable linker. This hydrolytically degradable linker.com their ability to deliver NO under physiological conditions. prises of repeat units derived from safe and biocompatible In light of the above drawbacks of the prior art, therefore, molecules such as glycolic acid, lactic acid, p-dioxanone and there is a need for new NO releasing therapeutic agents and caprolactone, key components of all commercially available compositions therefrom which are susceptible to hydrolytic absorbable medical devices. The hydrolytic degradation rate 55 degradation and release Nitric oxide and drug molecule in a of NO and drug releasing macromers and oligomers of the controlled manner without yielding any toxic and harmful by present invention is controlled by the number of repeat units products. in the linker as well as by the choice of the safe and biocom patible molecules from which the repeat units are derived. For SUMMARY OF INVENTION example, NO and drug releasing macromers and oligomers of 60 the present invention comprising of degradable linker con The present invention provides NO and, optionally, drug taining repeat units derived from glycolic acid will hydrolyze releasing macromers and oligomers wherein the rate, extent faster than the one comprising repeat units derived from p-di and site of release of NO and the drug molecule (if present) oxanone. Similarly, NO and drug releasing macromers and can be controlled independently of each other. NO and drug oligomers of the present invention comprising of degradable 65 releasing macromers and oligomers of the present invention linker containing repeat units derived from lactic acid and have highly controllable hydrolysis profiles, increased solu caprolactone should take much longer to hydrolyze than the bility, improved bioavailability, improved efficacy and US 8,062,653 B2 7 8 enhanced functionality. The controlled release profiles repre 0 or more independently selected repeats X are: sent slow, moderate and/or rapid release of drug and nitric any other repeat that is polyester polymerization com oxide. This release may be targeted to one or more specific patible with the above recited repeats X; organs or parts of the body. The hydrolytic degradation of the order and composition of repeats X is selected to pro Some specific NO and drug releasing macromers and oligo 5 vide a desired degradation of moiety -L-P R: mers of the present invention releases drug molecule as Such 1 or more independently selected repeats Y are: with no change in native chemical structure and efficacy. This —COCHO (glycolic ester moiety); invention provides greater control on the bioavailability of the —COCH(CH)O— (lactic ester moiety); drug and nitric oxide while retaining the inherent biological —COCHOCHCHO (dioxanone ester moiety); 10 —COCH2CH2CH2CH2CH2O (caprolactone ester properties of both. moiety); NO and drug releasing macromers and oligomers of the —CO(CH)O— where m is one of the numbers 2, 3 or present invention comprise of a drug molecule and a NO 4, or a number from 6 to 24 inclusive; or, releasing moiety linked to each other via a hydrolytically —COCHO(CHCHO), where n is integer between degradable macromeric or oligomeric chain. This hydrolyti 15 2-24 inclusive; cally degradable macromeric or oligomeric chain comprises 0 or more independently selected repeats Y are: of repeat units derived from safe and biocompatible mol any other repeat that is polyester polymerization com ecules such as glycolic acid, lactic acid, p-dioxanone and patible with the above recited repeats Y: caprolactone, key components of all commercially available the order and composition of repeats Y is selected to pro absorbable medical devices. vide a desired degradation of moiety -L-P R; and The hydrolytic degradation rate of NO and drug releasing R is according to one of the applicable following options (a), macromers and oligomers of the present invention is con (b) or (c): trolled by the number of repeat units in the linker as well as by (a) where P is — X-1, R can be an alkyl group, aryl, the choice of the safe and biocompatible molecules from alkyl-aryl, an alicyclic group or alkyl-alicyclic, Substi which the repeat units are derived. For example, NO and drug 25 tuted with one or more —O NO; and releasing macromers and oligomers of the present invention (b) where P is - Y - R can be NO; comprising of degradable linker containing repeat units (c) where D is according to (ii) or (iii), R can be -L'D' or derived from glycolic acid will hydrolyze faster than the one L'D'L"PR', comprising repeat units derived from p-dioxanone. Similarly, wherein, NO and drug releasing macromers and oligomers of the 30 L' is L with opposite orientation, and D' is D, where D present invention comprising of degradable linker containing is a biologically active Substance, and the linkage repeat units derived from lactic acid and caprolactone should L-P is chemically consistent with the recitations take much longer to hydrolyze than the ones wherein the for L-P, and degradable linker comprises of repeat units derived from L" is L., P is P except p is p", an integer from 1 to 20, glycolic acid and p-dioxanone. 35 and R' is Raccording to (a) or (b): In one embodiment, the present invention provides nitric wherein: oxide macromers and oligomers of formula A: if D is defined by (i) and X or Y comprises - CHCHCHCH-CHCOO– O (A) —COCH2CH2CH2CH2CH2O. , then p is an integer 40 from 2 to 100 inclusive; p-n-L R if L is —COO ... then the corresponding P is — X— , and, if L' is present, the last repeat X lacks the terminal O and L' is —O— or —NH-; and wherein: ifL is NH-, then the corresponding Pis——Y— , L is —O—, —COO— or —NH-; 45 and, if L' is present, the last repeat Ylacks the terminal O D is: and L' is —O— or —OC(O)—. (i) together or separately from L., a biologically active The inventive compounds are defined as being functional Substance, in which case q is 1 to 4 inclusive; ized with the defined X,Y and R substituents, which alter the (ii) a moiety consisting of C, H, O, S or N, predominantly native value or efficacy of the pre-functionalized compound composed of C and H, and adapted with L to terminate 50 by modifying the onset or length of action thereof. moiety P, in which case q is 1 (or 2) to 4 inclusive; Aryls are preferably C-6 or C-10, and can be further sub (iii) a polyester, polyether, mixed polyester/polyether, stituted with alkyl(s). Alicyclic rings are preferably C4 to polyurethane or polyester polyurethane polymer formed C10, and can be further substituted with alkyl(s). Alkyls are from monomers selected to provide at least qlinkages L., preferably C2 to C6. where q is an integer from 1 to 200 inclusive; 55 Integer p can be from 100 or less, 60 or less, or 40 or less, P is one of - X-1 or - Y - , wherein or 20 or less, or 10 or less, or 6 or less or 4 or less. Integer p can p is independently an integer from 1 to 100 inclusive; be 1 or more, 2 or more, 3 or more, or 4 or more. Integer p can 1 or more independently selected repeats X are: be from one of the lower limits to one of the upper limits here —CHCOO (glycolic acid moiety); recited. —CH(CH)COO (lactic acid moiety); 60 D is defined by (i) and X or Y comprises —CHCHOCHCOO (dioxanone moiety); —CHCHCHCH-CHCOO– O —CH2CH2CHCH-CHCOO— (caprolactone moi —COCH2CH2CH2CH2CH2O. , then in certain embodi ety); ments, p is an integer from 2, 3 or 4 to one of the upper options -(CH2)COO where y is one of the numbers 2, 3 or listed above. In certain embodiments, where D is defined by 4, or a number from 6 to 24 inclusive; or 65 (i) O (ii) and X Or Y comprises —(CH2CH2O). CHCOO where Z is an integer - CHCHCHCH-CHCOO– O between 2-24, inclusive; —COCH2CH2CH2CH2CH2O. , then p is an integer from 2 US 8,062,653 B2 10 to 100 inclusive. In certain embodiments, where D is defined In another embodiment, the present invention provides by (ii) and XorY comprises —CHCHCHCH-CHCOO– nitric oxide and drug releasing macromers and oligomers of or —COCH2CH2CH2CH2CH2O. , the limitations for p set formula V to XIII (where D-Drug, which is a biologically forth above in this paragraph apply. active Substance): Where D is according to (ii) it can have MW of 600 or less, 5 or 500 or less, or 400 or less, or 300 or less. By being pre dominately composed of Cand H it is meant that the moiety V has a predominately carbon-carbon skeleton. In certain ONO1 *x O Ygrid-'ix R YONO, embodiments, the moiety has a carbon-carbon skeleton, 10 optionally with oxo (O—) and hydroxy substitutions. VI In certain embodiments where D is according to (iii), q can O COO R be an integer from 11 to hih, inclusive, wherell is 1, 2, 5, 10, 20 oNo1" x1 x YONO, or 40, and hh is 4, 6, 10, 20, 40, 100 or 200. Where D is O R VII according to (i) or (ii), then q can be 1-3 inclusive, 1-2 or 1. 15 In certain embodiments, where D is according to (ii) or s Ygrid-'ix SoNo. (iii), and R is according to (c), p' is an integer that is 1 or more, NO VIII 2 or more, or 3 or more, and is 20 or less, 10 or less, 9 or less, ON O O 2 8 or less, 7 or less, 6 or less, or 5 or less (or a range therebe "y y tween, inclusive). In certain embodiments where D is accord H DX ing to (ii), D is a di-, tri- or quadra-acyl moiety, such as a ON O N NO Succinate (from Succinic acid), malonate, diglycolate, citrate, ity y or the like. H X Where R is according to (a) it can have MW of 600 or less, H or 500 or less, or 400 or less, or 300 or less. 25 ON N N NO It should be noted that, except where specifically noted, the "y ty chemical moieties L and Pabove are written to insert in the XI formula with the same orientation as presented (i.e., they are not reversible left to right except as specifically noted). R All individual elements within each iteration of --L-P - 30 ONO1 *x “Ygrid-"x YONO, R. can be independently selected according to the definitions XII herein. In certain embodiments where D is according to (iii). Some monomers of the polyester, polyether, mixed polyester/poly oxo~ x'\grgery ether, polyurethane or polyester polyurethane polymer pro 35 XIII vide two linkages L (independently selected). In certain H NO embodiments, monomers provide at most one linkage L. os-X"Yggerty 2 L', L" and L are independently selected according to the definitions herein. D' and D are independently selected according to the definitions herein. R' and R are indepen 40 In still another embodiment, the present invention provides dently selected according to the definitions herein. NO and drug releasing macromers and oligomers of the for In certain embodiments, the non-hydrocarbon functional mula XIV to XXI: ities in the nitric oxide macromer or oligomer, aside from D where D is a bioactive substance, comprise ether, ester, 45 amide, halo, hydroxy and nitric oxide. XIV In one embodiment, the present invention provides nitric oxide and drug releasing macromers and oligomers of for so R YONO, mula I to IV: R

50 on." GDRUG) "ix YONO, HN ty NO II OOC COO R 55 ONO1 *x SDRUG) x YONO, HN NO XVI III y R 60 IV ON, GDRG) co, YONO, XVII HN y NO R 65 wherein D is according to recitals (i) or (ii) for Formula A. In oxo~x" GDRUG) "ix YONO, one embodiment, D is according to recital (i) US 8,062,653 B2 11 12 -continued In yet another embodiment, the present invention provides XVIII a method for the treatment of diseases including but not limited to cancer and cardiovascular diseases which comprise administering to a Subject in need thereof by means of con so "Sono, trolled drug delivery atherapeutically effective amount of one O O R or more of the NO and drug releasing macromers and oligo ONO1 “x GDRUG) x YONO, mers of the present invention. R XIX In still another embodiment, the present invention provides COO n a pendant polymer or oligomer providing monomer accord H x ONO 10 ing to formula B or C: ONity N guertyN NO XX (B) COOH A 15 H H ON N N NO y y (C) XXI A HN NO ty B O R oxo~"w"Ygni?er"x"SoNo. wherein the component elements, excepting A and B, are consistent with the pendant moieties associated with D as In certain analogs of Formulas V-XXI, Drug is replaced by 25 defined by (iii). A and B are independently —OH, -NH2 or D, which is according to recitals (i) or (ii) for Formula A. —CO.H. In yet still another embodiment, the present invention pro vides NO and drug releasing macromers and oligomers DETAILED DESCRIPTION OF THE PRESENT according to formulas (I-XXI) wherein the drug molecules INVENTION include but are not limited to non-steroidal anti-inflammatory 30 drugs (NSAID) such as Naproxen, Aspirin, Ibuprofen, Where L is a component of a biologically active Substance, Indomethacin, Diclofenac and Tylenol or an antibiotic. and when L is —O the biologically active substance typi The present invention also provides implantable medical cally has a hydroxy incorporating that oxygen, or is provided devices and medical device coatings comprising an effective as an acyl derivative of the hydroxy. In this case, formula A amount of one or more of the NO and drug releasing mac 35 where P is - Y - tends to provide forms that regen romers and oligomers of the present invention physically erate the hydroxy. Where P is — X , , it tends to admixed with a polymer whereina polymer can be absorbable provide forms including ether acids upon hydrolysis. or non-absorbable. Thus, the present invention provides at Where L is a component of a biologically active Substance, least two means of enhancing the biocompatibility of the and when L is COO ... the biologically active substance medical device and/or providing for in-situ controlled release 40 typically has a carboxylic acid or salt thereof incorporating of NO and drug at the treatment site. that moiety, or is provided as an ester derivative. Exemplary embodiments of implantable medical devices Where L is a component of a biologically active Substance, and coatings comprising of NO and drug releasing mac and when L is —NH , the biologically active substance romers and oligomers of the present invention include, but are typically has an amine or salt thereof incorporating that moi not limited to cardiovascular drug-eluting stents, diagnostic 45 ety, or is provided as an amide derivative. catheters, guide wires, guide catheters, PTCA balloon cath It will be understood that the macromer or oligomer seg eters (for percutaneous transluminal coronary angioplasty) in ments of formula A (or formula B or C described below) blood vessels, in-dwelling sheaths (venous and arterial), contain one or more repeats of Group A: intraaortic balloon pump catheters, intravascular sensors, —CHCOO (glycolic acid moiety); —CH(CH) extracorporeal blood loop circuits, intravenous grafts/shunts 50 COO (lactic acid moiety); —CH2CHOCH2COO– and adhesion prevention barriers including meshes and coat (dioxanone moiety); —CH2CH2CHCH-CHCOO– ings therefore wherein NO and drug are released in-situ such (caprolactone moiety); -(CH2)COO ; or that restenosis is treated, prevented or inhibited. —(CHCHO). CHCOO ; or In another embodiment, present invention also provides a —COCHO (glycolic ester moiety); -COCH(CH) drug delivery system, comprising: an effective amount of one 55 O— (lacticester moiety); - COCHOCH2CHO— (di or more of the NO and drug releasing macromers and oligo oxanone ester moiety); - COCHCHCHCH mers of the present invention physically admixed, embedded CHO (caprolactone ester moiety); —CO or dispersed into the absorbable or non-absorbable polymer (CH), O—; or —COCHO(CH2CH2O), . and the polymer is in the form of a polymeric matrix. The presence of the above monomers tends to assure that a In still another embodiment, the present invention provides 60 useful degradation profile will be obtained. However, it will an anti-inflammatory or anti-oxidant or antimicrobial or a be understood that additional, compatible monomers can be pharmaceutical composition comprising an effective amount included in the macromer or oligomer segments. These can be of one or more of the NO and drug releasing macromers and identified by one of ordinary skill. In certain embodiments, oligomers of the present invention wherein said composition the Group A repeats the majority of repeats. In certain is in a form Suitable for oral, enteral, parenteral, topical, 65 embodiments, the Group A repeats comprise 60% or more, or transdermal, ocular, vitreal, rectal, nasal, pulmonary, or vagi 70% or more, or 80% or more, or 90% or more, or 95% or nal administration. more of the number of repeats. In certain embodiments, the US 8,062,653 B2 13 14 number of non-Group A repeats is less than half the repeats, In certain embodiments, the macromer or oligomer seg and no more than 1, or 2, or 3. ments of formula A (or formula B or C described below) contain one or more repeats of Group C: In certain embodiments, the macromer or oligomer seg —CHCOO (glycolic acid moiety); —CH(CH) ments of formula A (or formula B or C described below) COO (lactic acid moiety); —CH2CHOCH2COO– contain one or more repeats of Group B: (dioxanone moiety); O —CHCOO (glycolic acid moiety); —CH(CH) —CH2CH2CHCH-CHCOO— (caprolactone moi COO (lactic acid moiety); —CHCHOCHCOO– ety); (dioxanone moiety); —CH2CH2CHCH-CHCOO– —COCHO (glycolic ester moiety); —COCH(CH) (caprolactone moiety); -(CH2)COO– where y is one O— (lacticester moiety); COCHOCHCH-O-(di of the numbers 2, 3 or 4: or —(CH2CH2O). CHCOO– OX8O ester moiety); O where Z is an integer between 2-24 inclusive; or —COCHCHCHCHCHO (caprolactone ester moiety). —COCHO (glycolic ester moiety); —COCH(CH) In certain embodiments, the Group C repeats the majority O— (lacticester moiety); —COCHOCH2CH2O (di of repeats. In certain embodiments, the Group C repeats com OXaO ester moiety); 15 prise 60% or more, or 70% or more, or 80% or more, or 90% —COCHCHCHCHCHO (caprolactone ester or more, or 95% or more of the number of repeats. In certain moiety); —CO(CH)O— where m is one of the num embodiments, the number of non-Group C repeats is less than bers 2, 3 or 4; or COCHO(CHCHO), . half the repeats, and no more than 1, or 2, or 3. In certain In certain embodiments, the Group B repeats the majority embodiments, p is 40 or less, or 20 or less, or 10 or less, or 8 of repeats. In certain embodiments, the Group B repeats com 20 or less or 6 or less or 4 or less, the Group C repeats are 2 or prise 60% or more, or 70% or more, or 80% or more, or 90% more, 3 or more, 4 or more, 5 or more, or 10 or more. or more, or 95% or more of the number of repeats. In certain The present invention also provides NO and drug releasing embodiments, the number of non-Group B repeats is less than macromers and oligomers wherein the macromer or oligomer half the repeats, and no more than 1, or 2, or 3. is selected from the following formulas (where n=2, 3 or 4):

O ouls r 'N-1N1 ONO. O O MeO

O O ~~~ 'Nu-1S-1a ONO. O O MeO

O

oulsO pi -1--1aONO O O MeO

O

O O pi u1--1aONO

O O MeO

O

O NO O O O O1 O O N-sh- YNO, ls O H3C N H3C ls, H

O O O oh NO O O s' O YNO, ul O ul N O HC N HC H US 8,062,653 B2 15 -continued O O O sO 2pi n NO2 -h pi -N-1- o1 NO2 l O H3C N H

O OAc O u1--1a NO --~~ pi O1 O OAc

O O O~~~ O N-r- O YNO, O OAc O O

O O O ~~~. on 1- YNO, O OAc O O US 8,062,653 B2 17 18 -continued O

O ONO O O O pi O

O ONO.

O

O s O 1.-1.--pi ONO

O O O ONO. O CIO on 1 ON lo O O O

O oulsO pi -N-1- ONO. o O O ON O O ouls -N-1- O CIO O pi ONO2 ON No ouls O O O

O O

O ouls O piN-N-1- ONO ON ouls O O o pi O O O O O O re-O YNO, O O ON1 N H O

O O NO O O ~~~~pi N-1N1-1 O O ON1 N H

ON No ouls N H US 8,062,653 B2 19 20 -continued O

O O pi -N-1- ONO.

ON No NullsO HN O

O O

ONO O O

O O O pi O 1N1-N-ONO2

ON O HN O No O o-NO2 O O

O

O O pi -n-n ONO

ON No susO HN O o-NO2 O O O

O O pi -1-1- ONO. ON Sri O sh HN O O O

ONO. O

O O pi -N-1- ONO

ON No susO HN O o-NO2 O O

O

O O N-1--1api ONO ON Sri O 1. HN O O O

ONO

O

O O pi -N-1- ONO. ON sus HN O Sr. O O O

ONO. US 8,062,653 B2

-continued O

O O pi u1--1aONO2 ON Sr.O s HN O O O

ONO O O

O O --~~pi O 1N1\-1ONO. ON Sr.O s HN O O O

ONO O O

O O --~~pi O 1N1-N-ONO2 ON No O sh. HN O O O

ONO O

O O O Cr?. --~~ -nu-nu-N:pi ON O HN O nO O O O O OQ NO

The present invention also provides NO and drug releasing acyl moiety. For example the macromer or oligomer can be macromers and oligomers wherein D is according to (ii), Such selected from the following formulas: as the macromers or oligomers where D is a di-, tri- or quadra

O

ONO ONO US 8,062,653 B2 23 24 rt-ro-continued - 3

ONO ONO O OH O

O O

rO O O~ O O O O O O O O

O O O O O

ONO. OS- O ONO.

ONO

- 3

ONO ONO US 8,062,653 B2 25 26 -continued O

ONO~~~ O --- O

O

O ouls O 1N1-N-ONO2 Nulls O 1. O O

O O O ---

--CCO r O O us rocreO ouls 1N1-N-ONO2

O ---O On ONO 1N1-19 r cr O

O

corrO O or-n-ro O O r O ------s----- ONO O - O O O

O O r 9N-1N1S ONO O US 8,062,653 B2 27 28 The present invention also provides NO and drug releasing mediates, cancer preventing agents, antioxidants, controlled macromers and oligomers wherein two or more drug mol release preparations, and solvents for drugs. Examples of ecules functionalized with a NO releasing moiety are knitted products, woven or non-woven, and molded products covalently linked to each other via a hydrolysable macromer include: burn dressings; hernia retaining patches or meshes; or a oligomer. 5 medicated dressings; facial Substitutes; gauze, fabric, sheet, The present invention also provides NO and drug releasing felt, or sponge for liver hemostasis; gauze bandages; arterial absorbable or non-absorbable polymers including but not graft or Substitutes; bandages for skin Surfaces; Suture knot limited to polyesters, polyurethanes, poly(ester-amides) and clip; orthopedic pins, clamps, screws, and plates; clips (e.g., combinations thereof prepared from macromers or oligomers for vena cava); staples; hooks, buttons, and Snaps; bone Sub bearing covalently attached NO and drug releasing pendant 10 stitutes (e.g., mandible prosthesis); intrauterine devices (e.g., groups. spermicidal devices); draining or testing tubes or capillaries; The rate of hydrolysis of the NO and drug releasing mac Surgical instruments; vascular implants or Supports; vertebral romers and oligomers of the present invention will depend discs; extracorporeal tubing for kidney and heart-lung upon a number of factors, including the number of repeat machines; and, artificial skin. units in the linker as well as by the choice of the safe and 15 In one embodiment, the present invention provides biocompatible molecules from which the repeat units are implantable medical devices comprising an effective amount derived. For example, NO and drug releasing macromers and of one or more of the NO and drug releasing macromers and oligomers of the present invention comprising of degradable oligomers of the present invention physically admixed with a linker containing repeat units derived from glycolic acid will polymer wherein a polymer can be absorbable or non-absorb hydrolyze faster than the one comprising repeat units derived able. Absorbable polymers that can be physically admixed from p-dioxanone. Similarly, NO and drug releasing mac with nitric oxide and drug releasing macromers and oligo romers and oligomers of the present invention comprising of mers of the present invention includes but are not limited to degradable linker containing repeat units derived from lactic polyesters, poly(lactide-co-glycolide), polycaprolactone, acid and caprolactone should take much longer to hydrolyze poly(p-dioxanone), polyglycolide, polyoxaesters, poly(es than the ones wherein the degradable linker comprises of 25 terurethanes), absorbable polyurethanes, poly(esteramides) repeat units derived from glycolic acid and dioxanone. Fur and combinations thereof. Non-absorbable polymers that can thermore, it is expected that the rate of hydrolysis will vary be physically admixed with nitric oxide and drug releasing with variation in number of repeat units in the degradable macromers and oligomers of the present invention includes linker. Thus, the desired time range may be obtained by but are not limited to polyethylene, polypropylene, polyure altering number of repeat units in the linker as well as by the 30 thanes, polyamides, polyethyleneglycols, polyacrylates, choice of the safe and biocompatible molecules from which polybutylenes and combinations thereof. the repeat units are derived. In another embodiment, the present invention provides The NO and drug releasing macromers and oligomers of coating composition for medical devices screw comprising an the present invention, upon contact with body fluids including effective amount of one or more of the NO and drug releasing blood or the like, undergoes gradual degradation (mainly 35 macromers and oligomers of the present invention physically through hydrolysis) with concomitant release of the dispersed admixed with a polymer whereina polymer can be absorbable drug for a Sustained or extended period. This may result in or non-absorbable. prolonged delivery (e.g., over 1-2,000 hours or 2-800 hours) Thus, the present invention provides at least two ways of of effective amounts (e.g., 0.0001 mg/kg/hour to 10 mg/kg/ enhancing the biocompatibility of the medical device and/or hour) of the drug. This dosage form may be administered as is 40 providing for in-situ controlled release of NO and drug at the necessary depending on the Subject being treated, the severity treatment site. of the affliction, and the judgment of the prescribing physi Exemplary embodiments of implantable medical devices C1a. and coatings comprising of NO and drug releasing mac As described herein, the NO and drug releasing macromers romers and oligomers of the present invention include, but are and oligomers of the present invention are expected to be 45 not limited to cardiovascular drug-eluting stents, diagnostic useful in medical applications/medical devices. Medical catheters, guide wires, guide catheters, PTCA balloon cath application/medical devices, as used herein, encompass eters (for percutaneous transluminal coronary angioplasty) in medical and biomedical applications and include all types of blood vessels, in-dwelling sheaths (venous and arterial), applications involved in the practice of medicine that would intraaortic balloon pump catheters, intravascular sensors, benefit from a material that decomposes harmlessly within a 50 extracorporeal blood loop circuits, intravenous grafts/shunts known period of time. Examples include medical and Surgical and adhesion prevention barriers including meshes and coat devices, which include drug delivery systems (e.g., a site ings therefore wherein NO and drug are released in-situ such specific or systemic drug delivery systems or matrices), tissue that the indication sought to be treated (e.g., restenosis) is engineering (e.g., tissue scaffold), stent coatings, stents, treated, prevented, inhibited or ameliorated. porous devices, implantable medical devices, molded articles 55 For coating applications, the polymer comprising the coat (e.g., vascular grafts, stents, bone plates, Sutures, implantable ing composition can usefully exhibit an inherent viscosity, as sensors, and barriers for Surgical adhesion prevention), measured in a 0.1 gram per deciliter (g/dl) of hexafluoroiso wound closure devices (e.g., Surgical clips, staples, and propanol (HFIP), of for example, between about 0.05-2.0 Sutures), coatings (e.g., for endoscopic instruments, Sutures, dl/g or about 0.10-0.80 d1/g. If the inherent viscosity is too stents, and needles), fibers or filaments (which may be 60 low, then the polymer may not have the integrity necessary for attached to Surgical needles or fabricated into materials the preparation of films or coatings for the Surfaces of various including Sutures or ligatures, multifilament yarn, sponges, Surgical and medical articles. Polymers with an inherent vis gauze, tubes, and sheets for typing up and Supporting dam cosity greater than about 2.0 dl/g can be used, though in many aged Surfaceabrasions), rods, films (e.g., adhesion prevention cases it may be difficult to do so. barriers), knitted products, foodstuffs, nutritional Supple 65 The amount of coating to be applied on the Surface of a ments, nutraceuticals, cosmetics, pharmaceuticals, biode braided suture can be readily determined empirically, and will gradable chewing gums, flavors, enhanced drugs, drug inter depend on the particular copolymer comprising the compo US 8,062,653 B2 29 30 sition and Suture chosen. In certain embodiments, the amount erably take the form of an ointment, cream, lotion, paste, gel. of coating applied to the Surface of the Suture may range from spray, aerosol, oil, or the like. Examples of carriers that con about 0.5-30 percent of the weight of the coated suture or ventionally used include Vaseline, lanoline, polyethylene gly from about 1.0-20 weight percent, or from 1-5 percent by cols, alcohols, and combination of two or more thereof. weight. If the amount of coating on the Suture were too great, NO and, optionally, drug releasing formulations Suitable then there may be an increased risk that the coating may flake for transdermal administration may be presented as discrete off when the Suture is passed through tissue patches adapted to remain in intimate contact with the epi When the article of the present invention is a metal stent, dermis of the recipient for a prolonged period of time. the amount of coating applied to the Surface of the article is an The NO and, optionally, drug releasing macromers and amount which creates a layer with a thickness ranging, for 10 oligomers of the present invention may be provided in the example, between about 2-20 microns on the stent or about form of foodstuffs or nutrition Supplements, such as being 4-8 microns. If the amount of coating on the stent were Such added to, admixed into, coated, combined or otherwise added that the thickness of the coating layer was greater too great, or to a foodstuff. The term foodstuff is used in its widest possible if the thickness was too low, then the desired performance of sense and includes liquid formulations such as drinks includ the stent as it is passed through tissue may not be optimal. 15 ing dairy products, biodegradable chewing gums, and other When the article of the present invention is a surgical foods, such as health bars, desserts, and the like. Food formu needle, the amount of coating applied to the Surface of the lations containing compounds of the invention can be readily article is an amount which creates a layer with a thickness prepared according to standard practices. ranging, for example, between about 2-20 microns on the NO and, optionally, drug releasing macromers and oligo needle or about 4-8 microns. If the amount of coating on the mers of the present invention used as medicaments or phar needle were such that the thickness of the coating layer was maceuticals are typically administered in a manner and too great, or if the thickness was too low, then the desired amount as is conventionally practiced. See, for example, performance of the needle as it is passed through tissue may Goodman and Gilman, The Pharmaceutical Basis of Thera not be optimal. peutics, 11" Edition. In another embodiment, present invention also provides a 25 NO and, optionally, drug releasing macromers and oligo drug delivery system, comprising: an effective amount of one mers of the present invention may have potent antioxidant or more of the NO and, optionally, drug releasing macromers activity and increased acidity of their aromatic component, as and oligomers of the present invention physically admixed, well as the improved biodegradation provided by the func embedded or dispersed into the absorbable or non-absorbable tionalization, and thus find wide application in pharmaceuti polymer and the polymer is in the form of a polymeric matrix. 30 cal and veterinary uses, in cosmetics such as more effective In still another embodiment, the present invention provides skin creams to prevent skin ageing, in Sun screens, in foods, an anti-inflammatory or anti-oxidant or antimicrobial or a health drinks, nutritional supplements, shampoos, and the pharmaceutical composition comprising an effective amount like. of one or more of the NO and, optionally, drug releasing The present invention also provides a nitric oxide and, macromers and oligomers of the present invention wherein 35 optionally, drug releasing pharmaceutical composition com said composition is in a form Suitable for oral, enteral, prising a nitric oxide and, optionally, drug releasing mac parenteral, topical, transdermal, ocular, vitreal, rectal, nasal, romers and oligomers of the invention and a second therapeu pulmonary, or vaginal administration. tic agent that is physically admixed, embedded or dispersed The most Suitable route in any given case will depend on within the polymer matrix of an absorbable or non-absorb the nature and severity of the condition being treated and on 40 able polymer. The invention also provides a NO releasing the nature of the particular active compound that is being pharmaceutical composition comprising a polymer of the used. The NO and drug releasing formulations of a pharma invention having a second therapeutic agent appended to the ceutical composition are typically admixed with one or more polymer (e.g. with bonds that will hydrolyze to release the pharmaceutically or veterinarially acceptable carriers and/or second therapeutic agent under physiological conditions). excipients as are well known in the art. 45 Dosages NO and, optionally, drug releasing formulations Suitable Useful dosages of the NO and, optionally, drug releasing for oral administration may be presented in discrete units, macromers and oligomers of the present invention can be Such as capsules, cachets, lozenges, or tablets, each contain determined by comparing their in vitro activity, and in vivo ing a predetermined amount of the active compound; as a activity of the therapeutic agent in animal models. Methods powder or granules; as a solution or a Suspension in an aque 50 for the extrapolation of effective dosages in mice, and other ous or non-aqueous liquid; as an oil-in-water or water-in-oil animals, to humans are knownto the art; for example, see U.S. emulsion; or the like Pat. No. 4.938,949. Additionally, useful dosages can be deter NO and, optionally, drug releasing compositions of the mined by measuring the rate of hydrolysis for a given poly present invention Suitable for parenteral administration con mer under various physiological conditions. The amount of Veniently comprise Sterile aqueous preparations of the NO 55 NO and, optionally, drug releasing macromers and oligomers releasing active compounds, which preparations are prefer required for use in treatment will vary not only with the ably isotonic with the blood of the intended recipient. particular molecule selected but also with the route of admin NO and, optionally, drug releasing formulations Suitable istration, the nature of the condition being treated and the age for rectal administration are preferably presented as unit dose and condition of the patient and will be ultimately at the Suppositories. 60 discretion of the attendant physician or clinician. NO and, optionally, drug releasing formulations Suitable The desired dose may conveniently be presented in a single for ocular or vitreal administration may be presented as NO dose or as divided doses administered at appropriate intervals, and drug releasing bioabsorbable coatings for implantable for example, as two, three, four or more sub-doses per day. medical devices, injectables, liquids, gels, Suspensions, or the The sub-dose itselfmay be further divided, e.g., into a number like. 65 of discrete loosely spaced administrations. NO and, optionally, drug releasing formulations or com In yet another embodiment, the present invention provides positions Suitable for topical administration to the skin pref a method for the treatment of diseases including but not US 8,062,653 B2 31 32 limited to cancer and cardiovascular diseases which comprise entacapone, epanolol, epimestrol, epinephrine, estradiol val administering to a Subject in need thereof by means of con erate, estriol, estriol Succinate, estrone, etamivan, etamsylate, trolled drug delivery atherapeutically effective amount of one ethaverine, ethoXZolamide, ethyl biscoumacetate, etillefrine, or more of the NO and, optionally, drug releasing macromers etiroXate, exalamide, exifone, fendosal, fenoldopam mesi and oligomers of the present invention. late, fenoterol, fenoxedil, fenticlor, flopropione, floredil, The quantity and type of NO and, optionally, drug releasing fluorescein, folescutol, formoterol, gallopamil, gentistic acid, macromers and oligomers incorporated into a composition glaziovine, glibenclamide, glucametacin, guajacol, comprising the medical device, medical device coating, drug halquinol, hexachlorophene, hexestrol, hexobendine, hexo delivery system, pharmaceutical, anti-inflammatory, anti prenaline, hexylresorcinol, hydroxyethyl salicylate, hydrox oxidative and antimicrobial formulations will vary depending 10 yStilbamidine isethionate, hymecromone, ifenprodil, on the rate and extent of release profile desired, amount of NO indomethacin, ipriflavone, isoetarine, isoprenaline, isoxSu and, optionally, drug releasing macromers and oligomers prine, itopride hydrochloride, ketobemidone, khellin, labe employed and the therapeutic effect desired. The product may talol, lactylphenetidin, levodopa. levomepromazine, levor contain blends of NO and, optionally, drug releasing mac phanol, levothyroXine, mebeverine, medrylamine, romers and oligomers of the present invention to provide the 15 mefexamide, mepacrine, mesalazine, mestranol, metarami desired release profile or consistency to a given formulation. nol, methocarbamol, methoxamine, methoXSalen, methyl Biologically Active Substances and Combination Therapies dopa, midodrine, mitoxantrone, morclofone, nabumetone, The nitric oxide and, optionally, drug releasing macromers naproxen, nitroxoline, norfenefrine, normolaxol, octopam and oligomers of the present invention can also be adminis ine, omeprazole, orciprenaline, oxillofrine, oxitriptan, oxy tered in combination with other therapeutic agents that are fedrine, oxypertine, oxyphenbutaZone, oxyphenisatin effective to treat a given condition to provide a combination acetate, oxyquinoline, papaverine, paracetanol, parethox therapy. Thus, the invention also provides a method for treat ycaine, phenacaine, phenacetin, phenazocine, phenolphtha ing a disease in a mammal comprising administering an effec lein, phenprocoumon, phentolamine, phloedrine, picota tive amount of a combination of a nitric oxide and drug mide, pimobendan, prenalterol, primaquine, progabide, releasing macromers and oligomers of the invention and 25 propanidid, protokylol, proxymetacaine, raloxifene hydro another therapeutic agent. The invention also provides a nitric chloride, repaglinide, reproterol, rimiterol, ritodrine, salac oxide and drug releasing pharmaceutical composition com etamide, Salazosulfapyridine, salbutamol, Salicylamide, Sali prising a nitric oxide and drug releasing macromers and oli cylic acid, Salmeterol, Salsalate, sildenafil, silibinin, gomers of the invention, another therapeutic agent, and a Sulmetozin, tamsulosin, teraZosin, terbutaline, tetroXoprim, pharmaceutically acceptable carrier. 30 theodrenaline, tioclomarol, tioXolone, alpha.-tocopherol (vi The NO and, optionally, drug releasing macromers and tamin E), tofisopam, tolcapone, tolterodine, tranilast, treto oligomers of the present invention are also useful for admin quinol, triclosan, trimazosin, trimetazidine, trimethobenza istering a combination of therapeutic agents to an animal. mide, trimethoprim, trimetozine, trimetrexate glucuronate, Such a combination therapy can be carried out in the follow troXipide, Verapamil, Vesnarinone, Vetrabutine, Viloxazine, ing ways: 1) another therapeutic agent can be physically 35 warfarin, Xamoterol. admixed, dispersed or embedded within the polymer matrix Other bioactive phenolics that can be used include acace of a absorbable polymer, and can be released upon degrada tin, 4-acetamido-2-methyl-1-naphthol, acet-aminophen, tion of the polymer; 2) another therapeutic agent can be albuterol, allenolic acid, aloe emodin, aloin, B-amino-4-hy appended to an absorbable polymer with bonds that hydro droxy-3,5-di-iodohydrocinnamic acid, N-(5-amino-2-hy lyze to release the therapeutic agent and NO under physi 40 droxyphenyl)-benzeneacetamide, 4-amino-1-naphthol, ological conditions. 3-aminosalicylic acid, 4-aminosalicylic acid, anacardic acid, Another aspect of the invention provides a method by p-anol, anthragallol, anthralin, anthranol, anthrarobin, which NO and, optionally, drug releasing macromers and anthrarufin, apigenin, apin, apocynin, aspidinol, aspirin, oligomers are prepared. The method involves the attachment baptigenin, benzestrol, benzoresorcinol, bisphenola, bisphe of NO releasing moiety to a drug molecule functionalized 45 nolb, butylated hydroxylanisole, butylated hydroxytoluene, with a hydrolysable linker moiety. The resultant NO releasing capobenic acid, trans-1-(3'-carboxy-4'-hydroxyphenyl)-2- functionalized drug molecules are more hydrolysable and (2".5"-dihydroxyphenyl)ethane, catechin, chlorogenic acid, biodegradable than the pre-functionalized drug molecule, m-chlorophenol, 5-chloro-8-quinolinol, chloroxylenol, chlo and provides controlled release of the biologically active rquinaldol, chromo-nar, chrysin, cinametic acid, clorophene, component and NO over a time period from several weeks to 50 coniferyl alcohol, p-coumaric acid, coumes-trol, coumetarol, four years, depending on the number of factors including the daphnetin, datiscetin, deoxyepinephrine, 3.5-diiodothyro number of repeat units in the linker as well as by the choice of nine, 3,5-di-iodotyrosine, dimethophrine, dioSmetin, diresor the safe and biocompatible molecules from which the repeat cinol, disoprofol, dopa, dopamine, drosophilin a, efloxate, units are derived. ellagic acid, embelin, Equol, eriodictyol, esculetin, esculin, Biologically active hydroxy compounds that can be used to 55 ethylnorepinephrine, ethylvanillin, eugenol, eupatorin, fena prepare NO and drug releasing macromers and oligomers of diazole, ferulic acid, fisetin, 3-fluoro-4-hydroxyphenylacetic the present invention include acenocoumarol, acetarSol, acti acid, fraxetin, fustin, galangin, gallacetophe-none, gallic noquinol, adrenalone, alibendol, amodiaquine, anethole, bal acid, gardenins, genistein, gentisyl alcohol, gepefrine, gera Salazide, bamethan, benserazide, bentiromide, benzarone, nylhydroqui-none, 6-gingerol, gossypol, guaiacol, guaifen benzquinamide, bevantolol, bifluranol, buclosamide, buphe 60 esin, harmalol, hematoxylin, hinderin, homoeriodictyol. niode, chlorotrianisene, chloroxylenol, cianidanol, homogentisic acid, homoVanillic acid, hydroxyamphet cinepazide, cinitapride, cinepazide, cinmetacin, clebopride, amine, 2-hyd-roxy-5-(2,5-dihydroxybenzylamino)-2-hy clemastine, clioquinol, cyclovalone, cynarine, denopamine, droxybenzoic acid, 4-hydroxy-3-methoxy-mandelic acid, dextroythyroxine, diacerein, dichlorophen, dienestrol, dieth n-(p-hydroxyphenyl)glycine, hydroxyprocaine, 8-hydrox ylstilbestrol, diflunisal, diiodohydroxyquinoline, dilazep, dil 65 ycuinoline, hypericin, irigenin, isoproterenol, isoquercitrin, evalol, dimestrol, dimoxyline, dioSmin, dithranol, dob isothebaine, kaempferol, liothyronine, luteolin, mangostin, utamine, donepezil, dopamine, dopexamine, doxazosin, 5.5'-methylenedisalicylic acid, n-methylepinephrine, mety US 8,062,653 B2 33 34 rosine, morin, mycophenolic acid, myricetin, naringenin, gomers of the present invention include Acemetacin, Bentiro nylidrin, orcinol, osalmid, osthole, Oxantel, paroxypropione, mide, Cinmetacin, Clometacin, Diflunisal, Fendosal, pentachlorophenol, 3-pentadecylcatechol, p-pentyloxy-phe Indometacin, Iophenoic acid, Naproxen, Repaglinide, Sala nol, phloretin, phloroglucinol, pinosylvine, plumbagin, pyro Zosulfapyridine, Salicylic Acid, Salsalate, and Sarpogrelate. catechol, pyrogallol, quercetagetin, quercetin, resacetophe Examples of biologically active hydroxyl-acids useful in none, rhamnetin, rhein, Sakuranetin, Salicyl alcohol, the present invention include 4-hydroxycinnamic acid, caf salicylanilide, 4-Salicyloylmorpholine, Salsalate, Scopoletin, feic acid, chlorogenic acid, ferulic acid, Sinapic acid, Vanillic Scutellarein, serotonin, (3,4,5-trihydroxyphenyl)methyl acid, Acemetacin, Bentiromide, Cinmetacin, Clometacin, enepropanedinitrile, thymol, thyropropic acid, thyroxine, Diflunisal, Fendosal, Indometacin, Iophenoic acid, tiratricol, tyrosine, Vanillic acid, and Vanillin. 10 Naproxen, Repaglinide, Salazosulfapyridine, Salicylic Acid, Further biologically active carboxylic acid and/or amine Salsalate, and Sarpogrelate. compounds that can be used to prepare a NO and drug releas Examples of biologically active amino/carboxylic acid ing macromers and oligomers of the present invention include compounds that can be used to prepare macromers and oli Acemetacin, Aceclofenac, Acediasulfone, Adipiodone, gomers of the present invention include Aceclofenac, Acedia Alminoprofen, Amisulpride, AmlexanoX, Amodiaquine, 15 Sulfone, Alminoprofen, Amlexanox, Anileridine, Baccofen, Amosulalol. Amoxicillin, Amsacrine, Anileridine, AZacy Balsalazide sodium, Benzocaine, Bumetanide, Carprofen, clonol, Baccofen, Balsalazide sodium, Bentiromide, Ben Carzenide, Diclofenac, Flufenamic acid, Furosemide, Ioben Zocaine, Bromopride, Bumetanide, Carprofen, Carvedilol, Zamic acid, Iocetamic acid, and Mefenamic acid. Carzenide, Cefprozil, Cinitapride, Cinmetacin, Clebopride, Examples of biologically active diamino compounds use Clenbuterol, Clometacin, Cromoglicic acid, Diclofenac, ful in the present invention include Amisulpride. Amodi Diflunisal, Eprosartan, EthoXZolamide, Fendosal, Flufe aquine, Amosulalol. Amoxicillin, Amsacrine, AZacyclonol, namic acid. Furosemide, Indometacin, Iobenzamic acid, Bromopride, Carvedilol, Cefprozil, Cinitapride, Clebopride, Iocarmic acid, Iocetamic acid, Iodoxamic acid, Ioglycamic Clenbuterol, EthoXZolamide, Nadoxolol, D-Norpseudoephe acid, Iophenoic acid, IotroXic acid, Mefenamic acid, Nadox drine, amino acids (L-lysine), and natural products. olol, Naproxen, Nedocromil, D-Norpseudoephedrine, parac 25 Examples of naturally occurring biologically active phe etamol Repaglinide, Salazosulfapyridine, Salicylic Acid, Sal nolics include bergaptol, caffeic acid, capsaicin, coumarin, salate and Sarpogrelate. daidzein, 2.5-dihydroxy-benzoic acid, ferulic acid, fla In a further aspect of the present invention one can blend vonoids, glycitein (isoflavone), 4-hydroxycinnamic acid, two or more of the NO and drug releasing macromers and 4-hydroxy-coumarin, isopimpinellin, resveratrol, synapic oligomers of the present invention. 30 acid, Vanillic acid, Vanillin, chalcones, soybean flavonoids Examples of biologically active dihydroxy compound that and derivatives thereof. can be used to prepare NO and drug releasing macromers and Capsaicin is a biologically active phenolic that is the active oligomers of the present invention include Adrenalone, Alfu component of cayenne pepper. The capsaicin is an amide of Zosin, Alibendol, Amrubicin, Apomorphine, Bamethan, Ben Vanillylamine and Cs to C branched fatty acids. Topical Zquinamide, Bevantolol, Bifluranol, Bisacodyl, Brodi 35 application of capsaicin Stimulates and blocks Small pain moprim, BunaZosin, Bupheniode, Carbidopa, Carbuterol, fibers by depleting them of the neurotransmitter substance P Cyclofenil, Cyclovalone, Daunorubicin, Dichlorophen, that mediates pain impulses. A cream made from 0.025%- Dienestrol, Diethylstilbestrol, Dimestrol, Dithranol, Done 0.075% capsaicin applied 4x daily may help peripheral neu pezil, Doxefazepam, Doxorubicin, Entacapone, Epi ropathic pain, post-herpetic neuralgia, trigeminal neuralgia, nepheine, Epirubicin, Esomeprazole, Etamivan, Etamsylate, 40 psoriasis and fibromyalgia. It is also useful for diabetic neu Etilefrine, EZetimibe, Fenticlor, Fluorescein, Folescutol, For ropathy, cluster headaches, earache, osteo- and rheumatoid moterol, Gefitinib, Hexestrol, Hexylresorcinol, Hydroxy arthritis. Capsaicin is a powerful pain reliever. ethyl salicylate, Ifenprodil, Isoetarine, ISOXSuprine, Itopride. Naproxen, paracetamol, acetaminophen and acetylsali HCl, Khellin, Labetalol, Mitoxantrone, Morclofone, Mox cylic acid are biologically active phenolics that belong to the averine, Normolaxol. Omeprazole, Oxilofrine, Oxepertine, 45 class of drugs called non-steroidal anti-inflammatory drugs or Phenacaine, Phenolphthalein, Prazosin, Tolcapone, NSAIDs. The NSAIDs provide relief by blocking the action Vesnarinone, and Vetradutine. of prostaglandins, which are hormone-like Substances that Examples of biologically active diamino compounds that contribute to pain, inflammation, fever and muscle cramps. can be used to prepare macromerSfoligomers of the present Phenolic moieties, synthetic and naturally occurring, are part invention include Amisulpride, Amodiaquine, Amosulalol, 50 of many drugs. Amoxicillin, Amsacrine, AZacyclonol, Bromopride, Pendant Polymers, Misc. Carvedilol, Cefprozil, Cinitapride, Clebopride, Clenbuterol, Where D is according to (iii), the macromers or oligomers EthoXZolamide, Nadoxolol, and D-Norpseudoephedrine. can be termed “pendant polymers. These comprise polymers Examples of biologically active hydroxy/amino com having pendant groups modified to have NO producing pounds that can be used to prepare macromers and oligomers 55 groups, or bioactive agents and NO producing groups. These of the present invention include Amisulpride, Amodiaquine, are often formed from monomers having NO-releasing and/ Amosulalol. Amoxicillin, Amsacrine, AZacyclonol, Bro or biologically active agent-releasing moieties. Modification mopride, Carvedilol, Cefprozil, Cinitapride, Clebopride, of polymers to provide NO-releasing and/or biologically Clenbuterol, EthoXZolamide, Nadoxolol, D-Norpseudo active agent-releasing moieties can also be conducted, in ephedrine, and paracetamol. 60 many cases through the use of appropriate protective groups Examples of biologically active dicarboxylic acid com for the pendant functionality used to attach NO-releasing pounds that can be used to prepare macromers and oligomers and/or biologically active agent-releasing moieties. of the present invention include Adipiodone, Cromoglicic Monomers having NO-releasing and/or biologically active acid, Eprosartan, Iocarmic acid, Iodoxamic acid, Ioglycamic agent-releasing moieties that can be used to form the pendant acid, Iotroxic acid, Nedocromil. 65 polymers of the present invention include but are not limited Examples of biologically active hydroxy/carboxylic acid to those according to formulas B and C (above). In Formulas compounds that can be used to prepare macromers and oli B and C, the terms L., L', L", P. P", D'and R' independently US 8,062,653 B2 35 36 have the same meaning as set forth above, and r is an integer applied to Formulas B and C are contemplated as part of the equal to 1 or 2. E is a moiety consisting of C, H, O, S or N. invention. predominantly of composed of Cand H. E. can have a molecu E can Substantially comprise a hydrocarbon, with a triva lar weight of 600 or less, or 500 or less, or 400 or less, or 300 lent or quaternary carbon directly linked by linkages com or less. A and Bareindependently —OH, -NH, or—CO.H. prising covalent bonds and, in most linkages, carbon to more (An acid or base form written anywhere in this specification reactive nitrogen, carbonyl or oxygen functionalities of A, B also encompasses salts thereof) All appropriate Subdefini and L. In some embodiments, the linkages from the trivalent tions of L,L,L", P. P. D'and R' set forth above apply to these or quaternary carbon to the nitrogen, carbonyl or oxygen terms as used with the monomer formulas A and B. In other functionalities of A, B and L are alkyl. words, all embodiments of Formula A that can logically be Examples of Such monomers include, without limitation:

HO r" HO ONO

O2. O OH O O O~ O OH

ONO

O

HO O oulsO 1n 1-ONO2

Nulls O O

HO O

OH

O NHX OH O O O O ~N~.O ONO. O

O O

HO O ouls orn --~sO 1n 1-ONO2 HO os--- O O O

O OH

O O N OH N--- ouls O H r O O US 8,062,653 B2 37 38 -continued O O

O r oulsO ~~~~ O ONO

OH OH

These diol monomers having the NO-releasing and/or bio In Formulas A and B, the entire structures can be regarded logically active agent-releasing moieties can be reacted with as the monomer (for building a polyester, polyether, mixed acid terminated polyesters to form pendant polyesters, can be polyester/polyether, polyurethane or polyester polyurethane reacted with isocyanate terminated polyurethanes to form 25 polymer), or the elements (A)(B)EL can be regarded as the pendant polyurethanes, can be reacted with acid terminated monomer. Both terminologies are used herein, but the context polyester urethanes to form pendant polyester urethanes. In makes the intended meaning clear. addition, these diol monomers having the NO-releasing and/ In certain embodiments, the non-hydrocarbon functional or biologically active agent-releasing moieties can be reacted ities in the monomer, aside from D where D is a bioactive with acids including diacids, isocyanates including diisocy 30 Substance, comprise ether, ester, amide, halo, hydroxy and anates and lactones including substituted lactones to form nitric oxide. polyesters and polyurethanes bearing pendant NO-releasing The chemistry illustrated below makes use of appropriate and/or biologically active agent-releasing moieties along the protecting groups to accommodate the various functionalities chain. 35 present. These protection group strategies are well known for The D moiety is substantially exemplified by biologically the amine, carboxylic, hydroxy and halo functionalities active agents. These agents well exemplify the kinds of func needed to practice the invention. tionalities that can be used to make the macromers and oli The definitions and examples provided in this application gomers of formula I. are not intended to be limiting, unless specifically stated. The repeats that are polyester polymerization compat 40 Furthermore, examples of nitric oxide and drug releasing macromers and oligomers of the present invention are pro ible i.e., those derived from monomers that can be serially vided for some embodiments of the current invention. It can attached to, or co-polymerized with, the monomers giving be extended to other species. This selection is not meant to rise to the Group A repeats. These will be recognized by those limit the scope of the invention in any way. Other variations in of skill in the art, and include, for example, diacids, diamines, the procedure may be readily apparent to those skilled in the diisocyanates and the like. 45 The macromer or oligomer is preferably applied in an art. effective amount. If it release NO as an active, NO is prefer Example 1 ably released as an effective amount. If, in addition, a bio logically active species is released, such is preferably Synthesis of released as an effective amount. To treat the indications of the 50 2-(6-methoxy-naphthalen-2-yl)-propionic acid invention, an effective amount of a pharmaceutical com benzyloxy-carbonyl methyl ester pound will be recognized by clinicians but includes an amount effective to treat, reduce, ameliorate, eliminate or prevent one or more symptoms of the disease sought to be treated or the condition sought to be avoided or treated, or to 55 otherwise produce a clinically recognizable favorable change Acetone, TEA in the pathology of the disease or condition. Benzylchloroacetate Applicant provides herein below claims to (a) macromer or --- oligomer, (b) compositions thereof (c) medical devices O COOH thereofand (d) methods of treatment therewith. The invention 60 MeO includes combination of the macromer? oligomer claims that O are not logically precluded. The invention includes group (b). (c) or (d) claims as written to depend on any of the combina ouls O tions of the macromer? oligomer claims discussed above, and O any combination of the claims of Such groups (not logically 65 MeO precluded) as written to depend on any of the combinations of the macromer? oligomer claims discussed above. US 8,062,653 B2 39 40 To a mixture of Naproxen (25 grams) and triethylamine (23 NMR spectroscopy in CDC1: "H NMR (CDC1) & 1.60 (d. ml) in acetone (150 ml) was added benzyl chloroacetate (24 3H, CH), 3.88 (s, 1H, OCH), 3.94 (m, 1H, CH), 4.54 (q, 2H, grams) drop wise, and the mixture was stirred at 50° C. OCH2), 7.06 (m, 2H, Ar), 7.39 (d. 1H, Ar), 7.64 (m, 3H, Ar). temperature for three hours. The reaction mixture was poured onto cold water, and crude 2-(6-Methoxy-naphthalen-2-yl)- Example 3 propionic acid benzyloxy-carbonyl methyl ester was filtered, Synthesis of dried and purified by recrystallizing from a mixture of ethyl 2-(6-methoxy-naphthalen-2-yl)-propionic acid acetate:hexane to give pure 2-(6-Methoxy-naphthalen-2-yl)- 4-bromo-butoxy carbonyl methyl ester propionic acid benzyloxycarbonyl methyl ester (39 grams) as 10 a white powder. m.p: 95.3-97.3°C. The pure product was characterized using H NMR spectroscopy in CDCls: & 1.60 (d. 3H, CH), 3.80 (m, 4H, CH and OCH), 4.56 (q, 2H, O Acetone, TEA 1,4- OCH2), 5.12 (q, 2H, OCH2), 7.06 (m, 2H, Ar), 7.30 (m, 6H, 15 Dibromobutane Ar), 7.64 (m, 3H, Ar) ouls OH -- O Example 2 MeO O Synthesis of 2-(6-methoxy-naphthalen-2-yl)-propionic acid oulsO 1N1N1 Br carboxymethyl ester O MeO

25 O To a mixture of 2-(6-Methoxy-naphthalen-2-yl)-propionic ouls Ethylacetate acid carboxymethyl ester (30 grams) and triethylamine (21.9 O Pol/C, H2 Her ml) in acetone (200 ml) was added 1,4-dibromobutane (90 O MeO grams) drop wise, and the mixture stirred at room temperature O 30 for 24 hours. The reaction mixture was poured onto cold water, and crude 2-(6-Methoxy-naphthalen-2-yl)-propionic OH acid 4-bromo-butoxy carbonyl methyl ester was extracted into dichloromethane. After drying over sodium Sulphate, O MeO dichloromethane was distilled off under reduced pressure, 35 and the residue was purified by column chromatography To a solution of 2-(6-methoxy-naphthalen-2-yl)-propionic using hexane as an eluant to get 18 grams of 2-(6-Methoxy acid benzyloxy carbonyl methyl ester (45 grams) in ethyl naphthalen-2-yl)-propionic acid 4-bromo-butoxy carbonyl acetate (200 ml), was added 50% wet Palladium on carbon methyl ester as light brown syrup. The pure product was (10%, 9 grams), and the mixture was stirred under an atmo 40 characterized using H NMR spectroscopy in CDCls: & 1.52 sphere of hydrogen (4 Kg) overnight in a pressure vessel. The (d. 3H, CH), 1.62 (m, 4H, CHX), 3.16 (t, 2H, CH), 3.82 catalyst was removed by filtration and ethyl acetate was dis (m, 4H, CH and OCH), 3.98 (t, 2H, CH), 4.46 (q, 2H, tilled under vacuum. The crude product was precipitated by OCH2), 7.00 (m, 2H, Ar), 7.30 (d. 1H, Ar), 7.58 (m, 3H, Ar). adding hexane, filtered, dried, and purified by recrystalliza 45 Example 4 tion in a mixture of ethyl acetate:hexane to get pure 2-(6- Methoxy-naphthalen-2-yl)-propionic acid carboxymethyl Synthesis of ester (30 grams) as a white powder with a melting point of 2-(6-methoxy-naphthalen-2-yl)-propionic acid 131-132.5°C. The pure product was characterized using "H 3-nitrooxy-propoxy carbonyl methyl ester

O Acetonitrile AgNO 3 Hs NullsO 1-1-1

O MeO O

Nulls O 11-ONO2

O MeO US 8,062,653 B2 41 42 To a solution of 2-(6-Methoxy-naphthalen-2-yl)-propionic To a solution of methanol (2100 ml) and sulphuric acid (84 acid 4-bromo-butoxy carbonyl methyl ester (15 grams) in ml) was added 2-(6-Hydroxy-naphthalen-2-yl)-propionic acetonitrile (150 ml) was added Silver nitrate (8.7 grams), and acid (420 grams). The reaction mixture was refluxed for 6 the mixture was left for stirring with reflux overnight. The Hours. Methanol (1000 ml) was distilled, and the cooled reaction mixture was filtered and washed with acetonitrile, reaction mass was poured onto ice water to yield crude 2-(6- dried over sodium sulphate, the solvent distilled off under hydroxy-naphthalen-2-yl)-propionic acid methyl ester which reduced pressure, and the residue was purified by column chromatography using hexane:ethyl acetate as eluant to get was filtered, dried and recrystallized using a mixture of ethyl 13 grams of 2-(6-Methoxy-naphthalen-2-yl)-propionic acid acetate:hexane to yield pure product (400 grams, 89.5% 3-nitrooxy-propoxy carbonyl methyl ester as a light yellow 10 yield) as a white fluffy powder with a melting point of 89.5- syrup. The pure product was also characterized using "H 92°C. The pure product was characterized using H NMR NMR spectroscopy in CDC1: & 1.62 (m, 7H, CH2X and spectroscopy in CDC1 & 1.60 (d. 3H, CH), 3.70 (s, 3H, CH), 3.92 (s, 3H, OCH), 3.97 (q, 1H, CH), 4.12 (t, 2H, Ester), 3.88 (q, 1H, CH), 5.36 (bs, 1H, OH), 7.08 (m,2H, Ar), CH), 4.32 (t, 2H, CH), 4.61 (s. 2H, OCH2), 7.16 (m, 2H, 15 7.48 (m. 1H, Ar), 7.65 (m, 3H, Ar). Ar), 7.43 (d. 1H, Ar), 7.73 (m, 3H, Ar) Example 7 Example 5

Synthesis of Synthesis of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid 2-6-(2-chloro-acetoxy)-naphthalen-2-yl)-propionic acid methyl ester

48% HBr, 25 Reflux O COOH He MeO

Bromo acetyl bromide COOH O COOMe Her HO HO 35 A mixture of Naproxen (500 grams) and 48% HBr solution (1500 ml) was refluxed for 10 Hours, poured onto ice water (3000 ml), and stirred for 30 minutes. Crude 2-(6-hydroxy naphthalen-2-yl)-propionic acid was filtered, dried and 40 recrystallised from a mixture of ethyl acetate and hexane to give pure 2-(6-hydroxy-naphthalen-2-yl)-propionic acid O COOMe (380 grams, 81%) as a white powder with a melting point of 186-1889 C. nus O 45 Example 6

Synthesis of 50 To a solution of 2-(6-hydroxy-naphthalen-2-yl)-propionic 2-(6-Hydroxy-naphthalen-2-yl)-propionic acid acid methyl ester (20 grams) and pyridine (10.3 grams) in methyl ester dichloromethane (200 ml) maintained at 0-5° C. under N atmosphere was added dropwise bromoacetyl chloride (19.6 grams). The reaction was stirred at the same temperature for 55 one hour. The reaction mixture was washed with water (500 Methanol, Acid COOH - - ml) and 5% solution of sodium carbonate followed by drying over Sodium Sulphate and distillation to get crude compound, HO which was purified by column chromatography using hexane 60 as eluant to get pure 2-6-(2-bromo-acetoxy)-naphthalen-2- yl-propionic acid methyl ester (14 grams) as a dark brown COOMe syrup. The pure product was characterized using "H NMR spectroscopy in CDC1 & 1.55 (d. 3H, CH), 3.65 (s, 3H, HO 65 Ester), 3.82 (q, 1H, CH), 4.08 (s. 2H, OCH) 7.20 (dd. 1H, Ar), 7.4 (dd. 1H, Ar), 7.57 (d. 1H, Ar), 7.72 (d. 1H, Ar), 7.78 (d. 1H, Ar), 7.84 (d. 1H, Ar). US 8,062,653 B2 43 44 Example 8 naphthalen-2-yl)-propionic acid was filtered, dried and recrystallized from a mixture of ethyl acetate and hexane to Synthesis of 2-6-(2-nitrooxy-acetoxy)-naphthalen yield pure product (380 grams, 81%) as a white powder with 2-yl-propionic acid methyl ester a melting point of 186-188°C.

Example 10

Acetonitrile AgNO3 10 Synthesis of O COOMe ---- 2-(6-hydroxy-naphthalen-2-yl)-propionic acid benzyloxy carbonyl methyl ester Brsus O

15 Acetone, TEA OH Benzyl chloro acetate O COOMe He

ouls O HO To a solution of 2-6-(2-bromo-acetoxy)-naphthalen-2- yl-propionic acid methyl ester (14 grams) in acetonitrile O (150 ml) was added silver nitrate (20.2 grams). The solution 25 was stirred at room temperature overnight followed by stir O ring at 45-50° C. for 4-6 hrs. The reaction mixture was filtered O and washed with acetonitrile, dried over Sodium Sulphate, and HO the solvent was distilled off under reduced pressure. The 30 residue was purified by column chromatography using a mix ture of Hexane:Ethyl acetate as eluant, followed by recrystal To a mixture of 2-(6-hydroxy-naphthalen-2-yl)-propionic lisation from a mixture of toluene:hexane to get 5.5 grams acid (50 grams, 231.48 mmol), triethylamine (33 ml) in 2-6-(2-Nitrooxy-acetoxy)-naphthalen-2-yl)-propionic acid acetone (500 ml) was added benzyl chloroacetate (45 grams) methyl ester as off white powder. The pure product was char 35 drop wise, and the mixture stirred at 50° C. temperature for acterized using "H NMR spectroscopy in CDC1 & 1.56 (d. three hours. The reaction mixture poured onto cold water, 3H, CH), 3.65 (s.3H, Ester), 3.90 (q, 1H, CH), 5.258 (s. 2H, crude 2-(6-hydroxy-naphthalen-2-yl)-propionic acid benzy OCH) 7.20 (dd. 1H, Ar), 7.4 (dd. 1H, Ar), 7.57 (d. 1H, Ar), loxy carbonyl methyl ester extracted into ethyl acetate, 7.72 (d. 1H, Ar), 7.78 (d. 1H, Ar), 7.84 (d. 1H, Ar). The pure 40 washed with water, dried over sodium sulphate, the solvent product has a melting point of 72-74°C. distilled off, and purified by column chromatography with hexane:ethyl acetate as eluant to give pure 2-(6-hydroxy Example 9 naphthalen-2-yl)-propionic acid benzyloxy carbonyl methyl ester (41 grams) as a white powder with a melting point of Synthesis of 45 104-106.5°C. The pure product was characterized using "H 2-(6-hydroxy-naphthalen-2-yl)-propionic acid NMR spectroscopy in CDC1 & 1.57 (d. 3H, CH), 3.88 (q, 1H, CH), 4.60 (q, 2H, OCH2), 5.10 (q, 2H, OCH2), 7.04 (m, 2H, Ar), 7.27 (m, 7H, Ar), 7.60 (m, 3H, Ar). 50 48% HBr, Reflux Example 11 -e- O COOH Synthesis of MeO 55 2-(6-hydroxy-naphthalen-2-yl)-propionic acid carboxy methyl ester

COOH 60 Ethyl O acetate HO ouls O Pol/C,H Ho To a mixture of Naproxen (500 grams) and 48%HBr (1500 65 O ml) was refluxed for 10 hours. It was poured onto ice water HO (3000 ml) and stirred for 30 minutes. Crude 2-(6-Hydroxy US 8,062,653 B2 45 46 -continued residue was purified by column chromatography using hex ane as eluant to yield 24 grams of 2-(6-Hydroxy-naphthalen 2-yl)-propionic acid 4-bromo-butoxy carbonyl methyl ester OH as a light brown syrup. The pure product was characterized using "H NMR spectroscopy in CDC1 & 1.60 (d. 3H, CH4), HO 1.74 (m, 4H, CHX), 3.22 (t, 2H, CH), 3.90 (q, 1H, CH), 4.08 (t, 2H, CH), 4.55 (q, 2H, OCH2), 7.02 (m,2H, Ar), 7.30 To a solution of 2-(6-Hydroxy-naphthalen-2-yl)-propionic (d. 1H, Ar), 7.58 (m, 3H, Ar) acid benzyloxy carbonyl methyl ester (41 grams) in ethyl 10 acetate (400 ml) in a pressure vessel was added 50% wet Example 13 palladium on carbon (10%, 9 grams) and the mixture was stirred overnight under an atmosphere of hydrogen (5 Kg) at Synthesis of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid a temperature of 50° C. The catalyst was removed by filtration 15 and ethyl acetate distilled off (50%) under vacuum, and the 4-bromo-butoxy carbonyl methyl ester product precipitated by adding hexane, filtered and dried to get pure 2-(6-hydroxy-naphthalen-2-yl)-propionic acid car boxy methyl ester (30 grams) as a white powder with a melt O ing point of 186-188.5°C. The pure product was character ized using "H NMR spectroscopy in CDC1 & 1.60 (d. 3H, CH), 3.88 (s, 1H, OCH), 3.94 (m. 1H, CH), 4.54 (q, 2H, O OCH2), 7.06 (m, 2H, Ar), 7.39 (d. 1H, Ar), 7.64 (m, 3H, Ar). HO Cr 25 Acetonitrile Example 12 AgNO3 Synthesis of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid O 4-bromo-butoxy carbonyl methyl ester 30 o-s,11-ONO2

HO CO O O Acetone, TEA 1,4- To a solution of 2-(6-hydroxy-naphthalen-2-yl)-propionic Dibromo butane 35 ouls OH He acid 4-bromo-butoxy carbonyl methyl ester (20 grams) in O acetonitrile (200 ml) was added Silver nitrate (12.4 grams), HO and the mixture stirred at reflux temperature overnight. The reaction mixture was filtered and washed with acetonitrile, O 40 dried over sodium sulphate, the solvent distilled off under ouls 1N1N1 Br reduced pressure, residue re-dissolved in dichloromethane, O and the salts filtered off; then the organic layer was washed O HO with water (50 ml), dried over Sodium sulphate, the solvent 45 distilled off under reduced pressure, and the residue was To a mixture of 2-(6-hydroxy-naphthalen-2-yl)-propionic purified by column chromatography using hexane:ethyl acetate as an eluant to get 17 grams of 2-(6-hydroxy-naph acid carboxy methyl ester (30 grams) and triethylamine (24 thalen-2-yl)-propionic acid 4-nitrooxy-butoxy carbonyl ml) in acetone (300 ml) was added dropwise 1,4-dibromo methyl ester white powder. butane (96.5 grams) drop wise followed by stirring at room 50 temperature for 24 hours. The reaction mixture was poured Example 14 onto cold water, crude 2-(6-hydroxy-naphthalen-2-yl)-propi onic acid 4-bromo-butoxy carbonyl methyl ester was Synthesis of 2-6-(2-bromo-acetoxy)-naphthalen-2- extracted into ethyl acetate, and dried over Sodium Sulphate. yl-propionic acid 4-nitrooxy-butoxy carbonyl Ethyl acetate was distilled off under reduced pressure and the methyl ester

O

oulsO 1n 1-ONO2

O HO DCM, Pyridine Bromo acetyl bromide US 8,062,653 B2 47 48 -continued O

O oulsO 1N1-N-ONO2

nusO O

To a solution of 2-(6-hydroxy-naphthalen-2-yl)-propionic 10 -continued acid and 4-nitrooxy-butoxy carbonyl methyl ester (17 grams) and pyridine (5.7 ml) in dichloromethane (200 ml) main O tained at 0-5°C. under N atmosphere was added dropwise O bromo acetyl bromide (5.6 ml). The reaction mixture was stirred at the same temperature for one hour. The reaction 15 r O mixture was washed with water (25 ml) and a solution of 5% OAc Sodium carbonate (75 ml). The solution was dried over sodium sulphate and the solvent was distilled off to get crude 2-6-(2-Bromo-acetoxy)-naphthalen-2-yl)-propionic acid To a mixture of Aspirin (25 grams, 138.77 mmol) and 4-nitrooxy-butoxy carbonyl methyl ester. triethylamine (29 ml) in acetone (250 ml) was added drop wise benzyl chloro acetate (30.75 grams), followed by stir ring at 50° C. for five hours. The reaction mixture was poured Example 15 onto cold water, crude 2-Acetoxy-benzoic acid benzyloxy carbonyl methyl ester was filtered, dried and purified by Synthesis of 2-6-(2-nitrooxy-acetoxy)-naphthalen 25 recrystallisation from a (1:4) mixture of chloroform:hexane 2-yl-propionic acid 4-nitrooxy-butoxy carbonyl to give pure 2-Acetoxy-benzoic acid benzyloxy carbonyl methyl ester methyl ester (25 grams) as a white powder with a melting O

O oulsO 1N1-N-ONO2

nusO O

Acetonitrile AgNO3

O

O ouls O 1N1N1 ONO.

onosul O O

To a solution of 2-6-(2-Bromo-acetoxy)-naphthalen-2- 45 point of m.p. 91-92.5°C. The pure product was characterized yl-propionic acid 4-nitrooxy-butoxy carbonyl methyl ester using "H NMR spectroscopy in CDC1 & 2.30 (s.3H, OAc), (15 grams) in acetonitrile (150 ml) was added silver nitrate 4.82 (s. 2H, CH), 5.20 (s. 2H, CH2), 7.10 (d. 1H, Ar), 7.32 (10grams), and the mixture stirred at 40°C. temperature for (m, 6H, Ar), 7.56 (t, 1H, Ar), 8.18 (d. 1H, Ar). 24 hours. The reaction mixture was filtered and washed with acetonitrile, dried over sodium sulphate, the solvent distilled 50 off under reduced pressure, and the residue was purified by Example 17 column chromatography using hexane:ethyl acetate as eluant to get 10 grams of 2-6-(2-nitrooxy-acetoxy)-naphthalen-2- Synthesis of 2-acetoxy-benzoic acid carboxymethyl yl-propionic acid 4-nitrooxy-butoxy carbonyl methyl ester ester as a light yellow syrup. 55 Example 16

Synthesis of 2-acetoxy-benzoic acid benzyloxy O Ethylacetate carbonyl methyl ester 60 Pol/C, H2 O O Acetone, TEA r O Benzylchloroacetate O -e- OAc 65 OAc US 8,062,653 B2 49 50 -continued Example 19

OH Synthesis of 2-acetoxy-benzoic acid 4-nitrooxy-butoxy carbonyl methyl ester r 5 O OAc O 2-Acetoxy-benzoic acid benzyloxy carbonyl methyl ester 10 Acetonitrile (50 grams) was dissolved in ethyl acetate (150 ml) in a pres N-1--1a AgNO3 or Br He sure vessel and 50% wet palladium on carbon (10%, 10 O grams) was added. The reaction mixture was stirred under an OAc atmosphere of hydrogen (4 Kg) for 14 hours. The catalyst was O 15 removed by filtration and ethyl acetate was distilled offunder N-1a1a. vacuum. The crude was precipitated by adding hexane fol or ONO lowed by filtration, drying and purification by recrystallisa O tion using a mixture of ethyl acetate:hexane to yield pure OAc 2-Acetoxy-benzoic acid carboxymethyl ester (32 grams) as a white powder with a melting point of 130-131.5°C. The pure To a solution of 2-Acetoxy-benzoic acid 4-bromo-butoxy product was characterized using "H NMR spectroscopy in carbonyl methyl ester (20 grams) in acetonitrile (150 ml) was DMSO-d & 2.28 (s.3H, OAc), 4.8 (s. 2H, CH), 7.24 (d. 1H, added silver nitrate (13.6 grams). The reaction mixture was Ar), 7.55 (t, 1H, Ar), 7.74 (t, 1H, Ar), 8.10 (d. 1H, Ar), 13.20 25 refluxed for four hours. The reaction mixture was filtered and (bs, 1H, COOH). washed with acetonitrile, dried over sodium sulphate fol lowed by distillation of solvent under reduced pressure. The Example 18 residue was purified by column chromatography using hex 30 ane as eluant to get 15 grams of 2-acetoxy-benzoic acid Synthesis of 2-acetoxy-benzoic acid 4-bromo-butoxy 4-nitrooxy-butoxy carbonyl methyl ester as a light yellow carbonyl methyl ester liquid. The pure product was characterized using "H NMR spectroscopy in CDC1 & 1.80 (m, 4H, CHX), 2.34 (s, 3H, OAc), 4.22 (t, 2H, CH), 4.44 (t, 2H, CH), 4.80 (s. 2H, CH), 35 7.14 (d. 1H, Ar), 7.34 (t, 1H, Ar), 7.60 (t, 1H, Ar), 8.08 (d. 1H, O Ar.

OH Acetone, TEA 1,4-Dibromobutane Example 20 He r 40 O OAc O Synthesis of bromo-acetic acid 2-formyl-phenyl ester 9N-1N1\ r Br 45 O Br OAc

To a mixture of 2-acetoxy-benzoic acid carboxymethyl 50 OH 1. ester (30 grams), and triethylamine (26.5 ml) in acetone (200 CHO DCM, Pyridine CHO ml) was added dropwise 1,4-dibromo butane (109 grams). Bromo acetyl bromide The reaction mixture was left for stirring at room temperature -e- for 24 hours. The reaction mixture was poured onto cold water and crude 2-acetoxy-benzoic acid 4-bromobutoxy car 55 Salicylaldehyde bonyl methyl ester was extracted into dichloromethane fol lowed by drying over sodium sulphate. Dichloromethane was To a solution of Salicylaldehyde (50 grams) and pyridine distilled off under reduced pressure and the residue was puri (48.5 grams) in dichloromethane (500 ml) maintained at 0-5° fied by column chromatography using hexane as eluant to get 60 C. under nitrogen atmosphere was added dropwise bro 32 grams of 2-acetoxy-benzoic acid 4-bromo-butoxy carbo moacetyl bromide (210.6 grams). The reaction mixture was nyl methyl ester as a light yellow liquid. The pure product was stirred for one hour at the same temperature. The reaction characterized using "H NMR spectroscopy in CDC1 & 1.88 mixture was washed with 1000 ml of water and 1500 ml of 5% (m, 4H, CHX), 2.32 (s.3H, OAc), 3.39 (t, 2H, CH), 4.20(t, 65 sodium bicarbonate solution, dried over sodium sulphatefol 2H, CH), 4.75 (s.2H, CH), 7.10 (d. 1H, Ar), 7.23 (t, 1H, Ar), lowed by distillation of solvent under reduced pressure to get 7.50 (t, 1H, Ar), 8.10 (d. 1H, Ar) 60.0 grams of bromo-acetic acid 2-formyl-phenyl ester. US 8,062,653 B2 51 52 Example 21 Example 23 Synthesis of 2-hydroxy-benzoic acid benzyloxy Synthesis of nitrooxy-acetic acid 2-formyl-phenyl carbonyl methyl ester ester

O Br ONO. Acetone, TEA 1. 1. 10 OH Benzyl chloro acetate OH CHO Acetonitrile CHO O AgNO3 15 -- r O O To a solution of bromoacetic acid 2-formyl-phenyl ester OH (10 grams) in acetonitrile (150 ml) was added silver nitrate To a mixture of Salicylic acid (100 grams, 724 mmol) and (14.0 grams). The reaction mixture was stirred at room tem triethylamine (152 ml) in acetone (500 ml) was added drop perature for 35-38 hours. The reaction mixture was then fil wise benzyl chloroacetate (147 grams). The solution was tered and washed with acetonitrile, dried over sodium sul 25 stirred at 50° C. temperature for four hours. The reaction phate, and the solvent was distilled offunder reduced pressure mixture was poured onto cold water and the isolated crude to leave the residue which was purified by column chroma 2-hydroxy-benzoic acid benzyloxy carbonyl methyl ester tography using hexane:ethyl acetate as eluant to yield 3.0 was filtered, dried and purified by recrystallising from a mix grams of nitrooxy-acetic acid 2-formyl-phenyl esteras brown ture of ethyl acetate:hexane to yield pure 2-hydroxy-benzoic syrup. The pure product was characterized using "H NMR 30 acid benzyloxy carbonyl methyl ester (50 grams) as a white spectroscopy in CDC1 & 5.25 (s.2H, OCH), 7.20 (d. 1H, Ar), powder with a melting point of 75.5-77°C. 7.53 (dd. 1H, Ar), 7.63 (dd. 1H, Ar), 7.90 (d. 1H, Ar). Example 24

Example 22 35 Synthesis of 2-hydroxy-benzoic acid carboxymethyl ester Synthesis of 2-(2-nitrooxy-acetoxy)-benzoic acid

40 O

ONO. ONO. O EtOAcoPd/C, H2 r -- O O1. 1. 45 OH O CHO COOH Oxidation OH He r 50 O OH To a solution of nitrooxyacetic acid-2-formyl-phenyl ester (3.0 grams) in acetone (50 ml) was added potassium perman To a solution of 2-hydroxy-benzoic acid benzyloxy carbo ganate (3 grams) at 0°C. and stirred at the same temperature nyl methyl ester (55 grams) in ethyl acetate (300 ml) in a 55 pressure vessel was added 50% wet Palladium on carbon for 5-6 hours. Oxalic acid (15 grams) was added to the reac (10%, 15 grams). The reaction mixture was stirred under an tion mixture and the reaction mixture was washed with atmosphere of hydrogen (4 Kg) for 16 hours. The catalyst was acetone followed by filtration, the solution was dried over removed by filtration and ethyl acetate was distilled offunder sodium sulphate and the solvent was distilled off under vacuum to yield crude 2-hydroxy-benzoic acid carboxym reduced pressure. The residue was dissolved in dichlo 60 ethyl ester, which was precipitated from hexane. The precipi romethane and the organic layer was washed with water and tate was filtered, dried and purified by recrystallisation from a mixture of ethyl acetate:hexane to yield 33 grams of pure dried over sodium sulphate. The solvent was distilled off 2-hydroxy-benzoic acid carboxymethyl ester as a white pow under reduced pressure, purified by column chromatography der. The pure product was characterized using "H NMR spec using a mixture of hexane:ethyl acetate as an eluant to yield 65 troscopy in DMSO-d & 4.85 (s. 2H, CH), 7.00 (m, 2H, Ar), 1.0 grams of product (an off white powder). The product is 7.55 (t, 1H, Ar), 7.85 (d. 1H, Ar), 10.30 (bs, 1H, OH). The purified further to yield 2-(2-nitrooxy-acetoxy)-benzoic acid. pure product has a melting point of 131-132.5°C. US 8,062,653 B2 53 54 Example 25 pure product was characterized using "H NMR spectroscopy in H NMR (CDC1) & 1.85 (m, 4H, CHX), 4.25 (t, 2H, Synthesis 2-hydroxy-benzoic acid 4-bromo-butoxy CH), 4.55 (t, 2H, CH), 4.85 (s.2H, CH), 6.90 (m, 2H, Ar), carbonyl methyl ester 7.5 (t, 1H, Ar), 7.90 (d. 1H, Ar), 10.30 (s, 1H, OH). The pure 5 product has a melting point of 84-86.5°C.

O Example 27

OH Acetone, TEA 10 1,4-Dibromobutane Synthesis of 2-(2-bromo-acetoxy)-benzoic acid r He 4-nitrooxy-butoxy carbonyl methyl ester O OH O 15 N-1-N-1a O r Br DCM, Pyridine O ON1-1a Bromo acetyl OH or ONO Hebromide O OH To a mixture of 2-hydroxybenzoic acid carboxy methyl ester (33 grams), and triethylamine (36 ml) in acetone (400 O ml) was added dropwise 1,4-dibromo butane (146 grams). The reaction mixture was stirred at 40° C. for 16 hours. The N-1-N-1a reaction mixture was poured onto cold water to yield crude 25 r ONO. 2-Hydroxy-benzoic acid 4-bromobutoxy carbonyl methyl O ester which was extracted into dichloro methane and dried O over sodium sulphate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography using a mixture of hexane:ethyl acetate as 30 eluant to yield 40 grams of 2-hydroxybenzoic acid-4-bromo Br butoxy carbonyl methyl ester as a light yellow liquid. The pure product was characterized using "H NMR spectroscopy in H NMR (CDC1) & 1.95 (m, 4H, CHX), 3.40 (t, 2H, To a solution of 2-hydroxy-benzoic acid 4-nitrooxy-bu CH), 4.25 (t, 2H, CH), 4.85 (s.2H, CH), 6.90 (m, 2H, Ar), 35 toxy carbonyl methyl ester (20 grams) and pyridine (8 ml, 7.5 (t, 1H, Ar), 7.90 (d. 1H, Ar), 10.35 (s, 1H, OH). 98.91 mmol) in dichloromethane (300 ml) maintained at 0-5° C. under N. atmosphere was added dropwise bromoacetyl Example 26 bromide (8 ml). The reaction mixture was stirred at the same temperature for two hours. The reaction mixture was washed Synthesis of 2-hydroxy-benzoic acid 40 with water (200 ml) and a 5% solution of sodium carbonate 4-nitrooxy-butoxy carbonyl methyl ester (300 ml). The solution was dried over sodium sulphate and solvent was distilled off to yield crude 2-hydroxy-benzoic acid 4-nitrooxy-butoxy carbonyl methyl ester as light brown O syrup The pure product was characterized using H NMR 45 spectroscopy in H NMR (CDC1) & 1.70 (m, 4H, CHX), Acetonitrile, N-1-1a AgNO3 4.15 (t, 4H, CH), 4.35 (s. 2H, CH4), 4.70 (s. 2H, CH), 7.05 r Br -e- (d. 1H, Ar), 7.30 (t, 1H, Ar), 7.55 (t, 1H, Ar), 8.05 (d. 1H, Ar). O OH O 50 Example 28 'N-1S-1N r ONO Synthesis of 2-(2-nitrooxy-acetoxy)-benzoic acid O 4-nitrooxy-butoxy carbonyl methyl ester OH 55 To a solution of 2-hydroxy-benzoic acid 4-bromo-butoxy carbonyl methyl ester (30 grams) in acetonitrile (300 ml) was O added silver nitrate (30 grams) and stirred at 50° C. tempera O Acetonitrile, ture for eight hours. The reaction mixture was filtered and 60 O n1n 1\ono, AgNO3 washed with acetonitrile, dried over sodium sulphate, the -e- solvent distilled off under reduced pressure, and the residue C. r was dissolved in dichloromethane, filtered off the salts; organic layer washed with water (50 ml), dried over sodium O Sulphate, distilled under vacuum, and precipitated with hex 65 ane to yield 23 grams of 2-hydroxy-benzoic acid 4-nitrooxy Br butoxy carbonyl methyl ester as an off-white powder. The US 8,062,653 B2 55 56 -continued To a mixture of 2-(6-Hydroxy-naphthalen-2-yl)-propionic O acid carboxymethyl ester (35 grams), triethylamine (12 ml) in 'N-1S-1N dimethylformamide (350 ml) at 0°C. was added dichloro r ONO. 5 linker (12.5 grams). The reaction mixture was stirred at 60° C. O for 21 hours. The reaction mixture was poured onto cold O water and the crude product was extracted into ethyl acetate. The ethyl acetate extract was washed with 5% sodium bicar bonate solution and water followed by drying over sodium 10 sulphate. Ethyl acetate was distilled off and the product was ONO. purified by column chromatography with hexane:ethyl acetate as eluant to yield pure 2-(6-hydroxy-naphthalen-2- To a solution of 2-(2-bromoacetoxy)-benzoic acid-4-ni yl)-propionic acid 2-(2-2-[2-(6-hydroxy-naphthalen-2-yl)- trooxy-butoxy carbonyl methyl ester (15 grams) in acetoni 15 propionyloxy-acetoxy-acetoxy)-ethoxy carbonyl methoxy trile (150 ml) was added Silver nitrate (12.2 grams). The carbonyl methyl ester (13.4 grams) as a white powder with a solution was stirred at 50° C. temperature for twenty four melting point of 85-88°C. The pure product was character hours. The reaction mixture was filtered, washed with aceto ized via H NMR in (CDC1) & 1.55 (d. 3H, CH), 3.60 (s, 4H, nitrile, and dried over sodium sulphate. The solvent was dis CHX), 3.90 (q, 1H, CH), 4.55 (q, 2H, OCH), 5.20 (s, 1H, tilled off under reduced pressure. The residue was dissolved OH), 7.04 (d. 2H, Ar), 7.35 (d. 1H, Ar), 7.55 (d. 1H, Ar), 7.62 in dichloro methane, and the salts were filtered off. The (m. 2H, Ar). organic layer was washed with water (50 ml), dried over Sodium Sulphate, distilled under vacuum to yield 2-(2-ni Example 30 trooxy-acetoxy)-benzoic acid 4-nitrooxy-butoxy carbonyl 25 methyl ester, which was purified by column chromatography using a mixture of hexane:ethyl acetate The product was Synthesis of 2-(6-bromo-hexanoyloxy)-benzoic acid further precipitated with hexane to yield 7.5 grams of 2-(2- benzyloxy carbonyl methyl ester nitrooxy-acetoxy)-benzoic acid 4-nitrooxy-butoxy carbonyl methyl ester as a white powder. The pure product was char 30 acterized using 'HNMR spectroscopy in H NMR (CDC1) & & 1.75 (m, 4H, CHX), 4.20 (t, 2H, CH), 4.45 (t, 2H, CH), DCM, Pyridine 4.80 (s. 2H, CH), 5.30 (s.2H, CH), 7.15 (d. 1H, Ar), 7.45 (t, 6-Bromo 35 hexanoyl 1H, Ar), 7.65 (t, 1H, Ar), 8.15 (d. 1H, Ar). O chloride His Example 29 r O Synthesis of 2-(6-hydroxy-naphthalen-2-yl)-propi O onic acid 2-(2-(2-6-hydroxy-naphthalen-2-yl)-pro 40 OH pionyloxy-acetoxy-acetoxy)-ethoxy carbonyl methoxy carbonyl methyl ester

O

OH

O HO

O DMF, TEA ar O N-1No --- O US 8,062,653 B2 57 58 -continued -continued O O OH O r O r O O O O 10 O

15 Br Br To a solution of 2-(6-bromo-hexanoyloxy)-benzoic acid benzyloxy carbonyl methyl ester (10 grams) in Ethyl acetate To a solution of 2-Hydroxy-benzoic acid benzyloxycarbo (200 ml) in a pressure vessel, 50% wet palladium on carbon nyl methyl ester (10 grams) and pyridine (4.2 ml) in dichlo (10%, 3 grams) was added and the mixture stirred under an romethane (100 ml) at 0°C. under N atmosphere was added atmosphere of hydrogen (4 Kg) for 4 hours. The catalyst was dropwise 6-bromo hexanoyl chloride (9 grams). The reaction removed by filtration and Ethyl acetate was distilled under 25 vacuum. The product was precipitated by adding diisopropyl mixture was stirred at the same temperature for two hours. ether, filtered and dried to yield pure 2-(6-Bromo-hexanoy The reaction mixture was washed with water, 5% Sodium loxy)-benzoic acid carboxy methyl ester (4 grams) as a white carbonate, 5% Copper Sulphate and dried over Sodium sul powder with a melting point of 102-103°C. The final product phate. The solvent was distilled off to yield crude compound was analyzed by H NMR (CDC1+DMSO-d) & 1.50 (m, 2H, which was purified by column chromatography using a mix 30 CH), 1.70 (m, 2H, CH), 1.90 (m, 2H, CH), 2.55 (t, 2H, ture of hexane and ethyl acetate. The product was further CH), 3.40 (t, 2H, CH), 4.65 (s. 2H, CH,), 7.05 (d. 1H, Ar), precipitated with hexane to yield 12 grams of 2-(6-Bromo 7.35 (t, 1H, Ar), 7.55 (t, 1H, Ar), 8.05 (d. 1H, Ar). hexanoyloxy)-benzoic acid benzyloxy carbonyl methyl ester as white powder with a melting point of 59-60°C. The prod 35 Example 32 uct was characterized via H NMR (CDC1) & 1.50 (m. 2H, CH), 1.70 (m, 2H, CH), 1.85 (m, 2H, CH), 2.55 (t, 2H, Synthesis of 2-(6-nitrooxy-hexanoyloxy)-benzoic CH), 3.30 (t, 2H, CH), 4.70 (s.2H, CH), 5.15 (s.2H, CH), acid carboxy methyl ester 7.05 (d. 1H, Ar), 7.30 (m, 6H, Ar), 7.50 (t, 1H, Ar), 8.05 (d. 1H, Ar). 40 O OH Example 31 r O Acetonitrile 45 O Silver nitrate Synthesis 2-(6-bromo-hexanoyloxy)-benzoic acid carboxy methyl ester O

50

O Ethyl acetate Br r" Pol/C, H2 55

60

65 ONO. US 8,062,653 B2 59 60 To a solution of 2-(6-bromo-hexanoyloxy)-benzoic acid a mixture of hexane:Ethyl acetate to give pure 2-(6-nitrooxy carboxy methyl ester (20 grams) in acetonitrile (200 ml) at 0° hexanoyloxy)-benzoic acid (2.2.5-trimethyl-1,3dioxan-5- C. was added silver nitrate (18 grams) and stirred at room yl carbamoyl)-methyl ester (4 grams) as light yellow syrup. temperature for 16 hours, later at reflux temperature for 6 5 'HNMR (CDC1,) & 1.32 (s.3H, CH,), 1.34 (s.3H, CH,), 1.40 hours. The reaction mixture was filtered and washed with (s.3H, CH), 1.45 (m,2H, CH), 1.78 (m, 4H, CHX2), 2.64 acetonitrile and dried over Sodium sulphate. The solvent was (t, 2H, CH), 3.62 (d. 2H, CH), 3.92 (d. 2H, CH), 4.46 (t, distilled off under reduced pressure and the residue was dis 2H, CH), 4.70 (s. 2H, CH), 5.54 (s, 1H, NH), 7.12 (d. 1H, solved indichloro methane, washed with water and dried over Ar), 7.34 (t, 1H, Ar), 7.64 (t, 1H, Ar), 8.05 (d. 1H, Ar). Sodium sulphate. The dichloromethane was distilled under 10 vacuum to get crude product which was purified by column Example 34 chromatography using dichloromethane as eluant to yield 8 grams of 2-(6-nitrooxy-hexanoyloxy)-benzoic acid carboxy Synthesis of 2-(6-nitrooxy-hexanoyloxy)-benzoic methyl ester as white powder with a melting point of 87.5- acid (2-hydroxy-1-hydroxy methyl-1-methyl-ethyl 89.5° C. The final product was characterized by H NMR 15 carbamoyl)-methyl ester (DMSO-d) & 1.45 (m,2H, CH4), 1.70 (m, 4H, CH2X2), 2.60 (t, 2H, CH), 4.55 (t, 2H, CH), 4.75 (s.2H, CH), 7.25 (d. 1H, Ar), 7.45 (t, 1H, Ar), 7.70 (t, 1H, Ar), 8.00 (d. 1H, Ar). O H Example 33 N

Synthesis of 2-(6-nitrooxy-hexanoyloxy)-benzoic r O >< Methanol acid (2.2.5-trimethyl-1,3dioxan-5-yl carbamoyl)- O O PTSA -e- methyl ester 25 x"

30

ONO.

He 35

O OH OH

40

ONO O

45

ONO. O r:-O O To a solution of 2-(6-nitrooxy-hexanoyloxy)-benzoic acid X 50 (2.2.5-trimethyl-1,3dioxan-5-yl carbamoyl)-methyl ester (5.5 grams) in a mixture of Methanol (55 ml) and water (2.5 ml), was added p-toluenesulfonic acid (0.2 grams) and stirred at room temperature for 2 hours. The reaction mixture poured 55 onto cold water, extracted with Ethyl acetate, washed the organic layer with water, dried over Sodium Sulphate and ONO distilled under vacuum to get crude compound which was purified by column chromatography using Hexane:Ethyl To a mixture of 2-(6-Nitrooxy-hexanoyloxy)-benzoic acid acetate as eluant to get 1 grams of 2-(6-Nitrooxy-hexanoy carboxy methyl ester (10 grams), 2.2.5-Trimethyl-1,3di 60 loxy)-benzoic acid (2-hydroxy-1-hydroxy methyl-1-methyl oxan-5-yl amine (6 grams) and hydroxybenzotriazole (1.2 ethylcarbamoyl)-methyl ester as light yellow syrup. The grams) in acetonitrile (150 ml) at 0°C. was added EDC.HCl product was characterized by H NMR (DMSO-d) & 1.16 (s, (8grams) in small lots and stirred at room temperature for 18 3H, CH), 1.45 (m, 2H, CH), 1.70 (m, 4H, CHX2), 2.64 (t, hours. The reaction mixture poured onto cold water, extracted 65 2H, CH), 3.50 (m, 4H, CHX2), 4.55 (t, 2H, CH4), 4.70 (s, into ethyl acetate, dried over anhydrous Sodium Sulphate, 2H, CH), 4.80 (t, 2H, OHX2), 7.25 (d. 1H, Ar), 7.40 (m, 2H, distilled and purified by column chromatography using from Ar & NH), 7.70 (t, 1H, Ar), 8.00 (d. 1H, Ar). US 8,062,653 B2 61 62 Example 35

Synthesis of 6-bromo-hexanoic acid 6-(1-2-[2-(2- {2-6-(6-bromo-hexanoyloxy)-naphthalen-2-yl)- propionyloxy)-acetoxy)-acetoxyethoxycarbonyl methoxycarbonylmethoxycarbonyl-ethyl)-naphtha len-2-yl ester

s DCM,hexanoyl Pyridine chloride susO lu o1 n--- O O O O ~~~ ---> O

To a solution of 2-(6-hydroxy-naphthalen-2-yl)-propionic (11.2 grams) as white powder with a melting point of 49-50° acid methyl ester (12 grams) and Pyridine (4.12 grams) in 35 C. The pure product was characterized via H NMR in dichloromethane (120 ml) at 0°C. under N. atmosphere was (CDC1) & 1.60 (m, 5H, CH & CH), 1.80 (m,2H, CH), 1.90 added dropwise 6-bromo hexanoyl chloride (14.8 grams). (m. 2H, CH), 2.65 (t, 2H, CH), 3.45 (t, 2H, CH), 3.70 (m, The reaction mixture stirred at the same temperature for one 4H, CHX2), 4.00 (q, 1H, CH), 4.60 (q, 2H, CH), 7.20 (d. hour. The reaction mixture was washed with water (200 ml), 1H, Ar), 7.45 (d. 2H, Ar), 7.72 (m, 3H, Ar). 5%. Sodium bicarbonate solution (100 ml) and 5% Copper 40 sulphate solution (100 ml) followed by drying over sodium Example 36 sulphate. The solvent was distilled off to yield crude product which was purified by recrystallisation in a mixture of diiso Synthesis of 6-nitrooxy-hexanoic acid 6-(1-2-[2-(2- propylether:hexane to yield 6-bromo-hexanoic acid 6-(1-2- {2-6-(6-nitrooxy-hexanoyloxy)-naphthalen-2-yl)- 2-(2-(2-6-(6-bromo-hexanoyloxy)-naphthalen-2-yl)-pro 45 propionyloxy)-acetoxy)-acetoxy-ethoxycarbonyl pionyloxy-acetoxy)-acetoxy-ethoxycarbonyl methoxy methoxycarbonyl methoxy carbonyl-ethyl)-naph carbonyl methoxy carbonyl-ethyl)-naphthalen-2-yl ester thalen-2-yl ester urrO O O ~~~ -N-> O O

Acetonitrile AgNO3 US 8,062,653 B2 63 64 -continued

O - Cr sus r 'Nu-1a

O O O ~~~ ONO N-- O r O O

To a solution of 6-bromo-hexanoic acid 6-(1-2-[2-(2-2- To a solution of daidzein (4,7-dihydroxyisoflavone, 6-(6-bromo-hexanoyloxy)-naphthalen-2-yl-propiony loxy)-acetoxy)-acetoxy-ethoxy carbonyl methoxy carbonyl 25 grams) in dimethylformamide (250 ml) at room tempera methoxy carbonyl-ethyl)-naphthalen-2-yl ester (9 grams) in ture under N atmosphere was added 6-dromo hexanoyl acetonitrile (180 ml) at 0°C. was added silver nitrate (4.3 chloride (68 grams). The reaction mixture was cooled grams). The reaction mixture was stirred overnight at room to 0° C., and Pyridine (29 ml) was added dropwise temperature followed by stirring at 60° C. for 5 hours. The 25 to the reaction mixture. The solution was left for reaction mixture was filtered and washed with acetonitrile and dried over sodium sulphate. Acetonitrile was distilled off stirring at room temperature for 42 hours. The reaction to yield crude product which was dissolved in chloroform. mixture was poured onto cold water followed by The salts were filtered off and the solution was dried over extraction with ethyl acetate. The ethyl acetate layer Sodium sulphate after washing with water. The chloroform 30 was washed with 5% sodium carbonate solution followed was distilled off under reduced pressure and the residue was purified by recrystallisation from a mixture oftoluene:hexane by drying over Sodium sulphate. The ethyl acetate was to yield 6.1 grams of 6-nitrooxy-hexanoic acid 6-(1-2-[2-(2- distilled off to yield the crude compound and the crude {2-6-(6-nitrooxy-hexanoyloxy)-naphthalen-2-yl)-propio product was precipitated in hexane and washed with isopro nyloxy-acetoxy)-acetoxy-ethoxycarbonyl methoxy carbo 35 pyl alcohol followed by filtration to yield 42 grams nyl methoxy carbonyl-ethyl)-naphthalen-2-yl ester as white of 6-Bromo-hexanoic acid 3-4-(6-bromo-hexanoyl powder with a melting point of 45.3-47°C. The pure product was characterized via H NMR in (CDC1) & 1.55 (m, 2H, oxy)-phenyl]-4-oxo-4H-chromen-7-yl ester as off CH), 1.65 (d. 3H, CH), 1.80 (m, 4H, CHX2), 2.65 (t, 2H, white powder with a melting point of 102-104°C. The CH), 3.65 (s, 4H, CHX2), 4.00 (q, 1H, CH), 4.95 (t, 2H, 40 pure product was characterized via H NMR in CH), 4.60 (q, 2H, CH), 7.20 (d. 1H, Ar), 7.50 (d. 2H, Ar), (CDC1) & 1.60 (m, 4H, CHX), 1.85 (m, 8H, CHX), 7.80 (m, 3H, Ar). Example 37 2.65 (m, 4H, CHCO X), 3.58 (t, 4H, CHBrX), Synthesis of 6-bromo-hexanoic acid 3-4-(6-bromo 7.16 (m, 3H, Ar), 7.26 (d. 1H, Ar), 7.60 (d. 2H, Ar), 8.06 (s, hexanoyloxy)-phenyl-4-oxo-4H-chromen-7-yl ester 1H, Ar), 8.35 (d. 1H, Ar).

OH DMF, Pyridine 6-Bromo hexanoyl chloride US 8,062,653 B2 65 66 Example 38

Synthesis of 6-nitrooxy-hexanoic acid 3-4-(6-ni trooxy-hexanoyloxy)-phenyl-4-OXO-4H-chromen-7- yl ester ~~~ O O O O

O O--~~ Br

Acetonitrile Silver nitrate

ON~~~ O O O O

O O --~-lii

To a solution of 6-bromo-hexanoic acid 3-4-(6-bromo -continued hexanoyloxy)-phenyl-4-OXO-4H-chromen-7-yl ester (5 30 grams) in acetonitrile (50 ml) at 0°C. was added Silver nitrate O (7.2 grams). The reaction mixture was stirred at room tem perature for 4 hours followed by further stirring under reflux r O n1n 1\ ONO. conditions for 28 hours. The reaction mixture was filtered and 35 O washed with acetonitrile followed by drying over sodium O sulphate. Acetonitrile was distilled off under reduced pres sure and the residue was precipitated in cold water. The pre O cipitate was filtered and recrystallized from a mixture of toluene and hexane to yield 4 grams of 6-nitrooxy-hexanoic 40 acid 3-4-(6-nitrooxy-hexanoyloxy)-phenyl-4-OXO-4H chromen-7-yl ester as off-white powder with a melting point of 100-102°C. The pure product was characterized via H NMR in a mixture of (CDC1 and DMSO-d) & 1.60 (m, 4H, 45 Br CHX), 1.76 (m, 8H, CHX), 2.64 (m, 4H, CHCO X), 4.52 (t, 4H, CHONOX), 7.12 (d. 2H, Ar), 7.22 (d. 1H, Ar), 7.32 (s. 2H, Ar), 7.68 (d. 2H, Ar), 8.2-18 (d. 1H, Ar), 8.45 (s, To a solution of 2-hydroxy-benzoicacid-4-nitrooxy-bu 1H, Ar). 50 toxy carbonyl methyl ester (15 grams) and pyridine (6 ml) in dichloromethane (150 ml) at 0°C. under N. atmosphere was Example 39 added 6-bromohexanoyl chloride (13.5 grams) dropwise. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was washed with water, 5% Synthesis of 2-(6-bromo-hexanoyloxy)-benzoic acid 55 4-nitrooxy-butoxy carbonyl methyl ester Sodium carbonate solution and 5% copper Sulphate solution. The solution was dried over sodium sulphate and solvent was distilled off. The residue was purified by column chromatog raphy using a mixture of hexane:ethyl acetate as an eluant to 60 DCM, Pyridine yield 16 grams of 2-(6-bromo-hexanoyloxy)-benzoic acid 6-Bromo 4-nitrooxy-butoxy carbonyl methyl ester as light yellow O hexanoyl syrup. The pure product was characterized using "H NMR chloride or On 11aONO. Her (CDC1) & 1.50 (m. 2H, CH), 1.70 (m, 6H, CHX), 1.85 (m, O 65 2H, CH), 2.55 (t, 2H, CH), 3.35 (t, 2H, CH), 4.15 (s. 2H, OH CH), 4.35 (bs, 2H, CH), 4.70 (s.2H, CH), 7.00 (d. 1H, Ar), 7.25 (t, 1H, Ar), 7.55 (t, 1H, Ar), 8.05 (d. 1H, Ar). US 8,062,653 B2 67 68 Example 40 To a solution of 2-(6-bromo-hexanoyloxy)-benzoic acid 4-nitrooxy-butoxy carbonyl methyl ester (4 grams) in aceto nitrile (40 ml) was added silver nitrate (2.7 grams). The reac Synthesis of 2-(6-nitrooxy-hexanoyloxy)-benzoic tion mixture was stirred at room temperature for twenty acid 4-nitrooxy-butoxy carbonyl methyl ester hours. The reaction mixture was filtered and washed with acetonitrile, and dried over sodium sulphate. The solvent was distilled off under reduced pressure and the residue was dis solved in dichloromethane. The salts were filtered off and the O 10 organic layer was washed with water followed by drying over O n1N1N sodium sulphate. The dichloromethane was distilled off or ONO under vacuum and the residue was purified by column chro O O Acetonitrile matography using a mixture of hexane:ethyl acetate to yield 3 Silver nitrate -e- grams of 2-(2-nitrooxy-hexanoyloxy)-benzoic acid 4-ni 15 trooxy-butoxy carbonyl methyl ester as light yellow syrup. O The pure product was characterized using "H NMR (CDC1) & 1.50 (m,2H, CH), 1.75 (m, 8H, CHX), 2.55 (t, 2H, CH), 4.15 (t, 2H, CH), 4.35 (m, 4H, CHX), 4.70 (s. 2H, CH), 7.00 (d. 1H, Ar), 7.25 (t, 1H, Ar), 7.55 (t, 1H, Ar), 8.05 (d. 1H, Br Ar). Example 41 Synthesis of Aspirin Dimer Diol

O r OH O OH

HO O O O ouls 1-N-1 -- Crs O

To a mixture of 2-hydroxy-benzoic acid carboxymethyl -continued 50 O ester (22.8 grams) and triethylamine (22.6 ml) in acetone (200 ml) was added dichloro linker (10 grams). The reaction mix N-1-N-1- ture was stirred at room temperature for 1 hour and then r ONO. 55 O refluxed for 18 hours. The reaction mixture was poured onto O cold water and crude product was extracted into ethyl acetate. It was washed with 5% sodium bicarbonate solution and O water, followed by drying over sodium sulphate. The solvent 60 was distilled off and precipitated with diisopropyl alcohol to give 8 grams of pure Aspirin dimer diol as a white powder with a melting point of 99-102°C. The product was charac

65 terized by H NMR (DMSO-d) & 4.40 (s. 2H, CH), 4.90 (s, ONO 2H, CH), 5.15 (s. 2H, CH), 7.05 (m, 2H, Ar), 7.62 (t, 1H, Ar), 7.90 (d. 1H, Ar), 10.30 (s, 1H, ArOH). US 8,062,653 B2 69 70 Example 42 Synthesis of Dibromo Aspirin Dimer HO O O O r O sus O1N1 O rO-- O Br O O O OH

O O O O rouls 1n- J-O

Br

To a solution of Aspirin dimer diol (8 grams) and pyridine as light yellow syrup. The pure product was characterized by (4.2 ml) in dichloromethane (150 ml) at 0°C. under N *H NMR (CDC1,) & 1.55 (m. 2H, CH,), 1.75 (m, 2H, CH.), atmosphere was added dropwise 6-bromohexanoyl chloride 1.90 (m,2H, CH), 2.65 (t, 2H, CH), 3.40 (t, 2H, CH), 4.40 (10 grams). The reaction mixture was stirred at the same 35 (s. 2H, CH), 4.72 (s. 2H, CH), 4.90 (s. 2H, CH), 7.10 (d. temperature for four hours. The reaction mixture was washed 1H, Ar), 7.35 (t, 1H, Ar), 7.70 (t, 1H, Ar), 8.10 (d. 1H, Ar). with water (200 ml), 5% sodium bicarbonate solution and 5% copper Sulphate Solution. It was dried over Sodium Sulphate and the solvent was distilled off to yield crude product, which Example 43 was purified by column chromatography using mixture of 40 hexane:ethyl acetate to get dibromo Aspirin dimer (11 grams) Synthesis of Dinitro Aspirin Dimer Br

O

O Acetonitrile O O O AgNO3 He r Nulls O1N1 O ^o --O O O O O

Br US 8,062,653 B2 71 72 -continued ONO

O O O O rouls 1n 19 J-C

ONO.

To a solution of dibromo Aspirin dimer (9 grams) in aceto- The invention claimed is: nitrile (150 ml) at 0°C. was added silver nitrate (5.1 grams) so 1. A nitric oxide oligomer of formula A: and stirred at room temperature for three hours followed by heating at 50° C. for 5 hours. The reaction mixture was (A) filtered and washed with acetonitrile and dried over sodium -N - sulphate. The solvent was distilledoffand the crude was taken is D P g into chloroform. The salts were filtered off and washed with water and dried over sodium sulphate. The solvent was dis- wherein: tilled offunder reduced pressure and the residue was purified b is —O— or —COO—; by column chromatography using a mixture of hexaneethyl 40 R. together or separately from L., a biologically active acetate to yield 6 grams of dinitro Aspirin dimer as light Substance, in which case q is 1 to 4 inclusive; yellow syrup. The pure product was characterized by H P is a polyester that is one of X-1, , where mono NMR (CDC1) & 1.55 (m, 2H, CH), 1.70 (m, 4H, CHX), mer X is polymerization compatible with 2.10 (t, 2H, CH), 4.35 (s. 2H, CH), 4.45 (t, 2H, CH), 4.70 —CH-COO , or - Y - , where monomer Y is (s. 2H, CH,), 4.90 (s, 2H, CH,), 7.05 (d. 1H, Ar), 7.35 (t, 1H, Elization compatible with —COCHO , Ar), 7.55 (t, 1H, Ar), 8.15 (d. 1H, Ar). p is independently an integer from 2 to 100 inclusive; Publications and references, including but not limited to 1 or more independently selected repeats X are: patents and patent applications, cited in this specification are —CHCOO (glycolic acid moiety); herein incorporated by reference in their entirety in the entire 50 —CH(CH)COO (lactic acid moiety); portion cited as if each individual publication or reference —CH2CH2OCHCOO— (dioxanone moiety); were specifically and individually- indicated- to be incorpo- —CH2CH2CHCH-CHCOO—ety); (caprolactone moi rated by reference herein as being fully set forth. Any patent -(CH2)COO where y is one of the numbers 2, 3 application to which this application claims priority is also 55 or 4, or a number from 6 to 24 inclusive; or incorporated by reference herein in the manner described —(CHCHO). CHCOO where Z is an integer above for publications and references. between 2-24, inclusive: While this invention has been described with an emphasis theprovide order and a desired composition degradation of repeats of moiety X is -L-P selected R: to upon preferred embodiments, it will be obvious to those of 60 1 or more independently selected repeats Y are: ordinary skill in the art that variations in the preferred devices —COCHO-(glycolic ester moiety); and methods may be used and that it is intended that the —COCH(CH)O— (lactic ester moiety); invention may be practiced otherwise than as specifically —COCHOCHCHO (dioxanone ester moiety); —COCH2CH2CH2CH2CH2O— (caprolactone ester described herein. Accordingly, this invention includes all 65 moiety); modifications encompassed within the spirit and scope of the —CO(CH), O— where m is one of the numbers 2,3 invention. or 4, or a number from 6 to 24 inclusive; or, US 8,062,653 B2 73 74 —COCHO(CH2CH2O), where n is integer -continued between 2-24 inclusive; IV H the order and composition of repeats Y is selected to provide a desired degradation of moiety -L-P R; and 5 Codrir'sso, R is according to one of the applicable following options (a) or (b): 3. The oligomer of claim 1, wherein the majority of repeats (a) where P is — X-R can be an alkyl group, aryl, X or Y of formula A comprise repeats of Group B: alkyl-aryl, an alicyclic group or alkyl-alicyclic, Sub —CHCOO (glycolic acid moiety); stituted with one or more —O NO; and 10 —CH(CH)COO (lactic acid moiety); —CH2CH2OCHCOO— (dioxanone moiety); (b) where P is - Y - R can be NO; —CH2CH2CHCH-CHCOO— (caprolactone moiety); wherein if L is —COO then the corresponding P is -(CH2)COO where y is one of the numbers 2, 3 or 4: — X— ; and O 15 —(CHCHO). CHCOO : wherein the biologically active substances are selected —COCHO (glycolic ester moiety); from the group consisting of phenols, thiophenols, naph COCH(CH)O (lactic ester moiety); thols, flavonoids, isoflavonoids, coumarins, chromones, —COCHOCH2CH2O— (dioxanone ester moiety); chalcones, cinnamic acids, benzoic acids, acetophe —COCH2CH2CH2CH2CH2O (caprolactone ester nones, benzophenones, alkaloids, catechins, catechols, moiety); —CO(CH)O— where m is one of the num aminoalcohols, aminosalicyclic acids, hydrocinnamic bers 2, 3 or 4; or —COCH O—(CH2CH2O), . acids, phenolic acids, resorcinols, indoles and hydro 4. The oligomer of claim 1, wherein the majority of repeats quinones. X or Y of formula A comprise repeats of Group C: -CHCOO–: 2. The oligomer of claim 1, wherein the oligomer is accord CH(CH)COO : ing to one of Formulas I to III: 25 —CHCHOCHCOO : —CHCHCHCH-CHCOO–: —COCHO : COCH(CH)O : —COCHOCHCHO ; or Cod'ix"Soo, 30 —COCHCHCHCHCH-O-. II 5. The oligomer of claim 1, wherein 2 or more of repeats X orY of formula A comprise repeats of Group C, where p is 10 or less, wherein Group C repeats are —CHCOO ... —CH III (CH)COO–; CHCHOCHCOO. : CHCHCHCH 35 CHCOO–; COCHO ; –COCH(CH)O ; – CO CHOCH2CHO ; or -COCHCHCHCHCHO-. 6. The oligomer of claim 1, wherein the oligomer is one of the following (where n=2, 3 or 4):

O ouls r N-1 n-1\ ONO O O MeO

O O ~~~ 'Nu-1N1\ ONO. O O MeO

O

ouls O pi -n-n ONO O O MeO

O

O O pi -N-n ONO.

O O MeO US 8,062,653 B2 75 -continued

O OAc

O O cy O 1N1- O YNO, O OAc

O -N-n NO h-n-r pi O1 O OAc

O O ~~~ O -sh-- O YNO, O OAc

O O O~~~ O ohn-1- O Y NO, O US 8,062,653 B2 77 78 -continued O O

O O

O n-n-r on-1- n NO O O O YN, -NO2 O O O cy O -sh-- O n NO O O O O o-NO2 O O O

O O

onO on-1- n NO O O O Y-N, -NO2 O O

O ONO O on-1N1pi

ON !---,O O

O O O

O O O on-1- ONO.

ON P- O O O

O ONO. O ohn-1-1pi oNh N---,O O O

O ONO O OT oNh N---,pi O O O

O Nulls O pi -n-n ONO.

ON N---,O O O US 8,062,653 B2

-continued O sus -n-n O CO O pi ONO ON No susO O O

O O

O NullsO 's-n-npi ONO. ON Nulls O O O pi O O O O O O in- O SNO, O O ON1 N H O

O O NO

pi O O ON1 N H O

O O O pi ONO.

ON No Null, O HN O

O O

ONO. O O

O O O pi O 1N1-N-ONO2

ON O HN O

No O y \ e NO2 O O O O

O O O pi ONO. ON Null, HN O No O \ e NO2 O O O O

O O O pi ONO ON No~! O s', HN O O O US 8,062,653 B2

-continued O

O O pi -n-n ONO. ONsy Null,O HN \ NO O e 2 O O O

O

O O pi -nu-n ONO ON O HN O

No~!O 's O

ONO.

O

O O 's-n-npi ONO. ONSrin ouls HN O O O

ONO.

O

O O pi -nu-n ONO ON O HN O

Sr.O s O

ONO

O O US 8,062,653 B2 83 84 7. The oligomer of claim 1, wherein the oligomer is one of the following:

O O O O

ONO.

ONO O O N------rO r O O O O O

O O O O

ONO O OH O ONO O r r O O O O O O O O O O

O O O O O

O O ONO :S- O ONO

ONO.

US 8,062,653 B2 87 88 -continued O OH O O O ouls 1n 1-ONO2:

> O--> O O O O O

c O rO N-1N1 SoNo.

8. A composition comprising two or more distinct oligo -continued mers of claim 1. VII 9. The composition of claim 8, where one or more of the oligomers comprises a biologically active Substance. ON (DRG) coo- 1Nono, 10. The oligomer of claim 1, wherein D or D-L comprises VIII a antineoplastic, cardiovascular, anti-inflammatory, pain-re ducing, antioxidant agent. ONS 1“god"Ny No. 11. A method of treating cancer, a cardiovascular indica XI tion, inflammation, pain, or an indication treatable with an 25 antioxidant agent comprising administering the oligomer of ONO1 “Yx OOC (DRG) six Sono, claim 10, which includes the corresponding biologically XIV active agent. 12. A composition comprising an oligomer of claim 1 and °N Sono, a pharmaceutically acceptable excipient. 30 13. An implantable medical device comprising an oligomer ON Gorg) "Nix NoNo. of claim 1 and an admixed polymer. XVIII 14. The implantable medical device of claim 13, wherein COO Yx1 R YONO, the device is a stent, Suture, Surgical staple, mesh or bone 35 SCCW. R O O R 15. A coating composition for an implantable device, com ONO1 Yx 16 SDRG) Nix1 NoNo. prising an oligomer of claim 1 and an admixed polymer. 16. The oligomer of claim 1, wherein the oligomer is according to one of formulas V to VIII, XI, XIV, or XVIII, 17. The oligomer of claim 1, wherein one or more of where D-Drug, which is a biologically active substance 40 repeats X or Y of formula A comprise: according to (i): —CH2CH2OCHCOO— (dioxanone moiety); —CH2CH2CHCH-CHCOO— (caprolactone moiety); -(CH2)COO : —(CHCHO). CHCOO : R O O R 45 —COCHOCHCHO (dioxanone ester moiety); ONo1 y1 yx 1 YONO, —COCH2CH2CH2CH2CH2O— (caprolactone ester moi VI ety); R O COO R —CO(CH), O—; or ONO1) x16 Six1 YONO, —COCHO(CHCHO), . k k k k k UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8,062,653 B2 Page 1 of 1 APPLICATIONNO. : 12/508854 DATED : November 22, 2011 INVENTOR(S) : Rao S. BeZWada It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Col. 74, lines 1-6: In Claim 2, delete the entire line representing formula IV.

Signed and Sealed this Twenty-fourth Day of January, 2012

David J. Kappos Director of the United States Patent and Trademark Office