(12) Patent Application Publication (10) Pub. No.: US 2011/0263526 A1 SATYAM (43) Pub

Home , Antihypotensive agent, Cyclopentobarbital, Dimethocaine, Endopeptidase inhibitor, Mefruside, Meticrane

US 20110263526A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0263526 A1 SATYAM (43) Pub. Date: Oct. 27, 2011

(54) NITRICOXIDE RELEASING PRODRUGS OF CD7C 69/96 (2006.01) THERAPEUTICAGENTS C07C 319/22 (2006.01) CD7C 68/02 (2006.01) (75) Inventor: Apparao SATYAM, Mumbai (IN) A6IP 29/00 (2006.01) A6IP 9/00 (2006.01) (73) Assignee: PIRAMAL LIFE SCIENCES A6IP37/08 (2006.01) LIMITED, Mumbai (IN) A6IP35/00 (2006.01) A6IP 25/24 2006.O1 (21) Appl. No.: 13/092.245 A6IP 25/08 308: A6IP3L/04 2006.O1 (22) Filed: Apr. 22, 2011 A6IP3L/2 308: Related U.S. Application Data 39t. O 308: (60) Provisional application No. 61/327,175, filed on Apr. A6IP3/10 (2006.01) 23, 2010. A6IPL/04 (2006.01) A6IP39/06 (2006.01) Publication Classification A6IP3/02 (2006.01) (51) Int. Cl. A6IP 9/06 (2006.01) A 6LX 3L/7072 (2006.01) 39t. W 308: A6 IK3I/58 (2006.01) A6IP II/08 (2006.015 A6 IK3I/55 (2006.01) A63/62 (2006.015 A6 IK 3/495 (2006.01) A6 IK 3/4439 (2006.01) (52) U.S. Cl...... 514/50: 514/166; 514/172: 514/217; A6 IK 3L/455 (2006.01) 514/255.04: 514/338; 514/356; 514/412; A6 IK 3/403 (2006.01) 514/420; 514/423: 514/510,536/28.53:540/67; A6 IK 3/404 (2006.01) 540/591; 544/396; 546/273.7: 546/318: 548/452: A6 IK 3/40 (2006.01) 548/500: 548/537; 549/464; 558/275 A6 IK3I/265 (2006.01) C7H 9/06 (2006.01) (57) ABSTRACT CO7I 71/00 (2006.01) CO7D 22.3/26 (2006.01) The present invention relates to nitric oxide releasing pro C07D 295/14 (2006.01) drugs of known drugs or therapeutic agents which are repre CO7D 40/12 (2006.01) sented herein as compounds of formula (I) wherein the drugs CO7D 213/80 (2006.01) or therapeutic agents contain one or more functional groups C07D 209/52 (2006.01) independently selected from a carboxylic acid, an amino, a CO7D 209/26 (2006.01) hydroxyl and a sulfhydryl group. The invention also relates to C07D 207/34 (2006.01) processes for the preparation of the nitric oxide releasing CO7D 49.3/04 (2006.01) prodrugs (the compounds of formula (I)), to pharmaceutical C07C32.3/56 (2006.01) compositions containing them and to methods of using the A6IP 25/8 (2006.01) prodrugs. Patent Application Publication Oct. 27, 2011 US 2011/0263526 A1

Figure 1

Oxyhemoglobin in blood Oxyhemoglobin in blood

Oral bacteria Blood deoxyhemoglobin (by Bacterial Nitrate reductase)

Protons in Stomach/tissues

Xanthine Oxidase in tissues Xanthine Oxidase in tissues Cytochromes in liver/tissues Different pathways for oxidation and reduction of nitrate, nitrite and NO in the human body US 2011/0263526 A1 Oct. 27, 2011

NITRC OXDE RELEASING PRODRUGS OF used drugs to relieve pain, symptoms of arthritis and soft THERAPEUTICAGENTS tissue inflammation. Most patients with rheumatoid arthritis receive NSAIDs as first-line treatment which is continued for INCORPORATION BY REFERENCE prolonged periods. Although, NSAIDs provide anti-inflam 0001. This application is a non-provisional application matory and analgesic effects, they also have adverse effects and claims benefit under 35 U.S.C. 119(e) of Ser. No. 61/327, on the upper gastrointestinal (GI) tract. The occurrence of GI 175, filed on 23 Apr. 2010. toxicity appears to be strictly correlated to the mechanism of 0002 Any foregoing applications and all documents cited action of these drugs, namely the inhibition of the enzyme therein or during their prosecution (“application cited docu cyclooxygenase. In fact, inhibition of platelet cyclooxyge ments') and all documents cited or referenced in the applica nase, which causes prolonged bleeding time, and inhibition of tion cited documents, and all documents cited or referenced cyclooxygenase in gastrointestinal mucosa, which results in a herein (“herein cited documents'), and all documents cited or decreased synthesis of cytoprotective gastric prostaglandins, referenced in herein cited documents, together with any represent the major cause of serious gastrointestinal toxicity manufacturer's instructions, descriptions, product specifica (Symposium on “New Anti-inflammatory agents: tions, and product sheets for any products mentioned herein NO-NSAIDs and COX-2 inhibitors' part of the 11" interna or in any document incorporated by reference herein, are tional conference on Advances in prostaglandin and leukot hereby incorporated herein by reference, and may be rine research: Basic science and new clinical applications' employed in the practice of the invention. held in Florence (Italy), Jun. 4-8, 2000). This problem has 0003 Citation or identification of any document in this been solved by derivatisation of carboxylic acid group of application is not an admission that such document is avail able as prior art to the present invention. NSAIDs into its ester and amide derivatives. 0007 Another common approach to minimize adverse FIELD OF THE INVENTION effects of the known drugs or therapeutic agents consists of attaching a carrier group to the therapeutic agents to alter their 0004. The present invention relates to nitric oxide releas physicochemical properties and then Subsequent enzymatic ing prodrugs of known drugs or therapeutic agents which are represented herein as compounds of formula (I) wherein the or non-enzymatic mechanism to release the active drug mol drugs or therapeutic agents contain one or more functional ecule (therapeutic agent). The therapeutic agent is linked groups independently selected from the group consisting of a through a covalent linkage with specialized non-toxic protec carboxylic acid, an amino, a hydroxyl or a sulfhydryl group. tive groups or carriers or promoieties in a transient manner to The invention also relates to processes for the preparation of alter or eliminate undesirable properties associated with the the nitric oxide releasing prodrugs (the compounds of for parent drug to produce a carrier-linked prodrug. mula (I)), to pharmaceutical compositions containing them 0008 Indeed, a more recent strategy for devising a gastric and to methods of using the prodrugs. The present invention sparing NSAID involves chemically coupling a nitric oxide also relates to a bio-cleavable linker of formula (IA) capable (NO) releasing moiety to the parent NSAID. Nitric oxide is of forming a covalent linkage with a drug or a therapeutic one of the most important mediators of mucosal defense, agent (designated herein as D) containing one or more func influencing Such factors as mucus secretion, mucosal blood tional groups independently selected from a carboxylic acid, flow, ulcer repair and the activity of a variety of mucosal an amino, a hydroxyl or a sulfhydryl group and also processes immunocytes (Med Inflammation, 1995; 4: 397-405). Com for their synthesis. pounds that release nitric oxide in Small amounts over a prolonged period of time may also be very useful for the BACKGROUND OF THE INVENTION prevention of gastrointestinal injury associated with shock 0005. Many drugs (therapeutic agents) have undesirable and with the use of drugs that have ulcerogenic effects (Mus properties, for instance, low oral drug absorption, toxicity, cara M. N.; Wallace J. L. American Journal of Physiology, poor patient compliance etc., that may become pharmaco Gastrointestinal and liver physiology, 1999; 39:G 1313 logical, pharmaceutical, or pharmacokinetic barriers in clini 1316). Nitric oxide has been reported to play a critical role in cal drug application. Among the various approaches to mini maintaining the integrity of the gastroduodenal mucosa and mize the undesirable drug properties, while retaining the exerts many of the same effects as endogenous prostaglandins desirable therapeutic activity, the chemical approach using (Drugs Fut 2001; 26(5): 485). drug derivatisation offers perhaps the highest flexibility and 0009. Several mechanisms are considered to understand has been demonstrated as an important means of improving the protective effect of nitric oxide in the stomach including drug efficacy (Hyo-Kyung Hanand Gordon L. Amidon AAPS vasodilation of local mucosal blood vessels, inhibition of PharmSci. 2000; 2 (1), 48-58.). leukocyte adhesion and inhibition of caspase enzyme activity. 0006. The conventional approach that is adapted to mini The inactivation of caspase(s) appears to be an important mize the toxic side effects associated with the therapeutic factor in the GI tolerance of nitric oxide releasing NSAIDs agents has been to derivatise one or more functional groups (NO-NSAIDs). Caspases are a family of cysteine proteases present in the therapeutic agent or the drug molecule. The that resemble interleukin-113 (IL-113) converting enzyme derivatives are then assessed for their therapeutic efficacy as (ICE). These enzymes fall into two broad groups, i.e. caspase well as toxicity. The carboxylic acid group is often present as 1-like (including caspase-1, -4 and -5) and caspase-3-like an active functional group for derivatisation in several thera enzymes. Caspase-1 is primarily involved in cytokine release, peutic agents. Non-steroidal anti-inflammatory drugs cleaving pro-IL-1B to produce IL-1B. The ability of a range of (NSAIDs) represent the best characterized class of drugs for NO-NSAIDs to inhibit cytokine formation and caspase-1 therapeutic agents containing a carboxylic acid group as an (ICE) activity, thereby reducing the formation of pro-inflam active functional group. NSAIDs are also the most commonly matory IL-1B provides a possible explanation for the reduced US 2011/0263526 A1 Oct. 27, 2011 gastric damaging effect of these compounds (J. E. Keeble and oxide, the strategy of linking NO-releasing moieties has been P. K. Moore, British Journal of Pharmacology, 2002; 137: extended to a wide array of therapeutic agents selected from 295-310). cardiovascular drugs, for instance, Angiotensin converting 0010. In recent years, several NO-releasing non-steroidal enzyme (ACE) inhibitors, calcium antagonists and beta anti-inflammatory drugs (NO-NSAIDs) have been synthe blockers, antitumor agents, antihistamines, glucocorticoids, sized by an ester linkage formed through coupling of a NO etc. The aim of this strategy is to synthesize prodrugs that releasing chemical spacer group to the carboxylic acid moiety retain the pharmacological activity of the parent drug mol of a conventional NSAID. The use of various aliphatic, aro ecule coupled with the benefits of the biological actions of matic or heterocyclic chemical spacers makes it possible to NO in reducing the adverse effects of the parent drug mol alter various physicochemical properties and kinetics of nitric ecule. oxide release Berguad et al., Ann., N.Y. Acad. Sci. 1962: 0013 Another class of therapeutic agents which are well 360-371 (2002). The first NO-aspirin drug NCX 4016, known for their anti-inflammatory and immunosuppressive which was synthesized relatively recently, consists of an aspi effects are glucocorticoids. Due to their beneficial therapeutic rin molecule linked by an ester bond to a molecular spacer, effects, glucocorticoids are useful for the treatment of a vari which in turn, is linked to a nitro-oxy ester group (Dig Liver ety of inflammation related disorders and immune system Dis 2003: 35 (suppl 2): 9-19). A number of NO-NSAID disorders, especially autoimmune diseases such as rheuma hybrid compounds, namely NO-naproxen (HCT 3012), NO toid arthritis. However, their therapeutic application is limited flurbiprofen (HCT 1026), NO-ibuprofen, NO-diclofenac and due to adverse effects and toxicity associated with their use. NO-indomethacin have been disclosed in the patent numbers The adverse effects caused by glucocorticoids include hyper EP 722434B1, U.S. Pat. No. 6,613,784B1 and U.S. Pat. No. tension, peptic ulcers, gastrointestinal bleeding, increased 7.220,749B2 respectively. European Patent EP 722434B1 risk for infections, osteoporosis and hyperglycemia (Schacke discloses nitric esters of the derivatives of propionic acid, Het al., Pharmacol Ther 2002: 96:23-43). 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetic 0014 U.S. Pat. Nos. 6,610,676 and 7,524,836B2 disclose acid and S-benzoyl-1,2-dihydro-3H-pyrrolo 1,2-alpyrrole nitrate esters and nitroxy derivatives of steroidal compounds 1-carboxylic acid having anti-inflammatory and/or analgesic having anti-inflammatory, immunodepressive and angiostatic activity. U.S. Pat. No. 6,613,784B1 discloses nitro derivatives activity orgastrointestinal activity. The compounds are useful of NSAIDs, for instance, flurbiprofen, indomethacin, aspirin, in the treatment of morbid conditions wherein the steroids are naproxen and diclofenac. U.S. Pat. No. 7,220,749B2 dis generally used and confer greater benefit in terms of better closes novel nitrosated and/or nitrosylated derivatives of tolerability and efficacy. PCT Application Publication COX-2 selective inhibitors. U.S. Patent Application Publica WO2007099548A1 discloses 11 B-hydroxyandrosta-4-3-one tion no. 20080293781A1 describes O-acyl salicylic acid compounds which possess useful anti-inflammatory activity derivatives bearing a NO donor moiety. whilst having insignificant or no noteworthy side-effects at 0011 Further, NO releasing COX-2 (cyclooxygenase-2) efficacious doses. PCT Application Publication inhibitors comprising NO-releasing moieties attached WO2008.0958.09A1 discloses derivatives of known corticos through a chemical linker to the COX-2 inhibitor compounds teroids, containing a NO-releasing moiety which are useful in have been reported in the art. U.S. Pat. No. 7,199,154 B2 the treatment of illnesses wherein the known corticosteroid, discloses nitrosated or nitrosylated prodrugs for COX-2 parent or precursor Steroid, is generally applied, with selective inhibitors that are useful for treating COX-2 medi increased benefit in terms of pharmacological profile and ated diseases or conditions and which can be administered fewer or milder side effects than those of the parent corticos alone or in combination with low-dose aspirin. The com teroids. The compounds are useful in the treatment of inflam pounds are effective in treating chronic COX-2 mediated matory diseases, respiratory diseases, and autoimmune dis diseases or conditions, reducing the risk of thrombotic car orders among other disorders. diovascular events and possibly renal side effects and at the 0015 The approach and possibility of combining a few same time reduce the risk of GI ulceration and bleeding. US classes of drugs bearing different functional groups suscep Patent Application Publication no. 20060058363 A1 dis tible to derivatisation with NO-donating moieties has been closes nitric-oxide releasing prodrugs of celebrex and Valde described by Manlio Bolla et al., in Curr. Topic. Med. Chem. coxib which are useful in the treatment of COX-2 mediated 2005:5: 707-720. The review paper discloses four chemically diseases. The compounds may be used as a combination different NO-donating linkers hybridized with different therapy with low-dose aspirin to treat COX-2 mediated dis drugs possessing a derivatisable function. Free carboxylic eases or conditions while simultaneously reducing the risk of acids, alcohols (including phenols), thiols, and amines have thrombotic cardiovascular events. been demonstrated to be exploitable for such an approach. 0012 Nitric oxide (NO) also plays an important role in 0016. The NO-releasing derivatives and prodrugs of vari numerous physiological and patho-physiological conditions, ous therapeutic agents known in the art are in different phases e.g. blood pressure regulation, inflammation, infection, and of clinical development and there are reports suggesting that the onset and progression of malignant diseases (Lirk, P. a few of them have been suspended because of toxicity prob Hoffmann, G., and Rieder, J. Curr. Drug Targets Inflamm. lems. Therefore, there is a clear need for new, alternative and Allergy 2002; 1: 89-108). NO deficiency is recognized to be better NO-releasing nitrate ester prodrug compounds which a crucial factor in the initiation and progression of many can exhibit improved therapeutic properties. A thorough cardiovascular diseases and delivery of supplementary NO in investigation by the present inventor led to the discovery of the form of NO-donor drugs has long been an attractive thera nitric oxide releasing prodrugs or prodrug compounds which peutic strategy (Ian L. Megson, David J Webb, Expert Opin. can be obtained through derivatisation of a known drug or a Investig. Drugs, 2002; 11(5): 587-601). In recent years, with therapeutic agent containing one or more functional groups the advent of NO-NSAID approach and because of the ben independently selected from carboxylic acid, hydroxyl, eficial biochemical and pharmacological properties of nitric amino or Sulfhydryl functional groups. The nitric oxide US 2011/0263526 A1 Oct. 27, 2011

releasing prodrugs of the present invention are useful in the treatment of diseases or disorders that is characteristic of the -continued parent drug molecule from which the prodrug is derived. The (Y) nitric oxide releasing prodrugs of the invention exhibit com- O parable or Superior therapeutic effects compared to the parent drug molecule. The nitric oxide releasing prodrugs of known drugs or therapeutic agents as described in the present inven- 7 tion are expected to be safe to administer and have compa- NHR' O, rable or superior oral bioavailability compared to the parent (Y) drug molecules from which the prodrugs are derived. Further, O R8 O, owing to the strategy that is used to devise the nitric oxide releasing prodrugs of the present invention, the prodrugs or at O least certain prodrugs encompassed in the present invention are expected to be devoid of genotoxicity at a concentration at NHR which the compounds are expected to be used for the treat- O (Y) ment of the medical conditions or diseases for the treatment of H which the parent drug molecule is used. - 0017 Moreover, the nitric oxide releasing prodrugs of the d h invention are expected to overcome adverse effects, for O instance, gastrointestinal (GI) toxicity and cardiovascular s risks associated with the parent drug molecule. O O (Y) SUMMARY OF THE INVENTION l! d 0018. In one aspect, the present invention provides com- (Y) pounds of the following formula (I), which are prodrugs of O O known drugs or therapeutic agents; N- X Nu (Y) X X2 A O O O (I) O COH O, 1N1 in 11 n21 Sk SNO, J R2 N O RI H 7 (Y) wherein: NHR D is a drug containing one or more functional groups inde pendently selected from a carboxylic acid, an amino, a 8 h hydroxyl or a sulfhydryl group capable of forming a covalent bio-cleavable linkage with a biocleavable linker; s Y X' is a bond, oxygen, sulphur or NR; RHN (Y) X is a bond, oxygen or NR; R is a bond or hydrogen; l \ Y is C—O or a spacer group selected from: O O or

(Y) (Y) O; Ol JO, O HOC ) N l NH O R4 (Y) O R5 wherein in the spacer groups of formulae (Y) to (Y): O 0019 R is a bond, hydrogen, alkyl or a metal ion Selected from Sodium, potassium or calcium; s (Y) I0020 R is hydrogen, Ce alkyl or phenyl: O I0021) R' is hydrogen or a group (which is a side-chain H group of naturally occurring amino acids) selected from: N 0022 - CH, -CH(CH), —CHCH(CH), —CH (CH)CHCH, -CHCOH, -CHCH-COH, R6 O, - CH-OH, CH(CH)OH, —CH2SH, - CHCH-SCH3, —CHCHCHCH-NH, -CHs. US 2011/0263526 A1 Oct. 27, 2011

—CHCHs —CHCH-p-OH, -CH2CHCH-NHC a subject by administering a therapeutically effective amount (—NH)NH, -CHC(=O)NH, -CHCHC(=O) of the compound of the formula (I) to the subject. NH, —CH-indol-3-yl or —CH-imidazole; 0036. In yet another further aspect, the present invention 0023 X is oxygen, sulphur, SO, SO, or NR; provides the compounds of formula (I), which are the pro (0024) R' is hydrogen or a group selected from acetyl, drugs of known drugs or therapeutic agents, for use in the benzoyl, alkyloxycarbonyl, benzyloxycarbonyl, 9-fluo treatment of diseases or disorders capable of being treated by renylmethyloxy carbonyl or its pharmaceutically the parent drugs or therapeutic agents from which the pro acceptable ammonium salts; drugs are derived. I0025 R is hydrogen or C. alkyl: 0026 c is an integer from 0 to 2: BRIEF DESCRIPTION OF THE DRAWINGS 0027 d is an integer from 1 to 5; 0028 e is an integer from 1 to 4. 0037 FIG. 1 depicts the different pathways for oxidation Z' is (CH), where a is an integer from 0 to 3: and reduction of nitrates, nitrite and NO in the human body. Z is (CH), where b is an integer from 0 to 3: A is a bond, S, SO, SO, S. S. CH=CH, D-isosorbide skel DETAILED DESCRIPTION OF THE INVENTION eton, 1,4-anhydroerythritol skeleton, cycloalkylene, CRR', 0038. The present invention encompasses compounds of Co-Co-arylene, a 5- or 6-membered heteroarylene or a 5- or formula (I), as described herein, which are nitric oxide releas 6-membered heterocyclylene wherein said arylene, het ing prodrugs of known drugs or therapeutic agents useful in eroarylene and heterocyclylene may be unsubstituted or sub the treatment of diseases or disorders that are characteristic of stituted by one or more substituents independently selected the drugs from which the prodrugs of the present invention are from the group consisting of C alkyl, Calkoxy, hydroxy, derived. trifluoromethyl, cyano, amino and halogen; 0039. In general, the present invention provides prodrugs R and R'' are independently hydrogen or alkyl; or R and of known drugs or therapeutic agents represented herein by R' taken together with the carbon atom to which they are the compounds of formula (I) which primarily constitutes the attached form a cycloalkyl or a heterocyclic ring; following elements: R" is hydrogen and R is alkyl, cycloalkyl, aryl or aralkyl; or 0040 (a) a drug containing one or more functional R’ is hydrogen and R' is alkyl, cycloalkyl, aryl or aralkyl: groups independently selected from a carboxylic acid, with the proviso that: an amino, a hydroxyl or a sulfhydryl group capable of 0029 a) when A is S, then a and b is 3; or forming a covalent bio-cleavable linkage with a linker; 0030 b) when A is D-isosorbide skeleton or 1,4-anhy 0041 (b) a linker; droerythritol skeleton, then a and b is 0; 0.042 (c) optionally a spacer; and in all its stereoisomeric forms and mixtures thereof in all 0.043 (d) a nitrooxy (ONO) group. ratios or pharmaceutically acceptable salts thereof. 0044) The strategy for providing the prodrugs represented 0031. In another aspect, the present invention provides a herein by the compounds of formula (I) is applicable to any bio-cleavable linker of formula (IA) capable of forming a drug or therapeutic agent which possesses a functional group covalent linkage with a drug (designated herein as D) con Such as a carboxylic acid, an amino, a hydroxy or a sulfhydryl taining one or more functional groups independently selected group capable of covalently binding to a linker. The linker is from a carboxylic acid, an amino, a hydroxyl or a Sulfhydryl a bi- or multi-functional moiety having the desired covalent group: binding properties. 0045. The prodrugs the compounds of formula (I) of the present invention would undergo enzymatic cleavage in a (LA) X2 A O O O manner Such that the parent drugs and effective amounts of 1NZ 1 n2 Y YNO, nitric oxide are released in vivo and that the oral bioavailabil R2 ity of the parent drugs is nearly maintained. The prodrugs the O RI compounds of formula (I) of the present invention are expected to be safe to administer and may have oral bioavail wherein the variables Y,X, Z', A. Z. RandR areas defined ability comparable or Superior to that of the parent drug in respect of the compounds of formula (I). The linker of molecule. formula (IA) is non-toxic and facilitates release of nitric oxide 0046. Unless otherwise indicated, the following defini and serves as an important intermediate in the processes for tions are set forth to illustrate and define the meaning and the synthesis of nitric oxide releasing prodrugs of formula (I) scope of the various terms used to describe the invention which are the prodrugs of known drugs or therapeutic agents. herein and the appended claims. These definitions should not 0032. In yet another further aspect, the present invention be interpreted in the literal sense as they are not general provides processes for the preparation of the compounds of definitions and are relevant only for this application. formula (I). 0047. As used herein, the term “prodrug or prodrugs' 0033. In yet another further aspect, the present invention refers/refer to a compound/compounds which upon adminis provides processes for the preparation of the bio-cleavable tration to a Subject in need thereof undergoes chemical con linker of formula (IA). version by metabolic or chemical processes to release the 0034. In yet another aspect, the present invention provides parent drug in Vivo from which the prodrug is derived. a pharmaceutical composition comprising the compound of 0048. As used herein, the term “drug or “drugs” or formula (I) as an active ingredient and at least one pharma “therapeutic agents’ or “drug molecules' or “parent drug or ceutically acceptable excipient. "parent drug molecules' are used interchangeably. The term 0035. In yet another further aspect, the present invention 'drug or "drugs' as used herein refers to any compound, provides a method for the treatment of diseases or disorders in Substance, medicament or active ingredient having a thera US 2011/0263526 A1 Oct. 27, 2011 peutic or pharmacological effect, and which is Suitable for (OH) groups can be primary, secondary, tertiary or phenolic administration to a mammal, e.g., a human. More particu in nature including hydroxyl groups of hydroxamic acids larly, in the context of the present invention all the known and ketoximes of keto-containing drug molecules. drugs ortherapeutic agents containing one or more functional 0053 As used herein, the term "sulfhydryl groups of groups independently selected from a carboxylic acid, an drugs or therapeutic agents refer to drugs containing deriva amino, a hydroxyl, or a sulfhydryl group that are capable of tisable free sulfhydryl (SH) groups and these can be primary, forming a covalent bio-cleavable linkage with a linker. The secondary, tertiary and thiophenolic in nature. term “drug or "drugs' as used herein also encompasses 0054 As used herein, the term “halogen refers to fluo within its scope the “investigational drug(s) or “investiga rine, bromine, chlorine or iodine. tional agent(s) which refer to any new drug or agent cur 0055 As used herein, the term “halide” refers to fluoride, rently under clinical investigation, particularly those investi chloride, bromide, and iodide. gational drugs or agents that contain one or more functional 0056. As used herein, the term “aryl” refers to a monocy groups independently selected from a carboxylic acid, an clic or polycyclic aromatic hydrocarbon system having 6 to amino, a hydroxyl or a Sulfhydryl group capable of forming a 14 carbon atoms, preferably 6 to 10 ring carbon atoms, in covalent bio-cleavable linkage with a linker, which may later which at least one carbocyclic ring is present that has a con be established as therapeutically active agents by the regula jugated pi-electron system. Examples of (C-C) aryl ring tory bodies of different countries, are also encompassed system include phenyl, naphthyl, biphenyl or anthracenyl, within the scope of the term “drugs” or “therapeutic agents’ particularly preferred aryl ring system include phenyl and as used herein. For example, when the drug or the therapeutic naphthyl. Unless stated otherwise, the aryl ring system, for agent or the parent drug molecule contained in the com example, phenyl, naphthyl or anthracenyl, can be optionally pounds of formula (I) can be selected from anti-inflammatory substituted with one or more identical or different substitu and analgesic agents, cardiovascular agents, anti-allergic ents selected from the groups consisting of alkyl, halogen, agents, anti-cancer agents, anti-depressants, anti-convulsant hydroxyl, alkoxy, nitro, amino, trihaloalkyl, carbonyl (Such agents, anti-bacterial agents, anti-fungal agents, anti-viral as carboxyl, formate, carbamide, ester, ketone, aldehyde), agents, anti-malarial agents, anti-diabetic agents, anti-ulcer carbamate, Sulphamate, Sulphonate, Sulphate or a sulfhydryl agents, anti-oxidants or vitamins. group. The aryl residue can be bonded via any desired posi 0049. As used herein, the term “linker' or “linkers' or tion and in substituted aryl, the substituents can be located in “bio-cleavable linkers’ refers/refer to a chemical moiety or any desired position. For instance, in mono-Substituted phe moieties which forms/form a covalent linkage with the reac nyl residue, the substituent can be present in 2-, 3-, 4- or tive carboxylic acid, amino, hydroxyl or sulfhydryl group of 5-position. If the phenyl group carries two Substituents, they the drug or therapeutic agent to obtain a prodrug of the drug. can be located in 2.3-position, 2.4-position, 2.5-position, 2.6- This linker may be cleaved from the prodrug by chemical position, 3.4-position or 3.5-position. means, by enzymatic means, or by both the means. The linker 0057. As used herein, the term “arylene', by itself or as may be pharmacologically inert or may itself provide added part of another Substituent means, unless otherwise Stated, a beneficial pharmacological activity. divalent aryl radical having 6 to 14 ring carbon atoms, pref 0050. As used herein, the term “alkyl, alone or as part of erably 6 to 10 ring carbonatoms. The arylene group can have a Substituent of other groups, means a branched or straight a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or chain monovalent alkyl radical, preferably having one to six multiple condensed rings in which at least one is aromatic, carbon atoms Such that the alkyl group is designated as C.- (e.g., 1, 2, 3, 4-tetrahydronaphthyl, naphthyl), which is alkyl. This term is further exemplified by such radicals as optionally substituted with one or more groups selected from, methyl, ethyl, n-propyl, isopropyl. n-butyl, S-butyl, t-butyl. e.g., halogen, alkyl, alkoxy, trifluoromethyl. Representative Unless stated otherwise, the “term alkyl includes unsubsti arylene groups include, by way of example, 1.2-phenylene, tuted alkyl groups as well as alkyl groups Substituted by one 1.3-phenylene, 1,4-phenylene, naphthalene-1,5-diyl, naph or more substituents. A substituted alkyl refers to an alkyl thalene-2,7-diyl, and the like. residue in which one or more hydrogen atoms are optionally 0058 As used herein, the term “cycloalkyl refers to a replaced with Substituents, for example, halogen, hydroxyl, saturated mono-, bi- or polycyclic ring system containing a alkoxyl, carbonyl, amino, nitro, nitrooxy, alkylthio. Sulfhy specified number of carbon atoms. Unless otherwise stated, dryl, carbamate, Sulphamate, Sulphonate or an aryl group. cycloalkyl rings containing 3 to 7 carbonatoms are preferred. 0051. As used herein, the term “amino' functional group Representative cycloalkyl groups include cyclopropyl. of drug ortherapeutic agent refer to derivatisable primary and cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. secondary amines (both acyclic and cyclic) which also Further, unless otherwise stated, the term cycloalkyl includes include drugs containing derivatisable NH-containing func unsubstituted cycloalkyl or cycloalkyl which is optionally tional groups such as amide-NH. Sulfonamide-NH. carbam substituted with any one of the substitutents mentioned above ate-NH, sulfamate-NH, hydrazide-NH, hydrazone-NH. for aryl and the Substitution can be in any desired position. semicarbazone-NH, thiosemicarbazone-NH, urea-NH, and Cycloalkyl group comprises a saturated cycloalkyl ring sys also encompass drug molecules with derivatisable NH-con tem which does not contain any double bond within the rings taining heterocyclic Sub-structures such as aziridine, aziti and partially unsaturated cycloalkyl ring systems which may dine, dihydropyridine, indole, imidazole, benzimidazole, contain one or more double bonds within the ring system that thiozole, benzothiozole, oxazole, benzoxazole, pyrrole, pyr is stable and provided that the double bonds are not located in razol, benzopyrrozole, pyrrolidine, piperidine, triazole, ben a manner that an aromatic system results. Zotriazoles, tetrazole, and benzotetrazole. 0059. As used herein, the term “cycloalkylene' refers to a 0052. As used herein, the term “hydroxyl or “hydroxy” divalent Saturated carbocyclic hydrocarbon group. Unless functional group of drugs or therapeutic agents refer to drugs otherwise defined, such cycloalkylene groups typically con containing derivatisable hydroxyl groups i.e., these hydroxyl tain from 3 to 10 carbonatoms. Representative cycloalkylene US 2011/0263526 A1 Oct. 27, 2011 groups include, by way of example, cyclopropane-1,2-diyl. alanine, arginine, asparagine, aspartic acid, cysteine, glycine, cyclobutyl-1,2-diyl, cyclobutyl-1,3-diyl, cyclopentyl-1,2- glutamic acid, glutamine, histidine, isoleucine, leucine, diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,2-diyl, cyclohexyl lysine, methionine, proline, phenylalanine, serine, tryp 1,3-diyl, cyclohexyl-1,4-diyl, and the like. tophan, threonine, tyrosine, and Valine. The side-chain group 0060. As used herein, the term “aralkyl refers to an alkyl of naturally occurring amino acids being the group repre group Substituted with an aryl group, wherein the term alkyl sented as R in the spacer group of formula Y., the sub-group group is as defined above. Representative aralkyl groups that is defined in the variable Y in respect of the compounds of include -(CH2)-phenyl (whereing is an integer from 1 to 2) formula (I). Such as benzyl, phenethyl and the like. 0065. As used herein, the term “amino protecting group' 0061. As used herein, the terms "heterocyclyl or "hetero is intended to refer to a group that can be selectively attached cyclic ring refer to a saturated, partially unsaturated or aro to the nitrogen atom by chemical modification of an amino matic monocyclic or polycyclic heterocyclic ring system con group so as to selectively inhibit participation of the amino taining 3 to 14 ring atoms of which 1, 2, 3 or 4 are identical or group in chemical reactions. After the completion of said different heteroatoms selected from the group consisting of chemical reactions the amino protecting group may be selec nitrogen, oxygen and Sulphur. The heterocyclyl ring, for tively removed. Exemplary amino-protecting groups include, example, has 1 or 2 oxygenatoms and/or 1 or 2 Sulphur atoms carbamates (urethanes) Such as methyl, ethyl, 9-fluorenylm and/or 1 or 2 nitrogen atoms. In monocyclic groups, hetero ethyl (i.e., Fmoc or 9-fluorenylmethoxycarbonyl), 2.2.2- cyclic ring preferably is a 3-membered, 4-membered, trichloroethyl (i.e., Troc or trichloroethoxycarbonyl, 2-trim S-membered, 6-membered or 7-membered ring, more pref ethylsilylethyl (i.e., Teoc or trimethylsilylethoxycarbonyl), erably a S- or 6-membered ring comprising one to three 2-phenylethyl, 2-chloroethyl, 1,1-dimethyl-2.2.2-trichloro hetero atoms selected from the group consisting of nitrogen, ethyl, t-butyl (i.e., BOC or tert-butoxycarbonyl), benzyl (i.e., oxygen and Sulphur. Representative examples of Saturated Cbz or Z or benzyloxycarbonyl), 1-adamantyl, 2-adamantyl, heterocyclic rings include pyrrolidinyl, piperidinyl, piperazi p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, 2,4- nyl, tetrahydrofuryl, oxazolidinyl, dioxanyl and pyranyl. dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, Representative examples of unsaturated heterocyclic rings diphenylmethyl, 2-methylthioethyl, 2-methylsulfonylethyl, are furyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, 4-methylthiophenyl, 4-azidobenzyl, 3,5-dimethoxybenzyl, oxazolyl, isoxazolyl pyrazolyl, imidazolyl, tetrazolyl, triaz o-nitrobenzyl, 2-iodoethyl, phenyl, etc., and amides such as olyl, oxadiazolyl, thiadiazolyl, thiazolyl pyrimidinyl, pyrazi formyl, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, nyl and pyridazinyl. phenylacetyl, benzoyl, o-nitrophenylacetyl, o-nitrobenzoyl, 0062. In polycyclic groups, the term "heterocycle' or bromoacetyl, iodoacetyl, methoxyacetyl, etc., and cyclic imi "heterocyclic ring preferably comprises two fused rings (bi des Such as phthalimide, etc., and N-alkyl and N-arylamines cyclic), one of which is a S- or a 6-membered heterocyclic such as N-methyl, N-t-butyl, N-allyl, N-cyanomethyl, N-ben ring and the other is a 5- or 6-membered heterocyclic ring. Zyl. N-4-methoxybenzyl, N-2,4-dimethoxybenzyl, N-diphe Representative examples of polycyclic Saturated heterocycle nylmethyl, N-bis(4-methoxyphenyl)methyl, N-triphenylm are indolinyl, 1.2.3,4-tetrahydroquinolinyl and 1.2.3,4-tet ethyl (Tr), N-(methoxyphenyl)diphenylmethyl (MMTr), rahydroisoquinolinyl. Representative examples of polycyclic etc., and imine derivatives such as N-1,1-dimethylthiometh unsaturated heterocycle are quinolinyl, isoquinolinyl, ben yleneamine, N-benzylideneamine, N-p-methoxybenzylide Zoxazolyl, benzthiazolyl, benzofuranyl, thionaphthyl and neamine, N-diphenylmethyleneamine, etc. Additional indolyl. Unless stated otherwise, the heterocycle or heterocy examples of amino protecting groups listed in T. W. Greene, clic group can be unsubstituted or Substituted on the ring “Protective Groups in Organic Synthesis”, John Wiley and carbon atoms with one or more substituents. Each suitable Sons, New York, N.Y., 1991 are incorporated herein as a ring nitrogenatom in the heterocycle or heterocyclic ring can reference. Also, the procedures for the formation and cleav independently of the other be unsubstituted i.e., carry a age of the above mentioned amino protecting groups are hydrogen atom or can be substituted. Suitable examples of based on the known methods and their relevant references are substituents for the heterocyclic ring carbon and/or the nitro cited in T. W. Greene, “Protective Groups in Organic Synthe genatoms are: amino, halo, hydroxyl, alkyl, haloalkyl, cyano, sis”, John Wiley and Sons, New York, N.Y., 1991 and incor nitro, sulfhydryl and carboxyl. porated herein as a reference. 0063 As used herein, the term "heteroarylene' refers to a 0066. As used herein, the term “hydroxyl protecting divalent aromatic group having a single ring or two fused group' or “hydroxy protecting group', is intended to refer to rings containing at least one heteroatom, typically 1 to 3 a group that can be selectively attached to the oxygenatom by heteroatoms, selected from the group consisting of nitrogen, chemical modification of the hydroxyl group so as to selec oxygen or Sulfur in the ring. Unless otherwise defined. Such tively inhibit the participation of the hydroxyl group in heteroarylene groups typically contain from 5 to 10 total ring chemical reactions. After said chemical reactions the hydroxy atoms. Representative examples of heteroarylene groups protecting group may be selectively removed. Examples of include, divalent species of pyrrole, imidazole, thiazole, hydroxyl and phenolic-protecting groups include, ether oxazole, furan, thiophene, triazole, pyrazole, isoxazole, groups such as the alkyl ether group selected from methyl isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triaz ether, methoxymethyl ether, methylthiomethyl ether, tert ine, indole, benzofuran, benzothiophene, benzimidazole, buylthiomethyl ether, triphenylmethyl, tetrahydropyranyl benzthiazole, quinoline, isoquinoline, quinazoline, quinoxa (THP), (phenyldimethylsilyl)methoxy methyl ether, benzy line and the like, where the point of attachment is at any loxymethyl ether, p-methoxybenzyloxy-methyl ether, o-ni available carbon or nitrogen ring atom. trobenzyloxymethyl, p-nitrobenzyloxymethyl, t-butoxym 0064. As used herein, the term “side chain group of natu ethyl ether, menthoxymethyl ether, 2-methoxyethoxymethyl rally occurring amino acids” is intended to refer to the side ether, siloxymethyl ether, ethoxyethyl ether, 1-(2-chloroet chains of C.-amino acids selected from the group consisting of hoxy)-ethyl ether, 2.2.2-trichloroethoxymethyl ether, 2-(tri US 2011/0263526 A1 Oct. 27, 2011 methylsilyl)ethoxymethyl ether; and isopropyl ether, the aryl ality within a carboxylic acid group so as to inhibit participa ether group is selected from phenyl ether, p-chlorophenyl tion of the carboxylic acid group in chemical reactions. ether, p-methoxyphenyl ether, 2,4-dinitrophenyl ether, ben Examples of Such carboxylic acid protecting groups include, Zyl ether, p-methoxybenzyl ether, o-nitrobenzyl ether, and for example unsubstituted and Substituted alkyl esters such as 2,6-dichlorobenzyl ether, the alkylsilyl ether groups selected methyl, ethyl, t-butyl, benzyl, 9-fluorenylmethyl, methoxym from trimethyl-, triethyl- and triisopropyl-silyl ethers, mixed ethyl, methylthiomethyl, methoxyethoxymethyl, 2-(trimeth alkylsilyl ether groups selected from dimethylisopropylsilyl ylsilyl)ethoxymethyl, benzyloxymethyl, pivaloyloxymethyl, ether, tert-butyldimethylsilyl ether and diethylisopropylsilyl phenylacetoxymethyl, triisopropylsillylmethyl, cyanom ether; and the ester groups selected from acetate ester, for ethyl, acetol (hydroxyacetone), phenacyl, p-bromophenacyl, mate ester, benzylformate ester, mono-, di-, and trichloroac p-chlorophenacyl, p-methoxyphenacyl, carboxamidomethyl etate ester, trifluoroacetate ester, methoxyacetate ester, triph (Cam), etc., and 2-subtituted ethyl esters such as 2.2.2- enylmetoxyacetate ester, benzoate ester, phenylacetate ester, trichloroethyl, 2-haloethyl 2-(trimethylsilyl)ethyl, 2-meth pivalate ester, phenoxyacetate ester, p-chlorophenoxyacetate, ylthioethyl, 2-cyanoethyl, cyclopentyl, cyclohexyl, allyl, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpen phenyl, etc., and Substituted benzyl esters such as triphenyl tanoate, o-(dibromomethyl)benzoate, 2-formylbenzene methyl (trity1), diphenylmethyl (Dpm), 9-anthrylmethyl, sulfonate, 4-(methylth iomethoxy)butyrate, 2-(methylthi p-methoxybenzyl, etc., and silyl esters such as trimethylsilyl omethoxymethyl)benzoate, 2-(chloroacetoxymethyl)ethyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), benzoate, 2-L2-(benzyloxy)ethylbenzoate, 2-L2-(4- i-propyldimethylsilyl phenyldimethylsilyl, di-t-butylmeth methoxybenzyloxy)ethylbenzoate, monosuccinate, ylsilyl (DTBMS), and triisopropylsilyl (TIPS). Additional o-(methoxycarbonyl)benzoate, nitrate, benzyloxycarbonate, examples of carboxylic acid protecting groups are described benzyl, ethyl or methylcarbonate, methoxymethyl carbonate, in T. W. Greene, “Protective Groups in Organic Synthesis'. 9-fluorenylmethyl carbonate, 2.2.2-trichloroethyl carbonate, John Wiley and Sons, New York, N.Y., 1991. Also, the pro 2-(trimethylsilyl)ethyl carbonate, 2-(phenylsulfonyl)ethyl cedures for the formation and cleavage of the above men carbonate, 2-(methylthiomethoxy)ethyl carbonate, 2-(4-ni tioned carboxyl protecting groups are based on the known trophenyl)ethyl carbonate, methyl dithiocarbonate, 9-fluore methods and their relevant references are cited in T. W. nyl methoxycarbonate, t-butoxycarbonate, trichloroethylcar Greene, “Protective Groups in Organic Synthesis”, John bonate, 2-danySylethyl carbonate, 2-(4-nitrophenyl)ethyl Wiley and Sons, New York, N.Y., 1991 and incorporated carbonate, 2-(2,4-dinitrophenyl)ethyl carbonate, 2-cyano-1- herein as a reference. phenylethyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1- 0068. As used herein, the term "sulfhydryl protecting naphthyl carbonate, borates carbamates, Sulfonates and Sul group' or “thiol protecting group' is intended to refer to a phamate. Examples of protecting groups for 1,2-diols, 1.3- group that selectively blocks the thiol (SH) functionality so as diols, 2-hydroxybenzenethiols and catechols include, cyclic to inhibit participation of the thiol group in chemical reac acetals and ketals such as methylene acetal, ethylidene acetal, tions. Examples of such thiol protecting groups include, thio t-butylmethylidene ketal, 1-t-butylethylidene ketal, 1-phe ethers such as S-alkyl, S-benzyl, S-p-methoxybenzyl, S-o- or nylethylidene ketal, 1-(4-methoxyphenyl)ethylidene acetal, p-hydroxy- or acetoxybenzyl, S-p-nitrobenzyl, S-2,4,6-trim trichloroethylidene acetal, acrolein acetal, isopropylidene ethyl/trimethoxybenzyl, S-4-picolyl, S-2-quinolinomethyl, ketal (acetonide), cyclopentylidene ketal, cyclohexylidene S-9-Anthrylmethyl, S-9-Fluorenylmethyl, S-xanthenyl, ketal, cycloheptylidene ketal, benzylidene acetal, p-meth S-diphenylmethyl, S-substituted diphenylmethyl, S-triph oxybenzylidene acetal. 2,4-dimethoxybenzylidene acetal, enylmethyl, S-bis(4-methoxyphenyl)methyl, S-bis(4-meth 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, oxyphenyl)phenylmethyl (DMTr), S-t-butyl, S-1-Adaman 4-nitrobenzylidene acetal, mesitylene acetal, 1-naphthalde tyl, S-2-(4-pyridyl)ethyl, S-2-cyanoethyl, S-2- hyde acetal, benzophenone ketal, o-xylyl ether, camphor (trimethylsilyl)ethyl, S-2.2-bis(carboethoxy)ethyl, etc., and ketal, cyclic ortho esters such as methoxymethylene acetal, monothio acetals such as S-acetamidomethyl, S-trimethylac ethoxymethylene acetal, dimethoxymethylene ortho ester, etamidomethyl, S-benzamidomethyl, S-allyloxycarbony 1-methoxyethylene ortho ester, 1-ethoxyethylene ortho ester, laminomethyl, S-phenylacetamidomethyl, S-phthalimidom methylidine ortho ester, phthalido ortho ester, 2-oxacyclopen ethyl, S-methoxymethyl, S-isobutoxymethyl, tylidene ortho ester, butane-2,3-bisacetal, cyclohexane-1,2- S-benzyloxymethyl, S-2-tetrahydropyranyl, etc., and dithio diacetal, dispiroketal, silyl derivatives such as di-t-butylsi acetals such as S-benzylthiomethyl, S-phenylthiomethyl, lylene group, dialkylsilylene groups, 1.3-(1,1,3,3- etc., and silyl thioethers such as triisopropylsilyl, etc., and tetraisopropyldisiloxanylidene group, 1,1,3,3-tetra-t- thioesters such S-acetyl, S-benzoyl, S-trifluoroacetyl, etc., butoxydisiloxaneylidene group, cyclic carbonates, cyclic and thiocarbonates Such as S-2.2.2-trichloroethoxycarbonyl, boronates, phenylboronate and o-acetamidophenylboronate. S-t-butoxycarbonyl, S-benzyloxycarbonyl, etc., and thiocar Additional examples of hydroxyl protecting groups are bamates such as S-(N-ethylcarbamate), S-(N-methoxymeth described in T. W. Greene, “Protective Groups in Organic ylcarbamate), etc., and unsymmetrical disulfides Such as Synthesis”, John Wiley and Sons, New York, N.Y., 1991. S-ethyl disulfide, S-t-butyl disulfide, substituted S-phenyl Also, the procedures for the formation and cleavage of the disulfide, etc., and sulfenyl derivatives such as S-sulfonate, above mentioned hydroxyl protecting groups are based on the S-sulfenylthiocarbonate, S-3-nitro-2-pyridinesulfenyl sul known methods and their relevant references are cited in T. W. fide, etc., and protection of dithiols as dithioacetals and ketals Greene, “Protective Groups in Organic Synthesis”, John such as S.S'-methylene, S.S-isopropylidene and S.S. ben Wiley and Sons, New York, N.Y., 1991 and incorporated Zylidene derivatives. Also, protection of 1,2-aminothiols as herein as a reference. thiozolidine derivatives. The procedures for the formation 0067. As used herein, the term “carboxyl protecting and cleavage of the above mentioned sulfhydryl protecting group' or “carboxylic acid protecting group' is intended to groups are based on the known methods and their relevant refer to a group that selectively blocks the oxygen function references are cited in T. W. Greene, “Protective Groups in US 2011/0263526 A1 Oct. 27, 2011

Organic Synthesis”, John Wiley and Sons, New York, N.Y., 0074 The term "suitable oxidizing agent” refers to a suit 1991 and incorporated herein as a reference. able agent that causes oxidation of a molecule. The term 0069. The term “leaving groups' or “LGs” include, but are “oxidation” in chemistry refers to either elimination of hydro not limited to, (Substituted) alkoxy, aryloxy, nitrogen contain gen or replacement of hydrogen atom bonded to carbon with ing unsaturated heterocycles such as N-oxybenzotriazole, another more electronegative element such as oxygen. A imidazolyl, o- or p-nitrophenoxy, pentachloro-phenoxy, more general definition of oxidation involves an increase in N-oxysuccinimide, N,N'-dicyclohexylisoure-O-yl, N-hy oxidation state and loss of one or more electrons from anatom droxy-N-methoxyamino, and the like; acetates, formates, Sul or group. Examples of oxidation include transformations fonates Such as methanesulfonate, ethanesulfonate, benzene Such as conversion of an alcohol to a carbonyl compound Sulfonate, or p-toluenesulfonate, and the like; and halides (i.e., to aldehydes or ketones), aldehydes or ketones to car such as fluoride, chloride, bromide, or iodide. boxylic acid, aromatics to phenols, phenols to quinones, alk 0070 The term “coupling agent' or “carbonyl activating enes to diols, epoxides or ketones, Sulfides to Sulfoxides and agent” refers to a reagent that converts the carbonyl of a Sulfones, metals to metal cations and so on. Examples of carboxylic acid group into one that is more susceptible to “suitable oxidizing agents' include, but not limited to, chro nucleophilic attack and includes, but is not limited to. Such mium reagents such as chromium trioxide, chromium triox reagents as those found in “The Peptides'. Gross and Meien ide-pyridine, pyridinium chlorochromate (PCC), pyridinium hofer, Eds. Academic Press (1979), Ch. 2, and M. Bodan dichromate (PDC), oxidations involving dimethyl sulfoxide Szky, “Principles of Peptide Synthesis, 2.sup.nd Ed., and an activating agent such as oxalyl chloride or trifluoro Springer-Verlag Berlin Heidelberg, 1993, hereafter referred acetic anhydride (Swern oxidation), DCC and an acid catalyst to as “The Peptides” and “Peptide Synthesis” respectively. (Moffat oxidation), acetic anhydride or pyridine-sulfur triox Carbonyl group (i.e., aldehyde or keto group) of the drugs or ide, Dess-Martin Periodinane, Oxone, Oxammonium salts, drug molecules may be converted first to aldoxime, ketoxime, metal derivatives such as aluminum triisopropoxide, cyclo hydrazone, semicarbazone and the like, before coupling to pentadienyl Zirconium reagent (Cp2ZrH), manganese diox the linker. Specifically, carbonyl activating agents include ide, silver carbonate, silver (I) oxide, silver (II) oxide, per thionyl bromide, thionyl chloride, oxalyl chloride, and the manganate reagents such as potassium permanganate, like; esters of alcohols such as nitrophenol, pentachlorophe trimethylcetylammonium permanganate and n-butyl per nol, and the like; and compounds such as 1,1'-carbonyldiimi manganate, molybdenum reagents such as ammonium dazole (CDI), benzotriazole, imidazole, N-hydroxysuccinim molybdate (NH4)Mo.O.2H2O, cerium (IV) reagents ide, dicyclohexylcarbodiimide (DCC), 1-Ethyl-(3- Such as ceric ammonium Sulfate and ceric ammonium nitrate, dimethylaminopropyl)carbodiimide (EDAC), phosgene or its peroxides such as hydrogen peroxide and t-butyl hydroper equivalents, N,N-dimethylaminopyridine (DMAP) and the oxide (TBHP), per acids such as peracetic acid, trifluoroper like. acetic acid, perbenzoic acid and m-chloroperbenzoic acid, 0071. The terms “phosgene or its equivalents' refer to potassium persulfate, N-bromosuccinimide, osmium tetroX phosgene or it equivalents such as diphosgene, triphosgene, ide, oZone, Sodium periodate, ruthinium tetroxide, lead tet N,N'-Carbonyldiimidazole (CDI), N,N'-Dicyclohexylcarbo raacetate, selenium dioxide, and so on. diimide (DSC), 1,1-Bis6-(trifluoromethyl)benzotrazolyl 0075. The term "suitable reducing agent” refers to a suit carbonate (BTBC), alkoxycarbonyl chlorides, o?p-nitrosub able agent that causes reduction to a molecule. The term stituted phenoxycarbonyl chlorides, and the like. “reduction' in chemistry is generally defined as a decrease in 0072. The term “suitable solvent refers to a solvent that is oxidation state and again of one or more electrons. Examples inert to the ongoing reaction and Sufficiently solubilizes the of reduction include transformations such as conversion of reactants to effect the desired reaction. Examples of suitable aldehydes or ketones or acids or esters or epoxides to alco solvents include but are not limited to, dichloromethane, hols, amides or azides or imides orimines or nitriles or nitro chloroform, 1,2-dichloroethane, diethyl ether, tert-butylm groups or oximes to amines, alkenes or alkynes to alkanes, ethyl ether, acetonitrile, ethyl acetate, 1,3-dimethyl-2-imida Sulfonate esters or halocarbons to alkanes, cations to corre Zolidinone, tetrahydrofuran, dimethylformamide, benzene, sponding metal atoms, disulfide to Sulfhydryl and Sulfone or toluene, xylene, N,N-dimethylacetamide, N-methylpyrroli sulfoxide to sulfide. Examples of “suitable reducing agents' dine, chlorobenzene, dimethylsulfoxide, dimethoxyethane, include, but not limited to lithium aluminum hydride, sodium water, methanol, ethanol, isopropanol, pyridine, borohydride, potassium borohydride, sodium hydride, metal nitromethane, and the like or mixtures thereof. trialkoxyaluminum hydrides LiAlH(OR) such as LiAlH 0073. The term “suitable base' refers to a base, which acts (OMe), LiAlH(OEt) and LiAlH(O'Bu), Red-Al (so as a proton trap for any protons, which may be produced as a dium bis(2-methoxyethoxy)aluminum hydride, diisobutyla byproduct of the desired reaction, or to a base, which provides luminum hydride (Dibal or DIBAL-H)lithium a reversible deprotonation of an acidic proton from the sub triethylborohydride (Super-HydrideTM), zinc borohydride, strate and is reactive enough to effect the desired reaction metal/ammonium acyloxyborohydrdes M BH(OR), without significantly effecting any undesired reactions. Such as potassium triacetoxyborohydride, Sodium triacetoxy Examples of Such bases include, but are not limited to, Suit borohydride, tetramethylammonium triacetoxyborohydride, able metal carbonates, bicarbonates, and hydroxides (e.g., potassium tri-sec-butylborohydride (K-Selectride TM), lithium, sodium, potassium, magnesium, calcium and the lithium tri-sec-butylborohydride (L-Selectride TM), sodium like), Sodium/potassium/calcium hydride, sodium/potassium cyanoborohydride, boranes such diborane (BH), borane alkoxide (i.e., methoxide, ethoxide, tert-butoxide and the complex of dimethylsulfide (H.B.SMe), bis(1,2-dimethyl like), triethylamine, diisopropylethylamine, N-methylpyrro propyl)borane (disiamylborane), 9-borabicyclo3.3.1 lidine, N-methylmorpholine, tetramethylguinidine, or aro nonane (9-BBN), and catalytic reductions/hydrogenations matic nitrogen containing heterocycles such as pyridine, using metal catalysts such as platinum oxide, Pt/C. Pd oxide, 4-(dimethylamino)pyridine (DMAP), and the like. Pd hydroxide/C, Ni-borides, NiC, Raney Ni, copper US 2011/0263526 A1 Oct. 27, 2011

chromite, platinum black, Pt/Rh oxide, Pd/BaCO, Pd/C, hydroxyl or a Sulfhydryl group capable of forming a covalent Rh/C, Ni Cu, Raney Ni W1, Raney Ni W2, Raney Ni W3, bio-cleavable linkage with a linker of formula IA (as Raney Ni W4, Raney Ni W5, Raney Ni W6, Raney Ni W7, described herein); Raney Ni W8 and Raney cobalt, Li-Liq. NH, Na-Liq. NH X' is a bond, oxygen, sulphur, or NR; Zn dust, ZnCl2, Zinc amalgam Zn(Hg). Tin compounds such as tributyltin hydride (BuSnH), SnCl, Aluminum iso X is a bond, oxygen or NR; propoxide Al(O Pr)4), aluminum amalgam (Al/Hg), R is a bond or hydrogen; silanes such as Et SiH, PhMeSiH, Ph.SiH and so on. Y is C—O or a spacer group selected from: 0076. The term “pharmaceutically acceptable salts' refers to the salts of the compound of formula (I) of the invention which are toxicologically acceptable and pharmaceutically (Y) utilisable salts. The compound of formula (I), which contains O O, a basic functionality, can be used according to the invention in the form of their addition salts of organic or inorganic acids. l N The pharmaceutically acceptable acid addition salts of the prodrugs i.e. the compounds of formula (I) include Salts R4 which retain the biological effectiveness and properties of the (Y) free bases and which are not biologically or otherwise unde O R5 sirable. Examples of Suitable inorganic acids include hydro chloric acid, hydrobromic acid, Sulphuric acid, nitric acid, l O phosphoric acid, perchloric acid, boric acid, and other inor ganic acids known in the art. Examples of organic acids O, include: acetic acid, propionic acid, glycolic acid, pyruvic (Y) acid, oxalic acid, maleic acid, malonic acid, Succinic acid, O fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, Sulfanilic acid, 2-acetoxybenzoic acid, N toluenesulphonic acid, methane Sulphonic acid, ethane disul l phonic acid, isethionic acid, ketoglutaric acid, benzenesul R O, phonic acid and other organic acids known in the art. (Y) 0077. The compound of formula (I), which contains acidic group, can be used according to the invention as base addition t salts. Examples of pharmaceutically acceptable base addition salts include those salts derived from inorganic bases Such as alkali earth metal salts like sodium, potassium, lithium, alka NHR7 Ö, line earth metal salts like calcium, magnesium, aluminium (Y) salts or salts of organic bases such as lysine, arginine, triethy O R8 O, lamine, dibenzylamine, piperidine or as salts with ammonia. Particularly preferred are the ammonium salts of the prodrugs of the present invention i.e. the compounds of formula (I). The O pharmaceutically acceptable salts of the present invention can NHR be synthesized from the Subject compound which contains a basic or acidic moiety by conventional chemical methods. (Y) Generally the salts are prepared by contacting the free base or O acid with Stoichiometric amounts or with an excess of the N desired salt-forming inorganic or organic acid or base in a - Suitable solvent or dispersant or by anion exchange or cation 1 ) exchange with other salts. Suitable solvents are, for example, I ethyl acetate, ether, alcohols, acetone, tetrahydrofuran (Yg) (THF), dioxane or mixtures of these solvents. O O, 0078. In a first embodiment, the invention relates to com pounds of the formula (I), which are prodrugs of known drugs or therapeutic agents; ! (Y) O O, (I) X X2 A O O O D1 n 1 nz11 NZ2 Y YNO, Nuxu R2 (Y) O RI O CO2H O,

N-l. N J wherein H D is a drug containing one or more functional groups inde pendently selected from a carboxylic acid, an amino, a US 2011/0263526 A1 Oct. 27, 2011 10

in all its stereoisomeric forms and pharmaceutically accept -continued able salts thereof. (Y) 0091. It would be understood by a person having skill in NHR the art to which this invention relates that the functional H groups namely the carboxylic acid, amino, hydroxyl and Sulf N hydryl groups contained in the drug "D' in the compounds of formula (I) participate in the formation of a linkage with the O O, linker represented herein by the compound of formula IA 7 (Yi) through the variable “X” or 'Y' which constitute part of the t RHN formula (I) represented herein. In other words, the variableX' and Y (in part) are derived from the carboxylic acid or amino or hydroxyl or sulfhydryl functional groups of the drug “D’ l, \, O from which the nitric oxide releasing prodrugs of the present invention i.e. the compounds of formula (I), are derived. For (Y) instance, the variables X and Y in the compound of formula (I) represents the chemical functionality on the drug “D’ HOC represented by carboxylic acid (X'=bond and Y=C(O)), amino (X=NR andY=C(O)), hydroxyl (X'-oxygen) and sulfhydryl (X'=sulphur) functional groups which are - ) involved in the formation of covalent linkage with the cleav able linker of formula (IA). 0092. In a second embodiment, the invention encom where in the spacer groups of formulae (Y) to (Y): passes a compound of formula (I), wherein: (0079) R' is a bond, hydrogen, alkyl or a metalion; each of D, X', Z' and Z areas defined in the first embodiment 0080 R is hydrogen, C alkyl or phenyl: herein above; I0081) R' is hydrogen or a side-chain group of naturally occurring amino acids selected from: I0082 –CH, -CH(CH), —CHCH(CH), —CH 0093 X is oxygen; (CH)CHCH, -CHCOH, -CHCH-COH, A is selected from a bond, 1.2-phenylene, 1,3-phenylene, - CH-OH, CH(CH)OH, —CH2SH, 1,4-phenylene, 2.3-pyridine, 3.4-pyridine, 2.4-pyridine, 2.5- - CHCH-SCH3, —CHCHCHCH-NH, -CHs. pyridine, 2,6-pyridine, S, SO, SO, S. S. CH=CH, D-isos —CHCH, CHCH-p-OH, -CHCHCH-NHC orbide skeleton, 1,4-anhydroerythritol skeleton, cycloalkyl or (—NH)NH, -CHC(=O)NH, -CHCHC(=O) CRR 10, NH, —CH-indol-3-yl or —CH-imidazole; where R and R'' are independently selected from hydrogen I0083 X is oxygen, sulphur, SO, SO, or NR; or C, alkyl; or R and R' taken together with the carbon 10084) R' is hydrogen or an amino protecting group atom to which they are attached constitute a cycloalkyl group Selected from: acetyl, benzoyl, alkyloxycarbonyl, ben or a 5- or 6-membered heterocyclic ring containing one to two Zyloxycarbonyl, 9-fluorenylmethyloxy carbonyl or its hetero atoms selected from oxygen, Sulfur or nitrogen; pharmaceutically acceptable ammonium salts; R" is hydrogen and R is alkyl, cycloalkyl, aryl or aralkyl; or I0085 R is hydrogen or C, alkyl: R’ is hydrogen and R' is alkyl, cycloalkyl, aryl or aralkyl; I0086 c is an integer from 0 to 2: with the provisos that: I0087 d is an integer from 1 to 5: 0094) a) when A is S, thena and b is 3; or I0088 e is an integer from 1 to 4: 0.095 b) when A is D-isosorbide skeleton or 1,4-anhy Z' is (CH2): where a is an integer from 0 to 3: droerythritol skeleton, then a and b is 0; Z is (CH), where b is an integer from 0 to 3: in all its stereoisomeric forms and pharmaceutically accept A is selected from: a bond, S, SO, SO, S-S, CH=CH, able salts thereof. D-isosorbide skeleton, 1,4-anhydroerythritol skeleton, 0096. In a third embodiment, the invention encompasses a cycloalkylene, CRR', C.-Co-arylene, a 5- or 6-membered compound of formula (I), wherein: each of D, X, Z and Z heteroaylene or a 5- or 6-membered heterocyclylene wherein is as defined in the first embodiment herein above; said arylene, heteroarylene and heterocyclylene may be each of Y and X is as defined in the second embodiment unsubstituted or substituted by one or more substituents inde herein above; pendently selected from the group consisting of C alkyl, A is selected from a bond, CH=CH or CRR'; where Rand C. alkoxy, hydroxy, trifluoromethyl, cyano, amino and R" are independently selected from: hydrogen or C. alkyl; halogen; or Rand R' taken together with the carbon atom to which RandR'' are independently selected from: hydrogen or C. they are attached form a cycloalkyl or a 5- or 6-membered alkyl; or R and R' taken together with the carbon atom to heterocyclic ring; which they are attached form a cycloalkyl or a heterocyclic R" and Rare as defined in the second embodiment herein r1ng, above; R" is hydrogen; and R is alkyl, cycloalkyl, aryl or aralkyl; or in all its stereoisomeric forms and pharmaceutically accept R’ is hydrogen; and R' is alkyl, cycloalkyl, aryl or aralkyl; able salts thereof. with the provisos that: 0097. In a fourth embodiment, the invention encompasses I0089 a) when A is S, thena and b is 3; or a compound of formula (I), wherein: 0090 b) when A is D-isosorbide skeleton or 1,4-anhy each of D, X, Z and Z is as defined in the first embodiment droerythritol skeleton, then a and b is 0; and herein above; US 2011/0263526 A1 Oct. 27, 2011 each of Y and X is as defined in the second embodiment in all its stereoisomeric forms and pharmaceutically accept herein above; able salts thereof. A is selected from S, SO, SO or S S: provided that when A 0106. In a ninth embodiment, the invention encompasses a is S, thena and b is 3: compound of formula (I), wherein: D, the drug containing a R" and Rare as defined in the second embodiment herein carboxylic acid group capable of forming a covalent bio above; cleavable linkage with a linker, referred to in the first, second, in all its stereoisomeric forms and pharmaceutically accept third, fourth, fifth, sixth, seventh and eighth embodiments, is able salts thereof. selected from an anti-inflammatory and analgesic agent, a 0098. In a fifth embodiment, the invention encompasses a cardiovascular agent, an antiallergic agent, an anticancer compound of formula (I), wherein: agent, an antidepressant, an anticonvulsantagent, an antibac each of D, X, Z and Z is as defined in the first embodiment terial agent, an antifungal agent, an antiviral agent, an anti herein above; malarial agent, an antidiabetic agent, an antiulcer agent, a each of Y and X is as defined in the second embodiment Vitamin or an antioxidant. herein above; 0107. In this embodiment, other variables X, X, Y, Z', A is selected from 1.2-phenylene, 1.3-phenylene, 1,4-phe Z: A R and R in the compounds of formula (I) are as nylene, 2.3-pyridine, 3.4-pyridine, 2.4-pyridine, 2.5-pyri defined hereinabove; provided that dine, 2.6-pyridine, D-isosorbide skeleton, 1.4-anhydroeryth ritol skeleton or cycloalkyl; provided that when A is 0.108 a) when A is S, thena and b is 3; or D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then 0.109 b) when A is D-isosorbide skeleton or 1,4-anhy a and b is 0; droerythritol skeleton, then a and b is 0; R" and Rare as defined in the second embodiment herein in all its stereoisomeric forms and pharmaceutically accept above; able salts thereof. in all its stereoisomeric forms and pharmaceutically accept 0110. In a tenth embodiment, the invention encompasses a able salts thereof. compound of formula (I), wherein: D, the drug containing a 0099. In a sixth embodiment, the invention encompasses a carboxylic acid group capable of forming a covalent bio compound of formula (I), wherein: cleavable linkage with a linker, is selected from an anti each of D, X', Z' and Z is as defined in the first embodiment inflammatory and analgesic agent, a cardiovascular agent, an hereinabove; antiallergic agent, an anticancer agent, an antidepressant, an each of X and Y is as defined in the second embodiment anticonvulsant agent, an antibacterial agent, an antifungal hereinabove; agent, an antiviral agent, an antimalarial agent, an antidia A is selected from a bond, 1.2-phenylene, 1.3-phenylene, betic agent, an antiulcer agent, a vitamin or an antioxidant; 1,4-phenylene, 2.3-pyridine, 3.4-pyridine, 2.4-pyridine, 2.5- X' is a bond; pyridine, 2,6-pyridine, S, SO, SO, S. S. CH=CH or CR'R'': where R and R'' are independently selected from Y is C—O; hydrogen or Ce alkyl; provided that when A is S, then a and b is 3: X is O: R" is hydrogen and R is alkyl: or R is hydrogen and R' is 10111 Z' and Z are as defined in the first embodiment alkyl: hereinabove; in all its stereoisomeric forms and pharmaceutically accept A is selected from a bond, 1.2-phenylene, 1.3-phenylene, able salts thereof. 1,4-phenylene, 2.3-pyridine, 3.4-pyridine, 2.4-pyridine, 2.5- 0100. In a seventh embodiment, the invention encom passes a compound of formula (I), wherein: pyridine, 2,6-pyridine, S, SO, SO, S. S. CH=CH, D-isos D is a drug containing a carboxylic acid group capable of orbide skeleton, 1,4-anhydroerythritol skeleton, cycloalkyl or forming a covalent bio-cleavable linkage with a linker of CRR 10, formula (IA) (as described herein); where R and R'' are independently selected from hydrogen X' is a bond; or C, alkyl; or R and R' taken together with the carbon X, Y, Z, Z, A, R' and Rare as defined in the first embodi atom to which they are attached constitute a cycloalkyl group ment hereinabove; or a 5- or 6-membered heterocyclic ring containing one to two with the provisos that: hetero atoms selected from oxygen, Sulfur or nitrogen; 0101 a) when A is S, then a and b is 3; or R" is hydrogen and R is alkyl, cycloalkyl, aryl or aralkyl; or 0102 b) when A is D-isosorbide skeleton or 1,4-anhy R’ is hydrogen; and R' is alkyl, cycloalkyl, aryl or aralkyl; droerythritol skeleton, then a and b is 0; with the provisos that: in all its stereoisomeric forms and pharmaceutically accept 0112 a) when A is S, thena and b is 3; or able salts thereof. 0113 b) when A is D-isosorbide skeleton or 1,4-anhy 0103) In an eighth embodiment, the invention encom droerythritol skeleton, then a and b is 0; passes a compound of formula (I), wherein: in all its stereoisomeric forms and pharmaceutically accept each of D and X is as defined in the seventh embodiment able salts thereof. hereinabove; 0114. In an eleventh embodiment, the invention encom each of X, Y, Z, ZA, RandR is as defined in the second passes a compound of formula (I), wherein: D, the drug embodiment hereinabove; containing a carboxylic acid group capable of forming a with the provisos that: covalent bio-cleavable linkage with a linker, is selected from 0.104) a) when A is S, then a and b is 3; or an anti-inflammatory and analgesic agent, a cardiovascular 0105 b) when A is D-isosorbide skeleton or 1,4-anhy agent, an antiallergic agent, an anticancer agent, an antide droerythritol skeleton, then a and b is 0; pressant, an anticonvulsant agent, an antibacterial agent, an US 2011/0263526 A1 Oct. 27, 2011 antifungal agent, an antiviral agent, an antimalarial agent, an A is selected from a bond, 1.2-phenylene, 1.3-phenylene, antidiabetic agent, an antiulceragent, a vitaminor an antioxi 1,4-phenylene, 2.3-pyridine, 3.4-pyridine, 2.4-pyridine, 2.5- dant; pyridine, 2,6-pyridine, S, SO, SO, S. S. CH=CH, D-isos each of X,Y,X, Z, Z, R' and Rareas defined in the tenth orbide skeleton, 1,4-anhydroerythritol skeleton, cycloalkyl or embodiment hereinabove; CRR'; where R and R'' are independently selected from A is selected from a bond, CH=CH or CRR': hydrogen or Calkyl: or RandR' taken together with the wherein, RandR'' are independently selected from hydro carbon atom to which they are attached constitute a gen or Calkyl; or RandR'taken together with the carbon cycloalkyl group or a 5- or 6-membered heterocyclic ring atom to which they are attached constitute a cycloalkyl group; containing one to two hetero atoms selected from oxygen, in all its stereoisomeric forms and pharmaceutically accept Sulfur or nitrogen; able salts thereof. R" is hydrogen and R is alkyl, cycloalkyl, aryl or aralkyl; or 0115. In a twelfth embodiment, the invention encom R’ is hydrogen; and R' is alkyl, cycloalkyl, aryl or aralkyl: passes a compound of formula (I), wherein: with the provisos that: D, the drug containing a carboxylic acid group capable of 0119 a) when A is S, thena and b is 3; or forming a covalent bio-cleavable linkage with a linker, is 0120 b) when A is D-isosorbide skeleton or 1,4-anhy selected from an anti-inflammatory and analgesic agent, a droerythritol skeleton, then a and b is 0; cardiovascular agent, an antiallergic agent, an anticancer in all its stereoisomeric forms and pharmaceutically accept agent, an antidepressant, an anticonvulsant agent, an antibac able salts thereof. terial agent, an antifungal agent, an antiviral agent, an anti I0121. In a fifteenth embodiment, in the compound of for malarial agent, an antidiabetic agent, an antiulcer agent, a mula (I) the anti-inflammatory and analgesic agent referred to Vitamin or an antioxidant; in the ninth, tenth, eleventh, twelfth, thirteenth and fourteenth each of X, Y,X, Z, Z, R' and R is as defined in the tenth embodiments hereinabove is generically selected from an embodiment hereinabove; opioid, Steroids (glucocorticoids) or a non-steroidal anti-in A is selected from S, SO, SO or S S: provided that when A flammatory drug (NSAID(s)) and is specifically selected is S, thena and b is 3: from aceclofenac, acemetacin, acetamidocaproic acid, ace and in all its stereoisomeric forms and pharmaceutically tylsalicylsalicylic acid, actarit, alclofenac, 3-alminoprofen, acceptable salts thereof. amfenac, 3-amino-4-hydroxybutyric acid, aspirin (acetylsa 0116. In a thirteenth embodiment, the invention encom lycilic acid), balsalazide, bendazac, benoxaprofen, brompro passes a compound of formula (I), wherein: fen, bromfenac, 5-bromosalicylic acid acetate, bucloxic acid, D, the drug containing a carboxylic acid group capable of bumadizone, butibufen, carprofen, cinchophen, cinmetacin, forming a covalent bio-cleavable linkage with a linker, is clidanac, clometacin, clonixin, clopirac, diacerein, selected from an anti-inflammatory and analgesic agent, a diclofenac, diflunisal, dipyrocetyl, enfenamic acid, enox cardiovascular agent, an antiallergic agent, an anticancer olone, etodolac, felbinac, fenbufen, fenclozic acid, fendosal, agent, an antidepressant, an anticonvulsant agent, an antibac fenoprofen, fentiazac, flufenamic acid, flunoxaprofen, fluo terial agent, an antifungal agent, an antiviral agent, an anti cortolone-21-acid, flurbiprofen, fosfosal, gentisic acid, malarial agent, an antidiabetic agent, an antiulcer agent, a ibufenac, ibuprofen, indomethacin, indoprofen, isofeZolac, Vitamin or an antioxidant; isoxepac, ketoprofen, ketorolac, lonazolac, loxoprofen, each of X, Y,X, Z, Z, R' and R is as defined in the tenth meclofenamic acid, mefenamic acid, mesalamine, metiazinic embodiment hereinabove; acid, mofeZolac, naproxen, niflumic acid, olsalazine, A is selected from 1.2-phenylene, 1.3-phenylene, 1,4-phe oxaceprol, oxaprozin, piraZolac, pirprofen, pranoprofen, pro nylene, 2.3-pyridine, 3.4-pyridine, 2.4-pyridine, 2.5-pyri tizinic acid, salicy Sulfuric acid, Salicylamide o-acetic acid, dine, 2.6-pyridine, D-isosorbide skeleton, 1.4-anhydroeryth Salsalate, Sulfasalazine, Sulindac, Suprofen, SuxibuZone, ritol skeleton or cycloalkyl; provided that when A is tiaprofenic acid, tolfenamic acid, tolmetin, tropesin, Ximo D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then profen, Zaltoprofen or Zomepirac. a and b is 0; in all its stereoisomeric forms and pharmaceutically accept 0.122 The representative example of an anti-inflammatory able salts thereof. and analgesic agent is a NSAID that is selected from aspirin, 0117. In a fourteenth embodiment, the invention encom diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, passes a compound of formula (I), wherein: ibuprofen, indomethacin, ketoprofen, ketorolac, naproxen, D, the drug containing a carboxylic acid group capable of Sulindac or tolmetin. forming a covalent bio-cleavable linkage with a linker, is (0123. Further in the fifteenth embodiment, the invention selected from an anti-inflammatory and analgesic agent, a encompasses a compound of formula (I); wherein the cardio cardiovascular agent, an antiallergic agent, an anticancer vascular agent referred to in the ninth, tenth, eleventh, twelfth, agent, an antidepressant, an anticonvulsant agent, an antibac thirteenth and fourteenth embodiments hereinabove is terial agent, an antifungal agent, an antiviral agent, an anti generically selected from an antihypertensive agent such as malarial agent, an antidiabetic agent, an antiulcer agent, a an angiotensin converting enzyme (ACE) inhibitor, a beta blocker, Sartan (angiotensin II blockers), an antithrombotic Vitamin or an antioxidant; and vasoactive agent, an anti-hyperlipidemic drug (including X' is a bond; HMG-CoA-reductase inhibitor (statins), fibrate, an antiangi Y is a spacer group as defined in the first embodiment here nal agent, an antiarrhythmic agent, an antihypotensive agent, inabove; a diuretic, a vasodilator or vasoprotectant and is specifically selected from acifran, acipimoX, acetylsalicylic acid, alace X is O: pril, gama-aminobutyric acid, angiotensin, argatroban, ator 0118 Z' and Z are as defined in the first embodiment vastatin, benazepril, benfurodil hemisuccinate, beraprost, hereinabove; beZafibrate, bumetanide, candesartan, capobenic acid, capto US 2011/0263526 A1 Oct. 27, 2011 pril, carmoxirole, caronapril, chromocarb, cilaZapril, ciprofi 0.135 A representative example of the antiallergic agent is brate, clinofibrate, clofibric acid, dalteparin, daltroban, dela an antihistamine that is selected from acrivastine, bepotast pril, dextrothyroxine, eicosapentaenoic acid, eledoisin, ine, cetirizine, feXofenadine, levocabastine, levocetirizine or enalapril, enalaprilat, enoxaparin, eprosartan, ethacrynic montelukast sodium. acid, fluvastatin, fosinopril, furosemide, gemfibrozil, ilo 0.136 Still further, in the fifteenth embodiment, the inven prost, imidapril, indobufen, isbogrel, heparin, lamifiban, tion encompasses a compound of formula (I); wherein the limaprost, lisinopril, lotrafiban, meglutol, melagatran, mer anticancer agent referred to in the ninth, tenth, eleventh, camphamide, mercaptomerin sodium, mercumallylic acid, twelfth, thirteenth and fourteenth embodiments hereinabove mersalyl, methyldopa, moexipril, moveltipril, nadroparin, is selected from acitretin (etretin), aminolevulinic acid, amsi omapatrilat, oZagrel, OXiniacic acid, perindopril, piretanide, larotene, butyric acid, eflornithine hydrochloride, melphalan, privastatin sodium, prostaglandin Equinapril, ramipril, revi methotrexate, minodronate (minodronic acid), retinoic acids parin Sodium salt, ridogrel, Sampatrilat, Saralasin, satigrel, (including 13-cis retinoic and all trans-retinoic acids), Sulin spirapril, taprostene, telmisartan, temocapril, thyropropic dac, tamibarotene or valproic acid. acid, ticrynafen, tinzaparin, tirofiban, trandolapril, triflusal, 0.137 Still further, in the fifteenth embodiment, the inven Valsartan, Xanthinol niacinate or Xenbucin. tion encompasses a compound of formula (I); wherein the 0.124. A representative example of the cardiovascular antidepressant (including antimaniacs and antipsychotics) agent is an ACE-inhibitor that is selected from benazepril, referred to in the ninth, tenth, eleventh, twelfth, thirteenth and enalapril, enalaprilat, lisinopril, perindopril, quinapril, rami fourteenth embodiments hereinabove is generically selected pril, ramiprilate, trandolapril, alacepril, captopril, ceronapril, from an antimaniac or an antipsychotic agent and is specifi cilaZapril, delapril, fosinopril, imidapril, moexipril, movel cally selected from amineptine, gabapentin, 5-hydroxytryp tipril, omapatrilat, Sampatrilat, spirapril or temocapril. tophan (oxitriptan), pregabalin, tianeptine, Valproic acid or 0.125. Another representative example of the cardiovascu vigabatrin. lar agent is a Sartan that is selected from candesartan, olm 0.138 Still further, in the fifteenth embodiment, the inven esartan, telmisartan or Valsartan. tion encompasses a compound of formula (I); wherein the 0126 Yet another representative example of the cardio anticonvulsant referred to in the ninth, tenth, eleventh, vascular agent is an antithrombotic and vasoactive agent that twelfth, thirteenth and fourteenth embodiments hereinabove is selected from acetylsalicylic acid, argatroban, beraprost, is selected from gabapentin, pregabalin, tiagabine, Valproic dalteparin, daltroban, enoxaparin, iloprost, indobufen, acid or vigabatrin. isbogrel, heparin, lamifiban, lotrafiban, melagatran, nadro 0.139 Still further, in the fifteenth embodiment, the inven parin, oZagrel, reviparin Sodium salt, ridogrel, satigrel, tap tion encompasses a compound of formula (I); wherein the rostene, tinzaparin, tirofiban or triflusal. antibacterial referred to in the ninth, tenth, eleventh, twelfth, 0127. Yet another representative example of the cardio thirteenth and fourteenth embodiments hereinabove is vascular agent is an anti-hyperlipidemic agent (statin and selected from acediasulfone, amdinocillin, p-aminosalicylic fibrate) that is selected from atorvastatin, bezafibrate, ceriv acid, amoxicillin, amphomycin, amplicillin, apalcillin, apicy astatin, ciprofibrate, clinofibrate, clofibric acid, fluvastatin, cline, aspoxicillin, azidocillin, azlocillin, aztreonam, bacitra gemfibrozil, pitavastatin, or pravastatin. cin, balofloxacin, benzoylpas, benzylpenicillin, betamipron, 0128. Yet another representative example of the cardio biapenem, carbenicillin, carindacillin, carumonam, cefaclor, vascular agent is an antianginal agent Such as limaprost. cefadroxil, cefalexin, cefamandole, cefatiam, cefatrizine, 0129. Yet another representative example of the cardio cefazedone, cefazolin, cefbuperaZone, cefclidin, cefdinir, vascular agent is an antiarrhythmic agent Such as capobenic cefditoren, cefepime, cefetamet, cefixime, cefimenoXime, acid. cefnetazole, cefiminox, cefodizime, cefonicid, cefoperaZone, 0130 Yet another representative example of the cardio ceforanide, cefoselis, cefotaxime, cefotetan, cefotiam, cefox vascular agent is an antihypotensive agent Such as angio itin, cefoZopran, cefpimizole, cefpiramide, cefpirome, tensin. cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, 0131 Yet another representative example of the cardio ceftibuten, ceftizoxime, ceftriaxone, cefprozil, cefuroxime, vascular agent is a diuretic that is selected from bumetanide, cefuZonam, cephacetrile sodium, cephalexin, cephaloglycin, ethacrynic acid, furosemide, mercamphamide, mercaptom cephaloridine, cephalosporin C, cephalothin, cephapirin erin sodium, mercumallylic acid, mersalyl, piretanide or tic Sodium, cephradine, cilastatin, cinoxacin, ciproflaxacin, cla rynafen. Vulinic acid, clavulanate, clinafloxacin, clometocillin, cycla 0.132. Yet another representative example of the cardio cillin, dicloxacillin, difloxacin, enoxacin, epicillin, ertap vascular agent is a vasodilator that is selected from benfurodil enem, fenbenicillin, fleroxacin, flomoxef, floxacillin, hemisuccinate, beraprost, eledoisin, iloprost, prostaglandin flumequine, fosfomycin, fropenem, fusidic acid, garenoxa E or Xanthinol niacinate. cin, gatifloxacin, gemifloxacin, grepafloxacin, hetacillin, 0.133 Yet another representative example of the cardio hydnocarpic acid, imipenem, lomefloxacin, loracarbef, lyme vascular agent is a vasoprotectant Such as chromocarb. cycline, merbromin, meropenem, metampicillin, methicillin, 0134 Still further, in the fifteenth embodiment, the inven meZlocillin, miloxacin, moxalactam, moxifloxacin, nadi tion encompasses a compound of formula (I); wherein the floxacin, nafcillin, nalidixic acid, negamycin, noprysulfa antiallergic agent referred to in the ninth, tenth, eleventh, mide, norfloxacin, ofloxacin, opiniazide, oxacillin, oxolinic twelfth, thirteenth and fourteenth embodiments hereinabove acid, panipenem, paZufloxacin, pefloxacin, penicillin(s), pen is generically selected from a steroidal bronchodilator, a mast imepicycline, phenethicillin, phthalylsulfacetamide, cell stabilizer or an antihistamine and is specifically selected phthalylsulfathiazole, pipemidic acid, piperacillin, piromidic from acrivastine, amlexanox, bepotastine, cetirizine, fex acid, propicillin, prulifloxacin, quinacillin, ritipenem, ofenadine, levocetirizine, lodoxamide, montelukast Sodium, rosoxacin, rufloxacin, Salazosulfadimidine, salbactam, sita nedocromil, olopatadine, pentigetide or tranilast. floxacin, sparfloxacin, Succinylsulfathiazole, Succisulfone, US 2011/0263526 A1 Oct. 27, 2011

Sulbenicillin, Sulfachrysoidine, Sulfaloxic acid, 4-sulfanil droxybutyric acid); an anthelmintic selected from antimony amidosalicylic acid, Sulfanilic acid, taZobactam, teicoplanin, Sodium thioglycollate, kainic acid or Stibocaptate; an anti temocillin, ticarcillin, tigemonam, to Sufloxacin, trovafloxa acne agent selected from adapalene, isotretinoin or all-trans cin, tyrocidine or Vancomycin. retinoic acid, an antiamebic agent selected from thiocarbam 0140. A representative example of the antibacterial agent izine or thiocarbarSone; an antiarthritic or antirheumatic is selected from amoxicillin, amplicillin, cefadroxil, cefal agent selected from actarit, bucillamine, diacerein, gold Sodium thiomalate, lobenzarit, allocupreide Sodium, exin, cefixime, cefotaxime, cefuroxime, cephalexin, clobuZarit or penicillamine; an antiasthmatic agent selected ciproflaxacin, gatifloxacin, nadifloxacin, nalidixic acid, nor from amlexanox, cilomilast (ariflo), cromolyn, domitroban, floxacin, ofloxacin, oxacillin, panipenem, salbactam or van montelukast, nedocromil, ramatroban or seratrodast; an anti comycin. gout/ucosuric agent selected from carprofen, probenecid, 0141 Still further, in the fifteenth embodiment, the inven orotic acid, oxycinchophen or ticrynafen; an antidiuretic tion encompasses a compound of formula (I); wherein the agent Such as oxycinchophen; an antiglaucoma agent Such as antifungal agent referred to in the ninth, tenth, eleventh, unoprostone; an antihypothyroid agent selected from tiratri twelfth, thirteenth and fourteenth embodiments hereinabove color thyroxine; an antiprostatic hypertrophy agent Such as is selected from amphotericin B, aZaserine, benzoic acid, epristeride; an antiprotozoal agent selected from eflornithine candicidin, lucensomycin, natamycin, nystatin, propionic or fumagillin; an antipsoriatic agent such acitretin; an anti acid, Salicylic acid or undecylenic acid (10-undecenoic acid). septic agent Such as mandelic acid; an anxiolytic agent 0142. Still further, in the fifteenth embodiment, the inven selected from calcium n-carbamoylaspartate or cloraZepic tion encompasses a compound of formula (I); wherein the acid; an astringent Such as bismuth Subgallate; a cathartic/ antiviral agent referred to in the ninth, tenth, eleventh, twelfth, laxative such as Sennosides; choleretic agents selected from thirteenth and fourteenth embodiments hereinabove is cholic acid, cicrotoic acid, clanobutin, cyclobutyrol, cynarin selected from foscarnet Sodium or Zanamivir. (e), dehydrocholic acid, deoxycholic acid, dimecrotic acid, exiproben, fencibutirol, florantyrone, menbutone, 3-(o-meth 0143 Still further, in the fifteenth embodiment, the inven oxyphenyl)-2-phenylacrylic acid, sincalide, tocamphyl or tion encompasses a compound of formula (I); wherein the trepibutone; an enzyme cofactor Such as pantothenic acid; an antimalarial agent referred to in the ninth, tenth, eleventh, estrogen such as methallenestril; a gastroprokinetic agent twelfth, thirteenth and fourteenth embodiments hereinabove selected from alvimopan or loxiglumide; a hemostatic agent is artesumate. selected from e-aminocaproic acid or tranexamic acid; a 0144. Still further, in the fifteenth embodiment, the inven hepatoprotectant selected from S-adenosylmethionine, tion encompasses a compound of formula (I); wherein the betaine, orazamide, timonacic (thioproline), methionine, pro antidiabetic agent referred to in the ninth, tenth, eleventh, toporphyrin IX, thioctic acid ortiopronin; an immunomodu twelfth, thirteenth and fourteenth embodiments hereinabove lator selected from bucillamine, ubenimex, pidotimod, pro is selected from mitiglinide, nateglinide or repaglinide. codazole, romurtide or thymopentin; immunosuppressant 0145 Still further, in the fifteenth embodiment, the inven selected from brequinar or mycophenolic acid; a mucolytic tion encompasses a compound of formula (I); wherein the selected from acetylcysteine, carbocysteine, erdosteine, leto antiulcer agent (including proton pump inhibitor) referred to Steine or stepronin; a muscle relaxant selected from baclofen in the ninth, tenth, eleventh, twelfth, thirteenth and fourteenth or carisoprodol; a nootropics/Cognitive enhancer selected embodiments hereinabove is selected from acetoxolone, from cetylcarnitine, hexacyclonate sodium or leteprinim; a prostaglandin analog selected from beraprost, carboprost, arbaprostil, carbenoXolone, cetraxate, ecabet, S-methylme limaprost, prostacyclin, prostaglandin E, prostaglandin E, thionine, proglumide, rebamipide, rosaprostol, rotraxate, prostaglandin F, rosaprostol, Sulprostone, trimoprostill or Sofalcone or trimoprostil. unoprostone; a sedative/hypnotic chloral selected from 0146 Still further, in the fifteenth embodiment, the inven betainem or calcium 2-ethylbutanoate; a dopamine receptor tion encompasses a compound of formula (I); wherein the agonist Such as carmoxirole; a 5C-Reductase inhibitor Such as vitamin referred to in the ninth, tenth, eleventh, twelfth, thir epristeride; a reverse transcriptase inhibitor Such as foScarnet teenth and fourteenth embodiments hereinabove is selected sodium; thromboxane A-receptor antagonist selected from from biotin (vitamin H or coenzyme R), folic acid (vitamin altroban, domitroban, ramatroban, ridogrel or seratrodastand M), menadoxime, nicotinic acid (niacin), pantothenic acid or a thromboxane A-synthase inhibitor selected fromisbogrel, vitamin Bs (a member of the B complex vitamins). oZagrel or ridogrel. 0147 Still further, in the fifteenth embodiment, the inven 0149. In a sixteenth embodiment, the invention encom tion encompasses a compound of formula (I); wherein the passes a compound of formula (I), wherein D, the drug con antioxidant (including free radical scavengers) referred to in taining a carboxylic acid group capable of forming a covalent ninth, tenth, eleventh, twelfth, thirteenth and fourteenth bio-cleavable linkage with a linker, is a non-steroidal anti embodiments hereinabove is selected from C-lipoic acid, inflammatory drug (NSAID); L-Carnitine, N-acetyl L-cysteine, N-acetyl carnosine, rax X' is a bond; ofelast, tetomilast or SCMC-Lys (S-carboxymethyl-L-cys Y is C—O or a spacer group as defined in the first embodi teine Lysine salt. HO). ment hereinabove; 0148 For the purpose of this invention, the fifteenth X is oxygen; embodiment also encompasses a compound of formula (I); each of Z', Z, A, R' and R is as defined in the second wherein the drug containing carboxylic acid group is generi embodiment hereinabove; and cally selected from the drugs that fall under several other with the provisos that: therapeutic areas (including those drugs that are classified on 0.150 a) when A is S, thena and b is 3; or the basis of their mechanism of action) and is specifically 0151 b) when A is D-isosorbide skeleton or 1,4-anhy selected from an abortifacient/interceptive Such as prostag droerythritol skeleton, then a and b is 0; landin E, an anesthetic selected from ecgonidine, ecgonine, in all its stereoisomeric forms and pharmaceutically accept hydroxydione sodium or gama-hydroxybutyrate (gama-hy able salts thereof. US 2011/0263526 A1 Oct. 27, 2011

0152. In a seventeenth embodiment, the invention encom in all its stereoisomeric forms and pharmaceutically accept passes a compound of formula (I), wherein D, the drug or a able salts thereof. therapeutic agent containing a carboxylic acid group capable 0.161. In a twenty-second embodiment, the invention of forming a covalent bio-cleavable linkage with a linker, is a encompasses a compound of formula (I), wherein: each of D non-steroidal anti-inflammatory drug (NSAID); and X is as defined in the twenty-first embodiment herein X' is a bond; above; Y is C—O; each of X, Y, Z and Z is as defined in the second embodi 0153 X is oxygen; ment hereinabove; each of Z, Z, RandR is as defined in the first embodiment A is selected from a bond, 1.2-phenylene, 1.3-phenylene, hereinabove; and 1,4-phenylene, 2.3-pyridine, 3.4-pyridine, 2.4-pyridine, 2.5- A is selected from a bond, CH=CH or CRR'; where Rand pyridine, 2.6-pyridine, S, SO, SO, S. S. CH=CH or R" are independently selected from hydrogen or C. alkyl; CRR'; where R and R'' are independently selected from or Rand R' taken together with the carbon atom to which hydrogen, Calkyl, they are attached constitute a cycloalkyl group; provided that when A is S, then a and b is 3: in all its stereoisomeric forms and pharmaceutically accept R" is hydrogen and R is alkyl: or R is hydrogen and R' is able salts thereof. alkyl: 0154) In an eighteenth embodiment, the invention encom in all its stereoisomeric forms and pharmaceutically accept passes a compound of formula (I), wherein: able salts thereof. wherein D, the drug containing a carboxylic acid group capable of forming a covalent bio-cleavable linkage with a 0162. In a twenty-third embodiment, the invention encom linker, is a non-steroidal anti-inflammatory drug (NSAID); passes a compound of formula (I), wherein: each of D, X', X, each of X, Y, X, Z, Z, R' and R is as defined in the Y. Z' and Z is as defined in the twenty-second embodiment seventeenth embodiment hereinabove; hereinabove, A is selected from S, SO, SO or S S: provided that when A A is selected from a bond, CH=CH or CRR'; where Rand is S, thena and b is 3: R" are independently selected from hydrogen or C alkyl: in all its stereoisomeric forms and pharmaceutically accept (0163 R' is hydrogen and R is alkyl, cycloalkyl, aryl or able salts thereof. aralkyl; or R is hydrogen and R' is alkyl, cycloalkyl, aryl or O155 In a nineteenth embodiment, the invention encom aralkyl; passes a compound of formula (I), wherein: in all its stereoisomeric forms and pharmaceutically accept D, the drug containing a carboxylic acid group capable of able salts thereof. forming a covalent bio-cleavable linkage with a linker, is a 0164. In a twenty-fourth embodiment, the invention non-steroidal anti-inflammatory drug (NSAID); encompasses a compound of formula (I), wherein: each of D. each of X, Y, X, Z, Z, R' and R is as defined in the X', X, Y, Z and Z is as defined in the twenty-second seventeenth embodiment hereinabove; A is selected from 1.2-phenylene, 1.3-phenylene, 1,4-phe embodiment hereinabove, nylene, 2.3-pyridine, 3.4-pyridine, 2.4-pyridine, 2.5-pyri A is selected from S, SO, SO, or S S: provided that when A dine, 2.6-pyridine, D-isosorbide skeleton, 1.4-anhydroeryth is S, then a and b is 3: ritol skeleton or cycloalkyl; provided that when A is R" is hydrogen and R is alkyl, cycloalkyl, aryl or aralkyl; or D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then R’ is hydrogen and R' is alkyl, cycloalkyl, aryl or aralkyl; a and b is 0; and in all its stereoisomeric forms and pharmaceutically accept in all its stereoisomeric forms and pharmaceutically accept able salts thereof. able salts thereof. 0.165. In a twenty-fifth embodiment, the invention encom 0156. In twentieth embodiment, the invention encom passes a compound of formula (I), wherein: D, the drug passes a compound of formula (I), wherein the non-steroidal containing an amino group capable of forming a covalent anti-inflammatory drug (NSAID) referred to in the sixteenth, bio-cleavable linkage with a linker, referred to in the first, seventeenth, eighteenth and nineteenth embodiments is as second, third, fourth, fifth, sixth, twenty-first, twenty-second, defined in the fifteenth embodiment hereinabove. A represen twenty-third, and twenty-fourth embodiments herein above, tative example of the non-steroidal anti-inflammatory drug is selected from an antiinflammatory and analgesic drug, a (NSAID) is selected from aspirin, diclofenac, naproxen, cardiovascular drug, an antiallergic agent, an anticancer indomethacin, Sulindac, flurbiprofen, ketoprofen, ibuprofen agent, an antidepressant, an anticonvulsantagent, an antibac or mesalamine. terial agent, an antiviral agent, an antifungal agent, an anti 0157. In a twenty-first embodiment, the invention encom malarial agent, an antidiabetic agent an antiulcer agent, an passes a compound of formula (I), wherein: D is a drug antioxidant or a vitamin. The twenty-fifth embodiment also containing an amino group capable of forming a covalent encompasses within its scope a drug containing an amino bio-cleavable linkage with a linker; group wherein the drug is selected from several other thera X' is NR; wherein R is a bond or hydrogen; peutic areas (including those drugs that are classified on the Y is C—O; basis of their mechanism of action). 0158 X;Y. Z'; Z: A R and R are as defined in the (0166 In this embodiment, other variables X'; X, Y, Z', second embodiment hereinabove; and Z: A, R' and R in the compounds of formula (I) are as with the provisos that: defined above: provided that 0159 a) when A is S, thena and b is 3; or 0.167 a) when A is S, thena and b is 3; or 0160 b) when A is D-isosorbide skeleton or 1,4-anhy 0168 b) when A is D-isosorbide skeleton or 1,4-anhy droerythritol skeleton, then a and b is 0; droerythritol skeleton, then a and b is 0; US 2011/0263526 A1 Oct. 27, 2011

in all its stereoisomeric forms and pharmaceutically accept rothiazide, chlorthalidone, ciclosidomine, cifenline, cilaza able salts thereof. pril, cilnidipine, cilostazol, clofenamide, clonidine, clopam 0169. In twenty-sixth embodiment, the invention encom ide, cloranolol, clorexolone, cyclopenthiazide, cyclothiazide, passes a compound of formula (I), wherein: the antiinflam debrisoquin, delapril, denopamine, diaZOxide, dihydralazine, matory and analgesic drug referred to in the twenty-fifth dilevalol, dimetofrine, disopyramide, disulfamide, dob embodiment hereinabove is generically selected from an utamine, docarpamine, dolfetilide, dopamine, dopexamine, opioid, a steroid (glucocorticoid) or a non-steroidal anti-in doxazosin, droprenilamine, edeserpidine, efonidipine, ele flammatory drug (NSAID(s)) and is specifically selected doisin, elgodipine, enalapril, enalaprilat, encamide, endrala from aceclofenac, acetaminophen, acetaminosalol, actarit, Zine, enoxaparin, enoXimone, epanolol, erythrophleine, alminoprofen, amfenac, aminochlorthenoxazin, 3-amino-4- esmolol, ethiazide, ethoXZolamide, etifelmin, etillefrin, hydroxybutyric acid, ampiroxicam, aminopropylon, anilleri etiroXate, fasudil, felodipine, fendiline, fenoldopam, fen dine, antrafenine, benorylate, benzpiperylon, p-bromoaceta quizone, flecamide, furosemide, gepefrine, guanabenz, gua nilide, bromfenac, bucetin, bucolome, bufexamac, nacline, guanaZodine, guanethidine, guanochlor, guanadrel, bumadizone, butacetin, capsaicine, carprofen, carsalam, cele guanfacine, guanoxabenz, guanoxan, heptaminol, hydracar coxib, clonixin, dezocine, diclofenac, difenamizole, difenpi bazine, hydralazine, hydrochlorothiazide, hydroflumethiaz ramide, enfenamic acid, etersalate, ethenZamide, ethoxazene, ide, ibopamine, imidapril, imolamine, indapamide, indecam etodolac, etofenamate, fepradinol, flipirtine, floctafenine, ide, indenolol, indoramin, irbesartan, isoXSuprine, isradipine, flufenamic acid, glafenine, ibuproxam, isoladol, isonixin, itramin tosylate, kallidin, ketanserin, labetalol, lacidipine, isoxicam, p-lactophenetide, lornoxicam, meclofenamic acid, lamifiban, landiolol, lercanidipine, levosimendan, lidofla mefenamic acid, meloxicam, mesalamine, mofebutaZone, Zine, lisinopril, lofexidine, loprinone, losartan, lotrafiban, nifenaZone, niflumic acid, nimeSulide, norlevorphanol, nor manidipine, mebutamate, mecamylamine, mefruside, mela morphine, oxametacine, paranyline, parecoxib, parsalmide, gatran, meobentine, mephentermine, mepindolol, metarami phenacetin, phenazopyridine, phenocol, phenopyrazone, nol, methazolamide, methoxamine, methyclothiazide, meth phenylramidol, piketoprofen, piminodine, piperylone, yldopa, methyl 4-pridyl ketone thiosemicarbazone, piroXicam, piritramide, propacetamol, ramifenaZone, Salver meticrane, metipranolol, metolaZone, metoprolol, mexilet ine, salacetamide, salicylamide, Salicylamide o-acetic acid, ine, mibefradil, midodrine, milrinone, minoxidil, moexipril, Sulfasalazine, talniflumate, tenidap, terofenamate, tinoridine, molsidomine, monatepil, moprolol, moricizine, moveltipril, tenoxicam, tolfenamic acid and Valdecoxib. Preferred moXonidine, muZolimine, nadolol, nadoxolol, nebivolol. examples of antiinflammatory drugs include acetaminophen, nicardipine, nicorandil, nifedipine, nifemalol, nilvadipine, bromfenac, celecoxib, diclofenac, etodolac, meloxicam, nimodipine, nipradillol, niSoldipine, nitrendipine, norepi mesalamine, nimeSulide, paracoxib, phenacetin or Valde nephrine, nylidrin, olmesartan, oXprenolol, oxyfedrine, pam coxib. abrom, paraflutizide, penbutolol, pentisomide, perhexyline, 0170 A representative example of the antiinflammatory perindopril, pheniprazine, phentolamine, pholedrine, picota and analgesic drug is selected from acetaminophen, bro mide, pildralazine, pilsicamide, pimethylline, pimobendan, mfenac, celecoxib, diclofenac, etodolac, meloxicam, pinacidil, pindolol, piretanide, plafibride, polythiazide, prac mesalamine, nimeSulide, paracoxib, phenacetin or Valde tolol, prazosin, prenalterol, prenylamine, procainamide, coxib. pronethalol, propafenone, propranolol, quinapril, quineth aZone, ramipril, ranolazine, raubasine, rescimetol, rescin 0171 Further in the twenty-sixth embodiment, the cardio namine, reserpiline, reserpine, rillmenidine, roxifiban, Sam vascular agent referred to in the twenty-fifth embodiment patrilat, Saralasin, sematilide, Sotalol, spirapril, Sulfinalol, hereinabove is generically selected from an antihypertensive Sulmazole, Suloctidil, Synephrine, Syrosingopine, talinolol. agent Such as an angiotensin converting enzyme (ACE) tasosartan, teclothiazide, temocapril, teraZosin, terodiline, inhibitor, a beta-blocker, a sartan (angiotensin II blockers), an tertatolol, theobromine, tiamenidine, tilisolol, timolol, antithrombotic and vasoactive agent, an anti-hyperlipidemic tinofedrine, tirofiban, tocamide, todralazine, tolazoline, tolip drug (including HMG-CoA-reductase inhibitor (statins), rolol, tolonidine, torsemide, trandolapril, triamterene, fibrate, an antianginal agent, an antiarrhythmic agent, an anti trichlormethiazide, trimaZosin, trimetazidine, tripamide, ura hypotensive agent, a calcium channel blocker, a cardiotonic pidil, Valsartan, Vesnarinone, Viduidil, Xamoterol, agent, a cardioprotective agent, a diuretic or a vasodilator and Xemilofiban, Xibenolol, Ximelagatran or Xipamide. is specifically selected from acadesine, acebutolol, acecam ide, adenosine, alacepril, alfuZosin, alprenolol, althiazide, 0172 A representative example of the cardiovascular amanozine, ambuside, amezinium methyl sulfate, amiloride, agent is an ACE inhibitor that is selected from alacepril, gama-aminobutyric acid, aminometradine, 2-amino-4-pi benazepril, ceronapril, cilaZapril, delapril, enalapril, enalap coline, amisometradine, amlodipine, amoSulalol, aminone, rilat, imidapril,lisinopril, moexipril, moveltipril, omapatrilat, angiotensin, aranidipine, argatroban, arotinolol, atenolol. perindopril, quinapril, ramipril, spirapril, temocapril or tran aZosemide, bamethan, barnidipine, benazepril, bendaZol. dollapril. bendroflumethiazide, benfluorex, benidipine, benzalbutyra 0173 Another representative example of the cardiovascu mide, benzylhydrochlorothiazide, benzthiazide, betahistine, lar agent is a beta-blocker that is selected from atenolol. bethanidine, betaxolol, bevantolol, bidisomide, bisoprolol. bupranolol, carvedilol, labetalol, metipranolol, metoprolol. bopindolol, bosentan, bradykinin, bucindolol, bucladesine, nadolol, pindolol, propranolol or timolol. bucumolol, budralazine, bufeniode, bufetolol, bufuralol, 0.174 Another representative example of the cardiovascu bumetanide, bunaZosin, bunitrolol, bupranolol, butalamine, lar agent is a sartan (angiotensin II blocker) that is selected butazolamide, buthiazide, butidrine, butofilolol, cadralazine, from Irbesartan, losartan, olmesartan or Valsartan; candesartan, capobenic acid, carazolol, cariporide, carmox 0.175 Yet another representative example of the cardio irole, caronapril, carteolol, carvedilol, celiprolol, cetamolol. vascular agent is an antithrombotic and vasoactive agent that chloraminophenamide, chlorazanil, chlormerodrin, chlo is selected from argatroban, ciloStaZol, droprenilamine, enox US 2011/0263526 A1 Oct. 27, 2011

aparin, lamifiban, lotrafiban, melagatran, perhexyline, pico chodilator, mast cell stabilizer or an antihistamine; and is tamide, plafibride, roxifiban, Suloctidil, tirofiban, specifically selected from amlexanoX, antazoline, astemizole, Xemilofiban or Ximelagatran. bambuterol, cetoxime, clobenzepam, desloratadine, epinas 0176 Yet another representative example of the cardio tine, mizolastine, Oxatomide, pemirolast, pentigetide, pifati vascular agent is an antianginal agent that is selected from dine (roxatidine acetate hydrochloride), repirinast, Salbuta amlodipine, bevantolol, bucumolol, bufuralol. elgodipine, mol, salmeterol, Suplatast, taZanolast, tranilast, tritoqualine imolamine, molsidomine, nicardipine, nicorandil, nifedipine, Or traXanoX. nifenalol, nipradillol, oxyfedrine, pronethalol, ranolazine, Sotalol, terodiline, toliprolol or trimetazidine. 0185. A representative example of the antiallergic agent is 0177 Yet another representative example of the cardio an antihistamine that is selected from antazoline, astemizole, vascular agent is an antiarrhythmic agent that is selected from cetoxime, clobenzepam, desloratadine, epinastine, mizolas acecamide, adenosine, bidisomide, bufetolol, butidrine, tine, pifatidine (roxatidine acetate hydrochloride) or tritoqua capobenic acid, cifenline, cloranolol, disopyramide, dolfetil line. ide, encamide, esmolol, flecamide, indecamide, landiolol. 0186 Still further in the twenty-sixth embodiment, the meobentine, mexiletine, moricizine, nadoxolol, pentisomide, anticancer agent referred to in the twenty-fifth embodiment pilsicamide, practolol, procainamide, propafenone, sematil hereinabove is selected from 9-aminocamptothecin, aminole ide, tocamide, tilisolol or Xibenolol. Vulinic acid, 3-aminopyridine-2-carboxaldehyde thiosemi 0.178 Yet another representative example of the cardio carbazone (3-ap), 3-aminopyridine-4-methyl-2-carboxalde vascular agent is an antihypotensive agent that is selected hyde thiosemicarbazone (3-amp/triapine/ocx-191/ocx from amezinium methyl sulfate, angiotensin, dimetofrine, 0191), amsacrine, ancitabine, anthramycin, azacitidine, dopamine, etifelmin, etillefrin, gepefrine, heptaminol, bicalutamide, bisantrene, bleomycins, bropirimine, buser mephentermine, metaraminol, methoxamine, midodrine, elin, carboplatin, carboquone, carmofur, carmustine, carubi norepinephrine, pholedrine or synephrine. cin, chlorozotocin, cisplatin, cladribine, cyclophosphamide, 0179 Yet another representative example of the cardio cytarabine, dacarbazine, dactinomycin, daunorubicin, decit vascular agent is a calcium channel blocker that is selected abine, defosfamide, demecolcine, diaziquone, 6-diazo-5- from amlodipine, aranidipine, barnidipine, benidipine, cilni oXo-1-norleucine (don), docetaxel, doxorubicin, ecteinasci dipine, efonidipine. elgodipine, felodipine, fendiline, israd dins, edatrexate, efaproxiral, eflornithine, eniluracil, ipine, lacidipine, lercanidipine, lidoflazine, manidipine, epirubicin, erlotinib, fluorouracil, gefitinib, gemcitabine, mibefradil, monatepil, nicardipine, nifedipine, nilvadipine, goserelin, histamine, hydroxyurea, idarubicin, ifosfamide, nimodipine, nisoldipine, nitrendipine, perhexyline, preny imatinib, improSulfan, lanreotide, leuprolide, liarozole, loba lamine or terodiline. platin, lomustine, lonafarnib, mannomustine, marimastat, 0180 Yet another representative example of the cardio melphalan, 6-mercaptopurine, methotrexate, methyl ami vascular agent is a cardiotonic agent that is selected from nolevulinate, miboplatin, mitoguaZone, mitoxantrone, niluta 2-amino-4-picoline, aminone, bucladesine, denopamine, mide, nimustine, nolatrexed, oxaliplatin, pemetrexed, pen dobutamine, docarpamine, dopamine, dopexamine, enoxi to statin, peplomycin, perfosfamide, phenamet, pirarubicin, mone, erythrophleine, ibopamine, levosimendan, loprinone, piritrexim, prinomastat, procarbazine, puromycin, raltitr milrinone, pimobendan, prenalterol, Sulmazole, Vesnarinone exed, tariquidar, temozolomide, thiamiprine, thioguanine, or Xamoterol. tiazofurin, tipifarnib, tirapazamine, troxacitabine, trimetrex 0181. Yet another representative example of the cardio ate, uracil mustard (uramustine), vindesine or Zorubicin. vascular agent is a cardioprotective agent that is selected from 0187. A representative example of the anticancer agent is acadesine or cariporide. selected from 9-aminocamptothecin, bicalutamide, carbopl 0182. Yet another representative example of the cardio atin, cyclophosphamide, cytarabine, daunorubicin, doc vascular agent is a diuretic agent that is selected from althi etaxel, doxorubicin, fluorouracil, gemcitabine, idarubicin, azide, amanozine, ambuside, amiloride, aminometradine, leuprolide, melphalan, methotrexate, tirapazamine, troxacit amisometradine, azosemide, bendroflumethiazide, benzthi abine, Vindesine or Zorubicin. azide, bumetanide, butazolamide, buthiazide, chlorami 0188 Still further in the twenty-sixth embodiment, the nophenamide, chlorazanil, chlormerodrin, chlorothiazide, antidepressant referred to in the twenty-fifth embodiment chlorthalidone, clofenamide, clorexolone, cyclothiazide, dis hereinabove also includes an antimaniac and antipsychotic ulfamide, ethiazide, ethoXZolamide, fenduizone, furosemide, agent and is specifically selected from S-adenosylmethion hydrochlorothiazide, mefruside, methazolamide, methy ine, amineptine, amisulpride, amoxapine, aripiprazole, ben clothiazide, meticrane, metolaZone, muZolimine, pamabrom, peridol, caroXaZone, carpipramine, clocapramine, clomac paraflutizide, piretanide, polythiazide, quinethaZone, ran, clospirazine, clozapine, demexiptiline, desipramine, teclothiazide, theobromine, torsemide, triamterene, trichlo droperidol, dulloxetine, fencamine, fluoxetine, fluspirilene, rmethiazide or Xipamide. fluvoxamine, 5-hydroxytryptophan (oxitriptan), indalpine, 0183 Yet another representative example of the cardio indeloxazine hydrochloride, iproclozide, iproniazid, isocar vascular agent is a vasodilator that is selected from bamethan, boxazid, levophacetoperane, maprotiline, metapramine, mil bendaZol, betahistine, bradykinin, butalamine, droprenil nacipran, minaprine, moclobemide, molindone, amine, eledoisin, fasudil, fendiline, isoxSuprine, itramintosy mosapramine, nemonapride, nialamide, nomifensine, late, kallidin, lidoflazine, nimodipine, nylidrin, pimethylline, nortriptyline, octamoxin, olanzapine, oxypertine, paroxetine, prenylamine, Suloctidil, tinofedrine, tolaZoline, trimetazidine pimozide, pipamperone, protriptyline, reboxetine, remoX or Viduidil. ipride, rolipram, roXindole, sertindole, Sertraline, spiperone, 0184 Still further in the twenty-sixth embodiment, the Sulpiride, Sultopride, tianeptine, timiperone, tofenacin, tra antiallergic agent referred to in the twenty-fifth embodiment nylcypromine, Viloxazine, benmoxine, rolicyprine or ziprasi hereinabove is generically selected from a steroidal bron done. US 2011/0263526 A1 Oct. 27, 2011

0189 A representative example of the antidepressant is methacycline, methicillin, 4'-(methylsulfamoyl)sulfanilanil selected from desipramine, dulloxetine, fluoxetine, fluvoxam ide, mezlocillin, micronomicin, mikamycin, minocycline, ine, moclobemide, nortriptyline, paroxetine, reboxetine or morphaZinamide, moxalactam, moxifloxacin, nafcillin, Sertraline. A representative example of the antidepressant negamycin, neomycin, netilmicin, nifuradene, nitrofuran includes an antimanic and antipsychotic agent that is selected toin, noprysulfamide, norfloxacin, novobiocin, opiniazide, from aripiprazole, clozapine, olanzapine or ziprasidone. oxacillin, oxytetracycline, panipenem, paromomycin, paZu (0190. Still further in the twenty-sixth embodiment, the floxacin, penamecillin, penethamate hydriodide, penicillin anticonvulsant agent referred to in the twenty-fifth embodi (S), penimepicycline, pexiganan, phenethicillin, phenyl ami ment hereinabove is selected from acetylpheneturide, albu nosalicylate, phthalylsulfacetamide, phthalylsulfathiazole, toin, 4-amino-3-hydroxybutyric acid, atrolactamide, n-ben picloxydine, pipacycline, pipemidic acid, piperacillin, piv Zyl-3-chloropropionamide, buramate, carbamazepine, ampicillin, pivoefalexin, polymyxin, porfiromycin, primycin, cinromide, clonazepam, decimemide, dimethadione, doxeni pristinamycin, protionamide, pyrazinamide, quinacillin, toin, ethoSuximide, ethotoin, felbamate, fosphenyloin, gaba quinupristin, ramoplanin, ribostamycin, rifabutin, rifalazil, pentin, lamotrigine, levetiracetam, licarbazepine, mepheny rifamide, rifamycin SV, rifampin, rifapentine, rifaximin, ris loin, mephobarbital, metharbital, methetoin, 5-methyl-5-(3- tocetin, ritipenem, rollitetracycline, Salazosulfadimidine, Sali phenanthryl)hydantoin, 3-methyl-5-phenylhydantoin, nazid, Sancycline, Sisomicin, sitafloxacin, Solasulfone, spar nitrazepam, Oxcarbazepine, oxicarbamazepine, phenace floxacin, spectinomycin, streptolydigin, Streptomycin, mide, phenetharbital, pheneturide, phenobarbital, phenylm streptonicozid, Subathizone, 4,4'-succinylsulfathiazole. Suc ethylbarbituric acid, phenyloin, phethenylate sodium, pre cisulfone, Sulbenicillin, Sulfachrysoidine, Sulfanilic acid, 2-p- gabalin, primidone, progabide, remacemide, rufinamide, Sulfanillylanilinoethanol, sulfinyldianiline, Sulfoxone Suclofenide, Sulthiame, talampanel, tetrantoin, topiramate, Sodium, 4'-sulfanilylsulfanilamide, Sulfoniazide, Sulfabenza valpromide, vigabatrin or Zonisamide. mide, Sulfacetamide, Sulfachlorpyridazine, Sulfacytine, Sul 0191) A representative example of the anticonvulsant fadiazine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, agentis selected from carbamazepine, felbamate, gabapentin, Sulfaethidole, Sulfaguanidine, Sulfaguanole, Sulfalene, Sulfa lamotrigine, levetiracetam, licarbazepine, oXcarbazepine, loxic acid, Sulfamerazine, Sulfameter, Sulfamethazine, Sul pregabalin, topiramate, valpromide, vigabatrin or Zonisa famethizole, Sulfamethomidine, Sulfamethoxazole, Sul mide. famethoxypyridazine, Sulfamethylthiazole, Sulfametrole, Sulfamidochrysoidine, Sulfamoxole, Sulfanilamide, 4-sulfa 0.192 Still further in the twenty-sixth embodiment, the nilamidosalicylic acid, p-sulfanilylbenzylamine, Sulfanily antibacterial agent referred to in the twenty-fifth embodiment lurea, n-sulfanillyl-3,4-Xylamide, Sulfaperine, Sul hereinabove is selected from acedapsone, acediasulfone, faphenazole, Sulfaproxyline, Sulfapyrazine, Sulfasomizole, acetosulfone sodium, ambaZone, amikacin, p-aminosalicylic Sulfasymazine, Sulfathiazole, Sulfathiourea, Sulfisomidine, acid, p-aminosalicylic acid hydrazide, amoxicillin, ampho Sulfisoxazole, Sultamicillin, Sulfatolamide, talampicillin, tau mycin, amplicillin, apalcillin, apicycline, arbekacin, rolidine, teicoplanin, temocillin, tetroXoprim, thiamphenicol, aspoxicillin, azidamfenicol, azidocillin, azlocillin, aztre thiazosulfone, thiacetazone, thiostrepton, ticarcillin, tige onam, bacampicillin, bacitracin, balofloxacin, bambermy monam, tiocarlide, tobramycin, toSufloxacin, trimethoprim, cins, benzoylpas, benzylsulfamide, betamipron, brodi trospectomycin, trovafloxacin, tuberactinomycin, tyrocidine, moprim, 5-bromosalicylhydroxamic acid, butirosin, Vancomycin, viomycin or Virginiamycin. capreomycin, carbenicillin, carindacillin, carumonam, cefa clor, cefadroxil, cefamandole, cefatiam, cefatrizine, cefaze 0193 A representative example of the anti-bacterial agent done, cefazolin, cefbuperaZone, cefdinir, cefcapene pivoxil, is selected from amoxicillin, amplicillin, cefadroxil, cefal cefclidin, cefditoren, cefepime, cefetamet, cefixime, cef exin, cefixime, cefotaxime, cefuroxime, cephalexin, menoxime, cefimetazole, cefiminox, cefodizime, cefonicid, chloramphenicol, chlortetracycline, ciproflaxacin, clavulan cefoperaZone, ceforanide, cefoselis, cefotaxime, cefotetan, ate, clinafloxacin, clindamycin, dapsone, doxycycline, cefotiam, cefoxitin, cefoZopran, cefpimizole, ce?piramide, ethambutol, gatifloxacin, gentamycin, nadifloxacin, nalidixic cefpirome, cefpodoxime proxetil, cefprozil, cefroxadine, cef acid, norfloxacin, oflaxacin, oxacillin, panipenem, penicil Sulodin, ceftazidime, cefteram, ceftezole, ceftibuten, cefti lins, salbactam, Streptomycin, Sultamicillin or Vancomycin. Zoxime, ceftriaxone, cefuroxime, cefuZonam, cephacetrile 0194 Still further in the twenty-sixth embodiment, the Sodium, cephalexin, cephaloglycin, cephaloridine, cepha antifungal agent referred to in the twenty-fifth embodiment losporin c. cephalothin, cephapirin Sodium, cephradine, hereinabove is selected from acrisorcin (9-aminoacrindine chloramine-B, chloramine-T, chloramphenicol, chlortetracy compound with 4-hexylresorcinol (1:1)), amphotericin B, cline, cilastatin, ciproflaxacin, clinafloxacin, clindamycin, anidulafungin, azaserine, bromosalicylchloranilide, buclosa clometocillin, clomocycline, cloxacillin, colistin, cyacet mide, candicidin, caspofungin, chlordantoin, exalamide, acide, cyclacillin, cycloserine, dalfopristin, dapsone, deme flucytosine, loflucarban, lucensomycin, magenta I, mepartri clocycline, deoxydihydrostreptomycin, dibekacin, diclox cin, micafungin, natamycin, nystatin, perimycin, pyrrolni acillin, dihydrostreptomycin, dirithromycin, doxycycline, trin, salicylanilide or tubercidin. enoxacin, enviomycin, epicillin, ertapenem, ethambutol, (0195 Still further in the twenty-sixth embodiment, the ethionamide, fenbenicillin, flomoxef, floxacillin, antiviral agent referred to in the twenty-fifth embodiment N2-forimicins, formylsulfisomidine, furazolium chloride, hereinabove is selected from abacavir, acyclovir, adefovir, furonazide, garenoxacin, gatifloxacin, gemifloxacin, genta amantadine, amidinomycin, amprenavir, atazanavir, atevird mycin, glyconiazide, na-beta-d-glucosylsulfanilamide, ine, capravirine, cidofovir, delavirdine, didanosine, dideoxy gramicidin(s), grepafloxacin, guamecycline, hetacillin, imi adenosine, efavirenz, emitricitabine, entecavir, famciclovir, penem, isepamicin, isoniazid, kanamycin(s), lenampicillin, ganciclovir, imiquimod, indinavir, lamivudine, lopinavir, lincomycin, lineZolide, lomefloxacin, loracarbef, lymecy mantadine, methisaZone, 5-(methylamino)-2-deoxyuridine cline, mafenide, meclocycline, meropenem, metampicillin, (madu), moroxydine, nelfinavir, nevirapine, oseltamivir, pen US 2011/0263526 A1 Oct. 27, 2011

ciclovir, residuimod, ribavirin, rimantadine, ritonavir, therapeutic areas (including those drugs that are classified on saquinavir, stallimycin, tenofovir, tipranavir, trimetazidine, the basis of their mechanism of action) and is specifically tromantadine, Valacyclovir, Valganciclovir, Vidarabine, Zal selected from: an abortifacient/interceptive such as Sulpros citabine or Zanamivir. tone; an anesthetic selected from ambucaine, benoximate, 0196. A representative example of the antiviral agent is benzocaine, betoxycaine, bupivacaine, butacaine, butamben, selected from abacavir, acyclovir, adefovir, amprenavir, cido butanilicaine, butethamine, carticaine, chloroprocaine hydro fovir, didanosine, efavirenz, emitricitabine, famciclovir, gan chloride, dibucaine hydrochloride, dimethocaine, diperodon ciclovir, indinavir, lamivudine, lopinavir, nelfinavir, nevirap hydrochloride, etidocaine, etoxadrol, B-eucaine, euprocin, ine, oseltamivir, penciclovir, ritonavir, saquinavir, hexylcaine hydrochloride, hydroxytetracaine, isobutyl trimetazidine, Valacyclovir, Valganciclovir, Vidarabine, Zal p-aminobenzoate, ketamine, lidocaine, leucinocaine mesy citabine or Zanamivir. late, mepivacaine, meprylcaine, metabutoxycaine, octacaine, (0197) Still further in the twenty-sixth embodiment, the orthocaine, pentobarbital, piridocaine, prilocalne, procaine, antimalarial agent referred to in the twenty-sixth embodiment hereinabove is selected from amodiaquine, chlorguanide, proparacaine, propoxycaine hydrochloride, pyrrocaine, ropi chloroquine, chlorproguanil, cycloguanil, hydroxychloro vacaine, tetracaine hydrochloride, thialbarbital, thiamylal, quine, mefloquine, 3-methylarsacetin, pamaquine, plas tolycaine, tricaine, trimecaine or urethan; an anorexic agent selected from a minorex, chlorphentermine, clobenzorex, mocid, primaquine, pyronaridine, quinocide or tafenoquine cloforex, clortermine, n-ethylamphetamine, fenfluramine, (0198 Still further in the twenty-sixth embodiment, the fenproporex, mefenorex, norpseudoephedrine, pentorex, antidiabetic agent referred to in the twenty-fifth embodiment phenmetrazine, phentermine, picilorex or methamphet hereinabove is selected from acetohexamide, buformin, carb amine; an anthelmintic agent selected from albendazole, utamide, chlorpropamide, fidarestat, glibornuride, gliclazide, amocarzine, amphotalide, becanthone, cyclobendazole, glimepiride, glipizide, gliquidone, glisoxepid, glyburide, gly diphenane, hycanthone, kainic acid, lucanthone, mebenda buthiazol(e), glybuzole, glyhexamide, glymidine, glypina Zole, niridazole, nitazoxanide, oxamniquine, pelletierine, mide, metformin, phenformin, pioglitaZone, repaglinide, piperazine, quinacrine, thiabendazole or thymyl N-isoamyl rosiglitaZone, tolaZamide, tolbutamide, tolcyclamide, trogli carbamate; an agent for treating alopecia Such as finasteride; taZone or Voglibose. an antiamebic agent selected from carbarSone, dehydroemet (0199 Still further in the twenty-sixth embodiment, the ine, diphetarSone, emetine, thiocarbarSone, glycobiarsol or antiulcer agent referred to in the twenty-fifth embodiment tetracycline; an antiandrogen agent such as flutamide or hereinabove includes a proton pump inhibitor and said anti nilutamide: an antiarthritic/antirheumatic agent selected ulceragent is selected from aldioxa, benexate HCl, carbenox from glucosamine, leflunomide or penicillamine; an antiasth olone, cetraxate, cimetidine, ebrotidine, ecabapide, esapra matic agent selected from domitroban, formoterol, pran Zole, esomeprazole, famotidine, irsogladine, lafutidine, lukast, ramatroban, Suplatast tosylate, traXanox, Zafirlukastor lansoprazole, leminoprazole, 5-methylmethionine, nizati Zileuton; an antidiarrheal agent selected from alkofanone, dine, omeprazole, pantoprazole, pirenzepine, polaprezinc, racecadotril or Zaldaride; an antidiuretic selected from des rabeprazole, ranitidine, rebamipide, rotraxate, roXatidine, mopressin, fely pressin, lypressin, ornipressin, terlipressin or telenzepine or troXipide. vasopressin; an antiemetic agent selected from alizapride, 0200 Still further in the twenty-sixth embodiment, the aprepitant, aZasetron, bromopride, clebopride, dolasetron, antioxidant referred to in the twenty-fifth embodiment here domperidone, granisetron, itasetron, methallatal, metoclo inabove includes a free radical scavenger and the antioxidant pramide, metopimazine, pipamazine, ramosetron, tri is selected from BTX-51072 (4,4-dimethyl-3,4-dihydro-2H methobenzamide or tropisetron; an antiglaucoma agent 1.2-benzoselenazine), carnosine, melatonin, (+)-R-prami selected from acetazolamide, brinzolamide, dorzolamide, pexole, SCMC-Lys (S-carboxymethyl-L-cysteine Lysine salt befunolol, bimatoprost, brimonidine or levobunolol; an anti HO), stobadine or Zeatin. gout agent selected from allopurinol, carprofen, colchicine or 0201 Still further in the twenty-sixth embodiment, the orotic acid; an antihyperthyroid agent selected from propy vitamin referred to in the twenty-fifth embodiment herein lthiouracil or thiobarbital; an antihypothyroid agent Such as above is selected from acetiamine (diacethiamine or D.A.T.), thyroxine; an antimigraine agent selected from almotriptan, benfotiamine (S-benzoylthiamine monophosphate or alpiropride, eletriptan, ergotamine, froVatriptan, lisuride, BTMP), biotin (vitamin H or coenzyme R), bisbentiamine methysergide, naratriptan, rizatriptan, Sumatriptan or Zolmi (O-benzoylthiamine disulfide), cetotiamine (O.S.-dicarbe triptan; an antimuscarinic/mydriatic agent selected from thoxythiamine or DCET), cobamamide (vitamin B coen ambutonium bromide, aminopentamide, benzetimide, Zyme), cyanocobalamin (vitamin B), folic acid (vitamin buZepide, camylofine, darifenacin, fempiverinium bromide or M), fursultiamine (thiamine tetrahydrofurfuryl disulfide), isopropamide iodide; an antiosteoporotic agent selected from hydroxocobalamin (vitamin B), nicotinamide, octo alendronic acid, incadronic acid or pamidronic acid; an anti tiamine, proSultiamine, thiamine (vitamin B) or vitamin Ks. prostatic agent used for treating hypertrophy selected from 0202 As has been indicated hereinabove that the twenty doxazosin, epristeride, mepartricin, tamsulosin or teraZosin; fifth embodiment also encompasses within its scope a com an antiprotozoal agent selected from acetarSone, Acranil R. pound of formula (I) wherein the drug or therapeutic agent aminitrozole, anisomycin, azanidazole, benznidazole, eflo containing an amino group is selected from the drugs belong rnithine, hydroxyStilbamidine, lauroguadine, melarsoprol, ing to several other therapeutic areas (including those drugs mepartricin, n-methylglucamine, nitaZoxanide, oxophenars that are classified on the basis of their mechanism of action). ine hydrochloride, pentamidine, propamidine, puromycin, Thus, for the purpose of this invention, the twenty-sixth pyrimethamine, quinapyramine, Stilbamidine, Suramin embodiment also encompasses a compound of formula (I); Sodium, tenonitrozole, trypan red or tryparsamide; an antip wherein the drug containing amino group is generically Soriatic agent such as 6-azauridine; an antiseptic agent selected from the class of drugs falling under several other selected from aminacrine, aminoquinuride, bisdequalinium US 2011/0263526 A1 Oct. 27, 2011 20 chloride, chlorhexidine, chloroaZodin, dequalinium chloride, selected from acecarbromal, allobarbital, amobarbital, dibromopropamidine, dodecarbonium chloride, ethacridine, amphenidone, aprobarbital, apronalide, barbital, brallobar hexamidine, hexetidine, iodopyrrole, laurolinium acetate, bital, bromisovalum, butalbital, butallylonal, butethal, butoc nitroakridin 3582, noxythiolin, oxymethurea or triclocarban; tamide, carbromal, carbubarb, carfimate, cyclobarbital, an antispasmodic agent selected from ambutonium bromide, cyclopentobarbital, dexmedetomidine, diethylbromoaceta aminopentamide, buZepide, camylofine, darifenacin, dro mide, ectylurea, enallylpropymal, ethinamate, febarbamate, taverine, etomidoline, femalamide, fempiverinium bromide, 5-furfuryl-5-isopropylbarbituric acid, glutethimide, halox hydramitrazine, isopropamide iodide, nicofetamide, octamy azolam, heptabarbital, hexethal sodium, hexobarbital, methi lamine, phenamacide hydrochloride, pramiverin, proglu tural, methyprylon, narcobarbital, nealbarbital, niaprazine, mide, racefemine or tiropramide; an antitussive agent pentobarbital, phenallymal, piperidione, propallylonal, selected from alloclamide, benzonatate or fominoben; an proxibarbal, reposal, rilmazafone, secobarbital Sodium, talb anxiolytic agent selected from abecarnil, azacyclonol, ben utal, tetrabarbital, Valdetamide, vinbarbital sodium or vinyl Zoctamine, bromazepam, calcium N-carbamoylaspartate, bital; a Vulnerary Such as allantoin: a drug that acts as an chlordiazepoxide, cloraZepic acid, cloxazolam, cyclarbam C.-adrenergic agonist selected from adrafinil, adrenalone, ate, emylcamate, ethyl etifoxine, flesinoxan, hydroxyphe amidephrine, apraclonidine, budralazine, clonidine, cyclo namate, loflazepate, lorazepam, mecloralurea, meprobamate, pentamine, dexmedetomidine, dimetofrine, diplivefrin, mexazolam, nordazepam, oxazepam, oxazolam, tybamate or ecabapide, ephedrine, epinephrine, fenoxazoline, guanabenz, valnoctamide; a cathartic agent/laxative selected from guanfacine, hydroxyamphetamine, ibopamine, indanazoline, bisoxatin acetate or oxyphenisatin acetate; a choleretic agent isometheptene, mephentermine, metaraminol, methoxamine, selected from osalmid or sincalide; a cholinergic agent methylhexaneamine, midodrine, mivaZerol, modafinil, moX selected from bethanechol chloride, eptastigmine, eseridine, onidine, naphazoline, norepinephrine, norfenefrine, octo guanidine, dexpanthenol, carbachol or physostigmine; a drine, octopamine, oxymetazoline, phenylephrine hydro decongestant selected from amidephrine, cyclopentamine, chloride, phenylpropanolamine, phenylpropylmethylamine, ephedrine, epinephrine, fenoxazoline, indanazoline, nap pholedrine, propylhexedrine, pseudoephedrine, rillmenidine, haZoline, nordefrin, octodrine, oxymetazoline, phenyleph synephrine, talipexole, tetrahydrozoline, tiamenidine, trama rine, phenylpropanolamine, phenylpropylmethylamine, pro Zoline, tuaminoheptane, tymazoline, tyramine or Xylometa pylhexedrine, pseudoephedrine, tetrahydrozoline, Zoline; a drug that acts as a B-adrenergicagonist selected from tramaZoline, tuaminoheptane, tymazoline or Xylometazoline; albuterol (salbutamol), bambuterol, bitolterol, carbuterol, an emetic such as cephaeline; an enzyme cofactor selected clenbuterol, clorprenaline, denopamine, dioxethedrine, from acetiamine, benfotiamine, bisbentiamine, cetotiamine, dopexamine, ephedrine, epinephrine, ethylnorepinephrine, dexpanthenol, fursultiamine, octotiamine, pantothenic acid, fenoterol, formoterol, hexoprenaline, ibopamine, isoetharine, prosultiamine, sapropterin, thiamine, thiamine diphosphate isoproterenol, mabuterol, metaproterenol, methoxyphe or thiamine disulfide; an agent that acts as an expectorant namine, oxyfedrine, pirbuterol, prenalterol, procaterol, pro selected from ambroXol or bromhexine; a gastroprokinetic tokylol, reproterol, rimiterol, ritodrine, salmeterol, Soterenol, agent selected from piboserod, alvimopan, cinitapride, terbutaline, tretoquinol, tulobuterol or Xamoterol; a drug that cisapride, loxiglumide, mosapride, prucalopride, renZapride acts as an O-adrenergic blocker selected from amoSulalol, or tegaserod; a hemostatic agent selected from adrenalone, arotinolol, doxazosin, ergoloid mesylates, fenspiride, ida cephalins, aminocaproic acid, carbazochrome Sodium Sul Zoxan, indoramin, labetalol, monatepil, praZosin, tamsulosin, fonate, ethamsylate, tranexamic acid, tolonium chloride or teraZosin, tolaZoline, trimaZosin or yohimbine; a drug that Vapreotide; a hepatoprotectant selected from S-adenosylme acts as a B-adrenergic blocker selected from acebutolol, amo thionine, citiolone, oraZamide, timonacic (thioproline), Sulalol, alprenolol, arotinolol, atenolol, befunolol, betaxolol, methionine, protoporphyrin ix or tiopronin; an immuno bevantolol, bisoprolol, bopindolol, bucindolol, bucumolol, modulator selected from bropirimine, thalidomide, uben bufetolol, bufuralol, bunitrolol, bupranolol, butidrine, buto imex, bucillamine, imiquimod, leflunomide, mitoxantrone, filolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, pidotimod, procodazole, romurtide or thymopentin; an cloranolol, dilevalol, esmolol, indenolol, labetalol, landiolol, immunosuppressant selected from azathioprine, gusperimus levobunolol, mepindolol, metipranolol, metoprolol. or mizoribine; a mucolytic agent selected from carbocysteine, moprolol, nadolol, nadoxolol, nebivolol, nifenalol, erdosteine, letosteine, mecysteine or stepronin; a muscle nipradillol, Oxprenolol, penbutolol, pindolol, practolol, prone relaxant selected from afloqualone, baclofen, carisoprodol. thalol, propranolol, Sotalol, Sulfinalol, talinolol, tertatolol. chlorphenesin carbamate, chlorZoxaZone, mephenoxalone, tilisolol, timolol, toliprolol orxibenolol; a dopamine receptor methocarbamol, phenprobamate, tizanidine, hexacarbacho agonist selected from bromocriptine, cabergoline, carmox line bromide, metaxalone ordantrolene; a mydriatic selected irole, dopexamine, fenoldopam, ibopamine, pergolide, from phenylephrine hydrochloride or yohimbine; a narcotic pramipexole, quinagolide, ropinirole, roXindole or talipex antagonist Such as amiphenazole; a neuroprotective agent ole; a dopamine receptor antagonist selected from amisul selected from aptiganel, licostinel, repinotan, riluzole, citi pride, amisulpride, clebopride, domperidone, metoclopra coline or memantine; a drug used as a nootropic/cognitive mide or mosapramine; an O-glucosidase inhibitor selected enhancer selected from amphetamine, atomoxetine, beme from acarbose or Voglibose; a matrix metalloproteinase gride, bifemelane, dextroamphetamine, etifelmin, inhibitor Such as batimastat; a monoamine oxidase inhibitor etryptamine, fencamfamine, fenethylline, fenozolone, ipida selected from iproclozide, iproniazid, isocarboxazid, lazabe crine, leteprinim, mefexamide, methylphenidate, modafinil, mide, moclobemide, mofegiline, octamoxin, phenelZine, nebracetam, nefiracetam, oxiracetam, pemoline, pipradrol, phenoxypropazine, pivalylbenzhydrazine or tranylcyprom piracetam, posatirelin, pramiracetam, Sulbutiamine, tacrine ine; a neutral endopeptidase inhibitor Such as ecadotril; a or Velnacrine; a drug which acts as a respiratory stimulant potassium channel blocker Such as fampiridine; a prolactin Such as almitrine; a drug which is used as a sedative/hypnotic inhibitor selected from metergoline or terguride; a protease US 2011/0263526 A1 Oct. 27, 2011

inhibitor selected from camostat, gabexate, nafamo.stat or 0214. In a thirty-second embodiment, the invention sepimostat; 5C-Reductase inhibitor Such as dutasteride; a encompasses a compound of formula (I), wherein: D, the reverse transcriptase inhibitor Such as stavudine; a serotonin drug containing a hydroxyl group capable of forming a cova receptor agonist Such as eltoprazine; a serotonin receptor lent bio-cleavable linkage with a linker, referred to in the antagonist Such as alosetron; and a thromboxane A-receptor twenty-seventh, twenty-eighth, twenty-ninth, thirtieth and antagonist Such as daltroban. thirty-first embodiments, is selected from an antiinflamma 0203. In a twenty-seventh embodiment, the invention tory and analgesic drug, a cardiovascular drug, a glucocorti encompasses a compound of formula (I), wherein: D is a drug coid, an antiallergic agent, anticancer agent, an antidepres containing a hydroxyl group capable of forming a bio-cleav sant, an anticonvulsant agent, an antibacterial agent, an able covalent linkage with a linker; antifungal agent, an antiviral agent, an antimalarial agent, an X' is oxygen; antidiabetic agent, an antiulcer agent, an antioxidant or a each of X, Y, Z': Z, A. R' and R is as defined in the first Vitamin. The thirty-second embodiment also encompasses embodiment hereinabove; within its scope a drug containing a hydroxyl group is with the provisos that: selected from the drugs that belong to several other therapeu 0204 a) when A is S, then a and b is 3; or tic areas (including those drugs that are classified on the basis 0205 b) when A is D-isosorbide skeleton or 1,4-anhy of their mechanism of action). In this embodiment, other droerythritol skeleton, then a and b is 0; variables X, X,Y,Z and Z: A, RandR in the compounds in all its stereoisomeric forms and pharmaceutically accept of formula (I) are as defined above; with the provisos that: able salts thereof. 0215 a) when A is S, thena and b is 3; or 0206. In a twenty eighth embodiment, the invention 0216 b) when A is D-isosorbide skeleton or 1,4-anhy encompasses a compound of formula (I), wherein: D and X' droerythritol skeleton, then a and b is 0; and are as defined in the twenty seventh embodiment herein in all its stereoisomeric forms and pharmaceutically accept above; each X, Y, Z, Z, A, R' and R is as defined in the able salts thereof. second embodiment hereinabove; 0217. In thirty-third embodiment, the invention encom with the provisos that: passes a compound of formula (I), wherein D, the drug con 0207 a) when A is S, then a and b is 3; or taining a hydroxyl group capable of forming a covalent bio 0208 b) when A is D-isosorbide skeleton or 1,4-anhy cleavable linkage with a linker, is a glucocorticoid: droerythritol skeleton, then a and b is 0; X' is a bond; in all its stereoisomeric forms and pharmaceutically accept X oxygen; able salts thereof. 0209. In a twenty ninth embodiment, the invention encom Y is spacer group as defined in the first embodiment herein passes a compound of formula (I), wherein: D and X’ are as above, defined in the twenty seventh embodiment hereinabove: Z, ZA, RandR are as defined in the second embodiment each of X, Y, Z and Z is as defined in the second embodi hereinabove; and ment hereinabove; with the provisos that: A is selected from 1.2-phenylene, 1.3-phenylene, 1,4-phe 0218 a) when A is S, thena and b is 3; or nylene, 2.3-pyridine, 3.4-pyridine, 2.4-pyridine, 2.5-pyridine 0219 b) when A is D-isosorbide skeleton or 1,4-anhy or 2.6-pyridine; droerythritol skeleton, then a and b is 0; R" is hydrogen and R is alkyl, cycloalkyl, aryl or aralkyl; or in all its stereoisomeric forms and pharmaceutically accept R’ is hydrogen and R' is alkyl, cycloalkyl, aryl or aralkyl; able salts thereof. in all its stereoisomeric forms and pharmaceutically accept 0220. In a thirty-fourth embodiment, the invention encom able salts thereof. passes a compound of formula (I), wherein each of D.X' and 0210. In a thirtieth embodiment, the invention encom X is as defined in the thirty-third embodiment hereinabove; passes a compound of formula (I), wherein: each of D.X', X, Y is a spacer group selected from: Y, Z and Z is as defined in the twenty eighth embodiment hereinabove, A is selected from a bond, CH=CH or CRR'; where Rand (Y) R" are independently selected from hydrogen or C, alkyl; O O, 0211) R' is hydrogen and R is alkyl, cycloalkyl, aryl or aralkyl; or R is hydrogen and R' is alkyl, cycloalkyl, aryl or luN aralkyl; R4 in all its stereoisomeric forms and pharmaceutically accept (Y) able salts thereof. O R5 0212. In a thirty-first embodiment, the invention encom passes a compound of formula (I), wherein: each of D, X', X. Y, Z and Z is as defined in the twenty eighth embodiment l O hereinabove, O, A is selected from S, SO, SO or S S: provided that when A (Y) is S, thena and b is 3: O 0213 R' is hydrogen and R is alkyl, cycloalkyl, aryl or H aralkyl; or R is hydrogen and R' is alkyl, cycloalkyl, aryl or aralkyl; in all its stereoisomeric forms and pharmaceutically accept R6 O able salts thereof. US 2011/0263526 A1 Oct. 27, 2011 22

oxaceprol, Oxametacine, oxycodone, oxymorphone, -continued oxyphenbutaZone, pentazocine, perisoxal, piroxicam, (Yi) phenazocine, phenoperidine, phenylramidol, phenylsalicy O O; late, rimexolone, salacetamide, Salicin, Salicylamide, Sal salate, Sulfasalazine, tenoxicam, tiXocortol, tramadol, Vimi Nuru nol or Ximoprofen, 0226. A representative example of the antiinflammatory Z", Z, A. R' and Rare as defined in the second embodiment and analgesic drug (consisting of glucocorticoids, NSAIDs hereinabove; and and opioids) is selected from acetaminophen, balasalazide, with the provisos that: budesonide, codeine, deflazacort, desomorphine, diflunisal, 0221) a) when A is S, then a and b is 3; or dihydrocodeine, dihydromorphine, eugenol, glucametacin, 0222 b) when A is D-isosorbide skeleton or 1,4-anhy halobetasol propionate, halometasone, hydrocortisone, droerythritol skeleton, then a and b is 0; hydromorphone, levorphanol, meloxicam, mesalamine, in all its stereoisomeric forms and pharmaceutically accept mometasone furoate, morphine, norlevorphanol, normor able salts thereof. phine, olsalzine, oxycodone, Oxymorphone, piroXicam, Sul 0223) In a thirty-fifth embodiment, the invention encom passes a compound of formula (I), wherein: the glucocorti fasalazine or tramadol. coid referred to in the thirty-third and thirty-fourth embodi 0227 Still further in the thirty-sixth embodiment, the car ments hereinabove is selected from 21-acetoxypregnenolone, diovascular agent referred to in the thirty-second embodiment alclometasone, algestone, amcinonide, beclomethasone, is generically selected from an antihypertensive agent Such as betamethasone, budesonide, chloroprednisone, ciclesonide, an angiotesnsin converting enzyme (ACE) inhibitor, a beta clobetasol, clobetaSone, clocortolone, cloprednol, corticos blocker, a Sartan (i.e., angiotensin II blockers), an antithrom terone, cortisone, deflazacort, desonide, desoximetaSone, botic and vasoactive agent, an anti-hyperlipidemic agent (in dexamethasone, diflorasone, diflucortolone, difluprednate, cluding HMG-CoA-reductase inhibitors (i.e., statins)), a enoXolone, fluazacort, flucloronide, fludrocortisone, flu fibrate, an antianginal agent, an antiarrhythmic agent, an anti methasone, flunisolide, fluocinolone acetonide, fluocinonide, hypotensive agent, a calcium channel blocker, a calcium fluocortin butyl, fluocortolone, fluorometholone, fluperolone regulator, a cardiotonic agent, a cardioprotective agent, a acetate, fluprednidene acetate, fluprednisolone, flurandreno diuretic, a vasodilator or a vasoprotectant; and is specifically lide, fluticasone, formocortal, halcinonide, halobetasol pro selected from acadesine, acebutolol, ajmaline, alprenolol, pionate, halometaSone, halopredone acetate, hydrocor ambuside, amoSulalol, angiotensin, arotinolol, atenolol, ator tamate, hydrocortisone, loteprednoletabonate, maZipredone, vastatin, bamethan, benzarone, benziodarone, beraprost, medrysone, meprednisone, methylprednisolone, mometa betaxolol, bevantolol, bisoprolol, bosentan, bradykinin, Sone furoate, paramethasone, prednicarbate, prednisolone, brovincamine, bucindolol, bucumolol, bufeniode, buflom prednisolone 21-diethylaminoacetate, prednisone, prednival, edil, bufuralol, bunitrolol, bupranolol, butofilolol, cadrala prednylidene, rimexolone, triamcinolone or triamcinolone Zine, calcifediol, calcitriol, canrenone (hydroxyl of its acetonide. ketoxime), carazolol. 1-carnitine (levocarnitine), carteolol. 0224. A representative example of the glucocorticoid is carvedilol, celiprolol, cerivastatin, cetamolol, chlorthalidone, selected from betamethasone, budesonide, dexamethasone, chromocarb, cicletanine, clobenfurol, clobenoside, convalla hydrocortisone, fludrocortisone, fluticasone, prednisolone or toxin, cyclandelate, denopamine, deslanoside, digitalin, triamcinolone. dihydrotachysterol, dilevalol, dimetofrine, diosmin, dobesi 0225. In a thirty-sixth embodiment, the antiinflammatory late calcium, dobutamine, dopamine, dopexamine, efloxate, and analgesic drug referred to in the thirty-second embodi eledoisin, enoXimone, epanolol, erythrophleine, escin, ment is generically selected from an opioid, a steroid (i.e., etafenone, ethacrynic acid, etillefrin, ezetimibe, fenofibrate, glucocorticoids) or a non-steroidal anti-inflammatory drug fenoldopam, fluvastatin, furazabol, gepefrine, gitoxin, guan (NSAIDs) and is specifically selected from acetaminophen, oXabenZ, heptaminol, ibudilast, ifenprodil, iloprost, inde acetaminosalol, 21-acetoxypregnenolone, alclometaSone, nolol, ipriflavone, isosorbide, isoxSuprine, kallidin, khellin, alfa-aluminum bis(acetylsalicylate), 3-amino-4-hydroxybu labetalol, lanatosides, leucocyanidin, levcromakalim, tyric acid, balsalazide, benzylmorphine, bisabolol, bucetin, limaprost, losartan, lovastatin, meglutol, mannitol, mepin budesonide, bufeXamac, buprenorphine, butorphanol, capsai dolol, metaraminol, methoxamine, methyldopa, metipra cine, chlorobutanol, ciramadol, codeine, deflazacort, diflo nolol, metoprolol, mevastatin, midodrine, moprolol, nadolol. rasone, desomorphine, desonide, desoximetasone, dezocine, naftopidil, nebivolol, neriifolin, nicomol, nicotinyl alcohol, diflorasone, diflucortolone, diflunisal, difluprednate, dihy nifenalol, nipradillol, norepinephrine, nylidrin, oleandrin, drocodeine, dihydromorphine, dihydroxyaluminum acetyl olmesartan, oXprenolol, oxyfedrine, penbutolol, pentrinitrol, salicylate, dimepheptanol, ditazol, enoXolone, eptazocine, perhexyline, phenactropinium chloride, phentolamine, ethylmorphine, etofenamate, eugenol, fendosal, fepradinol, pholedrine, pildralazine, pindolol, pirifibrate, pitavastatin, floctafenine, fluazacort, fluocinonide, fluocortin butyl, flu pravastatin Sodium, prenalterol, probucol, pronethalol, pro prednidene acetate, gentisic acid, glafenine, glucametacin, pranolol, proscillaridin, prostaglandin e, protheobromine, halcinonide, halobetasol propionate, halometasone, halopre protoveratrines, ouabain, quercetin, ranolazine, rescimetol, done acetate, hydrocortisone, hydromorphone, hydroxy resibufogenin, rutin Sampatrilat, Scillaren, Scillarenin, simv pethidine, ibuproxam, isoladol, isoxicam, ketobemidone, astatin, Sotalol, spironolactone, Sulfinalol, Suloctidil, Syneph p-lactophenetide, levorphanol, lornoxicam, loteprednol eta rine, talinolol, tertatolol, thyropropic acid, ticrynafen, bonate, maZipredone, meloxicam, meptazinol, mesalamine, timolol, tinofedrine, toliprolol, tricromyl, trimaZosin, troX metazocine, metopon, mometasone furoate, morphine, nal erutin, ubiquinones, Vincamine, Vicquidil, Xamoterol, Xanthi buphine, norlevorphanol, normorphine, olsalazine, nol niacinate or Xipamide. US 2011/0263526 A1 Oct. 27, 2011

0228. A representative example of the cardiovascular pentrinitrol, perhexyline, prostaglandin E, Suloctidil, agent is a beta-blocker that is selected from atenolol, bupra tinofedrine, tricromyl, Vincamine, Viduidilor Xanthinol niaci nolol, carvedilol, labetalol, metipranolol, metoprolol, nad nate. olol, pindolol, propranolol or timolol. 0242 Yet another representative example of the cardio 0229. Another representative example of the cardiovascu vascular agent is a vasoprotectant that is selected from ben lar agent is a Sartan selected from losartan or olmesartan. Zarone, chromocarb, clobenoside, dioSmin, dobesilate cal 0230. Another representative example of the cardiovascu cium, escin, leucocyanidin, quercetin, rutin or troXerutin. lar agent is an antithrombotic and vasoactive agent that is selected from beraprost, climprost, dalteparin, dipyridamole, 0243 Still further in the thirty-sixth embodiment, the anti enoxaparin, ifenprodil, iloprost, heparin, lamifiban, nadro allergic agent referred to in the thirty-second embodiment is parin, reviparin Sodium salt, Suloctidil, taprostene, tinzaparin, generically selected from a steroidal bronchodilator, a mast Xanthinol niacinate or Ximelagatran. cell stabilizer or an antihistamine and is specifically selected 0231. Yet another representative example of the cardio from amlexanox, bambuterol, beclomethasone, cetoxime, vascular agent is an anticoagulant that is selected from aceno ciclesonide, ebastine, feXofenadine, flunisolide, fluticaSone coumarol, anisindione, bromindione, clorindione, cou and its approved esters, n-hydroxyethylpromethazine chlo metarol, dicumarol, diphenadione, ethyl biscoumacetate, ride, hydroxy Zine, ibudilast, methyl prednisolone, mon ethylidene dicoumarol, fluindione, heparin, phenindione, telukast Sodium, pentigetide, repirinast, roXatidine, Salbuta phenprocoumon, tioclomarol or warfarin. mol, Salmeterol, Suplatast, terfenadine or tranilast. 0232 Yet another representative example of the cardio 0244. A representative example of the antiallergic agent is vascular agent is an anti-hyperlipidemic agent (i.e., statins, an antihistamine that is selected from cetoxime, ciclesonide, fibrates, etc.) that is selected from atorvastatin, cerivastatin, ebastine, n-hydroxyethylpromethazine chloride, hydrox eZetimibe, fenofibrate, fluvastatin, lovastatin, mevastatin, yZine, fexofenadine, roXatidine or terfenadine. pirifibrate, pitavastatin, pravastatin Sodium or simvastatin: 0245 Still further in the thirty-sixth embodiment, the anti 0233. Yet another representative example of the cardio cancer agent referred to in the thirty-second embodiment is vascular agent is an antianginal agent that is selected from selected from aclacinomycins, ancitabine, anthramycin, bevantolol, bucumolol, bufuralol, limaprost, nifemalol, nipradillol, oxyfedrine, pronethalol, ranolazine, Sotalol or arZoxifene, azacitidine, bicalutamide, bleomycins, bropir toliprolol. imine, broXuridine, buserelin, calusterone, capecitabine, 0234. Yet another representative example of the cardio carubicin, CC-1065 (NSC 298223), chlorozotocin, chromo vascular agent is an antiarrhythmic agent that is selected from mycins, cladribine, cytarabine, daunorubicin, decitabine, adenosine, amiodarone, bufetolol, butidrine, cloranolol. defosfamide, diethylstilbestrol, docetaxel, doxifluridine, dofetilide, esmolol, hydroquinidine, landiolol, lorajmine, doxorubicin, droloxifene, dromoStanolone, ecteinascidins, nadoxolol, pirmenol, practolol, prajmaline, propafenone, enocitabine, epirubicin, epitioStanol, estramustine, etanida Zole, etoposide, fenretinide, flavopiridol, formestane, fos pyrinoline, quinidine, tilisolol or Xibenolol. festrol, fulvestrant, gemcitabine, hydroxyurea, idarubicin, 0235 Yet another representative example of the cardio irinotecan, leuprolide, marimastat, melengestrol, menogaril. vascular agent is an antihypertensive agent that is selected 6-mercaptopurine, miltefosine, minodronate (minodronic from angiotensin, dimetofrine, dopamine, etillefrin, gepe acid), mitobronitol, mitolactol, mopidamol, nitracrine, frine, heptaminol, metaraminol, methoxamine, midodrine, nogalamycin, nordihydroguaiaretic acid (masoprocol), olivo norepinephrine, pholedrine or synephrine. mycins, paclitaxel and other known paclitaxel analogs, pen 0236. Yet another representative example of the cardio to statin, peplomycin, perfosfamide, pirarubicin, podophyllo vascular agent is a calcium channel blocker Such as etafenone. toxin, prinomastat, puromycin, ranimustine, resveratrol, 0237 Yet another representative example of the cardio roquinimex, rubitecan, Seocalcitol, Streptonigrin, Streptozo vascular agent is a calcium regulator that is selected from cin, temoporfin, teniposide, tenuaZonic acid, tiazofurin, topo calcifediol, calcitriol, dihydrotachysterol or ipriflavone. tecan, troxacitabine, valrubicin, vinblastine, Vincristine, Vin 0238 Yet another representative example of the cardio desine, Vinorelbine, Zorubicin or ZoSuquidar. vascular agent is a cardiotonic agent that is selected from 0246 A representative example of the anticancer agent is convallatoxin, denopamine, deslanoside, digitalin, dob selected from bicalutamide, capecitabine, CC-1065 (NSC utamine, dopamine, dopexamine, enoXimone, eryth 298223), cytarabine, daunorubicin, docetaxel, doxorubicin, rophleine, gitoxin, lanatosides, neriifolin, oleandrin, Ouabain, estramustine, etoposide, flavopiridol, gemcitabine, idarubi prenalterol, proscillaridin, resibufogenin, Scillaren, Scillare cin, irinotecan, leuprolide, paclitaxel and other active pacli nin, ubiquinones or Xamoterol. taxel analogs such as docetaxel, podophyllotoxin, resveratrol, 0239. Yet another representative example of the cardio topotecan, vinblastine or Vincristine. vascular agent is a cardioprotective agent is acadesine. 0247 Still further in the thirty-sixth embodiment, the anti 0240 Yet another representative example of the cardio depressant referred to in the thirty-second embodiment is vascular agent a diuretic that is selected from ambuside, can generically selected from an antimanic and antipsychotic renone, chlorthalidone, ethacrynic acid, isosorbide, mannitol, agent and is specifically selected from acetophenazine, S-ad protheobromine, spironolactone, ticrynafen or Xipamide. enosylmethionine, befloxatone, bromperidol, bupropion, 0241. Yet another representative example of the cardio butaperazine, carphenazine, clopenthixol (cis-isomer), vascular agent is a vasodilator that is selected from bamethan, clospirazine, dixyrazine, fenpentadiol, fluianisone, flupen benZiodarone, beraprost, bosentan, bradykinin, brovincam tixol (cis-form), fluphenazine, fluspirilene, haloperidol, 5-hy ine, bufeniode, buflomedil, clobenfurol, cyclandelate, eflox droxytryptophan (oxitriptan), hypericin, melperone, moper ate, eledoisin, etafenone, ibudilast, ifenprodil, iloprost, isox one, mosapramine, opipramol, penfluridol, pericyazine, Suprine, kallidin, khellin, nicotinyl alcohol, nylidrin, perimethazine, perphenazine, pipamperone, piperacetazine, US 2011/0263526 A1 Oct. 27, 2011 24 pipotiazine, pyriSuccideanol, quetiapine, roXindole, spiper posaconazole, ravuconazole, rubijervine, salicylanilide, sic one, Sultopride, timiperone, toloxatone, tramadol, trifluperi canin, 2,4,6-tribromo-m-cresol, tubercidin, viridian or Vori dol or Venlafaxine. conazole. 0248. A representative example of the antidepressant is 0254 Still further in the thirty-sixth embodiment, the anti selected from bupropion, tramadol or Venlafaxine. viral agent referred to in the thirty-second embodiment is 0249. A representative example of the antidepressant is an selected from abacavir, acyclovir, adefovir, amprenavir, ata antimaniac and antipsychotic agent that is selected from halo Zanavir, cidofovir, didanosine, dideoxyadenosine, edoXu peridol, quetiapine or trifluperidol. dine, emitricitabine, entecavir, floXuridine, ganciclovir, idoxuridine, indinavir, kethoxal, lamivudine, lopinavir, 0250 Still further in the thirty-sixth embodiment, the anti 5-(methylamino)-2-deoxyuridine (madu), nelfinavir, nevi convulsant referred to in the thirty-second embodiment is rapine, penciclovir, podophyllotoxin, residuimod, ribavirin, selected from 4-amino-3-hydroxybutyric acid, atrolacta ritonavir, saquinavir, Sorivudine, stavudine, tenofovir, mide, buramate organaxolone. tipranavir, trifluridine, tromantadine, Valganciclovir, Vidara 0251 Still further in the thirty-sixth embodiment, the anti bine, Zalcitabine, Zanamivir or zidovudine. bacterial agent referred to in the thirty-second embodiment is 0255. A representative example of the antiviral agent is selected from amikacin, p-aminosalicylic acid, p-aminosali selected from abacavir, acyclovir, adefovir, amprenavir, cido cylic acid hydrazide, amoxicillin, apalcillin, apicycline, fovir, didanosine, emitricitabine, ganciclovir, indinavir, lami arbekacin, aspoxicillin, azidamfenicol, azithromycin, bam Vudine, lopinavir, nelfinavir, nevirapine, penciclovir, bermycins, benzoylpas, biapenem, 5-bromosalicylhydrox ritonavir, saquinavir, stavudine, tenofovir, Valganciclovir, amic acid, butirosin, cefadroxil, cefamandole, cefatrizine, cefbuperaZone, cefdinir, cefiminox, cefonicid, cefoperaZone, Vidarabine, Zalcitabine, Zanamivir or zidovudine. cefoselis, ce?piramide, cefprozil, chloramphenicol, 0256 Still further in the thirty-sixth embodiment, the anti chloroxylenol, chlorquinadol, chlortetracycline, clofoctol, malarial agent referred to in the thirty-second embodiment is clomocycline, cloxacillin, cloxyquin, clarithromycin, clinda selected from amodiaquine, arteflene, artemisinin alcohol, mycin, colistin, dalfopristin, demeclocycline, deoxydihy bebeerines, cinchonidine, cinchonine, dihydroartemisinin, drostreptomycin, diathymosulfone, dibekacin, dihydrostrep fosmidomycin, gentiopicrin, halofantrine, hydroxychloro tomycin, dirithromycin, doxycycline, enviomycin, quine, lumefantrine, mefloquine, pyronaridine, quinine or ertapenem, erythromycin and its ester derivatives, ethambu yingzhaosu A. tol, flomoxef, forimicins, fropenem, fusidic acid, gentamy (0257 Still further in the thirty-sixth embodiment, the cin, glyconiazide, glucosulfone sodium, na-beta-d-glucosyl antidiabetic agent referred to in the thirty-second embodi Sulfanilamide, gramicidin(s), guamecycline, imipenem, ment is selected from acarbose, acetohexamide, miglitol, tro isepamicin, josamycin, kanamycin(s), leucomycins, linco glitaZone or Voglibose. mycin, lymecycline, meclocycline, merbromin, meropenem, 0258 Still further in the thirty-sixth embodiment, the anti methacycline, micronomicin, midecamycins, mikamycin, ulcer agent (including proton pump inhibitors) referred to in minocycline, miokamycin, moxalactam, nadifloxacin, neo the thirty-second embodiment is selected from arbaprostil, mycin, netilmicin, nifurpirinol, nifurtoinol, nitroxoline, enprostil, misoprostol, ornoprostil, gama-ory Zanol A, novobiocin, oleandomycin, oxytetracycline, panipenem, plaunotol, rebamipide, rioprostil, rosaprostol, Spizofurone paromomycin, phenyl aminosalicylate, pipacycline, poly (i.e., hydroxyl of its oxime derivative), telenzepine, teprenone myxin, primycin, pristinamycin, quinupristin, ramoplanin, (i.e., hydroxyl of its oxime derivative) or trimoprostil. ribostamycin, rifabutin, rifalazil, rifamide, refampicin, rifa (0259 Still further in the thirty-sixth embodiment, the anti mycin SV, rifampin, rifapentine, rifaximin, ristocetin, riti oxidant (including free radical scavengers) referred to in the penem, rokitamycin, rollitetracycline, rosaramicin, roXar thirty-second embodiment is selected from N-acetyl carnos Sone, roXithromycin, Salazosulfadimidine, Salinazid, ine, ascorbic acid, BN-82451, L-carnitine (levocarnitine), sancycline, sisomicin, spectinomycin, spiramycin, streptoly curcumin, dexanabinol, edaravone, (-) epigallocatechingal digin, Streptomycin, Streptonicozid, Sulfaloxic acid, 4-sulfa late, emoXipin, hydroxytyrosol, idebenone, luteolin, nicanar nilamidosalicylic acid, 2-p-sulfanillylanilinoethanol, teico tine, NZ-419, oxyresveratrol, probucol (including probucol planin, tellithromycin, thiamphenicol, thiostrepton, prodrugs such as AGI-1067 and AGI-1096), quercetin, reduc tobramycin, trospectomycin, tuberactinomycin, tyrocidine, tic acid, silybin, SCMC-Lys, tempol (4-hydroxy-tempo), Vancomycin, viomycin, Virginiamycin, Xanthocillin or alfa-tocopherol (vitamin E) or Zeatin. Xibornol. 0260 Still further in the thirty-sixth embodiment, the vita 0252. A representative example of the anti-bacterial agent min referred to in the thirty-second embodiment is selected is selected from amoxicillin, azithromycin, cefadroxil, cefpi from ascorbic acid, cobamamide (vitamin B coenzyme), ramide, chloramphenicol, clarithromycin, clindamycin, cloX cyanocobalamin (vitamin B), ergosterol (provitamine D), acillin, doxycycline, ethambutol, nadifloxacin, neomycin, fursultiamine (thiamine tetrahydrofurfuryl disulfide), oxytetracycline, panipenem, refampicin, rifaximin, spiramy hydroxocobalamin (vitamin B12), 1 O-hydroxycholecalcif cin, streptomycin or Vancomycin. erol, (1O-hydroxyvitamin D), inositol (vitamin B complex), 0253 Still further in the thirty-sixth embodiment, the anti menadiol (dihydroVitamin K), menaquinones or vitamin K fungal agent referred to in the thirty-second embodiment is (hydroxyl of its ketoxime), methylcobalamin, octotiamine, selected from acrisorcin (9-aminoacrindine compound with pantothenic acid (vitamin Bs), phylloquinone (hydroxyl of its 4-hexylresorcinol (1:1)), amphotericin B, anidulafungin, bro ketoxime), prosultiamine (dithiopropylthiamine or DTPT or mosalicylchloranilide, buclosamide, candicidin, caspofun TPD), pyridoxine hydrochloride (vitamine B hydrochlo gin, chlorphenesin, ciclopiroX, dermostatin, griseofulvin, fil ride), pyridoxal 5-phosphate, riboflavin (vitamin B or vita ipin, fluconazole, fungichromin, mepartricin, micafungin, min G or lactoflavin), riboflavin monophosphate (vitamin B natamycin, nystatin, lucensomycin, pecilocin, perimycin, phosphate), vitamin A, Vitamin D. Vitamin D. Vitamin Ks, US 2011/0263526 A1 Oct. 27, 2011

thiamine (vitamin B), thiamine disulfide (vitamin B disul drug selected from tiratricol or thyroxine; an antimigraine fide) or C-tocopherol (vitamin E Supplement). agent selected from methysergide or flumedroXone acetate; 0261. As has been indicated hereinabove that the twenty an antimuscarinic/mydriatic agent selected from atropine, second embodiment also encompasses within its scope a benactyzine, benzilonium bromide, bevonium methylsulfate, compound of formula (I) wherein the drug containing a biperiden, butropium bromide, n-butylscopolammonium hydroxyl group is selected from the group of drugs belonging bromide, cimetropium bromide, cinnamedrine, clidinium to several other therapeutic areas (including those drugs that bromide, cyclodrine, cyclopentolate, dexetimide, difemerine, are classified on the basis of their mechanism of action). Thus, eucatropine, fentonium bromide, flavoxate, flutropium bro for the purpose of this invention, the twenty-sixth embodi mide, glycopyrrolate, hexocyclium methyl sulfate, homatro ment also encompasses a compound of formula (I); wherein pine, hyoscyamine, ipratropium bromide, mepenZolate bro the drug containing hydroxyl group is generically selected mide, methScopolamine bromide, oxybutynin, from drugs falling under several other therapeutic areas (in oxyphencyclimine, oxyphenonium bromide, oxitropium bro cluding those drugs that are classified on the basis of their mide, penthienate bromide, phenglutarimide, pipenZolate mechanism of action) and is specifically selected from: an bromide, piperilate, poldine methylsulfate, procyclidine, Sco abortifacient/interceptive selected from epostane, gemeprost, polamine, Scopolamine n-oxide, telenzepine, tiemonium mifepristone, prostaglandin E or Sulprostone; an anabolic iodide, tiotropium bromide, tolterodine, tridihexethyl iodide, agent selected from androisoxazole, androstenediol, bolan trihexyphenidyl hydrochloride, tropicamide or trospium diol, bolasterone, clostebol, ethylestrenol, formebolone, chloride; an antiosteoporotic agent selected from alendronic mestanolone, methandriol, methenolone, methyltrienolone, acid, etidronic acid, ibandronic acid, pamidronic acid, ralox nandrolone, norbolethone, Oxabolone, quinbolone or tren ifene, risedronic acid or Zoledronic acid; an antiprostatic bolone; an androgen selected from boldenone, cloXotest hypertrophy agent selected from gestonorone caproate, osterone, fluoxymesterone, mesterolone, methandros mepartricin, osaterone or Oxendolone; an antiprotozoal agent tenolone, 17-methyltestosterone, 17C.-methyltestosterone selected from acetarSone, Acranil R, anisomycin, hydrox 3-cyclopentylenol ether, norethandrolone, normethandrone, yStilbamidine, melarsoprol, mepartricin, N-methylglucam Oxandrolone, oxymesterone, oxymetholone, stanolone, ine, metronidazole, nifuroxime, oxophenarsine hydrochlo stanozolol, testosterone or tiomesterone; an anesthetic ride, puromycin or secnidazole; an antipruritic agent selected selected from biphenamine, chloral hydrate, ecgonine, Y-hy from camphor, dichlorisone, halometasone, 3-hydroxycam droxybutyrate (Y-hydroxybutyric acid), hydroxytetracaine, phor, menthol, phenol or polidocanol; an antipsoriatic agent ketamine, lidocaine, methohexital sodium, orthocaine, oxet selected from anthralin, 6-azauridine, calcipotriene, chrysar hazaine, pentobarbital, polidocanol, pregnan-3-ol-20-one, obin, maxacalcitol, pyrogallol or tacalcitol; an antiseborrheic propofol, propipocaine, Salicylalcohol, thialbarbital, thiamy agent selected from chloroxine, piroctone, resorcinol ortioX lal or thiobutabarbital; an anorexic agent selected from dieth olone; an antiseptic agent selected from acetomeroctol, ben ylpropion, norpseudoephedrine, diphemethoxidine, metam ZOxonium chloride, bibrocathol, broxyquinoline, cethexo fepramone or mazindol; an anthelmintic agent selected from nium bromide, 4-chloro-m-cresol, dichlorobenzyl alcohol, aspidin, aspidinol, becanthone, dichlorophen, 4-hexylresor ethylhydrocupreine, hexachlorophene, 8-hydroxyquinoline, cinol, ivermectin, niclosamide, oxantel, triclofenol pipera isopropyl alcohol, mandelic acid, meralein Sodium, mercu Zine, hycanthone, lucanthone, oxamniquine or trichlorfon; an rophen, 2-naphthyl salicylate, nitroakridin 3582, noxythiolin, anti-acne agent selected from algestone acetophenide or ciot oxymethurea, phenoxyethanol, polynoxylin, pyrocatechol, eronel; an anti-alopecia agent selected from cioteronel, ciot C-terpineol, thymol or triclosan, an antispasmodic agent eronel or finasteride; an antiamebic agent selected from selected from amprotropine phosphate, benactyzine, benzilo arsthinol, bialamicol, chlorbetamide, chlorphenoxamide, nium bromide, bevonium methylsulfate, butropium bromide, diloxanide, 8-hydroxy-7-iodo-5-quinolinesulfonic acid, n-butylscopolammonium bromide, cimetropium bromide, iodoquinol, thiocarbamizine, glycobiarsol, secnidazole or cinnamedrine, clidinium bromide, difemerine, fentonium tetracycline; an antiandrogen agent selected from bicaluta bromide, flopropione, glycopyrrolate, hexocyclium methyl mide, bifluranol, cioteronel, cyproterone, delmadinone Sulfate, hyoscyamine, levomepate, mepenZolate bromide, acetate, nilutamide, osaterone or Oxendolone; an antiarthritic? methScopolamine bromide, oxyphencyclimine, oxyphe antirheumatic agent selected from aurothioglucose, glu nonium bromide, penthienate bromide, phloroglucinol, cosamine, bucillamine or kebuZone; an antiasthmatic agent pipenZolate bromide, piperilate, poldine methylsulfate, pro selected from beclomethasone, budesonide, cromolyn, dex penZolate, rociverine, Sultroponium, tiemonium iodide, tridi amethasone, formoterol, flunisolide, ibudilast, ketotifen, hexethyl iodide, tropenzile, flavoxate, tricromyl or trospium montelukast, nedocromil, oxatomide, pranlukast, seratro chloride; an antitussive agent selected from chlophedianol, dast, Suplatast tosylate, tiaramide, traXanox, triamcinolone clobutinol, cyclexanone, dropropizine, drotebanol, eprazi acetonide, Zafirlukast or Zileuton; an antidiarrheal agent none, pholcodine, Zipeprol, amicibone, morclofone or selected from catechin, loperamide or mebiquine; an antidi normethadone; an antiulcerative agent selected from acetox uretic drug selected from desmopressin, lypressin, ornipres olone, aldioxa, carbenoXolone, emprostil, misoprostol, orno sin, oxycinchophen, terlipressin or vasopressin; an antiemetic prostil, plaunotol, rioprostil, rosaprostol, rotraxate, agent selected from diphenidol, nabilone, ondansetron, teprenone, trimoprostil, spizofurone or Y-ory Zanol; an anxi oxypendyl or tetrahydrocannabinols; an antiglaucoma agent olytic agent selected from azacyclonol, cloraZepic acid (enol selected from bimatoprost, latanoprost, levobunolol, tra form), enciprazine, ethyl loflazepate (enol-form), flesinoxan, voprost or unoprostone; an antigout/uricoSuric agent selected flutazolam, hydroxyphenamate, hydroxy Zine, lorazepam, from allopurinol, benzbromarone, colchicine, Sulfinpyrazone mecloralurea or oxazepam; an astringent selected from alkan or oxycinchophen; an antihyperparathyroid drug selected nin, baicalein, bismuth Subgallate or tannic acid; a cathartic from doxercalciferol, maxacalcitol or paricalcitol; an antihy drug/laxative selected from aloe-emodin, aloin, bisoxatin perthyroid drug such as thibenzazoline; an antihypothyroid acetate, cellulose ethylhydroxyethyl ether, colocynthin, dan US 2011/0263526 A1 Oct. 27, 2011 26 thron, emodin, frangulin, glucofrangulin, oxyphenisatin aprobarbital, apronalide, barbital, bralobarbital, butabarbital acetate, phenolphthalein, phenolphthalol, Sennosides or phe sodium, butalbital, butallylonal, butethal, butoctamide, car noltetrachlorophthalein; a choleretic agent selected from ali bubarb, chloral formamide, C-chloralose, cinolazepam, bendol, cholic acid, cyclobutyrol, cyclovalone, cynarin(e). cyclobarbital, cyclopentobarbital, doxefazepam, ectylurea, dehydrocholic acid, deoxycholic acid, O-ethylbenzyl alcohol, enallylpropymal, ethchlorvynol, febarbamate, 5-furfuryl-5- exiproben, febuprol, fencibutirol, fenipentol, hymecromone, isopropylbarbituric acid, glutethimide, haloxazolam, hept menbutone, osalmid, 4,4'-OXydi-2-butanol, 4-Salicyloylmor abarbital, hexethal Sodium, hexobarbital, hexapropymate, homofenazine, lormetazepam, methyprylon, narcobarbital, pholine, taurocholic acid, Vanitiolide, trepibutone or metoch nealbarbital, pentaerythritol chloral, pentobarbital, phenally alcone; a cholinergic agent selected from muscarine, edro mal, piperidione, propallylonal, propiomazine proxibarbal, phonium chloride or dexpantheno; a contraceptive or pyrithyldione reposal, secobarbital sodium, talbutal, progestogen drug selected from allylestrenol, anagestone, temazepam, tetrabarbital, 2.2.2-trichloroethanol, vinbarbital chlormadinone acetate, delmadinone acetate, demegestone Sodium or vinylbital; a Vulnerary drug selected from allan desogestrel, dienogest, dimethisterone, drospirenone, toin, chitin, dextranome or thioglycerol; an O-adrenergicago dydrogesterone, elcometrine, ethinyl estradiol, ethisterone, nist agent selected from adrafinil, diplivefrin, hydroxyam ethynodiol, etonogestrel, fluorogestone acetate, gestodene, phetamine, mivaZerol, norfenefrine, octopamine, gestonorone caproate, 17-hydroxy-16-methylene-A-proges pseudoephedrine, pholedrine, Synephrine or tyramine; a terone, 17O-hydroxyprogesterone, lynestrenol, medroge B-adrenergic agonist agent selected from albuterol (Salbuta stone, medroxyprogesterone, megestrol acetate, mestranol, mol), bitolterol, carbuterol, clenbuterol, clorprenaline, diox norethindrone, norethynodrel, norgesterone, norgestimate, ethedrine, etafedrine, ethylnorepinephrine, fenoterol, hexo norgestrel, norgestrienone, norvinisterone, pentagestrone, prenaline, isoetharine, isoproterenol, mabuterol, progesterone, promegestone or trengestone; a decongestant metaproterenol, pirbuterol, procaterol, protokylol, reproterol, drug selected from amidephrine, cafaminol, ephedrine, epi rimiterol, ritodrine, Soterenol, terbutaline, tretoquinol, nephrine, nordefrin, oxymetazoline, phenylephrine, phenyl tulobuterol or Xamoterol; an O-adrenergic blocker drug propanolamine or pseudoephedrine; an emetic agent selected selected from labetalol, naftopidil or trimaZosin; a dopamine from apocodeine or cephaeline; an enzyme cofactor selected receptor agonist drug selected from apomorphine, from dexpanthenol, fursultiamine, octotiamine, pantothenic quinagolide or ropinirole; a dopamine receptor antagonist acid, proSultiamine, pyridoxal 5-phosphate, pyridoxine drug Such as illoperidone; a gonad-stimulating agent selected hydrochloride, riboflavin, riboflavin monophosphate, from epimestrol or LH-RH; a 5-Lipoxygenase inhibiting sapropterin, thiamine orthiamine disulfide: an estrogen drug agent such as tenidap; a matrix metalloproteinase inhibiting selected from benzestrol, colpormon, dienestrol (trans-trans agent selected from batimastat or prinomastat; a monoamine form), equilenin, equilin, estradiol, estriol, estrone, ethinyl oxidase inhibiting agent Such as toloxatone; a NMDA recep estradiol, hexestrol, mestranol, methestrol, moxestrol, tor antagonist Such as licostinel; a prolactin inhibiting agent mytatrienediol, quinestradiol or quinestrol; an expectorant Such as bromocriptine; a reverse transcriptase inhibiting drug selected from ambroXol, guaiacol, iodinated glycerol or agent Such as Zalcitabine; a serotonin receptoragonist Such as guaifenesin; a gastroprokinetic drug Such as alvimopan; a ergotamine; a serotonin receptor antagonist selected from hemostatic agent selected from adrenalone, algin, ami dolasetron or ketanserin and a topoisomerase I inhibitor Such nochromes, carbazochrome Salicylate, carbazochrome as 9-aminocamptothecin. Sodium Sulfonate, cephalins, cotamine, ellagic acid, etham 0262. In a thirty-seventh embodiment, the invention Sylate, oxidized cellulose or vapreotide; a hepatoprotective encompasses a compound of formula (I), wherein: D is a drug drug selected from S-adenosylmethionine, catechin or sily containing a Sulfhydryl group capable of forming a bio-cleav marin; an immunomodulator selected from amiprilose, lisofylline, ubenimex, inosine pranobex, bropirimine, len able covalent linkage with a linker; tinan, mitoxantrone, romurtide or thymopentin; an immuno X' is sulphur; Suppressant selected from everolimus, gusperimus, mizorib ine, mycophenolic acid, rapamycin or tacrolimus; a Y is C—O; mucolytic selected from domiodol or sobrerol; a muscle 0263 each X: Z'; Z: A, RandR is as defined in the first relaxant drug selected from chlorZoxaZone, eperisone, idro embodiment hereinabove; cilamide, inaperisone, mephenesin, methocarbamol, tolp with the provisos that: erisone ordantrolene; a mydriatic drug such as yohimbine; a narcotic antagonist agent selected from cyclazocine, levallor 0264 a) when A is S, thena and b is 3; or phan, nalmefene, nalorphine, naloxone or naltrexone; a neu 0265 b) when A is D-isosorbide skeleton or 1,4-anhy roprotective agent selected from lubeluzole or citicoline; a droerythritol skeleton, then a and b is 0; and nootropics/cognition enhancer drug selected from beme in all its stereoisomeric forms and pharmaceutically accept gride, choline alfoscerate, curcumin, donepezil, ethamivan, able salts thereof. exifone, hexacyclonate Sodium, homocamfin, idebenone, 0266. In a thirty-eighth embodiment, the invention nizofenone, oxiracetam, pipradrol, propentofylline pyritinol, encompasses a compound of formula (I), wherein: each of D pyrovalerone, sabeluzole, Sulbutiamine or Velnacrine; a pros and X is as defined in the thirty-seventh embodiment here taglandin analog selected from beraprost, carboprost, clin inabove; prost, enprostil, gemeprost, latanoprost, limaprost, misopros Each of X;Y,Z'; Z: A R and R is as defined in the second tol, ornoprostil, prostacyclin, prostaglandin E, prostaglandin embodiment hereinabove; E. prostaglandin F, rioprostil, rosaprostol, trimoprostill or with the provisos that: unoprostone; a respiratory stimulating agent selected from 0267 a) when A is S, thena and b is 3; or dimefline, lobeline, mepixanoXorpimeclone; a sedative/hyp 0268 b) when A is D-isosorbide skeleton or 1,4-anhy notic drug selected from aldol, allobarbital, amobarbital, droerythritol skeleton, then a and b is 0; US 2011/0263526 A1 Oct. 27, 2011 27 in all its stereoisomeric forms and pharmaceutically accept the basis of their mechanism of action) and is specifically able salts thereof. selected from an anesthetic selected from buthalital sodium 0269. In a thirty-ninth embodiment, the invention encom hydroxydione sodium, thialbarbital (Intranarcon), thiamylal, passes a compound of formula (I), wherein: each of D and X' thiobutabarbital or thiopental sodium; an antiarthritic/anti is as defined in the thirty-seventh embodiment hereinabove: each of X;Y. Z'; Z is as defined in the second embodiment rheumatic agent selected from bucillamine or penicillamine; hereinabove; an antihyperthyroid drug selected from methimazole, propy A is selected from a bond, 1.2-phenylene, 1.3-phenylene, lthiouracil or thiobarbital; an antiseborrheic agent such as 1,4-phenylene, 2.3-pyridine, 3.4-pyridine, 2.4-pyridine, 2.5- pyrithione; an antiseptic drug selected from noxythiolin or pyridine, 2,6-pyridine, S, SO, SO, S. S. CH=CH or thiocresol; a hepatoprotective agent such as tiopronin; an CRR'; where R and R'' are independently selected from immunomodulator Such as bucillamine or a Vulnerary drug hydrogen or Ce alkyl; Such as thioglycerol. provided that when A is S, then a and b is 3: R" is hydrogen and R is alkyl: or R is hydrogen and R' is 0277. In a specific embodiment, the invention encom alkyl: passes a bio-cleavable linker represented herein by the com in all its stereoisomeric forms and pharmaceutically accept pounds of formula (IA) which is capable of forming bio able salts thereof. cleavable covalent linkage with a drug having a carboxylic 0270. In a fortieth embodiment, the invention encom acid, hydroxyl, amino or sulfhydryl group: passes a compound of formula (I), wherein: each of D.X', X, Y. Z' and Z is as defined in the thirty-eighth embodiment hereinabove, (IA) X2 A O O O A is selected from a bond, CH=CH or CRR'; where Rand Y R" are independently selected from hydrogen or C alkyl: 1Nzi1 in 2 YNO, R" is hydrogen and R is alkyl, cycloalkyl, aryl or aralkyl; or R2 R’ is hydrogen and R' is alkyl, cycloalkyl, aryl or aralkyl; O RI in all its stereoisomeric forms and pharmaceutically accept able salts thereof. X is a bond, oxygen or NR; 0271 In a forty-first embodiment, the invention encom R is a bond or hydrogen; passes a compound of formula (I), wherein: each of D.X', X. Y. Z' and Z is as defined in the thirty-eighth embodiment Y is C—O or a spacer group selected from: hereinabove, A is selected from S, SO, SO or S S: provided that when A is S, thena and b is 3 (Y) R" is hydrogen and R is alkyl, cycloalkyl, aryl or aralkyl; or O O, R’ is hydrogen and R' is alkyl, cycloalkyl, aryl or aralkyl: in all its stereoisomeric forms and pharmaceutically accept l N able salts thereof. 0272. In forty-second embodiment, the invention encom R4 passes a compound of formula (I), wherein D, the drug con (Y) taining a sulfhydryl group referred to in the thirty-seventh, O R5 thirty-eighth, thirty-ninth, fourtieth and forty-first embodi ments, is selected from cardiovascular agents or glucocorti l O coids. The forty-second embodiment also encompasses within its scope a drug containing a sulfhydryl selected from O, the drugs that belong to several other therapeutic areas (in (Y) cluding those drugs that are classified on the basis of their O mechanism of action). In this embodiment, other variables X', X, Y, Z, ZA, R' and R in the compounds of formula N (I) are as defined above; with the provisos that: l 0273 a) when A is S, then a and b is 3; or R O, 0274 b) when A is D-isosorbide skeleton or 1,4-anhy (Y) droerythritol skeleton, then a and b is 0; O in all its stereoisomeric forms and pharmaceutically accept able salts thereof. 0275 Inforty-third embodiment, the cardiovascular agent referred to in the forty-second embodiment is selected from NHR7 Ö, captopril or omapatrilat. Further, in this embodiment the glu (Y) cocorticoid referred to in the forty-second embodiment is O R8 O, selected from tixocortol. 0276 For the purpose of this invention, the forty-second embodiment also encompasses a compound of formula (I); O wherein the drug containing Sulfhydryl group is generically NHR selected from the group of drugs falling under several other therapeutic areas (including those drugs that are classified on US 2011/0263526 A1 Oct. 27, 2011 28

Z' is (CH), where a is an integer from 0 to 3: -continued Z is (CH), where b is an integer from 0 to 3: (Y) A is selected from: bond, S, SO, SO, S. S. CH=CH, O D-isosorbide skeleton, 1,4-anhydroerythritol skeleton, N cycloalkylene, CRR', Co-Cio-arylene, a 5- or 6-membered l heteroarylene or a 5- or 6-membered heterocyclylene 1. ) wherein said arylene, heteroarylene and heterocyclylene may O, be unsubstituted or substituted by one or more substituents (Y) independently selected from the group consisting of C. O O, alkyl, C. alkoxy, hydroxy, trifluoromethyl, cyano, amino and halogen; l d RandR'' are independently selected from: hydrogen or C. (Y) alkyl; or R and R' taken together with the carbon atom to O O, which they are attached form a cycloalkyl or a heterocyclic r1ng, N-sul (0288) R' is hydrogen and R is alkyl, cycloalkyl, aryl or (Y) aralkyl; or R is hydrogen and R' is alkyl, cycloalkyl, aryl or O COH O, aralkyl; with the provisos that: N-l N J 0289 a) when A is S, thena and b is 3; or H 0290 b) when A is D-isosorbide skeleton or 1,4-anhy (Y) droerythritol skeleton, then a and b is 0; NHR in all its stereoisomeric forms and pharmaceutically accept H able salts thereof. N 0291. In an embodiment of the specific embodiment, the Y invention encompasses a compound of formula (IA), O O, wherein: (Yi) X is oxygen; O RHN Y is C—O; l O \, O 0292 A is selected from a bond, 1.2-phenylene, 1,3-phe nylene, 1,4-phenylene, 2.3-pyridine, 3.4-pyridine, 2.4-pyri (Y) dine, 2.5-pyridine, 2,6-pyridine, S, SO, SOS S, CH=CH, O; D-isosorbide skeleton, 1,4-anhydroerythritol skeleton, cycloalkyl or CRR': O HOC ) where RandR'' are independently selected from hydrogen l NH or C alkyl; or R and R' taken together with the carbon atom to which they are attached constitute a cycloalkyl group or a 5- or 6-membered heterocyclic ring containing one to two hetero atoms selected from oxygen, Sulfur or nitrogen; R" is hydrogen and R is alkyl, cycloalkyl, aryl or aralkyl; or where in the spacer groups of formulae (Y) to (Y): R’ is hydrogen and R' is alkyl, cycloalkyl, aryl or aralkyl; (0278) R' is a bond, hydrogen, alkyl or a metalion; with the provisos that: (0279 R is hydrogen, methyl or phenyl: 0293 a) when A is S, thena and b is 3; or 0280 R is hydrogen or a side-chain group of naturally 0294 b) when A is D-isosorbide skeleton or 1,4-anhy occurring amino acids selected from: droerythritol skeleton, then a and b is 0; (0281 - CH, -CH(CH), —CHCH(CH), —CH in all its stereoisomeric forms and pharmaceutically accept (CH)CHCH, -CHCOH, -CHCH-COH, able salts thereof. - CH-OH, CH(CH)OH, —CH2SH, 0295. In a further embodiment of the specific embodi —CHCH-SCH3, —CHCHCHCH-NH, -CH, ment, the invention encompasses a compound of formula —CHCHs —CHCH-p-OH, -CH2CHCH-NHC (IA), wherein: (—NH)NH, -CHC(=O)NH, -CHCHC(=O) X is oxygen; NH, —CH-indol-3-yl or —CH-imidazole; 0282 X is oxygen, sulphur, SO, SO, or NR; Y is C—O; (0283 R’ is hydrogen or an amino protecting group Selected from: acetyl, benzoyl, alkyloxycarbonyl, ben 0296 A is selected from a bond, 1.2-phenylene, 1,3-phe Zyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or its nylene, 1,4-phenylene, 2.3-pyridine, 3.4-pyridine, 2.4-pyri dine, 2.5-pyridine, 2,6-pyridine, S, SO, SOS S, CH=CH, pharmaceutically acceptable ammonium salts; D-isosorbide skeleton, 1,4-anhydroerythritol skeleton, 0284 R is hydrogen or methyl; cycloalkyl or CRR': 0285 c is an integer from 0 to 2: where RandR'' are independently selected from hydrogen 0286 d is an integer from 1 to 5; or C alkyl; or R and R' taken together with the carbon 0287 e is an integer from 1 to 4: atom to which they are attached constitute a cycloalkyl group US 2011/0263526 A1 Oct. 27, 2011 29 or a 5- or 6-membered heterocyclic ring containing one to two in all its stereoisomeric forms and pharmaceutically accept hetero atoms selected from oxygen, Sulfur or nitrogen; able salts thereof. R" is hydrogen and R is alkyl: or R is hydrogen and R' is 0301 In yet another further embodiment of the specific alkyl: embodiment, the invention encompasses a compound of for with the provisos that: mula (IA), wherein 0297 a) when A is S, thena and b is 3; or X is oxygen; 0298 b) when A is D-isosorbide skeleton or 1,4-anhy droerythritol skeleton, then a and b is 0; in all its stereoisomeric forms and pharmaceutically accept 0302 A is selected from a bond, CH=CH or CRR': able salts thereof. where R and R'' are independently selected from hydrogen 0299. In yet another embodiment of the specific embodi or Ce alkyl; ment, the invention encompasses a compound of formula R" is hydrogen and R is alkyl: or R is hydrogen and R' is (IA), wherein alkyl: X is oxygen; in all its stereoisomeric forms and pharmaceutically accept able salts thereof. Y is C—O; 0303. It would be understood by a person of skill in the art 0300 A is selected from a bond, 1.2-phenylene, 1,3-phe that in the compounds of formula (IA) when Y is “CO’ or nylene, 1,4-phenylene, 2.3-pyridine, 3.4-pyridine, 2.4-pyri designate any other group that contain a “CO', then the “CO’ dine, 2.5-pyridine, 2,6-pyridine, S, SO, SOS S, CH=CH must have been derived from a carboxyl-containing drug D. or CRR'; where RandR'' are independently selected from 0304. In specific embodiments, the invention encom hydrogen or Ce alkyl, provided that when A is S, thena and passes a compound of formula (I) from the following com b is 3. pounds: R" is hydrogen and R is alkyl: or R is hydrogen and R' is (a) Compounds of formula (I) wherein D is a drug containing alkyl: a carboxylic acid group:

CH3 O O N-1 ns1 S N-1\o ls O 1. O1 NO2

MeO

CH3 N-OS-1 N-on-on-ON- ^a NO S O O O O O CH o1Y-1 ns 1 n-1 NO MeO O CH

O O CH 21 o1N-1 No ls O 1. O1 NO N N

\ y \ ^n-N-N-N-iss, O CH3

US 2011/0263526 A1 Oct. 27, 2011 32

-continued

'N-1- SN-1N1 r O N OS NO2 O CH3 MeO

CH3 O N-1N1 S N-1N1 O O O YNO,

O O CH MeO

(b) Compounds of formula (I) wherein D is a drug containing an amino group:

H 1n-N O s O CH NO O O O O1 MeOOC COOEt

O EtOC N1So1N1l S ns1\-1 O. O. O SNO Na-On-1H \-On-On-On O CH3 O O O CH

NH O O O O NH -Q r SNO, O O O O le O CH3 O O le O CH3re,

US 2011/0263526 A1 Oct. 27, 2011 34

0305. In a specific embodiment, the invention encom passes linker compounds of formula (IA) from the following -continued group of representative linkers:

O CH : O--- O CH IA-L10-R1 's-s-s-s-s-s-s CH l, - - - O l 1N1 S ns-1S-1 O O O YNO, ror O CH O O CH

IA-L2-R1 O O O ------l r-rro.O CH3 ror O IA-L3-R1 O CH 1 N------O O O1 O O O O O IA-L4-R1 Y YNO, N-11° O O O CH IA-L13-R1 O O CH3 O O O O SYS, : l O CH IA-L5-R1 O H3C CH3 IA-L14-R1 O N-X- O O O CH ls 1. 1 NO O O CH3 O O O O N-6 :

IA-L6-R1 (Mixture of diastereomers) O O CH3 IA-L15-R1 O O CH 1 NullsO 1n 1\ O ls O 1. O1 NO Oe, 3 : 1 - NOV2 O O O O O O IA-L7-R1 (Mixture of diastereomers) O IA-L16-R1 O O CH

O N-s-s-s-s O CH : l O 1-in-1a O lsO 1. O -NO2 IA-L17-R1 O CH3 & 2' CH3 : ------Al-N-all- NO US 2011/0263526 A1 Oct. 27, 2011 35

respectively. Consequently, compounds of formula I can exist -continued in enantiomeric or diastereomeric forms or in mixtures IA-L18-R1 thereof. The processes for preparation can utilize racemates, O CH3 enantiomers or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they * No 1N1\s 1N1\o O O1 can be separated by conventional methods for example, chro IA-L19-R1 matographic techniques or fractional crystallization. 0307 The present invention also relates to processes for O CH the preparation of the compounds of formula (I) or pharma ceutically acceptable salts thereof. The compound of formula * lNo ~~ 1N1- O ls O1 NO (I) may be prepared by any of the general Schemes 1-21 as outlined herein below. Unless otherwise specified, the groups O A, Z', Z2, R", R2, R, R*, R5, R, R7, R8, R, R10 X, X2, X, IA-L20-R1 a, b, c, d, e are as defined in respect of formula (I) and/or formula (IA) above. The starting materials and reagents employed in the processes for preparation of compounds of formula (I) may be commercially available or may be pre pared by processes known in the art. O O O 0308 The symbols as used herein with particular refer N n NO ence to the processes for the preparation of the compounds of O CH formula (I) as illustrated in the following schemes 1-21, areas described herein below: 0309 The drug containing carboxylic acid group is des * Point of attachment to a suitable drug residue. ignated as D (D-COOH) and its derivatives are desig 0306 The compound of formula (I) and the bio-cleavable nated as D and D respectively. linker of formula (IA) contain asymmetric or chiral centers, 0310. The drug containing an amino group (D-Y— and therefore exist in different stereoisomeric forms. In the X'H, wherein Y is a bond, C=O, SO, or O(CO); structures shown herein, where the stereochemistry of any X'=NR wherein R is a bond or H) is designated in particular chiral atom is not specified, then all stereoisomers general as D. Further, the drug containing a hydroxyl or are contemplated and included as the compounds of the sulfhydryl group (D-X'H, wherein X'—O or S) is des invention. The term "chiral' refers to molecules which have ignated herein as D. The derivatives of the drug D, are the property of non-Superimposability of the mirror image designated herein as D, and D, respectively. The cohort, while the term “achiral” refers to molecules which are Superimposable on their mirror image partner. It is intended derivatives of the drug D are designated herein as D. that all stereoisomeric forms of the compounds of the inven D2. Ds. D-4, Ds. D-6. D7, Des: D9. Delo, D ls D-12, tion, including but not limited to, diastereomers and enanti Dis. D-14. Dis. D 63 D17, D 8s D19, D-20. D-21, omers, as well as mixtures thereof Such as racemic mixtures, D22, D-2s, D24, D-2s and D-26 respectively. form part of the present invention. Thus, compound of for 0311. The starting material or the precursors to the mula (I) and the linker of formula (IA) according to the linker are denoted herein by the symbols L. L. L. present invention which can exist as enantiomers can be L2 Las L. L. L. L. Land L. respectively. present in enantiomerically pure form, both as levorotatory 0312 The linker is denoted herein by the symbol L and and as dextrorotatory antipodes, in the form of racemates and its derivative is denoted herein by the symbol L. in the form of mixtures of the two enantiomers in all ratios. In 0313. The aldehyde, RC(=O)R’ (wherein, R' and R' the case of cis/trans isomerism the compound of formula (I) areas defined above), the starting material for the prepa and the bio-cleavable linker of formula (IA) includes both cis ration of the C-chloroformate of formula (X) is denoted and transform as well as mixtures of these forms in all ratios, herein by the symbol S. preferably exists in cis form. The preparation of individual 0314. The precursor for the spacer groups are denoted Stereoisomers of the compounds of the present invention i.e. herein by the symbols S. S. S. S. S. S. S. S. S. S. the compound of formula (I) and the bio-cleavable linker of and S. respectively. formula (IA), can be carried out, if desired, by separation of a 0315. The derivative of the spacer group precursor S, is mixture by methods known in the art. For instance, the race denoted herein by the symbol S. mic forms can be resolved by physical methods, such as fractional crystallisation or separation by chiral column chro 0316 The linker group obtained by coupling the linker matography. The individual optical isomers can be synthe L with the spacer group precursor or its derivatives (S, sised in the optically pure form by the use of enzymes or S. S. S. S.S, and S) are denoted herein by the sym through asymmetric synthesis. If, for instance, a particular bols L. L. L. L. L. L., and L, respectively. enantiomer of the compound of formula (I) of the present 0317. The linker group obtained by coupling the spacer invention is desired, it may be prepared by derivatisation with group precursor S, and the linker derivative L is denoted a chiral auxiliary whereby the resulting diastereomeric mix herein by the symbol L. ture is separated and the auxiliary group cleaved to provide 0318. The intermediates obtained by coupling the drug, the pure desired enantiomer. In case, the compound of for D (as defined herein) with the a) linker precursors (as mula (I) contains a basic functional group Such as amino oran defined above), b) linker (as defined above), c) linker acidic functional group Such as carboxyl, diastereomeric salts derivatives d) spacer precursors (as defined above); and are formed with an appropriate optically active acid or base, e) linker groups obtained by coupling spacer precursors US 2011/0263526 A1 Oct. 27, 2011 36

or its derivatives and the linker L1 (as defined above) are containing a carboxylic acid functional group is provided denoted by the Symbols I. I. I. I. I.e. If I I, I., I, I. herein below. One such process for the preparation of the II, II, I, and I, respectively. compound of formula (I), wherein D is a drug containing a 0319. In one embodiment, the processes for the prepara carboxylic acid group, consists of the following reaction steps tion of the compounds of formula (I), wherein D is a drug as outlined in the following Scheme 1:

Scheme 1 Step 1 R! R2 O O R -- -- O ClCO ls OCCl3 C ul-kO C Sa X Step 1" HO A OH LG A OR LG = Br Br A OH NZ 1 nz21 He- NZ11 nz21 R = H N11 nz21 La Lal Lal' (LG = a halide or tosylate, mesylate, etc.; R = H or a hydroxyl protecting group)

Step 2

D-COOM" + LG- Z 11 An Z. -OR Da2 Lal (M = Na', K", Cs" or Ca")

HO A OH Z Z2 D-COOH -- NZ Y NZ2 Y -e- D o1 N1 YOH D La Ia

D-COC + On Z - n-OZ Dal La

O R O O R R2 R2 D ls O 1. ZN A. 1. Zr OH -- C us O -kC D ls o1 Z N1 Z2 no lsO -k C Ia X Ial

O O RI R2 D ls o1 Z N1 Z2 no ls O -kO -NO (I) US 2011/0263526 A1 Oct. 27, 2011 37

Step 1 carboxylic acid group (D) or its reactive acid chloride (D) 0320. This process step involves reacting an aldehyde rep is then directly coupled with the compound of formula (L.) in resented by formula (S) (wherein, RandR areas defined in the presence of a coupling agent, for example, N,N-dicyclo any of the embodiments of the present invention), with triph hexylcarbodiimide (DCC) and an organic base, for example, osgene (or phosgene or diphosgene or any other phosgene triethylamine to form a compound intermediate (I). The substitutes known to those skilled in the art) in the presence of reaction of the drug containing carboxylate metal salt (D) a suitable organic base for example, pyridine at -10° to 40°C. with linker intermediate L (as obtained in step 1" above) in according to the method described in M.J. Coghlam and B.A. the presence of an organic solvent, for example dimethylfor Caley, Tetrahedron Letters, 1989, 2033-2036, to obtain the mamide (DMF) to obtain a compound of formula (I). chloroformate of formula (X). Step 3 Step 1" 0323. The compound intermediate (I) as obtained in step 0321. In this step, the linker L is converted to L wherein 2 above is further reacted with the chloroformate (X) obtained one of the hydroxyl group is converted to a leaving group in step 1 above in the presence of an organic base, for (LG) such as a halide or tosylate or mesylate and the other example, pyridine and an organic solvent, for example, hydroxyl group is either left unprotected or is protected by a dichloromethane (DCM) to obtain the intermediate com Suitable hydroxyl protecting group and the processes used for pound (I). The resulting compound (I) is subjected to the said conversions are generally known to those skilled in nitration using silver nitrate in the presence of an organic the art of organic synthesis. Solvent, for example, acetonitrile to form the compound of formula (I), and if desired, the compound of formula (I) is Step 2 converted to its pharmaceutically acceptable salt. 0322. In this step, the drug containing carboxylic acid 0324. In scheme 1, the variables D, R, R.Z, Z and Aare group D (D-COOH) is treated with carbonyl chloride, for as defined in any of the embodiments of the present invention example oxalyl chloride, in the presence of an organic Sol with reference to the compounds of formula (I) wherein D vent, for example, dichloromethane and dimethylformamide constitutes a drug containing carboxylic acid group. in catalytic amount to form a reactive carbonyl derivative 0325 Alternatively, the compounds of formula (I), such as the acid chloride of formula D. Also, the carboxylic wherein D is a drug containing a carboxylic acid group, can be acid group of the drug D is converted to its carboxylate metal prepared in accordance with a process involving the reaction salt (D), for example, to a cesium salt. The drug containing steps depicted in the following Scheme 2.

Scheme 2 Step 1: Synthesis of linker Intermediates L1 and L. O R1 HO N11 A n21OH -- us -kR2 -- HON11 A n21 O r O Sk C C O C R2 La O R1 X Lal

HO A Y O O O N1 NZ2 Sk R2YNO, O RI L1 Step 2: Synthesis of Drug-acid chloride D-COOH, -o- D-COC Da Dal Step 3:

Method A:

D-COOH + N 11 n 2"S">

-continued O O RI R2 D ls o1 Z N1 Z2 no ls O -k C (Ia)

D-COC + "N- n 2"S">< R2 Dal O R1 Lal Methods B: D-COOH + On-An- s D R2 O RI L

O O R1 Z Z2 NO D o1 N1 no O O1 (I)

D-COC -- Hon- A NZ2 "N">< -NO D R2 al O R1 L

Step 1 triethylamine also gives the compound of formula (I). Finally, the resulting compound (I) is subjected to nitration 0326 In this step, the linker (L) containing ONO group using silver nitrate in the presence of an organic solvent, for is produced by: (i) reacting C-chloroformate (X) (as obtained example acetonitrile to form the compound of formula (I), in step 1 of Scheme 1) with a compound of formula (L.) in the and if desired, the compound of formula (I) is converted to its presence of a base, for example, pyridine and a solvent, for pharmaceutically acceptable salt. example, dichloromethane (DCM) to obtain the compound of formula (L.); and (ii) Subjecting the resultant compound of formula (L.) to nitration using silver nitrate in the presence Method B: of an organic solvent, for example, acetonitrile. 0329. In this method, the drug (D) is directly coupled with the linker of formula (L), as obtained in step 1 above, in Step 2 the presence of a coupling agent, for example, N,N-dicyclo 0327. In this step, the drug containing carboxylic acid hexylcarbodiimide (DCC) and an organic base, for example, group D is converted to its reactive carbonyl derivative such 4-dimethylaminopyridine (DMAP) to form the compound of as an acid chloride of formula (D) as depicted in Step 2. formula (I). Alternatively, treatment of acid chloride (D) with the linker of formula (L.) in the presence of a base, for Scheme 1. example triethylamine also gives the compound of formula Step 3 (I), and if desired, the compound of formula (I) is converted to its pharmaceutically acceptable salt. Method A: 0330. In scheme 2, the variables D, R, R.Z, Z and Aare 0328. The drug D, is directly coupled with the linker of as defined in any of the embodiments of the present invention formula (L), as obtained in step 1 above, in the presence of with reference to the compounds of formula (I) wherein D a coupling agent, for example, N,N-dicyclohexylcarbodiim constitutes a drug containing carboxylic acid group. ide (DCC) and an organic base, for example, 4-dimethylami 0331. Another process for the preparation of compound of nopyridine (DMAP) to form the compound of formula (I). formula (I), wherein D is a drug containing a carboxylic acid Alternatively, treatment of the acid chloride (D) with the group, can be prepared in accordance with a process involv linker of formula (L.) in the presence of a base, for example ing the reaction steps depicted in the following Scheme 3. US 2011/0263526 A1 Oct. 27, 2011 39

-continued Scheme 3 Step 1 O -*n-An-O" Cl —- La Lib ACAC L: X = O L: X2 = NR3 --S-S-" O La2, Lib L2: X = O (I) L: X2 = NR Step 2 D-COOH -> D-COOM" -- Step 1 Da Da2 10332. In this step, the linkers of formula L (X=O) and L (X=NR, wherein R is as defined above) is reacted with (M = Na', K, Cs" or Ca2a") C-chloro acetyl chloride (ACAC) in the presence of a base, for example, triethylamine and a solvent, for example, dichlo romethane (DCM), to obtain the respective compounds of O formula L (X=O) and L (X=NR, wherein R is as defined above). La2, Lib Li: X = O Step 2 Li: X = NR 0333. The drug D is treated with a metal carbonate, for example, cesium carbonate or calcium carbonate, in the pres ence of an organic solvent, for example, N,N-dimethylforma O mide (DMF), to form the corresponding cesium or calcium salt of the drug (designated as D). The resultant cesium or calcium salt of the drug (D) is directly coupled with the compounds of formula L. and L, as obtained in the above ------O step 1, in the presence of an organic solvent, for example Ib DMF, to obtain an intermediate compound (I) (wherein Step 3 X—O or NR, wherein R is as defined above). O Step 3 ls X: A OH. " 0334. The compound of formula (I) as obtained in step 2 D r nz11 n21 above is further reacted with the chloroformate (X) (as O obtained in step 1 of Scheme 1) to obtain another intermediate compound (I). The intermediate compound (I) is further Ib subjected to nitration in the presence of silver nitrate and acetonitrile to obtain the compound of formula (I). 0335) In scheme 3, the variables D, R, R.Z, Z and Aare O RI as defined in any of the embodiments of the present invention with reference to the compounds of formula (I) wherein D C ulukO C - - constitutes a drug containing carboxylic acid group. X 0336 Another process for the preparation of compound of formula (I), wherein D is a drug containing a carboxylic acid group, can be prepared in accordance with a process involv ing the reaction steps depicted in the following Scheme 4. US 2011/0263526 A1 Oct. 27, 2011 40

of a coupling agent, for example, N,N-dicyclohexylcarbodi imide (DCC) or an organic base, for example, triethylamine Scheme 4 to obtain an intermediate compound (I). Step 1 Step 2 D-COOH + n 0338. The intermediate compound (I) as obtained in step 1 above is subjected to reduction using sodium borohydride in Da L N the presence of a solvent, for example, methanol, to form intermediate compound (I). Step 3 0339. The compound intermediate (I) is further reacted with the chloroformate (X) (as obtained in step 1 of Scheme 1) in the presence of an organic solvent, for example, dichlo romethane (DCM), and an organic base, for example, pyri dine, to obtain an intermediate compound (I). The interme D-COC – Hon-An-CHO diate compound (I) is subjected to nitration using silver Dal Lic nitrate and in the presence of an organic solvent, for example, acetonitrile to form a compound of formula (I). Step 2 (0340. In scheme 4, the variables D, R,R, Z, Zand Aare O as defined in any of the embodiments of the present invention with reference to the compounds of formula (I) wherein D D - o1- N1 - NCHO - constitutes a drug containing carboxylic acid group. 0341 An alternative process for the preparation of com Ic pound of formula (I), wherein D is a drug containing a car O boxylic acid group and the variable A is D-isosorbide skel eton, can be prepared in accordance with a process involving D ls O1 Z N1 Z2N1 OH the reaction steps depicted in the following Scheme 5. Ic Step 3 Scheme 5 O Step 1

D ls O -7S-7,1N1 OH " Ic1 C 1 O

O D ls O1 Z N1 Z2N1 O O Sk O YNO, R2 O RI (I)

Step 1 0337. In this step, the drug D, or its reactive carbonyl chloride derivative (D) (as obtained in step 2 of Scheme 1) is coupled with the compound of formula (L.) in the presence US 2011/0263526 A1 Oct. 27, 2011 41

of 0°-15°C. for a period of 24 hours according to the method -continued described in the reference J. F. Gilmar et al., EurJ Pharm Sci 2001, 14, 221-227, to form the intermediate compound (I). The cited reference is incorporated herein by reference. Step 2 0343. The intermediate compound (I) as obtained in step 1 above is further subjected to reduction using a hydrogena tion catalyst, 10% palladium/carbon (10% Pd on C) in the presence of an organic solvent selected from methanol or ethyl acetate according to the procedure described in the reference L. M. Moriarty et al., J Med Chem 2008, 51,7991 7999, to obtain another intermediate compound (I). The cited reference is incorporated herein by reference.

Step 3 (0344) The compound intermediate (I), as obtained in step 2 above, is further reacted with C-chloroformate (X) (as obtained in step 1 of scheme 1) in the presence of an organic Solvent, for example, dichloromethane (DCM) and an organic base, for example, pyridine to produce the intermediate com pound (I). The intermediate compound (I) is Subjected to nitration using silver nitrate and in the presence of an organic Solvent, for example, acetonitrile to obtain the compound of formula (I). (0345. In scheme 5, the variables D, R, R.Z' and Z areas defined in any of the embodiments of the present invention with reference to the compounds of formula (I) wherein D Step 1 constitutes a drug containing a carboxylic acid group. 0342. In this step, the reactive carbonyl derivative i.e. the 0346. Another process for the preparation of compound of acid chloride D of the drug D (as obtained in step 2 of formula (I), wherein D is a drug containing a carboxylic acid Scheme 1) is reacted with isosorbide-5-mononitrate (L) in group and the variable A is S, SO or SO, can be carried out in the presence of an organic base, for example, triethylamine accordance with the reaction steps depicted in the following and an organic solvent, for example, toluene at a temperature Scheme 6.

Scheme 6 Step 1 D-COOH -- HOS-As-OH N Da La

D ls o1 Z N1 Z2NOH Ia

D-COC + HOS-AN-OHZ Z. Dal US 2011/0263526 A1 Oct. 27, 2011 42

-continued Step 2 O ls Z. Z2 C O C D o1 NA1 No -- Sk R2 -- Ia O R (A = S) X

O O RI Z Z2 NO D ls o1 nA1 n O ul-kO O1 (I) (A = S)

Step 3 O O R1 Z. Z2 NO D ls o1 N1 no ul O ukO1 (I) (A = S) / N

O O RI O O RI Z Z2 NO Z Z2 NO D ls o1 N1 no usukiO o1 D ls o1 N1 no ul-kO O1 (I) A = S(O)

Step 1 Step 3 0347 In this step, the drug D, or its reactive carbonyl 0349 The compound of formula (I) (wherein A=S) as chloride derivative D (as obtained in step 2 of Scheme 1) is obtained in step 2 above is subjected to oxidation in the coupled with the compound of formula (L) (wherein, A is S) presence of an oxidising agent, for example, sodium perio in the presence of a coupling agent, for example, N,N-dicy date in water in the presence of an organic Solvent selected from methanol oracetone, to obtain the compound of formula clohexylcarbodiimide (DCC), an organic base, for example, (I) (wherein A=SO). Alternatively, the compound of formula dimethylaminopyridine (DMAP) and a solvent selected from (I) (wherein A=S) is treated with oxone in the presence of an dichloromethane (DCM) or tetrahydrofuran (THF) to obtain organic solvent, for example, methanol, to obtain the com the intermediate compound (I) (wherein, A is S). pound of formula (I) (wherein A=SO). Step 2 0350. In scheme 6, the variables D, R, R.Z' and Z areas defined in any of the embodiments of the present invention 0348. The compound intermediate (I) as obtained in step with reference to the compounds of formula (I) wherein D 1 above is reacted with the chloroformate (X) (as obtained in constitutes a drug containing carboxylic acid group. step 1 of Scheme 1) in the presence of a base, for example, 0351 A process for the preparation of the compound of pyridine and a solvent, for example, dichloromethane (DCM) formula (I), wherein D is a drug containing one or more to obtain an intermediate compound (I). The intermediate functional groups independently selected from an amino, a compound (I) is subjected to nitration using silver nitrate, in hydroxy or a Sulfhydryl group, can be carried out in accor the presence of an organic solvent, for example, acetonitrile, dance with the reaction steps depicted in the following to obtain the compound of formula (I) (wherein A=S). Scheme 7. US 2011/0263526 A1 Oct. 27, 2011 43

Scheme 7 Step 1 Hon-An- rk,O 'No, Her LG rk,Ni-n- O 'No, L1 Le Step 2

O D-Y-XIH -as- DY-x--a D, Y = a bond, C=O or S(O): D1, Y = a bond, C=O or S(O); X = NR (R = a bond): X = NR (R = a bond): D., Y = a bond, X = O or S; D4, Y = a bond, X = O or S; LG = a leaving group. D-Y-XH -e- D-Y-NECEO D, Y = a bond, C=O or S(O): D2, Y = a bond, C=O or S(O)2: X = NR (R = a bond): Step 3 LG Ni-n- O "No D-Y-XH + '' Di, or D O O RI

| HO A O O O D X O A O O O KNo.R2 Y r Zl Z2 r Sk R2 NO O O RI (I)

Step 1 disuccinimidyl carbonate (DSC) or 4-nitrophenyl chlorofor mate in the presence of a base, for example, triethylamine and 0352. In this step, the linker (L) (as obtained in step 1 of a solvent, for example, dichloromethane (DCM) to obtain the Scheme 2) is reacted with phosgene or its equivalent selected corresponding reactive carbonyl derivative of the drug D, or from diphosgene, triphosgene, N,N'-carbonyldiimidazole D designated hereinas D, and D respectively wherein LG (CDI), N,N'-disuccinimidyl carbonate (DSC) or 4-nitrophe is a Suitable leaving group selected from halide, imidazole, nyl chloroformate in the presence of a base, for example, N-hydroxysuccinimide or 4-nitrophenyl group. pyridine or triethylamine and a solvent, for example, dichlo 0354 Similarly, the drug containing an amino group D, romethane (DCM) to obtain the corresponding alkoxycarbo (D-Y X'H, wherein Y=a bond, C=O or S(O): X'=NR, nyl derivative of the linker L, designated herein as L. wherein R is H) is converted to its reactive isocyanate deriva wherein LG is a suitable leaving group selected from halide, tive D, by methods known to those skilled in the art i.e., imidazole, N-hydroxysuccinimide or 4-nitrophenyl group. either by the reaction of corresponding primary amine-con taining drug D, (D-Y X'H, wherein Y=a bond; X'—NR, Step 2 wherein R is H) with phosgene or its equivalent (Reference: 0353. The drug containing an amino group D (D-Y— Shriner, R. L. et al., Org. Synth. Coll. Vol. 2, (1943), 453) or X'H, wherein Y=a bond, C=O or S(O); X'=NR, wherein by the reaction of corresponding amide/sulfonamide-con R is a bond) or the drug containing a hydroxyl or sulfhydryl taining drug D, (D-Y X'H, wherein Y=C(=O) or S(O); group D (D-Y X'H, wherein Y=a bond; X'=O or S) is X'—NR, wherein R is H) with oxalyl chloride (Reference: reacted with phosgene or its equivalent selected from: diphos Speziale, A. J. et al., J. Org. Chem. 1962. 27, 3742 and gene, triphosgene, N,N'-carbonyldiimidazole (CDI), N,N'- Speziale, A. J. et al., J. Org. Chem. 1963, 28, 1805-1811). US 2011/0263526 A1 Oct. 27, 2011 44

Step 3 linker L in the presence of a base, for example, triethylamine and a solvent, for example, dichloromethane (DCM) to obtain 0355 The drug containing an amino group D (D-Y— the desired compound of formula (I). X'H, wherein Y=a bond, C=O or S(O); X'=NR, wherein 0357. In scheme 7, the variables D. A. R. R. Z' and Z are R is a bond or H) or the drug containing a hydroxyl or as defined in any of the embodiments of the present invention sulfhydryl group D (D-Y X'H, wherein Y=a bond; X'—O with reference to the compounds of formula (I) wherein D or S) is reacted with the compound (L) (as obtained in step 1 constitutes a drug containing a hydroxyl, a sulfhydryl or an above) or the reactive carbonyl derivative D, or D (as amino group. obtained in Step 2 above) of the drugs D, and D respectively 0358. A process for the preparation of the compound of is reacted with the linker (L) in the presence of a base, for formula (I), wherein D is a drug containing one or more example, triethylamine and a solvent, for example, dichlo functional groups independently selected from an amino, a romethane (DCM) to obtain the compound of formula (I). hydroxyl or a sulfhydryl group, can be carried out in accor 0356 Alternatively, the reactive isocyanate derivative D, dance with the reaction steps depicted in the following (as obtained in Step 2 above) of the drug D, is reacted with the Scheme 8.

Scheme 8 Step 1

O D-Y-XH He- DY-x--a Di, De D51, DC4 D, Y = a bond, C=O or S(O); D1, Y = a bond, C=O or S(O); X = NR (R = a bond): X = NR (R = a bond): D., Y = a bond, X = O or S; D4, Y = a bond, X = O or S; LG = a leaving group. D-Y-XH He D-Y-NCO Di, Y = a bond, C=O or S(O)2: D2, Y = a bond, C=O or S(O)2: X = NR (R = a bond): Step 1 Step 2

O DY-x--g -- -*n- a--" Di, or D4 La Lib \ L: X = O L: X2 = NR Dn1 X X2nz11 Ain 21 OH O le (Y = a bond, C(O) or SO) / D-Y-NECEO + -S-S-" D2 La Lib La: X = O US 2011/0263526 A1 Oct. 27, 2011 45

-continued Step 3 D X X2 A OH N1 nz11n21 D-Y-NECEO O Ie (Y = a bond, C(O) or SO) HO nz11n21A O O C O R R2 O R1 C usukO C Ial

D N-1 X X n/ A n 1 O O C D n-1 X X n1nA 1 Y r Zl Z2 SkR2 Y Zl Z2 O O RI O Iel (I) (Y = a bond, C(O) or SO)

0359 The drug containing an amino group D (D-Y— Step 1 above, is reacted with the compound of formula L. in X'H, wherein Y=a bond, C=O or S(O); X'=NR, wherein the absence or presence of a base, for example, triethylamine R is a bond) or the drug containing a hydroxyl or sulfhydryl and a solvent, for example, dichloromethane (DCM) to obtain group D (D-Y X'H, wherein Y=a bond; X'=O or S) is the compound of formula (I) which is finally nitrated using converted to its corresponding reactive carbonyl derivative designated herein as D, and D respectively (as depicted in silver nitrate in the presence of an organic solvent, for Step 2, Scheme 7). Similarly, the drug containing an amino example acetonitrile to form the compound of formula (I). group D (D-Y X'H, wherein Y-a bond, C=O or S(O); 0362. In scheme 8, the variables D. A. R. R. Z' and Z are X'=NR, wherein R is H) is converted to its reactive isocy as defined in any of the embodiments of the present invention anate derivative D (as depicted in Step 2, Scheme 7). with reference to the compounds of formula (I) wherein D constitutes a drug containing hydroxyl, Sulfhydryl or amino Step 2 group. 0360. In this step, the reactive carbonyl derivative D, of 0363 A process for the preparation of the compound of the drug containing an amino group D, (D-Y X'H, wherein formula (I), wherein D is a drug containing one or more Y=a bond, C=O or S(O): X'—NR, wherein R is a bond) functional groups independently selected from an amino, a or D of the drug containing a hydroxyl or a Sulfhydryl hydroxyl or a sulfhydryl group, can be prepared in accor group D (D-Y X'H, wherein Y=a bond; X'=O or S) as dance with a process involving the reaction steps depicted in obtained in Step 1 above, is reacted with the compound of formula (L.) (X=O) or the compound of formula (L.) the following Scheme 9. (X—NR, wherein R is as defined above) to obtain the intermediate compound (I). Similarly, the reactive isocyan ate derivative D of the drug containing an amino group D, Scheme 9 (D-Y X'H, wherein Y=a bond, C=O or S(O): X'=NR, Step 1 wherein R is H) is reacted with the compound of formula L., (X=O) or the compound of formula L., (X=NR, wherein HO A OH R is as defined above) to obtain the intermediate compound nz 1 n21 Hs (I). La Step 3 HO NZ11 A N21 O NPH 0361. The intermediate compound (I) as obtained in step La2 2 above is then reacted with the chloroformate (X) (as LG O A O obtained in step 1 of Scheme 1) to obtain the intermediate NZ11 N21Y npch compound (I), which is subjected to nitration using silver nitrate, in the presence of an organic solvent, for example, O acetonitrile, to obtain the compound of formula (I). Alterna tively, the reactive isocyanate derivative D, of the drug con La3 taining an amino group D, (D-Y X'H, wherein Y-a bond, C=O or S(O); X'=NR, wherein R is H) as obtained in US 2011/0263526 A1 Oct. 27, 2011 46

Step 2 -continued Step 2 0365. In this step, the drug containing an amino group D, LG O A O (D-Y X'H, wherein Y=a bond, C=O or S(O); X'—NR, NZ11 N21Y npch wherein R is a bond or H) or the drug containing a hydroxyl or sulfhydryl group D (D-Y X'H, wherein Y-a bond; O X'=O or S) is reacted with the compound of formula (L.) as La3 obtained in step 1 above in the presence of a suitable base, for D-Y-XH example, triethylamine and a solvent, for example, dichlo Di, D romethane (DCM) to form the intermediate compound (I). Di, Y = a bond, C=O or S(O)2: Removal of hydroxyl protecting group from the intermediate X = NR (R = a bond): compound (I) is carried out using a standard procedure in the D., Y = a bond, X = O or S; art to obtain the intermediate compound (Ia). D X O A Y O N1 NZ1 NZ2 NPGH Step 3 O 10366. In this step, the intermediate compound (I) is If reacted with the chloroformate (X) (as obtained in step 1 of Scheme 1) to obtain the intermediate compound (I2). The intermediate compound (I) is further subjected to nitration using silver nitrate in the presence of an organic solvent, for D n1 X O N1 Ain 21OH example, acetonitrile, to form the compound of formula (I). 0367. In scheme 9, the variables D. A. R. R. Z' and Z are O as defined in any of the embodiments of the present invention If with reference to the compounds of formula (I) wherein D Step 3 constitutes a drug containing a hydroxyl, a sulfhydryl or an amino group. 0368. An alternative process for the preparation of the compound of formula (I), wherein D is a drug containing one D X O A OH or more functional groups independently selected from a n 1 nzi1 in 21 X hydroxyl or a sulfhydryl group and the variable A is selected from the groups consisting of 1.2-, 1.3-, and 1,4-phenylene O and both, Z' and Z represent bond, can be prepared in accor Ie dance with the process involving the reaction steps depicted D n 1 X O NZ1 A n21 O O C in the following Scheme 10. R2 O O R1 Scheme 10 Step 1

D X O A O O O Y D-XH + HOCN - N -CHO n 1 NZ11 NZ2 Sk YNO, Z Z R2 D. O O RI Lif DX = O or S) (I) X Z Z2 D1 NA1 NCHO Step 1 O 0364. In this step, one of the hydroxyl groups of the linker diol (L) is selectively protected by a suitable hydroxyl pro tecting group by a standard method to obtain the correspond ing monoprotected compound of formula (L). The resultant compound of formula (L) is further treated with phosgene or its equivalents: diphosgene, triphosgene, N,N'-carbonyldi imidazole (CDI), N,N'-disuccinimidyl carbonate (DSC) or 4-nitrophenyl chloroformate in the presence of a base, for example, pyridine or triethylamine and a solvent, for example, dichloromethane (DCM) to obtain the compound of formula (Ls). US 2011/0263526 A1 Oct. 27, 2011 47

an organic base, for example, dimethylaminopyridine -continued (DMAP) and a solvent, for example, dichloromethane Step 2 (DCM) to obtain an intermediate compound (I). The inter mediate compound (I) is further subjected to reduction in the 2 -- presence of a reducing agent, for example, sodium borohy ------dride and in a solvent, for example, methanol to obtain O another intermediate compound (I). g Step 2 C O C 10370. The intermediate compound (I) is further reacted 1 < - with the chloroformate (X) (as obtained in step 1 of Scheme O R 1) to obtain another intermediate compound (I.2). The inter X mediate compound (I) is further subjected to nitration using X Z Z2 O O silver nitrate in the presence of an organic solvent, for D1 N1 N1 SK.R2 example, acetonitrile, to form the compound of formula (I). O O R1 0371. In scheme 10, the variables D, R, Rare as defined in any of the embodiments of the present invention with reference to the compounds of formula (I) wherein D consti tutes a drug containing a hydroxyl or a sulfhydryl group. It has already been indicated hereinabove that A=1.2-, 1.3-, and 1,4-phenylene and Z' and Z-bond. X Z Z2 O O O 0372 An alternative process for the preparation of the D1 r N1 N1 Sk R2YNO, compound of formula (I), wherein D is a drug containing O O RI carboxylic acid group and the variable Y is a spacer groupY (I)

Step 1 t O 0369. In this step, the drug containing hydroxyl or sulfhy dryl functional group D (D-Y X'H, wherein Y-a bond; O X'=O or S) is directly coupled with the compound of for mula (L.) (wherein A=1.2-, 1.3-, or 1.4-phenylene and Z' and =(wherein R is as defined above), can be prepared in accor Z-bond) in the presence of a coupling agent, for example, dance with a process involving the reaction steps depicted in N,N-dicyclohexylcarbodiimide (DCC) and in the presence of the following Scheme 11.

Scheme 11 Step 1 R5 R5

HO1. CO2H C 1. COC Si, Sh

R5 R5 Z Z2 O A OH 1. * Ho1 NA1 No -- C NZ11N72 Y C COC L O

HO A O O O Y -e- ls -- NZ 1 n2 Sk n NO C C COC R2 O RI Sh L US 2011/0263526 A1 Oct. 27, 2011 48

-continued Step 3 R5 O R5 O O A OH ls O A OH ls Cl NZ11N72 Y • O NZ11N72 Y D OM O O D2 Ih M = Na', K", Cs" or Cat O R

C usukO C

O R5

ls O A Y O O C D r Yrsark R2 1. O O R Ih

O R5

ls O A Y O O O NO R2 -S-S-S-SksO O RI (I)

Step 1 containing carboxylic acid group D is reacted with the com 0373) In this step, the compound of formula (S) is reacted pound of formula (L.) in the presence of an organic solvent, with phosphorous pentachloride or sulphonyl chloride to for example, N,N-dimethylformamide (DMF) to obtain the obtain the compound of formula (S). compound of formula (I). 0376. In scheme 11, the variables D, Z, ZA, R' and R' Step 2 are as defined in any of the embodiments of the present invention with reference to the compounds of formula (I) 0374. The compound (S) as obtained in step 1 above is wherein D constitutes a drug containing carboxylic acid further reacted with the compound of formula (L.) or the group or its metallic salt as specified above. linker (L) in the presence of a base, for example, triethy 0377. A process for the preparation of the compound of lamine and a solvent, for example, dichloromethane (DCM) formula (I), wherein D is a drug containing one or more to obtain the respective compound of formula (L.) or (L). functional groups independently selected from hydroxyl or Step 3 Sulfhydryl group and Y is a spacer group, Y 0375. In this step, the metallic salt D (wherein M"—Na', K", Ca" or Cs") of the drug containing carboxylic acid group D is directly coupled with the compound of for mula (L.) as obtained in step 2 above in the presence of an organic solvent, for example, N,N-dimethylformamide (DMF) to obtain an intermediate compound (I). The inter mediate compound (I) is further reacted with the chlorofor mate (X) (as obtained in step 1 of Scheme 1) to obtain another intermediate compound (I). The intermediate compound (I) is then subjected to nitration using silver nitrate in the presence of an organic solvent, for example, acetonitrile, to (wherein R is as defined above) can be prepared in accor form the compound of formula (I). Alternatively, the metallic dance with a process involving the reaction steps depicted in salt D (wherein M"—Na", K", Ca" or Cs") of the drug the following Scheme 12.

US 2011/0263526 A1 Oct. 27, 2011 50

-continued O R6 R6 O O R1 X ls Z Z2 ls R2 NO D Nx1l NN OnNzinz21 1 A O O O SNO, D1 s O1 NA1 No O O1 H R2 H O O R1 O (I) (I)

Step 1 step 1 of Scheme 7) in the presence of a base, for example, triethylamine and a solvent, for example, dichloromethane 0378. In this step, the compound of formula (S) (wherein (DCM) to obtain the intermediate compound (I). Removal of PG' is an amino protecting group as defined above and R is the protecting group from the intermediate compound (I) is as defined above) is reacted with the linker (L) in the pres carried out using a standard procedure known in the art to ence of a coupling agent, for example, N,N-dicyclohexylcar form the compound of formula (I). Alternatively, the drug bodiimide (DCC) and in the presence of an organic base, for derivative D, as obtained in Step 2 above is reacted with the example, dimethylaminopyridine (DMAP), and an organic linker (L) to form the compound of formula (I) after removal solvent, for example, dichloromethane (DCM) to obtain the of the protecting group from the protected intermediate of the compound of formula (L). The removal of the amino pro formula (I) thus obtained. Alternatively, the drug derivative tecting group PG' in the compound of formula (L.) is carried D., as obtained in Step 2, Scheme 7 (wherein, Y=a bond; out by a standard procedure known in the art to form com X'=O or S) is reacted with the compound (L) produced in pound of formula (L). reaction step 1 above to form a compound intermediate (I). The removal of protecting group PG in the compound inter Step 2 mediate (I) is carried out using any standard procedure known in the art to form the compound of formula (I). 0379. In this step, the drug containing a hydroxyl or sulf (0381. In scheme 12, the variables D, A, Z, Z, R' and R' hydryl group D (D-Y X'H, wherein Y=a bond; X =O or are as defined in any of the embodiments of the present S) is reacted with the compound of formula (S) in the pres invention with reference to the compounds of formula (I) ence of a coupling agent, for example, N,N-dicyclohexylcar wherein D constitutes a drug containing hydroxyl or sulfhy bodiimide (DCC), a suitable base, for example, dimethylami dryl group. nopyridine (DMAP) and an organic solvent, for example, 0382 An alternative process for the preparation of the dichloromethane (DCM) to obtain a reactive drug derivative compound of formula (I), wherein D is a drug containing one of formula (D). Removal of the aminoprotecting group PG' or more functional groups independently selected from from the reactive drug derivative (D) is carried out using a hydroxyl or Sulfhydryl group and Y is a spacer group selected standard procedure known in the art to obtain another reactive compound intermediate (D). The drug derivative (D) is from Y, further treated with phosgene or its equivalent selected from diphosgene, triphosgene, N,N'-carbonyldiimidazole (CDI), N,N'-disuccinimidyl carbonate (DSC) or 4-nitrophenyl chlo roformate in the presence of a base, for example, triethy lamine and a solvent, for example, dichloromethane (DCM) to obtain another reactive isocyanate intermediate (D). Step 3 (wherein d is as defined above) can be carried out in accor 0380. In this step, the drug derivative (D) as obtained in dance with the reaction steps as depicted in the following step 2 above is reacted with the compound (L) (as obtained in Scheme 13.

Scheme 13

O R1 -- a-- "NKNo2 -e- H O Z2 NO O RI R2 PG-4 -N-a O -Z N1 No ls O ukO1 Li US 2011/0263526 A1 Oct. 27, 2011

-continued O O R1

N Z Z NO PGA1 Nels1 No1 N1A. 2no ls O uk O1

L i Step 2

D-XH Y COH O + PGAN11'" —- N v-1 n D. S X d PG-4 X = O, S d Des Step 3 O O RI HO. A.. O O O O R R ls R2 n. 711 n 21 Ya 2 G1 No1 Zin A1 Z2no.1 ls No1 No1 NO Zi Z. r NKRI R2 NO H.N-1 no.1 Zin 1 Z No l O -k O1 NO2 Le L1 Lil

O O D1 X LG D D NECEO Yx d NH2 Yx d O D D-6 f De4

O O O RI X N Z Z NO DYx ---d O N71 A N72 Y O O Sk O SNO, D1 r 's-d O1 N1 2No lsO ukO1 R2 O O R1 O (I) (I)

Step 1 4-nitrophenyl chloroformate in the presence of a base, for example, triethylamine and a solvent, for example, dichlo 0383. In this step, the compound of formula (S) (wherein PG' is an aminoprotecting group as defined above) is reacted romethane to form another reactive compound i.e. the inter with the linker (L) in the presence of a coupling agent, for mediate isocyanate compound (D7). example, N,N-dicyclohexylcarbodiimide (DCC) and in the presence of an organic base, for example, dimethylaminopy Step 3 ridine (DMAP), and organic solvent, for example, dichlo 0385 The resulting drug derivative (D) is reacted with romethane (DCM) to obtain the compound of formula (L.). Removal of the amino protecting group PG in compound of the compound of formula (L) (as obtained in step 1 of formula (L.) is carried out by a standard procedure known in Scheme 7) in a solvent, for example, dichloromethane (DCM) the art to form the compound of formula (L, ). to obtain the compound of formula (I). Alternatively, the drug isocyanate derivative (D) as obtained in step 2 above is Step 2 reacted with the linker (L) in a solvent, for example, dichlo 0384 The drug containing a hydroxyl or sulfhydryl group romethane (DCM) to form the nitrate ester prodrug of for D (D-Y X'H, wherein Y=a bond; X'=O or S) is reacted mula (I). In an alternative synthesis, the drug derivative (D) with the compound of formula (S) in the presence of a (as obtained in Step 2, scheme 7, wherein Y-a bond) is coupling agent, for example, N,N-dicyclohexylcarbodiimide reacted with the compound (L.) as obtained in step 1, to form (DCC), a suitable base, for example, dimethylaminopyridine the nitrate ester prodrug of formula (I). (DMAP) and an organic solvent, for example, dichlo 0386. In scheme 13, the variables D, Z, Z. A. R' and R' romethane (DCM) to obtain the corresponding derivative of the drug (Ds). Removal of the amino protecting group PG' are as defined in any of the embodiments of the present from the drug derivative (Ds) is carried out using a standard invention with reference to the compounds of formula (I) procedure known in the art to form another reactive free wherein D constitutes a drug containing a hydroxyl or a amine drug derivative (D). The resulting free amine deriva Sulfhydryl group. tive (D) is further treated with phosgene or its safe equiva 0387 Another process for the preparation of the com lent selected from diphosgene, triphosgene, N,N'-carbonyl pound of formula (I), wherein D is a drug containing one or diimidazole (CDI), N, N'-disuccinimidyl carbonate (DSC), more functional groups independently selected from a US 2011/0263526 A1 Oct. 27, 2011 52 hydroxyl or a Sulfhydryl group and Y is a spacer group Step 1 selected from Y, 0388. In this step, the drug containing a hydroxyl or sulf hydryl group D (D-Y X'H, wherein Y=a bond; X'=O or O CO2H O S) is reacted with the compound of formula S. (wherein R is an amino protecting group (PG') as defined above) in the Null presence of a coupling agent, for example, N,N-dicyclohexy lcarbodiimide (DCC), a suitable base, for example, dimethy laminopyridine (DMAP) and an organic solvent, for example, (wherein c is as defined above) can be carried out in accor- dichloromethane (DCM) to obtain a reactive drug derivative dance with the reaction steps as depicted in Scheme 14. (Ds) and/or a reactive drug derivative (Do).

Scheme 14 Step 1 O NHR7

D Yx CO2H NHR -Y D-XH Des HOC CO2H NHR7 D. X = O or S) Se Na HOC XN D

D-9 Step 2 NHR7 O NHR7 HOC XN D D Nx CO2H O D-8 D-9

HO NZ11 A N72 Y O O O YNO, HOnz11 Ain 21 O O O SNO, R2 R2 O RI O R1 L1 L1

O NHR7 NHR7 O O R1 R2 D Nx O nz11 A nz21 O O SK O NO, D1 X O1 Z N1 Z2No ls O -k O1 NO R O O RI O

If i

O NH2 NH2 O O R1 R2 D O A O O O X Z Z2 ls -k NO sh- nz11 nz21 SK R NO, D1 O1 N1 No O O1 O O RI O

(I) (I) US 2011/0263526 A1 Oct. 27, 2011

Step 2 invention with reference to the compounds of formula (I) wherein D constitutes a drug containing hydroxyl or sulfhy 0389. The reactive drug derivative of formula Ds or the dryl group. reactive drug derivative of formula Do (as obtained in step 1 0391 Another process for the preparation of the com above) is directly coupled with the nitrate ester containing pound of formula (I), wherein D is a drug containing one or linker (L) (formed in reaction step 1 of Scheme 2) in the more functional groups selected from a hydroxyl or a sulfhy presence of a coupling agent, for example, N,N-dicyclohexy dryl group and Y is a spacer group selected from lcarbodiimide (DCC), a suitable base, for example, dimethy laminopyridine (DMAP) and an organic solvent, for example, dichloromethane (DCM) to obtain the intermediate com pound (I) and the intermediate compound (I) respectively. Removal of the amino protecting group R from each of the l d intermediate compounds (I) and (I) is carried out by a standard procedure known in the art to obtain the respective compounds of formula (I). (wherein d is as defined above) can be carried out in accor 0390. In scheme 14, the variables D, Z, ZA, R' and R' dance with the reaction steps as depicted in the following are as defined in any of the embodiments of the present Scheme 15.

Scheme 15

D D-XH DX = O or Sl US 2011/0263526 A1 Oct. 27, 2011 54

-continued O O O RI O O O R1 R2 Z Z2 NO HO ul-1 No1 N1 no ls O ukO1 HO ---d o1 Z.N1 Z2No ls O -k C L' HOCNCOH Sf

HO N1 Ain 21 O O Sk O YNO, HO A O O C R2 R2 O RI O RI

L1 Lal

Step 1 (L) is further coupled with a drug containing a hydroxyl or 0392. In step 1, the drug containing a hydroxyl or sulfhy sulfhydryl group D (D-Y X'H, wherein Y=a bond; X'—O dryl group D (D-Y X'H, wherein Y=a bond; X =O or S) or S) in the presence of a coupling agent, for example, N.N- is reacted with a dicarboxylic acid compound of formula (S) dicyclohexylcarbodiimide (DCC), a suitable base, for in the presence of a coupling agent, for example, N,N-dicy example, dimethylaminopyridine (DMAP) and an organic clohexylcarbodiimide (DCC), a suitable base, for example, solvent, for example, dichloromethane (DCM) to obtain the dimethylaminopyridine (DMAP) and an organic solvent, for corresponding reactive drug derivative (I). The intermediate example, dichloromethane (DCM) to obtain the correspond compound of the formula (I) is coverted to the final com ing reactive drug derivative (Do). pound of formula (I) as described above. In yet another approach, the nitrate linker of formula (L) is coupled with Step 2 dicarboxylic acid of the formula (S) followed by the drug 0393. The reactive drug derivative (Do) as obtained in containing a hydroxyl or sulfhydryl group D (D-Y X'H, step 1 above is further coupled with the linker compound of whereinY-abond; X'=O or S) in the presence of a coupling formula (L.) in the presence of a coupling agent, for example, agent, for example, N,N-dicyclohexylcarbodiimide (DCC), a N,N-dicyclohexylcarbodiimide (DCC), a suitable base, for suitable base, for example, dimethylaminopyridine (DMAP) example, dimethylaminopyridine (DMAP) to obtain the and an organic solvent, for example, dichloromethane (DCM) intermediate compound (I). The resulting intermediate com to obtain the final nitrate compound of formula (I). pound (I) is further reacted with the chloroformate (X) (as 0394. In scheme 15, the variables D, Z, ZA, R' and R' obtained in step 1 of Scheme 1) to obtain another intermediate are as defined in any of the embodiments of the present compound of formula (I). The intermediate compound of invention with reference to the compounds of formula (I) formula (I) is then Subjected to nitration using silver nitrate wherein D constitutes a drug containing a hydroxyl or a in the presence of an organic solvent, for example, acetoni Sulfhydryl group. trile, to obtain the compound of formula (I). Alternatively, the drug derivative (Do) is coupled directly with the linker (L) 0395 Alternative process for the preparation of the com (as obtained in Step 1". Scheme 1) to obtain the intermediate pound of formula (I), wherein D is a drug containing one or chloro compound of formula (I) which is converted to the more functional groups independently selected from a nitrate compound of the formula (I) as described above. In a hydroxyl or a sulfhydryl group and Y is a spacer group more direct approach, the drug derivative (Do) is coupled selected from Y, directly with the nitrate containing linker L (as obtained in Step 1, Scheme 2) to obtain the final compound of formula (I). In another approach, the chloro compound of the formula (L) is coupled first with a dicarboxylic acid of the formula (S) in the presence of a coupling agent, for example, N.N- luru dicyclohexylcarbodiimide (DCC), a suitable base, for example, dimethylaminopyridine (DMAP) and an organic (wherein X is as defined above) can be carried out in accor solvent, for example, dichloromethane (DCM) to obtain the dance with the reaction steps as depicted in the following corresponding derivative (L). This compound of formula Scheme 16.

US 2011/0263526 A1 Oct. 27, 2011 56

-continued

D. D-XH DX = O or S

O O O R1 O O O RI X Z Z2 ls NO X Z. Z2 HO--- us o1 N1 no O R2O1 HO o1 N1 no O R2C L' Lal'

Step 1 to directly afford the compound of formula (I). In another 0396 The drug containing a hydroxyl or sulfhydryl group approach, the drug containing a hydroxyl or sulfhydryl group D (D-Y X'H, wherein Y=a bond; X'=O or S) is reacted D (D-Y X'H, wherein Y=a bond; X'=O or S) is coupled with the compound of formula (S) in the presence of a with the linker compound of formula (L.) in the presence of suitable base, for example, dimethylaminopyridine (DMAP) a coupling agent, for example, N,N-dicyclohexylcarbodiim and a solvent, for example, dichloromethane (DCM) to form ide (DCC), a suitable base, for example, dimethylaminopy the reactive drug derivative (D). Similarly, reactions of the ridine (DMAP) and an organic solvent, for example, dichlo linkers of formula (L.) or (L) with cyclic anhydride com romethane (DCM) to form the compound intermediate (I), pound of formula (S) in the presence of a suitable base, for which is finally converted to the compound of formula (I) as example, dimethylaminopyridine (DMAP) and an organic described above. In yet another approach, reaction of the drug solvent, for example, dichloromethane (DCM) afforded the containing a hydroxyl or sulfhydryl group D (D-Y X'H, respective linker intermediates of formula (L.) and (L) whereinY-abond; X'=O or S) with the linker compound of respectively. formula (L.) in the presence of a coupling agent, for example, N,N-dicyclohexylcarbodiimide (DCC), a suitable base, for Step 2 example, dimethylaminopyridine (DMAP) and an organic 0397. The reactive drug derivative (D) as obtained in solvent, for example, dichloromethane (DCM) directly step 1 above is then coupled with the linker of formula (L.) in afforded the final compound formula (I). the presence of a coupling agent, for example, N,N-dicyclo hexylcarbodiimide (DCC), a suitable base, for example, dim 0398. In scheme 16, the variables D, Z, ZA, R' and R' ethylaminopyridine (DMAP) and an organic solvent, for are as defined in any of the embodiments of the present example, dichloromethane (DCM) to form the compound invention with reference to the compounds of formula (I) intermediate (I). The compound intermediate (I) is further wherein D constitutes a drug containing hydroxyl or sulfhy reacted with the chloroformate (X) (as obtained in step 1 of dryl group. Scheme 1) to obtain another intermediate compound of for 0399. An alternative process for the preparation of the mula (I). The intermediate compound of formula (I) is then compound of formula (I), wherein D is a drug containing one Subjected to nitration using silver nitrate in the presence of an or more functional groups independently selected from a organic solvent, for example, acetonitrile, to obtain the com hydroxyla Sulfhydryl group and Y is a spacer group selected pound of formula (I). In another approach, the compound of from Y= formula (D) is reacted with the linker intermediate of for mula (L) in the presence of a coupling agent, for example, N,N-dicyclohexylcarbodiimide (DCC), a suitable base, for example, dimethylaminopyridine (DMAP) and an organic solvent, for example, dichloromethane (DCM) to form the compound intermediate (I), which is converted to the final compound of formula (I) as described above. Alternatively, the compound of formula (D) is reacted with the linker intermediate of formula (L) in the presence of a coupling agent, for example, N,N-dicyclohexylcarbodiimide (DCC), a suitable base, for example, dimethylaminopyridine (DMAP) (wherein R7 and R is as defined above) can be carried out in and an organic solvent, for example, dichloromethane (DCM) accordance with the reaction steps as depicted in Scheme 17.

US 2011/0263526 A1 Oct. 27, 2011 58

-continued O Rs O O RI O R8 O O R1 D- ass ls o-N17so2 l O k -NO: PNx ls ------ZS-S-S-NO22 ls -k NHR

O Rs O O RI O R8 O O R1 D Z. Z2 NO D ls Z Z2 ls uk NO s's ls o1 NA1 no lsO kO1 Yx --- NA1 no O O1 NH2 NH2 (I) (I)

Step 1 reaction step 1 of Scheme 7) in the presence of a base, for (0400. The compound of formula (S) (wherein PG' is a example, triethylamine and a solvent, for example, dichlo hydroxyl protecting group defined above and R7 and Rareas romethane (DCM) to obtain the compound of formula (I) defined above) is reacted with the linker (L) in the presence (wherein Y is a spacer of formula Y and R is an amino of a coupling agent, for example, N,N-dicyclohexylcarbodi protecting group as defined above). Alternatively, the drug imide (DCC), a suitable base, for example, dimethylami derivative (D) is reacted with the linker (L) in the presence nopyridine (DMAP), and organic solvent, for example, of a base, for example, triethylamine and a solvent, for dichloromethane (DCM) to form the compound of formula example, dichloromethane (DCM) to obtain the compound (L). Removal of the protecting group PG' in the compound (I) (wherein Y is a spacer group of formula Y and R7 is an of formula (L.) is carried out by a standard procedure known amino protecting group as defined above). The compound of in the art to afford compound of formula (L). formula (I), (whereinY is a spacergroup of formula Y. and R' is an amino protecting group as defined above) can alterna Step 2 tively be obtained by reacting the drug derivative (D) as 04.01 The drug containing a hydroxyl or sulfhydryl group obtained in Step 2, Scheme 7 (wherein Y-a bond; X" is O or D (D-Y X'H, wherein Y=a bond; X'=O or S) is reacted S. LG-Leaving group) with the compound (L) as obtained with the compound of formula (S) in the presence of a in reaction step 1 above, in the presence of a Suitable base, for coupling agent, for example, N,N-dicyclohexylcarbodiimide example, triethylamine and a solvent, for example, dichlo romethane (DCM). Removal of the amino protecting group (DCC), a suitable base, for example, dimethylaminopyridine R’ in the compound of formula (I), (wherein Y is a spacer (DMAP) and an organic solvent, for example, dichlo group of formula Y and R is an amino protecting group as romethane (DCM) to obtain a reactive drug derivative of defined above) is carried out using any standard procedure formula Di2 (wherein R is hydrogen oranamino protecting known in the art to obtain the compound of formula (I) group as defined in the first embodiment herein above). Removal of the protecting group PG from the drug deriva (wherein R,-hydrogen). tive (D) is carried out using a standard procedure known in 0403. An alternative process for the preparation of the the art to obtain another reactive drug derivative of formula compound of formula (I), wherein D is a drug containing one (D). The resulting drug derivative (D) is further treated or more functional groups selected from a hydroxyl or a with phosgene or its equivalent selected from diphosgene, Sulfhydryl group (D,") and Y is a spacer group selected from triphosgene, N,N'-carbonyldiimidazole (CDI), N,N'-disuc Y= cinimidyl carbonate (DSC) or 4-nitrophenyl chloroformate in the presence of a base, for example, triethylamine and a O CO2H O solvent, for example, dichloromethane (DCM) to afford another reactive drug derivative of formula (D). -- Step 3 0402. The drug derivative (D) as obtained in step 2 (wherein c is as defined above) can be carried out in accor above is reacted with the compound (L) (as obtained in dance with the reaction steps as depicted in Scheme 18.

US 2011/0263526 A1 Oct. 27, 2011 60

Step 1 Step 3 04.04. In this step, the compound of formula (S) (wherein 04.06) The drug derivative (D) is reacted with the com PG is a suitable carboxyl protecting group and PG' is a pound of formula (L) (as obtained in step 1 of Scheme 7) in Suitable amino protecting group as defined above and c is as the presence of a base, for example, triethylamine and a defined above) is reacted with the linker (L) in the presence of a coupling agent, for example, dicyclohexylcarbodiimide solvent, for example, dichloromethane (DCM) or alterna (DCC), a suitable base, for example, dimethylaminopyridine tively, the drug derivative (D2) is reacted with the linker (L) (DMAP) and an organic solvent, for example, dichlo in the presence of a base, for example, triethylamine and a romethane (DCM) to obtain the compound of formula (L). solvent, for example, dichloromethane (DCM) to get the Removal of the protecting group PG in the compound of compound intermediate (I). Alternatively, the drug deriva formula (L) is carried out by a standard procedure known in tive (D) as obtained in Step 2, Scheme 7 (whereinY=abond; the art to get the compound of formula (L). X' is O or S. LG-Leaving group) is coupled with the com pound of formula L (as obtained in Step 1 above) to obtain an intermediate compound (I). Removal of the carboxylic Step 2 acid protecting group PG in the intermediate compound (I) 04.05 The drug containing a hydroxyl or sulfhydryl group or the compound intermediate (I) is carried out using a D (D-Y X'H, wherein Y=a bond; X'=O or S) is reacted standard procedure known in the art to obtain the compound with the compound of formula (S) in the presence of a cou pling agent, for example, dicyclohexylcarbodiimide (DCC), a of formula (I). suitable base, for example, dimethylaminopyridine (DMAP) 0407. An alternative method for obtaining the compound and an organic solvent, for example, dichloromethane (DCM) of formula (I), wherein D is a drug containing one or more to get the corresponding reactive drug derivative of formula functional groups selected from a hydroxyl or a sulfhydryl Ds, wherein PG is a carboxylic acid protecting group as group and Y is a spacer group selected from Y, defined above). The removal of the protecting group PG from the drug derivative (Ds) is carried out using a standard procedure known in the art to obtain another reactive drug derivative of formula (D). The drug derivative (D) is further treated with phosgene or its safe equivalent selected from diphosgene, triphosgene, N,N'-carbonyldiimidazole (CDI), N,N'-disuccinimidyl carbonate (DSC) or 4-nitrophe nyl chloroformate in the presence of a base, for example, triethylamine and a solvent, for example, dichloromethane (wherein the group R is an aminoprotecting group as defined (DCM) to afford another reactive drug derivative of formula above and e is also defined above) involves the reaction steps (D17). depicted in the following Scheme 19.

Scheme 19 Step 1

NHR7 NHR7 'Szi- n2 'N-N-No NH Oa - A n-On 10a-On NHPG-4 -- R2 2 -e- PG-4 8 Zl Z2 1 NK 2 NO R HOC 8 O R O O RI S; L L'

NHR7

O A O O O PGA1 8 NZ11N72 Y Sk YNO, R2 O O R1 US 2011/0263526 A1 Oct. 27, 2011

-continued Step 2 D NHR7 NHR7 D-xH " NHPG-4 -X NHPG-4 X = O or S) HOC 8 D 8 S; O De 18

NHR7 NHR X NCO X NH2 D1 S- D1 8 O O

De20 D19 Step 3

NHR7 LG. O. A. O. O. O HO. , . A O. O. O - a HN On 1-A - On 10'S -On Zrzirk, No, Szrzik, No, 8 Z1 NZ2 NK R2 NO O R R2 O O R R O O R L1 Le L' NHR7 O NHR7 X NCO Y D D 8 X NH2 Nx11 No D1 8 O D4 O De20 De 19 NHR NHR H X N Oa - A O O O X HN O A O O O D1 8 NZ nz21 SK, No. D1 8 r NZ1 nz21 r SkR2 YNO, O O O RI O O O R1 (I) (I")

NH2 NH2 Y X O n 1 A n 21 O O O n X HN O A O O O D 8 Z Z SC NO D1 8 1 NZ11 nz21 r Sk NO, O O O R1 R O O O R (I)

Step 1 Step 2 0408. In this step, the compound of formula (S) (wherein R7 and PG are suitable amino protecting groups) is reacted 04.09. The drug containing a hydroxyl or sulfhydryl group with the linker (L) in the presence of a coupling agent, for D (D-Y X'H, wherein Y=a bond; X'=O or S) is reacted example, dicyclohexylcarbodiimide (DCC), a suitable base, with the compound of formula (S) in the presence of a cou for example, dimethylaminopyridine (DMAP) and an organic pling agent, for example, dicyclohexylcarbodiimide (DCC), a solvent, for example, dichloromethane (DCM) to yield the suitable base, for example, dimethylaminopyridine (DMAP) compound of formula (L.). Selective removal of the protect and an organic solvent, for example, dichloromethane (DCM) ing group PG in compound of formula (L, ) is carried out by to form a reactive drug derivative of formula (Ds). Selective a standard procedure known in the art to afford the compound removal of the protecting group PG from the drug derivative of formula (L.). (Ds) is carried out using a standard procedure known in the US 2011/0263526 A1 Oct. 27, 2011 62 art to give another reactive drug derivative of formula (Do). amino protecting group R in the compounds of formulae (I) The drug derivative (Do) is further treated with phosgene or and (I") (whereinY is a spacer of formulaY, wherein R’ is an its equivalent selected from diphosgene, triphosgene, N,N'- amino protecting group as defined above) is carried out using carbonyldiimidazole (CDI), N,N'-disuccinimidyl carbonate a standard procedure known in the art to obtain the respective (DSC) or 4-nitrophenyl chloroformate in the presence of a compounds of formula (I) (wherein R7-hydrogen as defined base, for example, triethylamine and a solvent, for example, above). dichloromethane to afford another reactive drug isocyanate derivative of formula (Do. Step 3 0411. An alternative process for the preparation of the 0410. The drug derivative (D) as obtained in step 2 compound of formula (I), wherein D is a drug containing one above is reacted with the compound of formula (L) (as or more functional groups independently selected from a obtained in step 1 of Scheme 7) in the presence of a base, for hydroxyl or a sulfhydryl group and Y is a spacer group example, triethylamine and a solvent, for example, dichlo selected from Y= romethane (DCM) or the drug derivative (Do) is reacted with the linker (L) in the presence of a base, triethylamine for example, and a solvent, for example, dichloromethane O RHN (DCM) to yield the compound of formula (I") (whereinY is a spacer group of formulaY, wherein R’ is an amino protecting O O group as defined above). Alternatively, the drug derivative (D) as obtained in Step 2, Scheme 7 (wherein Y-abond; X' is O or S; LG-Leaving group) is coupled with the compound of formula L., (as obtained in Step 1 above) to obtain a (wherein R is as defined above) can be carried out in accor compound of formula (I) (wherein Y=Y, wherein R’ is an dance with the reaction steps as depicted in the following amino protecting group as defined above). Removal of the Scheme 20. US 2011/0263526 A1 Oct. 27, 2011 63

US 2011/0263526 A1 Oct. 27, 2011

Step 1 Scheme 7) in the presence of a base, for example, triethy 0412. In this step, the compound of formula (S) (wherein lamine and a solvent, for example, dichloromethane (DCM) PG' is a suitable hydroxyl protecting group and R7 is a suit or alternatively, the drug derivative (D) is reacted with the able amino protecting group) is reacted with the linker (L) in linker (L) in the presence of a base, for example, triethy the presence of a coupling agent, for example, dicyclohexy lamine and a solvent, for example, dichloromethane (DCM) lcarbodiimide (DCC), a suitable base, for example, dimethy to obtain a compound of formula (I") (wherein Y is a spacer laminopyridine (DMAP) and an organic solvent, for example, group of formula Y., wherein R is as defined above). Alter dichloromethane (DCM) to obtain the compound of formula natively, the drug derivative (D) as obtained in Step 2. (L). Removal of the protecting group PG in compound of Scheme 7 (wherein Y-a bond; X" is O or S; LG-Leaving formula (L.) is carried out by a standard procedure known in group) is coupled with the compound of formula L (as the art to obtain the compound of formula (L). obtained in Step 1 above) to obtain the compound of formula Step 2 (I) (whereinY is a spacer group of formulaY, wherein R is 0413. The drug containing a hydroxyl or sulfhydryl group an amino protecting group as defined above). Removal of the D (D-Y X'H, wherein Y=a bond; X'=O or S) is reacted amino protecting group R in the compounds of formulae (I) with the compound of formula (S) in the presence of a and (I") (whereinY is a spacer group of formulaY) is carried coupling agent, for example, dicyclohexylcarbodiimide out using a standard procedure known in the art to yield the (DCC), a suitable base, for example, dimethylaminopyridine nitrate ester prodrug of formula (I) (wherein R'-hydrogenas (DMAP) and an organic solvent, for example, dichlo defined above). romethane (DCM) to obtain the corresponding reactive 0415. An alternative method for the preparation of the derivative of the drug represented by formula (D). compound of formula (I), wherein D is a drug containing one Removal of the protecting group PG from the drug deriva or more functional groups selected from a hydroxyl or a tive (D) is carried out using a standard procedure known in sulfhydryl group and Y is a spacer group selected from Y, the art to obtain another reactive drug derivative of formula (D). The drug derivative (D) is further treated with phosgene or its equivalent selected from diphosgene, triph osgene, N,N'-carbonyldiimidazole (CDI), N,N'-disuccinim idyl carbonate (DSC) or 4-nitrophenyl chloroformate in the presence of a base, for example, triethylamine and a solvent, for example, dichloromethane (DCM) to obtain another reac tive drug derivative of formula (D). Step 3 0414. The drug derivative (D) is reacted with the com involves the reaction steps as depicted in the following pound of formula (L) (as obtained in reaction step 1 of Scheme 21. US 2011/0263526 A1 Oct. 27, 2011 66 US 2011/0263526 A1 Oct. 27, 2011 67

ponunuoo

gdens US 2011/0263526 A1 Oct. 27, 2011

Step 1 triethylamine and a solvent, for example, dichloromethane 0416) In this step, the compound of formula (S) (wherein (DCM) or alternatively, the drug derivative (D) is reacted PG' is a suitable hydroxyl protecting group and PG is a with the linker (L) in the presence of a base, for example, Suitable carboxylic acid protecting group) is reacted with the triethylamine and a solvent, for example, dichloromethane linker L (as obtained in Step 1, Scheme 7) in the presence of (DCM) to obtain an intermediate compound (I). Similarly, a coupling agent, for example, dicyclohexylcarbodiimide the drug derivative D as obtained in Step 2, Scheme 7 (DCC), a suitable base, for example, dimethylaminopyridine (wherein Y-a bond; X is O or S; LG-Leaving group), is reacted with the compound of formula L (as obtained in (DMAP) and an organic solvent, for example, dichlo Step 1 above) to get another intermediate compound (I). romethane (DCM) to obtain the compound of formula (L). Removal of the carboxylic acid protecting group PG in the Selective removal of the protecting group PG in the com intermediate compound (I) or in the intermediate compound pound of formula (L.) is carried out by a standard procedure (I) is carried out using a standard procedure known in the art known in the art to obtain the compound of formula (L). to obtain the respective compounds of formula (I). Step 2 0419. Although not specified in the above general syn thetic schemes, it is understandable to any person skilled in 0417. The drug derivative D as obtained in Step 2. the art that if the said drugs or therapeutic agents contain one Scheme 7 (wherein Y-a bond; X" is O or S; LG-Leaving or more additional derivatizable functional groups such as group) is reacted with the compound of formula (S) in the amino, carboxyl, hydroxyl (including phenolic), or sulfhy presence of a Suitable base, for example, triethylamine and an dryl groups, those functional groups may need to be selec organic solvent, for example, dichloromethane (DCM) to tively protected, if it is necessary, by any widely used suitable obtain a reactive drug derivative of formula (D). Removal protecting groups and Subsequently deprotected, if it is nec of the protecting group PG from the drug derivative (D) is essary, at appropriate stages of the processes for the prepara carried out using a standard procedure known in the art to tion of the compound of formula (I), which are the nitric oxide obtain another reactive derivative of the drug represented by releasing prodrugs of known drugs ortherapeutic agents, and formula (Ds). The drug derivative (Ds) is further treated Such selective protection and deprotection reactions are car with phosgene or its safe equivalent selected from diphos ried out as described in Theodora W. Greene and Peter G. M. gene, triphosgene, N,N'-carbonyldiimidazole (CDI), N,N'- Wuts, “Protective Groups in Organic Synthesis”, 3" edition, disuccinimidyl carbonate (DSC) or 4-nitrophenyl chlorofor John Wiley and Sons, Inc. New York (1999), the disclosure of mate in the presence of a base, for example, triethylamine and the relevant portion is incorporated herein by reference. To a solvent, for example, dichloromethane (DCM) to form illustrate this feature, conversion of a drug containing two or another reactive drug derivative of formula (D). more types of functional groups, for example atorvastatin, to the corresponding nitric oxide-releasing prodrug of atorvas Step 3 tatin (NO-Atorvastatin) of formula (I) via selective protection 0418. The drug derivative (Ds) as obtained in step 2 and if necessary, deprotection of the hydroxyl groups of the above is reacted with the compound of formula (L) (as drug at appropriate stages of their synthesis as shown in obtained in step 1 of Scheme 7) in the presence of a base, Scheme 22.

US 2011/0263526 A1 Oct. 27, 2011 70

III ^^^

OOH

ponu?uoo

US 2011/0263526 A1 Oct. 27, 2011

Method A: described above in Method A. If desired, the compound of formula (I) thus obtained is converted to its pharmaceutically 0420. In Step A, two hydroxyl groups of the drug, for acceptable salt. example Atorvastatin (D-COH) are protected by a suitable protecting group, for example as an acetonide, by a generally 0426. The organic base, used in any reaction steps of the known procedure, to obtain the partially protected drug processes for the preparation of the compound of formula (I) (D). In Step A, the partially protected drug (D) as as depicted in the aforementioned schemes, may be selected obtained in step A above is coupled with a linker diol (L) by from but not limited to triethylamine, diisopropylethylamine, a method described in Step 2 of Scheme 1, to afford the 4-(dimethylamino) pyridine (DMAP), pyridine or mixtures intermediate alcohol (I). In Step A, the acetonide protect thereof. ing group in the intermediate (I) is removed by a method 0427. The organic solvent used in any reaction steps of the generally known to those skilled in the art to obtain the processes for the preparation of the compound of formula (I) intermediate triol (I). In Step A, the intermediate alcohol may be selected from but not limited to dichloromethane (I) as obtained in step A above is further reacted with (DCM), chloroform, dimethylformamide (DMF), tetrahydro C-chloroformate (X) in the presence of an organic base, for furan (THF), acetonitrile, ethyl acetate, diethyl ether or mix example, pyridine and an organic solvent, for example, tures thereof. dichloromethane (DCM) to obtain the selectively acylated intermediate compound (I). In the final Step, the interme 0428 The coupling agent used in a reaction step involving diate chloride (I) is subjected to nitration using silver nitrate coupling for the preparation of the compound of formula (I) in the presence of an organic solvent, for example, acetoni may be selected from but not limited to N,N'-dicyclohexyl trile to form the compound of formula (I), and if desired, the carbodiimide (DCC), O-(Benzotriazol-1-yl)-N,N,N',N'-tet compound of formula (I) is converted to its pharmaceutically ramethyluronium hexafluorophosphate (HBTU), benzotria acceptable salt. Zol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(benzotriazol-1-yl)-N.N.N', Method B1 (B2/B3: N'-tetramethyluronium tetrafluoroborate (TBTU), N,N'-di cyclohexylcarbodiimide/N-hydroxybenzotriazole (DCC/ 0421. In Step 1, the two hydroxyl groups of the drug, for HOBT), 1-Ethyl-(3-dimethylaminopropyl)carbodiimide example Atorvastatin (D-COH)are protected by any suitable hydrochloride (EDAC. HCl) and benzotriazol-1-yl-oxy-tris hydroxyl protecting groups that are likely to be cleaved in (dimethylamino)phosphonium hexafluorophosphate (BOP) Vivo (i.e., under biological conditions), by a method generally known to those skilled in the art, to obtain a partially protected and EDAC. HC1/HOBT, drug (D), which can be converted to the compounds of 0429. The present invention also relates to the process of formula (I) by any of the following methods: resoluting the racemic mixture of the compound of formula 0422 Method B1: In Step 2, the partially protected drug (I) or a pharmaceutically acceptable salt thereof: (D), as obtained in step 1 above, is coupled with a linkerdiol (L) by a method described in Step 2 of Scheme 1, to afford (I) the intermediate alcohol (I). In Step 3, the intermediate X X2 A O O O alcohol (I) as obtained in step 2 above is further reacted D1 n 1 NZ Y NZ2 Y Sk Y NO, with C-chloroformate (X) in the presence of an organic base, R2 for example, pyridine and an organic Solvent, for example, O RI dichloromethane (DCM) to obtain the intermediate com pound (I). In the final Step, the intermediate (I) is also wherein D, X, Y, X, A, Z, Z, R' and Rare as defined converted to the compound of formula (I) as described in the above, the process of resoluting the racemic mixture com final step of Method A. prises reacting the racemic compound of formula (I) with a 0423 Method B2: In Step 2, the partially protected car chiral auxiliary in the presence of a solvent, crystallising out boxyl-containing drug (D) as obtained in step 1 above is the required diastereoisomeric salt and Subsequently treating coupled with a linker intermediate (L) by a method described in Step 3 (i.e., Method A) of Scheme 2, to afford the it with a base to obtain the desired enantiomer of the com intermediate chloride (I), which is finally converted to the pound of formula (I) compound of formula (I) as described in the Final step of 0430. It has been indicated herein that the prodrugs the Method A. compounds of formula (I) of the present invention would 0424 Method B3: In Step 2, the partially protected Ator undergo enzymatic cleavage in a manner Such that the parent vastatin (D) as obtained in step 1 above is directly coupled drugs and effective amounts of nitric oxide are released in with the nitrate containing linker (L) by a method described vivo. On this basis, the inventor provides herein a plausible in Step 3 (i.e., Method B) of Scheme 2, to afford the com mechanism of cleavage of nitric oxide-releasing prodrugs pound of formula (I), and if desired, the compound of formula (the compound of formula I). The plausible mechanism by (I) is converted to its pharmaceutically acceptable salt. which the parent drug(s) designated herein as D and nitric 0425 Method C: In Step 1, sodium or calcium salt of the oxide (i.e., possibly in nitrate form) can be released in vivo atorvastain (D-COR, wherein, R=Na" or Ca") is reacted from the NO-Prodrugs as shown in Scheme M1. In the with linker bromide (L) in the presence of an organic Sol scheme that depicts plausible mechanism of cleavage of nitric vent, for example DMF to afford the intermediate alcohol of oxide-releasing prodrugs (the compound of formula I), dis the formula (I). The resulting intermediate alcohol (I) is ulfide linker (L1)-containing NO-Prodrug is used for illustra converted to the compound of formula (I), as already tive purpose only. US 2011/0263526 A1 Oct. 27, 2011 72

Scheme M1: Plausible Mechanism of Drug and NO release Drug-CO2H S O RI R2 Released Carboxylin -- A -- -ss-s-s-k- Intermediate GSH-Conjugate

Glutathione (GSH) Path 1 (When X = a bond; X = O)

O C.1n-n1n- GS - "YKNo.R2 O RI NO-Prodrug of Formula I (Drug is an amino carboxylhydroxylsulfydryl containing drug) If R = Hydrogen, then R* = Alkyl: X = NR, a"'" bond, O or S If R - Alkyl, then R2 = Hydrogen

GSH Path 2 (When X = O or S or NR, X = O

Drug a -- -- s/N O (o n XIH O r S GS -1 Ns-1N-1 C< R2 NO Released Drug \f / O R1 / Intermediate GSH-Conjugate

S GHS v + CO2 GS-SG

O -- NO; O S Nitrate \ / RI R2 An aldehyde except formaldehyde | Bioreduction

NO Nitric Oxide

0431 Understandably, the release of parent drug and nitric examples of formula I is expected to occur via enzymatic oxide (i.e., in the form of nitrate/nitrite) from NO-prodrugs cleavage of linkages between the drug and linker as shown in containing non-disulfide linkers as found in many other the following Scheme M2. US 2011/0263526 A1 Oct. 27, 2011 73

Scheme M2: Plausible Mechanism of Drug and NO release Drug Yx O R1 /l. Y Z Z2 y -k NO Enzymatic hydrolysis O / x21 N1 no O O1 O Y- Enzymatic hydrolysis H1 NH NO-Prodrug of Formula I (Drug is an amino carboxylhydroxylsulfydryl containing drug) If R = Hydrogen, then R2 = Alkyl: X = NR, a bond, O or S If R = Alkyl, then Ré2 = Hydrogen

Enzymatic Cleavage (When X = O or SNR, X2 = O ) Drug-XH or Drug-CO2H R2 Released free drugs H. -7S -7s -- H clo-k NO (when X = a bond) X A. OH No O r Released Linker A Probable Intermediate N CO This may O biodegrade l -- NO further Nitrate

An aldehyde except formaldehyde | Bioreduction | NO Nitric Oxide

0432. The nitrate ion (NO) thus released from the NO prodrug would get reduced to nitrite in vivo by the action of -continued oral bacteria (i.e., by bacterial nitrate reductase) or Xanthine NO + H2O Oxidase in tissues as shown in the following equation: Nitrate 0433. Further reduction of nitrite to nitric oxide (NO) NO Bacterial Nitrate reductase would readily occur in many different ways. Under non 2e 2H Her enzymatic acidic conditions in the human body (in stomach Nitrate O or tissue) or by Xanthine Oxidase in tissues or by Cyto Xanthine Oxidases in tissue chromes in liver/tissues nitrite would get converted to nitrous acid which would further dissociateto water and dinitrogen trioxide which in turn would dissociate further to nitrogen dioxide and NO as shown in the following equations:

NO -- H -e- HNO Nitrite Nitrous acid US 2011/0263526 A1 Oct. 27, 2011 74

-continued Ascorbic acid NO3 NO Dehydro Ascorbic acid -- 2HNO2 -> Dinitrogen + H2O + Nitrioxide H2O trioxide

NO NO Nitrogen -- Nitric Oxide dioxide

0434. As shown in the above equation, in the presence of variety of routes such as oral, for example in the form of pills, Vitamin C (Ascorbic acid) and polyphenols, nitrous acid thus tablets, coated tablets, capsules, granules or elixirs. Admin generated is directly reduced to NO without yielding nitrogen istration, however, can also be carried out rectally, for dioxide (Green L. C. et al., Nitrate biosynthesis in man. Proc example in the form of Suppositories, or parentally, for Natl AcadSci USA 1981, 78, 7764-8). example, intravenously, intramuscularly or Subcutaneously, 0435 The released NO has an extremely short half-life in the form of injectable sterile solutions or Suspensions, or (less then 1 s) in circulating blood (Kelm M. Nitric oxide topically, for example in the form of solutions or transdermal metabolism and breakdown, Biochim Biophy's Acta 1999, patches, or in other ways, for example in the form of aerosols 1411, 273-289). NO and nitrite react with oxyhemoglobin to or nasal sprays. yield nitrate and methemoglobin (Doyle MP, et al., Oxidation 0440 The pharmaceutical composition according to the of nitrogen oxides by bound dooxygen in hemoproteins. J invention is prepared in a manner known per se, and by Inorg Biochem 1981, 14,351–358: Dyle MP, et al., Kinetics utilizing methods well-known to one skilled in the art. Phar and mechanism of the oxidation of human deoxyhemoglobin maceutically acceptable inert inorganic and/or organic carri in nitrites. J Biol Chem 1981,256, 12393-8). The half-life of ers and/or additives can be used in addition to the prodrug nitrite in blood is 20-30 minutes (Dejam A. et al., Nitrite compound of formula (I) and/or its pharmacologically infusion in humans and nonhuman primates: endocrine acceptable salts. For the production of pills, tablets, coated effects, pharmacokinetics, and tolerance formation, Circula tablets and hard gelatin capsules it is possible to use, for tion 2007, 116, 1821-31) whereas nitrate has a circulating example, lactose, corn starch or derivatives thereof, gum ara half-life of several hours (Tannenbaum S R. Nitrate and bic, magnesia or glucose, etc. Carriers for Soft gelatin cap nitrite: origin in humans. Science 1979, 205, 1332, 1334-7; Sules and Suppositories are, for example, fats, wax, natural or Green LC, et al., Nitrate biosynthesis in man. Proc Natl Acad hardened oils, etc. Suitable carriers for the production of Sci USA 1981, 78, 7764-8). Solutions, for example, injection solutions, or of emulsions or 0436. As mentioned in the above equations, there are sev syrups are, for example, water, physiological sodium chloride eral pathways for oxidation and reduction of nitrate, nitrite Solution or alcohols, for example, ethanol, propanol, or glyc and NO in the body and some of them are summarized in the erol, Sugar Solutions, such as glucose Solutions or mannitol following diagram (Joel Petersson, 2008. Nitrate, Nitrite and solutions, or a mixture of the various solvents which have Nitric oxide in Gastric Mucosal Defense, Doctoral Disserta been mentioned. tion, 2008, pages 17-18 and the relevant references cited 0441 The pharmaceutical composition of the invention therein) See FIG. 1. also contains additives such as, for example, antioxidants, 0437. It is reported that most of the circulating plasma emulsifiers, preservatives, colouring agents and flavouring nitrate is excreted through the kidneys (Green L. C. et al., agents. The pharmaceutical composition may also contain Nitrate biosynthesis in man. Proc Natl Acad Sci USA 1981, two or more prodrug compounds of formula (I) and/or their 78,7764-8), but about 25% of the plasmanitrate is recycled in physiologically tolerable salts. Furthermore, in addition to at the human body to yield nitrite and NO (Tannenbaum SR, et least one prodrug compound of formula (I) or (II) and/or its al., The effect of nitrate intake on nitrate formation in human physiologically tolerable salts, the pharmaceutical composi saliva. Food Cosmet Toxicol 1976, 14, 549-52) as shown in tion can also contain one or more other therapeutically or the above FIGURE. prophylactically active ingredients. 0438. The present invention furthermore relates to a phar 0442. It would be understood by persons skilled in the art maceutical composition containing an effective amount of the that the amount of the compound of formula I (prodrugs of compound of formula (I) which is a nitric oxide releasing known drugs or therapeutic agents) that is contained in the prodrug of a known drug or a therapeutic agent or its physi pharmaceutical composition will depend upon the amount of ologically tolerable salts, along with a pharmaceutically the parent drug molecule included therein. Generally, the acceptable carrier, and to a process for the production of the amount of the prodrug used in the treatment methods is that pharmaceutical composition, which comprises converting the amount which effectively achieves the desired therapeutic compound of formula (I) into a Suitable administration form effect in subjects being treated for a particular disease. Natu using an appropriate pharmaceutically acceptable and physi rally, the dosages of the various prodrugs encompassed in the ologically tolerable excipient, and if appropriate, using fur compounds of formula (I) will vary somewhat depending ther Suitable active compounds, additives or auxiliaries. upon the parent drug molecule, rate of in vivo drug hydrolysis 0439. The compound of formula (I), which are the nitric etc. oxide releasing prodrugs of known drugs or therapeutic 0443) The pharmaceutical composition contains about 1 agents, can be administered to a subject in need thereof in a to 99, preferably about 1 to 80% and most preferably from US 2011/0263526 A1 Oct. 27, 2011

about 10 to 70% by weight of the prodrug compound of when the drug or the parent drug molecule contained in the formula (I) and/or the physiologically tolerable salts of pro compounds of formula (I) is a cardiovascular agent which is drug compound of formula (I). The effective amount of the known for its use in the treatment of cardiovascular diseases active ingredient of prodrug compound of formula (I) and/or Such as the coronary artery diseases, atheroscerosis, angina, rheumatic heart disease and other related disorders such as its physiologically tolerable salts in the pharmaceutical com hypertension, the compounds of formula (I) of the present position in order to obtain a desired therapeutic effect varies invention can also be used for the treatment of similar dis from 1 to 5000 mg. The desirable dosage of the pharmaceu eases or conditions. tical composition to be administered can vary over a wide 0446. Thus, the diseases or disorders that can be treated range. The selected dosage level can be readily determined by using the compounds of formula (I) of the present invention a skilled medical practitioner in the light of the relevant cir include but are not limited to inflammatory conditions or cumstances, including the condition (diseases or disorder) to disorders, cardiovascular diseases, cancer, allergies, psycho be treated, the chosen route of administration depending on a logical disorders, neurological disorders, cerebrovascular number of factors, such as age, weight and physical health disorders, convulsions, eye diseases, ear diseases, nose and and response of the individual patient, pharmacokinetics, oropharynx diseases, diseases of respiratory system, diseases severity of the disease and the like, factors known in the of gastrointestinal tract system, diseases of genito-urinary medical art. However, in order to obtain desirable effects, it system, skin diseases, musculo-skeletal diseases, endocrinal would be recommended to administer the pharmaceutical disorders, metabolism disorders such as diabetes, infectious composition in the form of oral tablets (tablets, capsules) for diseases such as bacterial infections and fungal infections, a day/week/month and in a dosage ranging from 1 mg to 5000 viral infections etc. mg, preferably 1 mg to 2000 mg, in a single dosage form or a 0447 Accordingly, in one aspect the present invention is multi-dosage form. related to a method of treating a disease or disorder where a 0444 The range set forth above is illustrative and those chronic, Sustained and selective release of the constituent skilled in the art will be able to determine the optimal dosing drug or therapeutic agent D or nitric oxide contained in the of the prodrugs, the compounds of formula (I) of the present compounds of formula (I) is beneficial; comprising adminis invention selected based on clinical experience and the medi tering to a mammal or a human in need of the treatment a cal indication or disease to be treated in a subject in need of therapeutically effective amount of the compound of formula the treatment. (I). 0445 Another aspect of the present invention is to provide 0448. In another aspect, the present invention also relates methods for the treatment of various medical conditions or to a method of treating a disease in a human or mammal where diseases or disorders in a subject comprising administering to a chronic, Sustained and selective release of the constituent a subject in need thereofatherapeutically effective amount of drug or therapeutic agent D or nitric oxide contained in the a compound of formula (I). It has already been indicated compounds of formula (I) is beneficial; comprising adminis herein above that the compounds of formula (I) of the present tering to said mammal atherapeutically effective amount of invention are prodrugs of known drugs or therapeutic agents the pharmaceutical composition containing the compounds containing a functional group independently selected from a of formula (I). carboxylic acid, an amino, a hydroxyl or a sulfhydryl group. 0449 Moreover, the compounds of formula (I), which are The specific class of therapeutic agents encompassed within the prodrugs of known drugs or therapeutic agents, in all the scope of the invention are described herein above. likelihood are advantageous over the parent drug molecules According to the present invention, the diseases or disorders or prodrugs of the parent molecule knownhitherto in the prior or the medical conditions for the treatment of which the art in terms of increased bioavailability, reduced adverse compounds of formula (I) of the present invention are used effect, for instance, gastric irritability caused by NSAIDS etc. are those for which the parent drug molecule (represented by Moreover, representative compounds encompassed in the the variable D which encompasses specific therapeutic compounds of formula (I) have been found to be devoid of agents) is conventionally used by a medical practitioner. For genotoxicity at a concentration at which the compounds are instance, when the drug or the parent drug molecule con expected to be used for the treatment of the medical condi tained in the compounds of formula (I) is an anti-inflmmatory tions or diseases for the treatment of which the parent drug and analgesic agent which are known for their use in the molecule is used. treatment of inflammatory disorders or inflammatory condi 0450. It is understood that modifications that do not sub tions, the compounds of formula (I) of the present invention stantially affect the activity of the various embodiments of can be used for the treatment of inflammatory conditions or this invention are included within scope of the invention disorders selected from: inflammatory bowel disease, inflam disclosed herein. Accordingly, the following examples are mation, rheumatoid arthritis, juvenile rheumatoid arthritis, intended to illustrate but not to limit scope of the present psoriatic arthritis, osteoarthritis, refractory rheumatoid invention. arthritis, chronic non-rheumatoid arthritis, osteoporosis/bone EXPERIMENTAL resorption, Crohn's disease, gout, atherosclerosis, vasculitis, 0451. The abbreviations and terms that are used herein: amyloidosis, chronic recurrent uveitis, ulcerative colitis, BOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)phospho cachexia, psoriasis, plasmocytoma, endometriosis, Behcet’s nium hexafluorophosphate disease, Wegenrer's granulomatosis, autoimmune disease, immune deficiency, common variable immunodeficiency DMF: N,N-Dimethylformamide (CVID), chronic graft-Versus-host disease, trauma and trans 0452. DSC: N,N'-Disuccinimidyl carbonate plant rejection, adult respiratory distress syndrome, pulmo nary fibrosis, ankylosing spondylitis, skin delayed type CDI: N,N'-Carbonyldiimidazole hypersensitivity disorders, Alzheimer's disease, systemic DCC: N,N'-Dicyclohexylcarbodiimide lupus erythematosus or allergic asthma. Further, for instance, DMAP: 4-Dimethylaminopyridine US 2011/0263526 A1 Oct. 27, 2011 76

0453 EDAC. HCl: 1-Ethyl-(3-dimethylaminopropyl)car uct, was eluted with 10% EtOAc in petroleum ether. The bodiimide hydrochloride desired mono-acylated title compound, which was eluted HBTU: 0-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluro with 20% EtOAc in petroleum ether, was obtained as a white nium hexafluorophosphate solid. Yield: 12.0 g (63.1%); H NMR (CDC1, 300 MHz): 8 TBTU: 0-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluro 1.58 (d. J=7.2 Hz, 3H), 2.77 (t, J=5.7 Hz, 2H), 2.86 (t, J=6.9 nium tetrafluoroborate Hz, 2H), 3.77 (t, J=5.7 Hz, 2H), 3.87 (q, J=7.2 Hz, 1H), 3.91 (s, 3H), 4.28-4.42 (m, 2H), 7.08-7.17 (m, 2H), 7.40 (dd. EtOH: Ethanol J=8.4, 1.5 Hz, 1H), 7.64-7.73 (m, 3H); MS m/z. 384.1 LAH: Lithium Aluminum Hydride M+NHI". 04.54 EtO: Diethyl ether Step 2: Preparation of (2S)-2-((2-(1-chloroethoxy) THF: Tetrahydrofuran carbonyloxy)ethyl) disulfanyl)ethyl 2-(6-methox 0455 DMSO: Dimethylsulfoxide ynaphthalen-2-yl)propanoate (CD1-L1-R1-CI) TEA: Triethylamine 0461 O.-chloroethyl chloroformate (CI-R1-CI, 1.1 mL, 11.5 mmol) was added drop-wise to a solution of (S)-2-((2- DIPEA: N,N-Diisopropylethylamine hydroxyethyl)disulfanyl)ethyl 2-(6-methoxynaphthalen-2- DCM: Dichloromethane yl)-propanoate (CD1-L1-OH, 3.5g, 9.6 mmol) in 30 mL of DCM at 0°C. under nitrogen atmosphere. To this stirred 04.56 EtOAc or EA: Ethyl acetate mixture was added a solution of pyridine (1.2 mL, 14.3 mmol) DME: Dimethoxyethane in 5 mL of DCM over 5 minutes. The mixture was stirred at 0° C. under nitrogen atmosphere for 30 minutes when TLC MeOH: Methanol analysis of the mixture indicated completion of the reaction. 0457 PE: Petroleum ether The mixture was diluted with DCM (-65 mL), washed with RT: Room temperature 1N HCl (3x100 mL), saturated sodium bicarbonate (1x100 TFA: Trifluoroacetic acid mL) and brine (2x50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to afford a HOBT: N-Hydroxybenzotriazole yellow oily residue which was purified by column chroma HPLC: High Performance Liquid Chromatography tography (200 g silica gel, 200-400 mesh, eluted with 10% EtOAc in petroleum ether) to afford the title compound, CD1 TLC: Thin Layer Chromatography L1-R1-CI as a slight greenish yellow colored oil. Yield: 3.2g RT: Room Temperature (70.8%); H NMR (CDC1,300 MHz): & 1.58 (d. J=6.9 Hz, 3H), 1.82 (d. J=5.7 Hz, 3H), 2.83-2.93 (m, 4H), 3.87 (q, J=7.2 0458 Examples of the compounds of formula I which are HZ, 1H), 3.91 (s.3H), 4.27-4.43 (m, 4H), 6.41 (q, J=6.0 Hz, the prodrugs of the drugs containing an carboxylic acid 1H), 7.10-7.18 (m, 2H), 7.40 (dd, J=8.4, 1.5 Hz, 1H), 7.67 (br group: s, 1H), 7.71 (d. J=8.4 Hz, 2H); MS m/z. 491.25 M+NH". Example 1 Step 3: Preparation of (2S)-2-((2-((1-(nitrooxy) (2S)-2-((2-((1-(nitrooxy)ethoxy)carbonyloxy)ethyl) ethoxy)carbonyloxy)ethyl)disulfanyl)-ethyl 2-(6- disulfanyl)ethyl 2-(6-methoxynaphthalen-2-yl)pro methoxynaphthalen-2-yl)propanoate (I-CD1-L1-R1) panoate (I-CD1-L1-R1) 0459. This compound was synthesized in 3 steps as shown 0462 Silver nitrate (1.4g, 8.1 mmol) was added to a in Scheme 1 and the experimental procedure is described solution of (2S)-2-((2-(1-chloroethoxy)carbonyloxy)ethyl) below: disulfanyl)ethyl 2-(6-methoxynaphthalen-2-yl)propanoate (CD1-L1-R1-CI, 3.2g, 6.8 mmol) in 35 mL of ACN and the Step 1: Preparation of (S)-2-((2-hydroxyethyl)disul mixture was refluxed in dark at 85-90° C. for 30 minutes when fanyl)ethyl 2-(6-methoxy-naphthalen-2-yl) pro TLC analysis of the mixture indicated complete conversion. panoate NO-Naproxen (CD1-L1-OH) The mixture was cooled and filtered through celite. The fil trate was concentrated and the residue (~3.5 g) was purified 0460. A solution of DCC (13.0g, 62.6 mmol) in DCM (25 by column chromatography (150 g of silica gel, 200-400 mL) was added drop-wise over 5 minutes to a stirred solution mesh, eluted with 10% EtOAc in petroleum ether) to afford of naproxen (CD1, 12.0 g, 52.2 mmol), bis(2-hydroxyethyl) 2.3 g of slightly impure product which was purified again by disulfide (HO-L1-OH, 13.4g, 104.3 mmol) and DMAP (1.3 column chromatography 100 g of silica gel, 200-400 mesh, g, 10.4 mmol) in 250 mL of DCM at 0°C. and the mixture was eluted with petroleum ether/DCM (2:3) to afford the pure stirred for 3 h when TLC analysis of the mixture indicated title compound (I-CD1-L1-R1) as greenish oil. Yield: 1.8 g. completion of the reaction. The mixture was filtered and the (84%); H NMR (CDC1, 300 MHz): & 1.56-1.61 (m, 6H), filtrate was washed with water (2x100 mL) and brine (1x100 2.81-2.90 (m, 4H), 3.87 (q, J–7.2 Hz, 1H), 3.91 (s, 3H), mL). The organic layer was separated, dried over NaSO and 4.30-4.38 (m, 4H), 6.91 (q, J=5.7 Hz, 1H), 7.10-7.17 (m, 2H), concentrated in vacuo to give the crude product which was 7.40 (dd, J=8.4, 1.8 Hz, 1H), 7.65-7.73 (mor distortedt,3H): purified by column chromatography (600 g of silica gel. 'CNMR (CDC1, 75.47 MHz): & 17.5, 18.6, 30.5, 30.8, 45.5, 150-300 mesh). The expected bis-naproxen derivative (i.e., 55.4, 64.1, 67.4, 96.4, 105.7, 119.2, 126.1, 126.3, 127.3, CD1-L1-CD1), which was formed as a minor undesired prod 129.0, 129.4, 133.8, 135.5, 152.6, 157.8, 174.5; MS m/z: US 2011/0263526 A1 Oct. 27, 2011 77

522.1 M+Na"; HRMS ESI (m/z): M+Na" calculated for 4.56 (t, J=6.6 Hz, 2H), 6.32 (t, J=6.0 Hz, 1H), 7.13 (dd, J=7.8, CHNNaOS: 522,0863; Found: 522,0869 (Mass 0.9 Hz, 1H), 7.34 (dt, J=7.8, 0.9 Hz, 1H), 7.59 (dt, J=7.8, 1.5 Accuracy: 1.15 ppm). HZ, 1H), 8.06 (dd, J=7.8, 1.5 Hz, 1H); MS m/z: 474.0 M+Na". Example 2 Step 3: Synthesis of 2-((2-((1-(nitrooxy)butoxy)car 2-((2-((1-(nitrooxy)butoxy)carbonyloxy)ethyl)disul bonyloxy)ethyl)disulfanyl)ethyl 2-acetoxybenzoate fanyl)ethyl 2-acetoxybenzoate NO-Aspirin/Salicylic (I-CD2-L1-R2) acid (I-CD2-L1-R2) 0466 Silver nitrate (0.9 g, 5.0 mmol) was added to a 0463. This compound was synthesized in 3 steps as shown solution of 2-((2-(1-chlorobutoxy)-carbonyloxy)ethyl) dis in Scheme 1 and the experimental procedure is described ulfanyl)ethyl 2-acetoxybenzoate (CD2-L1-R2-CI, 1.5 g, 3.3 below: mmol) in 15 mL of ACN at RT under a nitrogen atmosphere (covered the reaction flask with aluminum foil to minimize Step 1: Synthesis of 2-((2-hydroxyethyl)disulfanyl) exposure of reaction mixture to light) and the mixture was ethyl 2-acetoxybenzoate (CD2-L1-OH) stirred at RT for overnignt (~16 h). HPLC analysis of the 0464 A solution of aspirin acid chloride (CD2-CI, 7.0 g, mixture indicated complete conversion. The mixture was 35.3 mmol, freshly prepared from aspirin by using oxalyl diluted with 10 mL of DCM and filtered through a small pad chloride/DMF/DCM method) in 20 mL of DCM was added of celite to remove the insoluble salts. The filtrate was con drop-wise to a stirred solution of 2-hydroxyethyl disulfide centrated to give 2.0 g of oily residue which was purified by (HO-L1-OH, 10.9 g, 70.5 mmol) and Triethylamine (7.35 column chromatography (50.0 g of silica gel, 200-400 mesh, mL, 52.89 mmol) in 50 mL of DCM at 0°C. under nitrogen eluted with 8% EtOAc in petroleum ether) to afford the title atmosphere and the mixture was stirred at RT for overnight, compound as yellow oil. Yield: 0.4 g (27%). (Note: additional when TLC analysis of the mixture indicated completion of the -0.35 g (-19%) of impure product (-80% pureby HPLC) was reaction. The mixture was diluted with 25 mL of water and also obtained); H NMR (CDC1,300 MHz): & 1.00 (t, J–7.5 100 mL of DCM. The organic layer was separated and Hz, 3H), 1.43-1.58 (m, 2H), 1.83-1.92 (m, 2H), 2.38 (s.3H), washed with aqueous sodium bicarbonate (2x100 mL) and 2.99 (t, J=6.6 Hz, 2H), 3.05 (t, J=6.6 Hz, 2H), 4.47 (t, J–6.6 brine (1x100 mL), dried over NaSO and concentrated in Hz, 2H), 4.55 (t, J=6.6 Hz, 2H), 6.85 (t, J=6.0 Hz, 1H), 7.13 vacuo to give 10.0 g of crude oil which was purified by (dd, J=7.8, 0.9 Hz, 1H), 7.34 (dt, J=7.8, 0.9 Hz, 1H), 7.59 (dt, column chromatography (225.0 g of silica gel, 150-300 mesh, J=7.8, 1.5 Hz, 1H), 8.05 (dd, J–7.8, 1.8 Hz); C NMR eluted with 5-30% ethyl acetate in petroleum ether) to afford (CDC1, 75.47 MHz): & 12.9, 16.2, 20.6, 32.7, 36.2, 36.6, the title compound (CD2-L1-OH) as yellow oil. Yield: 5.2g 62.3, 65.8, 97.9, 122.4, 123.3, 125.6, 131.3, 133.6, 150.3, (46.6%); H NMR (CDC1,300 MHz): 8 2.26 (bt, J–4.2 Hz, 152.3, 163.6, 169.1; MS m/z:477.1 M+H,500.1 M+Na". 1H), 2.38 (s.3H), 2.90 (t, J=6.0 Hz, 2H), 3.05 (t, J=6.6 Hz, Example 3 2H), 3.69 (distorted q or m, 2H), 4.57 (t, J=6.6 Hz, 2H), 7.13 (dd, J=8.1, 0.9 Hz, 1H), 7.34 (dt, J=7.8 Hz, 1H), 7.60 (dt, (2S)-((Z)-4-(1-(nitrooxy)ethoxy)carbonyloxy)but-2- J=7.8, 1.5 Hz, 1H), 8.06 (dd, J=7.8, 1.5 Hz); MS m/z: 339.0 enyl) 2-(6-methoxynaphthalen-2-yl)propanoate NO M+Na". Naproxen (I-CD1-L2-R1) Step 2: Synthesis of 2-((2-(1-chlorobutoxy)carbony 0467. This compound was synthesized in 4 steps as shown loxy)ethyl)disulfanyl)ethyl 2-acetoxybenzoate (CD2 in Scheme 1 and the experimental procedure is described L1-R2-CI) below: 0465 Pyridine (73.0 uL, 0.9 mmol) followed by diphos Step 1: Preparation of (S)-2-6-methoxynaphthalen-2- gene (1.1 mL, 9.3 mmol) were added to a stirred solution of yl)propanoyl chloride (CD1-CI) butyraldehyde (1.0g, 13.9 mmol) in 3 mL of dry DCM at RT 0468 DMF (-3-4 drops) followed by oxalyl chloride under a nitrogen atmosphere and the mixture was stirred at RT (11.0 mL, 130.4 mmol) were added drop-wise to a stirred for 3 h. About 50% of the solvent was distilled offin vacuo solution of naproxen (DC1, 25.0g, 108.7 mmol) in 200 mL of and kept the mixture under nitrogen atmosphere. To this DCM at RT under a nitrogen atmosphere over 10 minutes. stirred mixture at 0°C. under nitrogen was added a solution of The mixture was stirred at RT under nitrogen atmosphere for 2-((2-hydroxyethyl)disulfanyl)ethyl 2-acetoxybenzoate 3 h. The mixture was concentrated in vacuo to afford crude (CD2-L1-OH, 1.5 g, 4.6 mmol) in 4 mL of dry DCM followed by pyridine (1.1 mL, 13.9 mmol) and the mixture was stirred naproxen acid chloride as a yellow solid, which was used as at 0°C. for 30 minutes when TLC analysis of the mixture such in the next step. Yield: 27.0 g (quantitative). indicated completion of the reaction. The mixture was diluted Step 2: Preparation of (SZ)-4-hydroxybut-2-enyl with 10 mL of DCM, washed with 1N HCl (3x15 mL), 2-(6-methoxynaphthalen-2-yl)-propanoate (CD1-L2 saturated sodium bicarbonate (3x15 mL) and brine (2x10 mL). The organic layer was dried over anhydrous Na2SO and OH) concentrated in vacuo to give a oily residue (2.5 g) which was 0469 A solution of naproxen chloride (5.0g, 20.0 mmol) purified by column chromatography (40.0 g of silica gel. in 10 mL of DCM was added to a stirred solution of cis-2- 200-400 mesh; eluted with 5-8% of EtOAc in petroleum butene-1,4-diol (HO-L2-OH, 5.3 mL, 60.0 mmol) in 100 mL ether) to afford the title compound as yellow oil. Yield: 1.6 g. of DCM at 0°C. under a nitrogen atmosphere. To this stirred (80%); H NMR (CDC1,300 MHz): 80.98 (t, J–7.5Hz,3H), mixture was added triethylamine (4.2 mL, 30.0 mmol) drop 1.47-1.62 (m, 2H), 1.96-2.17 (m, 2H), 2.38 (s, 3H), 3.00 (t, wise over 15 minutes and the resulting mixture was stirred at J=6.6 Hz, 2H), 3.06 (t, J=6.6 Hz, 2H), 4.48 (t, J=6.6 Hz, 2H), 0° C. for 30 minutes and at RT for overnight (~12 h), when US 2011/0263526 A1 Oct. 27, 2011

TLC analysis of the mixture indicated formation of two prod 7.40 (dd, J=8.4, 1.8 Hz, 1H), 7.64-7.74 (mor distortedt,3H): uct spots (i.e., mono and bis-acylated products). The mixture CNMR (CDC1, 75.47 MHz): & 17.5, 18.6, 45.5,55.4, 60.3, was washed with saturated sodium bicarbonate (3x100 mL), 64.1, 96.3, 105.7, 119.2, 126.1, 126.3, 126.7, 127.4, 129.0, brine (3x100 mL), dried over anhydrous NaSO and concen 129.3, 129.4, 133.9, 135.5, 152.6, 157.8, 1744; MS m/z: trated to afford 7.0 g of crude oily residue which was purified 456.1 M+Na"; HRMS ESI (m/z): M+Na" calculated for by column chromatography (150.0 g of silica gel, 200-400 CHNNaO: 456.1265; Found: 456.1266 (Mass Accu mesh, eluted with 10% EtOAc in petroleum ether to isolate racy: 0.88 or -0.22 ppm). the bis-acylated compound and with 20% EtOAc in petro leum ether to isolate the desired mono-acylated product). The Example 4 title compound was obtained as a white solid. Mp: 69-71°C.; Yield: 4.5 g (75%); H NMR (CDC1,300 MHz): & 1.57 (d. (Z)-4-(1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl J=6.9 Hz, 3H), 1.99 (brs, 1H), 3.85 (q, J=6.9, 7.2 Hz, 1H), nicotinate NO-Niacin (I-CD3-L2-R1) 3.91 (s, 3H), 4.18 (t, J=4.8 Hz, 2H), 4.60-4.73 (m, 2H), 0472. The title compound was synthesized in 3 steps as 5.50-5.62 (m, 1H), 5.75-5.85 (m. 1H), 7.09-7.17 (m, 2H), shown in Scheme 2 and the experimental procedure is 7.38 (dd, J–8.4, 1.5 Hz, 1H), 7.65 (brs, 1H), 7.70 (d. J=8.7 described below: Hz, 2H); MS m/z: 323.1 M+Na". Step 1: Preparation of (Z)-1-chloroethyl 4-hydroxy Step 3: Preparation of (2S)-((Z)-4-(1-chloroethoxy) but-2-enyl carbonate (HO-L2-R1-CI) carbonyloxy)but-2-enyl) 2-(6-methoxynaphthalen-2- 0473 C-Chloroethyl chloroformate (CI-R1-CI, 20.0 mL, yl)propanoate (CD1-L2-R1-CI) 187.0 mmol) was added drop-wise to a stirred solution of 0470 C-chloroethyl chloroformate (CI-R1-C1, 1.6 mL, cis-2-butene-1,4-diol (HO-L2-OH, 15.0 g, 170.2 mmol) and 16.4 mmol) was added drop-wise to a stirred solution of pyridine (27.0 mL, 340.0 mmol) in 200 mL of DCM at 0°C. (SZ)-4-hydroxybut-2-enyl 2-(6-methoxynaphthalen-2-yl) over a period of 10 minutes and the mixture was stirred at 0° propanoate (CD1-L2-OH, 4.1 g, 13.7 mmol) in 50 mL of C. for 1 h. TLC analysis of the mixture indicated completion DCM at 0°C. under a nitrogen atmosphere. To this stirred of the reaction. The mixture was diluted with 100 mL of DCM mixture was added a solution of pyridine (1.7 mL. 20.4 mmol) and washed with 1 NHCl (2x200 mL), water (2x150 mL), and in 5 mL of DCM over 5 minutes. The mixture was stirred at 0° brine (2x150 mL). The organic layer was dried over NaSO C. under nitrogen for 30 minutes and at RT for 3 h when TLC and concentrated in vacuo to obtain an oil which was purified analysis of the mixture indicated completion of the reaction. by column chromatography (silica gel 100-200 mesh, eluted The mixture was diluted with DCM (-75 mL), washed with with 5% EtOAc in petroleum ether) to afford the title com 1N HCl (3x100 mL), saturated sodium bicarbonate (1x100 pound as a colorless oil. Yield: 16.0 g (48.5%); H NMR mL) and brine (2x100 mL). The organic layer was dried over (CDC1,300 MHz): & 1.85 (d. J=5.7 Hz, 3H), 4.30 (d. J=6.3 anhydrous NaSO and concentrated in vacuo to give agreen Hz, 2H), 4.75-4.90 (m, 2H), 5.65-5.76(m, 1H), 5.90-5.99 (m, ish oily residue which was used as Such in the next step as its 1H), 6.43 (q, J=5.7 Hz, 1H); C NMR (CDC1, 125.77 purity was >90% (by HPLC) and its proton NMR and mass MHz): 8 25.2, 58.4, 64.1, 84.7, 124.1, 134.7, 1529; MS m/z: spectral data was consistent with the expected structure. 217.1 M+Na". Yield: 5.0 g (89.9%); H NMR (CDC1,300 MHz): & 1.57 (d. J=7.5 Hz,3H), 1.81 (d. J=5.7 Hz, 3H), 3.86 (qJ=7.2 Hz, 1H), Step 2: Preparation of (Z)-4-hydroxybut-2-enyl 3.91 (s.3H), 4.61-4.82 (m, 4H), 5.66-5.79 (m, 2H), 6.39 (dq, 1-(nitrooxy)ethyl carbonate (HO-L2-R1) J=1.2, 6.0 Hz, 1H), 7.10-7.17 (m, 2H), 7.38 (dd, J–8.4, 1.5 0474 Silver nitrate (15.7g, 92.5 mmol) was added to a HZ, 1H), 7.65 (d. J=1.2 Hz, 1H), 7.70 (d. J=8.7 Hz, 2H); MS solution of (Z)-1-chloroethyl 4-hydroxybut-2-enyl carbonate m/Z: 429.1 M+Na". (HO-L2-R1-CI, 12.0 g. 61.7 mmol) in acetonitrile (120 mL) and the mixture was stirred at 80°C. for 2 h. HPLC analysis Step 4: Preparation of (2S)-((Z)-4-(1-(nitrooxy) of the mixture indicated completion of conversion. The mix ethoxy)carbonyloxy)but-2-enyl 2-(6-methoxynaph ture was cooled to RT and filtered through celite. The filtrate thalen-2-yl)propanoate (I-CD1-L2-R1) was concentrated to give the residue which was re-dissolved 0471 Silver nitrate (3.1 g, 18.8 mmol) was added to a in 200 mL of DCM and filtered through celite to remove the solution of (2S)-((Z)-4-(1-chloroethoxy)carbonyloxy)but separated silver chloride. The filtrate was washed with water 2-enyl) 2-(6-methoxynaphthalen-2-yl)propanoate (CD1-L2 (2x100 mL) and brine (2x100 mL), dried over NaSO and R1-C1, 5.0 g, 12.3 mmol) in 50 mL of ACN and the mixture concentrated in vacuo to give the crude product as yellow oil, was refluxed in dark at 85-90° C. for -40 min when TLC which was used as such in the next step. Yield: 8.9 g (65.3%); analysis of the mixture indicated complete conversion. The "H NMR (CDC1,300 MHz): & 1.60 (d. J=6.0 Hz, 3H), 1.99 mixture was cooled, diluted with DCM (~70 mL) and filtered (s, 1H), 4.28 (t, J=6.3 Hz, 2H), 4.80 (d. J–7.2 Hz, 2H), through celite. The filtrate was concentrated and the residue 5.64-5.75 (m, 1H), 5.90-5.98 (m, 1H), 6.93 (q, J=5.7 Hz, 1H). was re-dissolved in DCM (~50 mL) and the separated silver Step 3: Preparation of (Z)-4-(1-(nitrooxy)ethoxy) salt was filtered again through celite. The filtrate was concen carbonyloxy)but-2-enyl nicotinate (I-CD3-L2-R1) trated to give 7.0 g of residue which was purified by column chromatography (150.0 g of silica gel 200-400 mesh, eluted 0475. A solution of (Z)-4-hydroxybut-2-enyl 1-(nitrooxy) with 7-10% EtOAc in petroleum ether) to afford the title ethyl carbonate (HO-L2-R1, 0.6 g. 2.8 mmol) and pyridine compound as a white solid. Mp: 76-78° C.; Yield: 5.0 g (0.5 mL, 5.6 mmol) in 4 mL of DCM was added drop-wise to (93.7%); H NMR (CDC1,300 MHz): & 1.55-1.62 (m, 6H), a stirred suspension of nicotinoyl chloride hydrochloride 3.86 (q, J–7.2 Hz, 1H), 3.91 (s, 3H), 4.65-4.72 (m, 4H), (CD3-CI. HCl, 0.5g, 2.8 mmol) in 6 mL of DCM at 0° C. 5.65-5.79 (m, 2H), 6.89 (q, J=5.7 Hz, 1H), 7.10-7.18 (m, 2H), under a nitrogen atmosphere over 10 minutes and the result

US 2011/0263526 A1 Oct. 27, 2011

7.11-7.19 (m, 2H), 7.42 (bd, J=8.7 Hz, 1H), 7.68 (brs, 1H), 1H), 5.83-5.93 (m, 1H), 6.88 (brs, 1H), 6.98-7.19 (m, 14H); 7.72 (d. J=8.7 Hz, 2H); MS m/z: 472.1 M+Na". MS m/z: 669.3 M+H, 691.3 M+Na". Example 12 Step 3: (3R,5R)-((Z)-4-hydroxybut-2-enyl) 7-(2-(4- (3R,5R)-((Z)-4-(1-(nitrooxy)ethoxy)carbonyloxy) fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcar but-2-enyl) 7-(2-(4-fluorophenyl)-5-isopropyl-3- bamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5- (CD8-L2-OH) dihydroxyheptanoate NO-Atorvastatin (I-CD8-L2 0489 Montmorillonite Clay K-10 powder (1.8 g) was R1) added to a solution of (Z)-4-hydroxybut-2-enyl 2-((4R,6R)- 0486 This compound was synthesized in 5 steps as shown 6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenyl in Scheme 22 (via methodA) and the experimental procedure carbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan is described below: 4-yl)acetate CD8(PG')-L2-OH (4.5 g. 6.7 mmol) in 150 mL of methanol and the mixture was stirred at RT for 10 days Step 1: 2-((4R.6R)-6-(2-(2-(4-fluorophenyl)-5-iso when TLC analysis of the mixture indicated ~90% conver propyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1- sion. The mixture was filtered through celite and the filtrate yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid was concentrated and the crude residue (~4.0 g) thus obtained CD8(PG') was used as such in the next step. For obtaining analytical sample, a small amount (~100 mg) of this crude product was 0487. To a stirred suspension of atorvastatin calcium salt purified by column chromatography on silica gel (200-400 (10.0 g, 8.7 mmol) and 2,2-dimethoxypropane (5.3 mL, 43.3 mesh) using 2% acetone in DCM as eluent. The pure title mmol) in acetone (500 mL) at 0°C. was added concentrated sulfuric acid (-0.5 mL added drop wise) and the mixture was compound was obtained as a white solid. "H NMR (CDC1, Stirred at 0°C. for 3 hand at RT for additional 2 h. TLC of the 300 MHz): & 1.22-1.32 (m, 2H), 1.55 (d. J=6.9 Hz, 6H), mixture indicated ~90% conversion to the acetonide. The 1.65-1.72 (m, 2H), 2.20 (brs, 2H), 2.43 (d. J=6.0 Hz, 2H), mixture was concentrated in vacuo and about half of the 3.01 (brs, 1H), 3.54-3.65 (m, 1H), 3.70-3.80 (m, 1H), 3.90 residue (~7.0 g) was used as such in the next step. The remain 4.03 (m. 1H), 406-4.22 (m, 2H), 4.27 (d. J=6.6 Hz, 2H), 4.73 ing half of the crude product (-8.0 g) was purified by column (d. J=6.9 Hz, 2H), 5.60-5.70 (m, 1H), 5.82-5.95 (m. 1H), 6.87 chromatography on silica gel (200-400 mesh) using 5% (brs, 1H), 6.97-7.26 (m. 14H); MS m/z: 629.3 M+H",651.3 acetone in DCM to yield the pure title compound as white M+Na". solid; Purity by HPLC: 99.29% at 210 nm. "H NMR (CDC1, 300 MHz): & 1.34 (s, 3H), 1.39 (s.3H), 1.25-142 (m, 2H), Step 4: (3R,5R)-((Z)-4-(1-chloroethoxy)carbony 1.54 (d. J=7.2 Hz, 6H), 1.63-1.73 (m, 2H), 2.47 (dq, J=15.9, loxy)but-2-enyl) 7-(2-(4-fluorophenyl)-5-isopropyl 10.0, 6.6 Hz, 2H), 3.45-3.65 (m, 1H), 3.67-3.75 (m, 1H), 3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5- 3.80-393 (m, 1H), 4.05-4.25 (m, 2H), 6.89 (brs, 1H), 6.98 dihydroxyheptanoate (CD8-L2-R1-CI) 7.21 (m, 14H); MS m/z: 599.3 M+H", 621.3 M+Na". 0490 C-Chloroethyl chloroformate (CI-R1-CI, 0.8 mL, Step 2: (Z)-4-hydroxybut-2-enyl 2-((4R.6R)-6-(2-(2- 7.2 mmol) was added drop-wise to a solution of (3R,5R)-((Z)- (4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcar 4-hydroxybut-2-enyl) 7-(2-(4-fluorophenyl)-5-isopropyl-3- bamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3- phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihy dioxan-4-yl)acetate CD8(PG')-L2-OH) droxyheptanoate (CD8-L2-OH, 3.8 g. 6.0 mmol) in 100 mL of DCM at 0°C. under a nitrogen atmosphere. To this stirred 0488 1.1'-Carbonyldiimidazole (CDI, 3.4g, 21.0 mmol) mixture was added pyridine (6.2 mL, 76.4 mmol) and the was added as solid (in one lot) to a solution of 7.0 g (11.7 mixture was stirred at 0°C. under nitrogen for 1 h and at RT mmol) of 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl for overnight. TLC analysis of the mixture indicated -30% 3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2- completion. Additional amounts of C.-Chloroethyl chlorofor dimethyl-1,3-dioxan-4-yl)acetic acid (CD8(PG') in DCM mate (0.8 mL) and pyridine (0.9 mL) were added to the (100 mL) at RT and the mixture was stirred at RT for 1.5 h mixture at RT and mixture was stirred at RT for 1 h when TLC when TLC analysis indicated formation of the corresponding analysis of the mixture indicated about 40% conversion. CDI intermediate. This mixture was added to a suspension of Another 1.6 mL of C.-Chloroethyl chloroformate (total added: cis-2-butene-1,4-diol (HO-L2-OH, 4.2 g, 48.0 mmol) in 3.2 mL) and 1.8 mL of pyridine (total amount of pyridine DCM (150 mL) at 0°C. over a period of 20 minutes and the added: 3.6 mL) were added and the mixture was stirred for mixture was stirred at 0°C. for 4 hand at RT for 2 days. TLC additional 3 h when TLC analysis of the mixture indicated analysis of the mixture indicated completion of the reaction. ~70% product formation. The mixture was washed with 1N The mixture was washed with water (3x200 mL), brine HCl (3x100 mL), aqueous sodium bicarbonate (3x100 mL) (2x100 mL), dried over anhydrous sodium sulfate and con and brine (2x100 mL). The organic layer was dried over centrated in vacuo to afford 6.5g of a crude semisolid which NaSO and concentrated in vacuo to afford the crude product was purified by column chromatography on silica gel (150 as a sticky semisolid which was purified by column chroma 300 mesh) using 2% acetone in DCM as eluent. The pure title tography on silica gel (200-400 mesh) using 2% acetone in compound was obtained as a white solid, Yield: 4.7 g (58. DCM as eluent. The pure title compound was obtained as a 8%); H NMR (CDC1, 300 MHz): & 1.31 (s, 3H), 1.37 (s, light blue colored semisolid. Yield: 2.0 g (45.4%); H NMR 3H), 1.30-1.45 (m, 2H), 1.54 (d. J=6.9 HZ, 6H), 1.62-1.73 (m, (CDC1, 300 MHz): 81.25-1.60 (m, 2H), 1.56 (d. J=6.9 Hz, 2H), 2.42 (dq, J=15.6, 8.7, 6.0 Hz, 2H), 3.50-3.65 (m. 1H), 6H), 1.60- 1.80 (m, 2H), 1.88 (d. J–8.4 Hz, 3H), 2.20 (s, 1H), 3.66-3.77 (m. 1H), 3.78-3.92 (m, 1H), 405-4.23 (m, 3H), 2.44 (d. J=6.0 Hz, 2H), 3.50-3.67 (m, 1H), 3.72-3.82 (m, 1H), 4.26 (d. J=6.6 Hz, 2H), 4.70 (d. J=6.9 Hz, 2H), 5.57-5.68 (m, 3.90-4.05 (m, 1H), 4.10-4.30 (m, 2H), 4.73 (d. J=4.5 Hz, 2H), US 2011/0263526 A1 Oct. 27, 2011

4.82 (d. J–4.8 Hz, 2H), 5.82 (t, J=4.5 Hz, 2H), 6.43 (q, J–5.7 TLC analysis of the mixture indicated formation of a new HZ, 1H), 6.88 (s, 1H), 6.97-7.27 (m. 15H); MS m/z. 735.3 product. The mixture was diluted with DCM (-200 mL), M+H". washed with cold water (4x100 mL), 1N sodium bicarbonate (3x100 mL), and brine (2x100 mL). The organic layer was Step 5: (3R,5R)-((Z)-4-(1-(nitrooxy)ethoxy)carbo dried over NaSO and concentrated to give the crude product nyloxy)but-2-enyl) 7-(2-(4-fluorophenyl)-5-isopro as yellow oil which was purified by column chromatography pyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)- (silica gel 200-400 mesh, eluted with 20% EtOAc in petro 3,5-dihydroxyheptanoate NO-Atorvastatin (I-CD8 leum ether) to afford the title compound as yellow oil. Yield: L2-R1) 8.0 g (52.5%); H NMR (CDC1,300 MHz): 81.62 (d. J=7.2 0491 Silver nitrate (0.7 g, 3.9 mmol) was added to a Hz, 3H), 1.73-1.83 (m, 2H), 3.56 (t, J=6.0 Hz, 2H), 3.91 (s, solution of (3R,5R)-((Z)-4-(1-chloroethoxy)carbonyloxy) 3H), 3.97 (q, J=7.2 Hz, 1H), 4.25 (t, J=6.0 Hz, 2H), 4.59 (q, but-2-enyl) 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- J=20.4, 15.9 Hz, 2H), 7.09-7.17 (m, 2H), 7.42 (dd, J–8.4, 1.8 (phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyhep HZ, 1H), 7.69 (s, 1H), 7.72 (s, 1H), 8.00 (s, 1H); MS m/z. tanoate (CD8-L2-R1-CI, 1.9 g, 2.6 mmol) in 50 mL of ACN 369.1 M+Na". and the mixture was refluxed in dark at 85-90° C. for 3h when HPLC analysis of the mixture indicated complete conversion (Note: Retention time (T) of starting material and product Step 3: Preparation of (2S)-2-(3-((1-chloroethoxy) were the same and there was no precipitation of silver chlo carbonyloxy)propoxy)-2-oxoethyl 2-(6-methox ride in the reaction mixture. It was for that reason that the ynaphthalen-2-yl)propanoate (CD1-L6-R1-CI) mixture was refluxed for 3 h long). The mixture was cooled and filtered over celite. The filtrate was concentrated and the 0495 C.-Chloroethyl chloroformate (CI-R1-CI, 2.7 mL, residue thus obtained was purified by column chromatogra 27.7 mmol) followed by pyridine (2.8 mL, 34.5 mmol) were phy on silica gel (200-400 mesh) by using 4% acetone in added drop-wise to a stirred solution of 2-(3-hydroxypro DCM to afford the title compound as light yellow semisolid poxy)-2-oxoethyl 2-(6-methoxynaphthalen-2-yl)propanoate which solidified on standing. Mp: 56-58 C.; Yield: 1.5 g. (CD1-L6-OH, compound from step b above, 8.0 g, 23.0 (76.0%); H NMR (CDC1,300 MHz): & 1.25-1.35 (m, 2H), mmol) in 50 mL of HPLC grade DCM at 0°C. under nitrogen 1.56 (d. J–7.2 Hz, 6H), 1.61 (d. J=5.4 Hz, 3H), 1.45-1.80 (m, over 10 minutes and the mixture was stirred for ~40 minutes 3H), 2.44 (d. J=6.0 Hz, 2H), 3.50-3.67 (m, 2H), 3.72-3.82 (m, when TLC analysis of the mixture indicated completion of the 1H), 3.90-4.20(m, 1H),408-4.25 (m, 2H), 4.74 (d. J=5.1 Hz, reaction. After the usual aqueous work-up as described in 2H), 4.80 (d. J=5.1 Hz, 2H), 5.80-5.85 (m, 2H), 6.88 (brs, analogues experimental step above, the crude product was 1H), 6.93 (q, J=5.7 Hz, 1H), 6.98-7.22 (m. 14H); MS m/z: used as such in the next reaction. Yield: 10.0 g (96.0%); H 762.3 M+H, 784.3 M+Na". NMR (CDC1,300 MHz): & 1.62 (d. J=6.9 Hz, 3H), 1.82 (d. J=5.7 Hz,3H), 1.87-198 (m, 2H), 3.91 (s.3H), 3.97 (q, J=7.2 Example 13 HZ, 1H), 4.13-4.26 (m, 4H), 4.59 (q, J–21.3, 15.9 Hz, 2H), 6.40 (q, J=5.7 Hz, 1H), 7.09-7.19 (m,2H), 7.42 (dd, J–8.4, 1.8 (2S)-2-(3-((1-(nitrooxy)ethoxy)carbonyloxy)pro HZ, 1H), 7.70 (s, 1H), 7.71 (d mixed with singlet, J=8.1 Hz, poxy)-2-oxoethyl 2-(6-methoxynaphthalen-2-yl) 2H); MS m/z. 475.1 M+Na". propanoate NO-Naproxen (I-CD1-L6-R1) 0492. This compound was prepared in four steps as shown Step 4: Preparation of (2S)-2-(3-((1-(nitrooxy) in Scheme 3 and the experimental procedure is described ethoxy)carbonyloxy)propoxy)-2-oxoethyl 2-(6-meth below: oxynaphthalen-2-yl)propanoate (I-CD1-L6-R1) Step 1: Preparation of linker 3-hydroxypropyl 0496 Silver nitrate (5.3 g, 31.5 mmol) was added to a 2-chloroacetate (CI-L6-OH) stirred solution of 2-(3-(1-chloroethoxy)carbonyloxy)pro poxy)-2-oxoethyl 2-(6-methoxynaphthalen-2-yl)propanoate 0493 2-Chloroacetyl chloride (5.0 g, 44.2 mmol) fol (CD1-L6-R1-CI, compound from step 3 above, 9.5g, 20.9 lowed by TEA (9.2 mL, 66.4 mmol) were added drop-wise to mmol) in 70 mL of ACN and the mixture was refluxed gently a stirred solution of propane-1,3-diol (10.0 g, 132.7 mmol) in (at 85-90° C.) for 40 minutes when HPLC analysis of the 150 mL of DCM at 0°C. under nitrogen over 15 min and the mixture indicated completion of the reaction. The mixture mixture was stirred at RT for 4h when TLC analysis (HSO was cooled and diluted with DCM (-200 mL) and filtered spray) of the mixture indicated formation of a new product over celite. The filtrate was concentrated and the residue was CI-L6-OH as the major product. The mixture was concen re-dissolved in DCM (~100 mL) and filtered to remove the trated and the crude product thus obtained was used as such in precipitated silver salt. This process was repeated twice to the next step. remove most of the silver salt from the crude product. The Step 2: Preparation of (S)-2-(3-hydroxypropoxy)-2- residue thus obtained was purified by column chromatogra oxoethyl 2-(6-methoxynaphthalen-2-yl)propanoate phy (300.0 g silica gel, 200-400 mesh, eluted with 15-20% EtOAc in petroleum ether) to afford the title compound as (CD1-L6-OH) light yellow oil. Yield: 7.3 g (72.5%); H NMR (CDC1,300 0494. A solution of 3-hydroxypropyl 2-chloroacetate (CI MHz): & 1.60 (d. J=5.4 Hz, 3H), 1.64 (d. J–7.2 Hz, 3H), L6-OH, crude product obtained from the first step, ~44.0 1.89-1.98 (m, 2H), 3.94 (s.3H), 3.99 (q, J=7.2 Hz, 1H), 4.16 mmol) in 75 mL of DMF was added to naproxen cesium (10.0 (t, J=6.3 Hz, 2H), 4.21 (t, J=6.3 Hz, 2H), 4.63 (dq, J–21.0, g, 65.7 mmol, freshly prepared by treating naproxen with 15.9, 1.2 Hz, 2H), 6.93 (q, J=5.7 Hz, 1H), 7.12-7.19 (m, 2H), equimolar amount of cesium carbonate) in 25 mL of DMF 7.45 (dd, J=8.4, 1.8 Hz, 1H), 7.72 (s, 1H), 7.73 (d mixed with and the mixture was stirred at RT for overnight (~ 16 h) when singlet, J=8.4 Hz, 2H); MS m/z: 502.1 M+Nal", 518.1 US 2011/0263526 A1 Oct. 27, 2011

IM+K"; HRMS ESI (m/z): M+Na" calculated for solid. Yield: 7.0 g (60.1%); H NMR (DMSO-de, 300 MHz): CHNNaO: 502.1320; Found: 502.1330 (Mass Accu 8 2.26 (s.3H), 7.35 (dd, J=8.1, 0.9 Hz, 1H), 7.52 (dt, J=7.8, racy: -1.99 ppm). 0.9 Hz, 1H), 7.58-7.63 (two m, 1H), 7.73 (t, J=8.1 Hz, 1H), 0497. The compounds of examples 14 and 15 were pre 7.77-7.84 (m, 2H), 7.89 (distortedd, J–7.5 Hz, 1H), 8.21 (dd. pared by following the experimental procedure described for J=7.8, 1.5 Hz, 1H), 10.05 (s, 1H). preparing the compound of example 13. The characterization data for the compounds of examples 14 and 15 is described Step 2: Synthesis of 3-(hydroxymethyl)phenyl below: 2-acetoxybenzoate (CD2-L9-OH) Example 14 0502 Sodium borohydride (79 mg, 2.1 mmol) was added to a solution of 3-formylphenyl 2-acetoxybenzoate (CD2-L9 (2S)-2-(4-(1-(nitrooxy)ethoxy)carbonyloxy)bu CHO, 2.8 g., 9.9 mmol) in 30 mL of THF/MeOH (9:1) at 0°C., toxy)-2-oxoethyl 2-(6-methoxynaphthalen-2-yl)pro and the mixture was stirred at that temperature for 20 minutes panoate NO-Naproxen (I-CD1-L7-R1) when TLC analysis of the mixture indicated completion of the reaction. The mixture was slowly poured into 10 mL of ice 0498. The title compound was obtained as colorless vis cold 1N HCl and extracted with ethyl acetate (2x100 mL). cous oil. Yield (last step): 51.0%; H NMR (CDC1, 300 The organic layer was washed with brine (1x100 mL), dried MHz): & 1.55-1.68 (m, 10H), 3.91 (s.3H), 3.97 (q, J–7.2 Hz, over anhydrous NaSO and concentrated in vacuo to give a 1H), 4.07-4.17 (m, 4H), 4.59 (dd, J-21.0, 15.9 Hz, 2H), 6.92 Solid residue which was purified by column chromatography (q, J=5.7 Hz, 1H), 7.10-7.17 (m, 2H), 7.43 (dd, J–8.4, 1.5 Hz, (silica gel 100-200 mesh, eluted with a gradient of EtOAc in 1H), 7.70 (s, 1H), 7.71 (d mixed with singlet, J=8.1 Hz, 2H): petroleum ether and finally with DCM) to afford the title MS m/z: 493.1 M+H", 516.1 M+Na". compound as a white solid. Yield: 2.2 g (78.0%); H NMR Example 15 (DMSO-d 300 MHz): 8 2.25, (s, 3H), 4.54 (d. J=5.7 Hz, 2H), 5.34 (t, J=5.7 Hz, 1H Exchangeable with DO), 7.08 (d. (2S,3aS,6aS)-2-(nitrooxy)-4,13-dioxo-3,5,12-trioxa J=7.8 Hz, 1H), 7.16 (s, 1H), 7.25 (d. J=7.5 Hz, 1H), 7.33 (d. 8,9-dithiatetradecan-14-yl 1-(S)-2-((S)-1-ethoxy-1- J=8.1 Hz, 1H), 7.43 (t, J–7.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), oXo-4-phenylbutan-2-ylamino)propanoyl)octahydro 7.77 (t, J–7.8 Hz, 1H), 8.15 (distorted dd, J=7.2, 1.5 Hz, 1H). cyclo-pentablpyrrole-2-carboxylate NO-Ramipril (I-CD9-L8-R1) Step 3: Synthesis of 3-(((1-chloroethoxy)carbony loxy)methyl)phenyl 2-acetoxybenzoate (CD2-L9 0499. The title compound was obtained as colorless oil. Yield (last step): 36.0%; H NMR (CDC1, 500 MHz): 8 R1-CI) 1.20-1.32 (m, 6H), 1.60 (d. J=5.5 Hz, 3H), 1.50-2.17 (m, 0503 A solution of C-chloroethyl chloroformate (C-R1 10H), 2.40-2.52 (m, 1H). 2.60-2.76 (m, 2H), 2.78-2.88 (m, CI, 0.18 mL, 1.3 mmol) in 1 mL of DCM was added drop 1H), 2.91-2.98 (m, 4H), 3.18 (t, J–6.5 Hz, 1H), 3.65 (q, J=6.5 wise to a stirred solution of 3-(hydroxymethyl)phenyl 2-ac HZ, 1H), 4.18 (q, J=7 Hz, 2H), 4.31 (q, J–7.5 Hz, 1H), 4.39 etoxybenzoate (CD2-L9-OH, 0.3 g, 1.1 mmol) and pyridine 4.47 (m, 4H), 4.56 (d. J=16.0 Hz, 1H), 4.65-4.71 (m, 1H), (0.1 mL, 1.3 mmol) in dichloromethane (3 mL) at 0°C. The 4.80 (d.J=16.0 Hz, 1H), 6.93 (q, J=5.5 Hz, 1H), 7.14-7.29 (m, mixture was stirred at 0°C. for 30 minutes when TLCanalysis 5H); MS m/z: 744.1 M+H". of the mixture indicated completion of the reaction. The mix ture was diluted with DCM (~10 mLl), washed with water Example 16 (1x10 mL) and brine (1x10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give an oily crude 3-(((1-(nitrooxy)ethoxy)carbonyloxy)methyl)phenyl product which was purified by column chromatography on 2-acetoxybenzoate NO-Aspirin/Salicylic acid silica gel by eluting with a gradient of EtOAC in petroleum (I-CD2-L9-R1) ether to afford the title compound as colorless viscous oil. 0500. The title compound was synthesized in four steps as Yield: 0.4 g (93.7%); H NMR (CDC1,300 MHz): & 1.85 (d. shown in Scheme 4 and the experimental procedure is J=5.7 Hz,3H), 2.33 (s.3H), 5.26 (AB qJ=12.3 Hz, 2H), 6.45 described below: (q, J=5.7 Hz, 1H), 7.16-7.27 (m, 3H), 7.38-7.51 (d. J=7.5 Hz, 1H), 7.38-7.50 (m, 2H), 7.67 (dt, J=7.8, 1.5 Hz, 1H),8.23 (dd, Step 1: Synthesis of 3-formylphenyl J=7.8, 1.5 Hz, 1H). MS m/z. 410.1 M+NH, 415.0 2-acetoxybenzoate (CD2-L9-CHO) M+Na". 0501) A solution of 3-hydroxybenzaldehyde (HO-L9 Step 4: Synthesis of 3-(((1-(nitrooxy)ethoxy)carbo CHO, 5.0 g, 40.9 mmol) and triethylamine (12.4 g/14.4 mL, nyloxy)methyl)phenyl 2-acetoxybenzoate (I-CD2 122.8 mmol) in 50 mL of DCM was added drop-wise to a stirred solution of aspirin acid chloride (freshly prepared L9-R1) from 14.7 g (81.9 mmol) of aspirin by using oxalyl chloride/ 0504 Silver nitrate (0.2g, 0.9 mmol) was added in one lot DMF method) in 100 mL of DCM at 0° C. and the mixture to a stirred solution of 3-(((1-chloroethoxy)carbonyloxy)me was stirred at RT for overnight when TLC analysis of the thyl)benzyl 2-acetoxybenzoate (CD2-L9-R1-C1, 1.4g, 3.5 mixture indicated completion of the reaction. The mixture mmol) in ACN (20 mL) at RT and the mixture was stirred at was diluted with 100 mL of DCM and washed with water 60-70° C. for 2 h when TLC analysis of the mixture indicated (100 mL) and brine (100 mL), dried over anhydrous NaSO completion of the reaction The mixture was cooled to RT, and concentrated in vacuo to give a solid residue which was diluted with 10 mL of DCM and filtered over celite pad. The purified by column chromatography (silica gel 100-200 filtrate was concentrated and the residue thus obtained was mesh, eluted with a gradient of EtOAc in petroleum ether and purified by column chromatography on silica gel and eluted finally with DCM) to afford the title compound as a white with a gradient of EtOAc in petroleum ether to afford the title US 2011/0263526 A1 Oct. 27, 2011

compound as yellow viscous oil. Yield: 0.3 g (81.2%); H 737-748 (m, 4H), 7.58 (dt, J=7.8, 1.5 Hz, 1H), 8.09 (d. J=1.5 NMR (CDC1, 300 MHz): & 1.62 (d. J=5.7 Hz, 3H), 2.33 (s, HZ, 1H); MS m/z:407.1 M+H, 429.1 M+Na". 3H), 5.24 (AB q, J=12.3 Hz, 2H), 6.97 (q, J=5.7 Hz, 1H), 7.18-7.27 (m,3H), 7.31 (d. J=7.8 Hz, 1H), 7.37-7.53 (m, 2H), Step 3: Synthesis of 3-(((1-(nitrooxy)ethoxy)carbo 7.67 (t, J=7.8, 1 H), 8.24 (dd, J=7.8, 1.5 Hz, 1H); MS m/z: nyloxy)methyl)benzyl 2-acetoxybenzoate (I-CD2 437.1 M+NH, 442.1 M+Na". L10-R1) 0508 Silver nitrate (0.9 g, 5.2 mmol) was added in one lot Example 17 to a stirred solution of 3-(((1-chloroethoxy)carbonyloxy)me thyl)benzyl 2-acetoxybenzoate (CD2-L10-R1-CI, 1.4g, 3.5 3-(((1-(nitrooxy)ethoxy)carbonyloxy)methyl)benzyl mmol) in ACN (20 mL) at RT and the mixture was stirred at 2-acetoxybenzoate NO-Aspirin/Salicylic acid 80° C. for 1.5 h. The mixture was cooled to RT and filtered (I-CD2-L10-R1) over celite pad. The filtrate was concentrated and the residue thus obtained was partitioned between EtOAc (75 mL) and 0505. The title compound was synthesized in three steps water (75 mL). The organic layer was washed with brine as shown in Scheme 1 and the experimental procedure is (1x75 mL), dried over anhydrous NaSO and concentrated to give an oily crude residue which was purified by column described below: chromatography (silica gel, 40.0 g, 200-400 mesh 30% EtOAc in hexane) to afford the title compound as yellow oil. Step 1: Synthesis of 3-(hydroxymethyl)benzyl Yield: 1.1 g (74.0%); H NMR (CDC1,300 MHz): & 1.63 (d. 2-acetoxybenzoate (CD2-L10-OH) J=6.0 Hz,3H), 2.17 (s.3H), 5.24 (s. 2H), 5.32 (s.2H), 6.96 (q, J=6.0 Hz, 1H), 7.11 (d. J=9.0 Hz, 1H), 7.31-744 (m, 5H), 0506 A solution of aspirin acid chloride (3.0 g, 16.7 7.58 (dt, J=6.0 Hz, 1H), 8.07 (dd, J=1.8 Hz, 1H); MS m/z: mmol, freshly prepared from aspirin using oxalyl chloride/ 434.2 M+H, 456.1 M+Na". DMF method) in dichloromethane (15 mL) was added to a 0509. The compounds of examples 18-20 were prepared stirred solution of 1,3-benzenedimethanol (HO-L10-OH, 2.3 by following the experimental procedure described for pre g, 16.6 mmol) and triethylamine (6.96 mL, 49.9 mmol) in paring the compound of example 17. The characterization dichloromethane (12 mL) at 0°C. The mixture was stirred at data for the compounds of examples 18-20 is described RT for 8 h when TLC analysis of the mixture indicated below: completion of the reaction. The mixture was concentrated and the residue was partitioned between ethyl acetate (100 mL) Example 18 and water (50 mL). The organic layer was separated, washed (6-(((1-(nitrooxy)ethoxy)carbonyloxy)methyl)pyri with brine (1x50 mL), dried over anhydrous NaSO and din-2-yl)methyl 2-acetoxybenzoate NO-Aspirin/ concentrated in vacuo to give the crude oily residue which Salicylic acid (I-CD2-L11-R1) was purified by column chromatography (silica gel, 150.0 g, 200-400 mesh, 30% EtOAc in hexane) to afford the title 0510. The title compound was also obtained as yellow oil. compound as colorless oil. Yield: 1.9 g (38.2%); H NMR Yield (last step): 68.0%; H NMR (CDC1,300 MHz): & 1.64 (d. J=5.7 Hz, 3H), 2.27 (s, 3H), 5.29-5.34 (distorted AB (CDC1, 300 MHz): 8 1.99 (t, J=5.7 Hz, 1H), 2.14 (s, 3H), quartet or m, 2H), 5.44 (s. 2H), 6.98 (d. J=5.7 Hz, 1H), 7.14 4.73 (d. J=5.4 Hz, 2H), 5.33 (s. 2H), 7.10 (d. J=8.1 Hz, 1H), (dd, J=8.1, 0.9 HZ, 1H), 7.31-7.42(m,3H), 7.61 (dt, J–7.8, 1.8 7.30-743 (m, 5H), 7.58 (dt, J=7.8, 1.5 Hz, 1H), 8.08 (dd, HZ, 1H), 7.78 (t, J=7.8 Hz, 1H), 8.12 (dd, J=7.8, 1.8 Hz, 1H): J=7.8, 1.5 Hz, 1H); MS m/z: 301.1 M+H, 323.1 M+Na)". MS m/z. 435.1 M+H", 457.1 M+Na". Step 2: Synthesis of 3-(((1-chloroethoxy)carbony Example 19 loxy)methyl)benzyl 2-acetoxybenzoate (CD2-L10 (4-(((1-(nitrooxy)ethoxy)carbonyloxy)methyl)cyclo R1-CI) hexyl)methyl 2-(2-(2,6-dichlorophenylamino)phe 0507 C-Chloroethyl chloroformate (CI-R1-CI, 0.5 mL, nyl)acetate NO-Diclofenac (I-CD6-L12-R1) 4.6 mmol) was added drop-wise to a stirred solution of 3-(hy 0511. The title compound was obtained as pale yellow droxymethyl)benzyl 2-acetoxybenzoate (CD2-L10-OH, 1.1 gum. Yield (last step): 54.0%; H NMR (CDC1, 300 MHz): g, 3.8 mmol) and pyridine (0.6 mL, 7.6 mmol) in dichlo 8 0.85-198 (m, 10H), 1.61 (d. J=5.7 Hz, 3H), 3.83 (s. 2H), romethane (12 mL) at 0°C. The mixture was stirred at 0°C. 3.97-4.16 (m, 4H), 6.57 (d. J–7.8 Hz, 1H), 6.91-7.04 (m, 4H), for 30 minutes when TLC analysis of the mixture indicated 7.14 (dt, J–7.8, 1.2 Hz, 1H), 7.25 (dd, J=7.5, 1.2 Hz, 1H), 7.36 completion of the reaction. The mixture was concentrated in (d. J–7.8 Hz, 2H); MS m/z. 555.1 M+H, 577.1 M+Na". vacuo and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was separated and Example 20 washed with brine (1x50 mL), dried over anhydrous NaSO 4-(1-(nitrooxy)ethoxy)carbonyloxy)cyclohexyl and concentrated in vacuo to give an oily crude product which 2-(2-(2,6-dichlorophenylamino)phenyl)acetate NO was purified by column chromatography (silica gel, 60.0 g, Diclofenac (I-CD6-L13-R1) 200-400 mesh, 30% EtOAc in hexane) to afford the title compound as colorless oil. Yield: 1.4 g (91.0%); H NMR 0512. The title compound was obtained as pale yellow (CDC1, 300 MHz): & 1.84 (d. J=5.7 Hz, 3H), 2.18 (s, 3H), gum. Yield (last step): 66.0%; H NMR (CDC1, 300 MHz): 5.26 (d. J–2.1 Hz, 2H), 5.33 (s. 2H), 6.45 (q, J=5.7 Hz, 1H), & 1.63 (d. J=5.7 Hz, 3H), 1.67-2.00 (m, 8H), 3.82 (s. 2H), 7.11 (dd, J=8.1, 0.6 Hz, 1H), 7.34 (dt, J=7.8, 0.9 Hz, 1H), 4.73-4.83 (m, 1H), 4.89-4.98 (m, 1H), 6.57 (d. J=7.8 Hz, 1H), US 2011/0263526 A1 Oct. 27, 2011

6.89-7.04 (m, 4H), 7.14 (dt, J=7.8, 1.5 Hz, 1H), 7.25 (dd. The crude product was purified by column chromatography J=7.5, 1.2 Hz, 1H), 7.36 (d. J=8.1 Hz, 2H); MS m/z. 527.6 (80.0 g of silicagel, 200-400 mesh, eluted with 10% EtOAc in M+H". petroleum ether) and the following two products were sepa rated: Example 21 0516 Less polar CD1-L14-R1-CI-A: HPLC analysis of this isolated product (single spot on TLC) was shown to (2S)-4-(1-(nitrooxy)ethoxy)carbonyloxy)tetrahydro contain two diastereomers with retention times (T) of 9.414 furan-3-yl 2-(6-methoxynaphthalen-2-yl)propanoate & 9.508 min (peak ratio: 42:54): Obtained as an oil. Yield: 1.1 |NO-Naproxen (I-CD1-L14-R1-A & I-CD1-L14-R1 g (43.0%). "HNMR (CDC1,300 MHz, (mixture of diastere B) (Mixture of diastereomers) omers)): 81.42 (d. J=6.0 Hz, 1.5H), 1.57 (t, J=7.2 Hz, 3H), 0513. The title compound was synthesized in 3 steps as 1.74 (d.J=6.0Hz, 1.5 Hz), 3.71-3.87(m, 2H), 3.87-3.94 (mor shown in Scheme 1 and the experimental procedure is q buried under methoxy singlet, 1H), 3.91 (s.3H), 4.01-4.15 described below: (m. 2H), 5.15-5.40 (m, 2H), 5.83, 6.35 (two q in ~1:1, J=5.7 HZ, 1H (i.e., 0.5H each)), 7.15-7.19 (m, 2H), 7.38 (d. J–8.7 Step 1: Synthesis of (2S)-4-hydroxytetrahydrofuran HZ, 1H), 7.64 (d. J=6.9 Hz, 1H), 7.69 (d. J=8.7 Hz, 2H); MS 3-yl 2-(6-methoxynaphthalen-2-yl)propanoate (CD1 m/Z: 445.1 M+Na". L14-OH) 0517 More polar CD1-L14-R1-CI-B: HPLC analysis of this isolated product (single spot on TLC) was shown to 0514. A solution of naproxen acid chloride (CD1-1, contain two diastereomers with retention times (T) of 9.386 freshly prepared from 10.0 g (43.4 mmol) of naproxen using and 9.476 min (43:56): Obtained as an oil. Yield: 1.0 g (38. oxalyl chloride/DMF method) in 20 mL of DCM was added 5%). 'HNMR (CDC1, 300 MHz, (mixture of diastere to a stirred solution of 1,4-anhydroerythritol (HO-L14-OH, omers)): 81.59 (d, overlapping with the doublet at 1.61 ppm, 9.1 g (~7.1 mL), 86.9 mmol) and TEA (18.0 mL, 130.0 mmol) J–7.2 Hz, 1.5H) 1.61 (d, overlapping with the doublet at 1.59 in 20 mL of DCM at 0°C. over a period of 30 minutes and the ppm, J=7.2 Hz, 1.5H), 1.73 (d. J=5.7 Hz, 3H), 1.85 (d. J=6.0 mixture was stirred at 0°C. for 1.5h when TLC analysis of the Hz, 3H), 3.61-4.17 (m, 5H), 3.93 (s.3H), 5.24-5.34 (m, 2H), mixture indicated formation of a major mono adduct along 6.30-6.45 (m, 1H), 7.10-7.18 (m, 2H), 7.42 (dt, J=1.5, 8.4 Hz, with the expected minor bis-adduct. The mixture was diluted 1H), 7.66-7.77 (m, 3H); MS m/z. 445.1 M+Na". with saturated sodium bicarbonate (~100 mL) and the organic layer was separated. The aqueous layer was extracted with Step 3: Synthesis of (2S)-4-(1-(nitrooxy)ethoxy) DCM (2x100 mL). The organic extracts were combined, carbonyloxy)tetrahydrofuran-3-yl 2-(6-methox dried over anhydrous NaSO filtered and concentrated to ynaphthalen-2-yl)propanoate (I-CD1-L14-R1-A or give 12.0 g of crude residue which was purified by column B) (Mixture of diastereomers A & B) chromatography (silica gel 150-300 mesh, the bis-adduct and 0518 Silver nitrate (0.5g, 3.2 mmol. 1.2 eqs.) was added other non-polar impurities were eluted with 5-10% EtOAc in to a solution of (2S)-4-(1-chloroethoxy)carbonyloxy)tet petroleum ether and the desired mono-adduct was eluted with rahydrofuran-3-yl 2-(6-methoxynaphthalen-2-yl)propanoate 13-15% EtOAc in petroleum ether) to afford the title com (CD1-L14-R1-CI-A, Less polar product A, 1.1 g, 2.6 mmol. pound as a white solid. Yield: 8.0 g (58.2%); H NMR 1.0 eq.) in 10 mL of ACN and the mixture was refluxed at (CDC1, 300 MHz) (Mixture of diastereomers): & 1.609, 85-90° C. for 2 h when TLC analysis of the mixture indicated 1.614 (two overlapping doublets, J=6.9, 7.2 Hz, 3H), 3.52-3. completion of the reaction with the formation of two product 72 (m, 2H), 3.77-4.10 (m, 5H), 3.91 (s.3H), 4.30 (q, J=5.7, spots (i.e., less polar (spot) product I-CD1-L14-R1-Aa and 5.4 Hz, 0.5H), 4.40 (q, J=5.7, 5.4 Hz, 0.5H), 5.07-5.19 (m, more polar (spot) product I-CD1-L14-R1-Ab). The reaction 1H), 7.09-7.20 (m, 2H), 7.37-7.44 (m or distorted doublet, mixture was diluted with 10 mL of DCM, filtered over celite 1H), 7.66-7.76 (m, 3H); MS m/z. 317.1 M+H", 339.1 and the filtrate was concentrated and the residue was dis M+Na', 355.1 M+K". solved again in 20 mL of DCM and washed with water (3x20 Step 2: Synthesis of (2S)-4-(1-chloroethoxy)carbo mL), brine (1x20 mL), dried over anhydrous NaSO and nyloxy)tetrahydrofuran-3-yl 2-(6-methoxynaphtha concentrated to give an oily residue which was purified by column chromatography (40.0 g of silica gel, 200-400 mesh, len-2-yl)propanoate (CD1-L14-R1-CI-A & CD1 eluted with 5-8% EtOAc in petroleum ether) to afford the title L14-R1-CI-B) (Mixture of diastereomers A & B) compound as the following diastereomeric mixtures: 0515 C.-Chloroethyl chloroformate (CI-R1-CI, 1.0 g (0.8 0519 Less polar (spot) product I-CD1-L14-R1-Aa: mL), 7.6 mmol. 1.2 eqs.) followed by pyridine (0.8 mL, 9.5 HPLC analysis of this product was shown to contain two mmol. 1.5 eqS.) were added drop-wise to a stirred solution of diastereomers with retention times (T) of 9.44 & 9.53 min (2S)-4-hydroxytetrahydrofuran-3-yl 2-(6-methoxynaphtha (peak ratio: 43:56); obtained as a viscous oil. Yield: 0.2g len-2-yl)propanoate (CD1-L14-OH, 2.0 g. 6.3 mmol. 1.0 eq.) (14.4%); HNMR (CDC1, 300 MHz, (mixture of diastere in 20 mL of DCM at 0°C. under nitrogen and the mixture was omers in ~43:56)): 81.21-1.28 (m, 3H), 1.51-1.62 (m, 3H), stirred at 0°C. for 2 hand at RT for 1 h when TLC analysis of 3.91 (s.3H), 3.83-3.89 (m,3H), 4.00-4.13 (m, 2H), 5.18-5.34 the mixture indicated completion of the reaction. The mixture (m. 2H), 6.65 (q, J=5.7 Hz, 0.5H), 6.86 (q, J=5.7 Hz, 0.5H), was diluted with 20 mL of DCM and washed with 1N HC1 7.11-7.16 (m, 2H), 7.38 (d. J=8.4 Hz, 1H), 7.65-7.71 (m,3H): (3x40 mL), aqueous sodium bicarbonate (3x40 mL), dried MS m/z. 472.1 M+Na". over anhydrous NaSO and concentrated to give 2.0 g of 0520 More polar (spot) product I-CD1-L14-R1-Ab: crude product as slightly yellow colored oil. Although TLC HPLC analysis of this product was shown to contain two analysis of the crude product indicated two major new spots diastereomers with retention times (T) of 9.39 & 9.48 min or products (CD1-L14-R1-CI-A and CD1-L14-R1-CI-B), (peak ratio: 43:56): Obtained as a green viscous oil. Yield: 0.7 HPLC analysis of the same crude product revealed 4 peaks. g (55.9%); HNMR (CDC1, 300 MHz, (mixture of diastere US 2011/0263526 A1 Oct. 27, 2011

omers in -45:55)): & 1.47-1.62 (m, 6H), 3.61-3.82 (m, 3H), (dt, J=7.8, 1.2 Hz, 1H), 7.59 (dt, J–7.8, 1.5 Hz, 1H), 8.02 (dd, 3.91 (s, 3H), 3.85-3.91 (m, buried under OCH signal, 1H), J=7.8, 1.5 Hz, 1H), MS m/z: 422.1 M+Na". 4.15-3.95 (m, 2H), 5.19-5.33 (m, 2H), 6.80 (q, J=5.7 Hz, 0.5H), 6.95 (q, J=5.7 Hz, 0.5H), 7.12-7.16 (m, 2H), 7.31-7.42 Example 23 (m. 1H), 7.67-7.72 (m, 3H); MS m/z: 472.1 M+Na". (3S,6R)-6-((1-(nitrooxy)ethoxy)carbonyloxy) 0521. The following isomers were obtained by following hexahydrofuro3,2-bfuran-3-yl2-acetoxybenzoate the same procedure involving the treatment of (2S)-4-(1- chloroethoxy)carbonyloxy)tetrahydrofuran-3-yl 2-(6-meth |NO-Aspirin/Salicylic acid (I-CD2-L15-R1) (Mix oxynaphthalen-2-yl)propanoate (CD1-L14-R1-CI-B, the ture of diastereomers) more polar product B, 1.0g, 2.4 mmol. 1.0 eq.) with 0.5 g (2.8 0528. The title compound was synthesized in 4 steps as mmol. 1.2 eqS.) of silver nitrate: shown in Scheme 5 and the experimental procedure is 0522) Less polar (spot) product I-CD1-L14-R1-Ba: HPLC described below: analysis of this product was shown to contain two diastere 0529 Steps 1 and 2: Synthesis of (3S,6R)-6-hydroxy omers with retention times (T) of 9.44 & 9.53 min (peak hexahydrofuro3.2-bfuran-3-yl 2-acetoxybenzoate (CD2 ratio: 43:56): Obtained as a viscous oil. Yield: 0.6 g (64.0%); L15-OH) 'HNMR (CDC1,300 MHz, (mixture of two diastereomers in 0530. This known compound (CD2-L15-OH) was synthe -47:53)): & 1.21-1.28 (m, 3H), 1.51-1.62 (m, 3H), 3.76-3.89 sized according to the method described by Moriarty et al., J. (m,3H), 3.91 (s.3H), 4.00-4.13 (m, 2H), 5.18-5.36 (m, 2H), Med. Chem. 51,7991-7999, 2008. Thus, 6.0 g of 10% Pd/C 6.56(q, J=5.7 Hz, 0.5H), 6.86, (q, J=5.7 Hz, 0.5H), 7.11-7.16 was added to a solution of (3S,6R)-6-(nitrooxy)hexahydro (m. 2H), 7.38 (d. J=8.4 Hz, 1H), 7.65 (s, 1H), 7.70 (d. J–8.4 furo3,2-bfuran-3-yl 2-acetoxybenzoate (CD2-L15-ONO. Hz, 2H); MS m/z: 472.1 M+Na". 6.3 g, 17.8 mmol; This known compound was prepared 0523 More polar (spot) product I-CD1-L14-R1-Bb: according to the method described by Gilmer et al., Eur. J. HPLC analysis of this product was shown to contain two Pharm. Sci. 14, 221-227, 2001) in 100 mL of 1:1 MeOH and diastereomers with retention times (T) of 9.39 & 9.48 min EtOAc and the mixture was stirred under one atmosphere of (peak ratio: 43:56): Obtained as a green viscous oil. Yield: 0.3 hydrogen for 16 h when TLC analysis of the mixture indi g (25.0%); 'HNMR (CDC1,300 MHz, (mixture of two dias cated completion of the reaction. The mixture was passed tereomers in -39:45)): & 1.42-1.61 (m, 6H), 3.61-3.89 (m, through a small pad of celite and solids were washed with 100 3H), 3.91 (s.3H), 3.86-4.15 (m, 4H), 5.21-5.35 (m, 2H), 6.80 mL of fresh 1:1 mixture of MeOH and EtOAC. The used (q, J=5.7 Hz, 0.5H), 6.95 (q, J=5.7 Hz, 0.5H), 7.12-7.15 (m, catalyst was disposed off carefully. The filtrate was concen 2H), 737-7.42 (m, 1H), 7.66-7.72 (m, 3H); MS m/z: 472.1 trated to give 6.0 g of oily residue which was purified by M+Na". column chromatography (60.0 g of silica gel, 200-400 mesh, 0524. The compound of example 22 was prepared by fol eluted with DCM followed by 5% MeOH in DCM). The title lowing the experimental procedure described for preparing compound (CD2-L15-OH) was obtained as colorless viscous the compound of example 21. The characterization data of the oil. Yield: 5.4 g (98.0%): 'HNMR (CDC1, 300 MHz) (Mix compound is described below: ture of diastereomers): 8 2.36 (S. 3H), 3.59, 3.62 (two dou blets in ratio of ~4:5, J=6.0, 5.7 Hz, respectively, 1H), 3.90, 3.93 (two doublets in ratio of ~5:4, J=6.0, 5.7 Hz, respec Example 22 tively, 1H), 4.06, 4.09 (two doublets in ratio of -3:7, J=3.3 Hz, 4-(1-(nitrooxy)ethoxy)carbonyloxy)tetrahydrofuran 3.6 Hz, respectively, 1H), 4.14. 4.18 (two singlets in ratio of 3-yl 2-acetoxybenzoate NO-Aspirin/Salicylic acid -7:3, 1H), 4.33 (q, J–11.7, 5.7 Hz, 1H), 4.57 (unsymmetrical d, J=4.2 Hz, 1H), 4.68 (t, J=4.8 Hz, 1H), 5.44 (d. J=3.3 Hz, (I-CD2-L14-R1-A & I-CD2-L14-R1-B) (Mixture of 1H), 7.11 (dd, J=8.1, 0.6 Hz, 1H), 7.32 (dt, J=7.8,0.9 Hz, 1H), diastereomers) 7.55-7.63 (m, 1H), 7.99 (dd, J=7.8, 1.8 Hz, 1H); MS m/z: 0525. As expected, the title compound was obtained as 331.1 M+Na". mixture of diastereomers, I-CD2-L14-R1-A or I-CD2-L14 R1-B and they were isolated and characterized as described Step 3: Synthesis of (3S,6R)-6-(1-chloroethoxy) below: carbonyloxy)hexahydrofuro3.2-bfuran-3-yl 2-ac 0526 Less polar diastereomer I-CD2-L14-R1-A: etoxybenzoate (CD2-L15-R1-CI-A or CD2-L15-R1 Obtained as oil. Yield: 0.3 g (24.4%), T3.95 min (HPLC CI-B) (Mixture of diastereomers) Method: Isocratic at 1:1 ACN/water); 'HNMR (CDC1, 300 0531 C.-Chloroethyl chloroformate (CI-R1-CI, 0.4 mL, MHz): & 1.43 (d. J=5.7 Hz, 3H), 2.35 (s, 3H), 3.91-402 (m, 3.9 mmol. 1.2 eqs.) followed by pyridine (0.4 mL, 4.9 mmol. 2H), 4.07-4.23 (m, 2H), 5.38 (q, J=5.4 Hz, 1H), 5.56 (q, J–5.4 1.5 eqs.) were added drop-wise to a stirred solution of (3S, HZ, 1H), 6.84 (q, J=5.7 Hz, 1H), 7.12 (d. J=8.1 Hz, 1H), 7.33 6R)-6-hydroxyhexahydrofuro3.2-bfuran-3-yl 2-acetoxy (distorted dt, J–7.8, 0.9 HZ, 1H), 7.59 (dt, J=7.8, 1.5 Hz, 1H), benzoate (CD2-L15-OH, 1.0 g, 3.2 mmol. 1.0 eq.) in 5 mL of 8.02 (dd, J–7.8, 1.5 Hz, 1H), MS m/z: 422.1 M+Na". DCM at 0° C. under nitrogen (over ~10 minutes) and the 0527. More polar diastereomer I-C2-L14-R1-B: Obtained mixture was stirred at 0°C. for 30 minutes and at RT for 1 h as oil. Yield: 0.2 g (20.3%); T =3.56 min (HPLC Method: when TLC analysis of the mixture indicated completion of the Isocratic at 1:1 ACN/water); 'HNMR (CDC1, 300 MHz): 8 reaction. The mixture was diluted with 20 mL of DCM and 30 1.57 (d. J=5.7 Hz, 3H), 2.35 (s.3H), 3.88, 3.92 (two doublets, mL of 1N HC1. The layers were separated. The organic layer ~4:5, J=5.7, 5.4 Hz, respectively, 1H), 3.97, 4.00 (two dou was washed with 1 NHCl (1x20 mL), aqueous sodium bicar blets, ~2:3, J-3.9 Hz, each, 1H), 4.12, 4.16 (two doublets, bonate (3x25 mL), brine (2x20 mL), dried over anhydrous ~3:2, J=5.4 Hz, each, 1H), 4.18, 4.22 (two doublets, ~5:4, Na2SO and concentrated to give 1.2 g of crude product as a J=6.3 HZeach, 1H), 5.38 (q, J=5.4 Hz, 1H), 5.53 (q, J=5.7 Hz, gum. TLC analysis of the crude product indicated two major 1H), 6.87 (q, J=5.7 Hz, 1H), 7.11 (dd, J=8.1, 0.6 Hz, 1H), 7.33 new spots or products (CD2-L15-R1-CI-A and CD2-L15 US 2011/0263526 A1 Oct. 27, 2011

R1-CI-B). The crude product was purified by column chro 1.61 (d. J=5.7 Hz, 3H), 2.35 (s.3H), 3.89, 3.92 (two doublets matography (30.0 g of silica gel, 200-400 mesh, eluted with in ratio of ~1:3, J=5.4 Hz, each, 1H), 3.96, 4.00 (two doublets 15-20% EtOAc in petroleum ether) and the following two in ratio of -3:1, J=3.9 HZeach, 1H), 4.03, 4.06 (two doublets products were separated: in ratio of ~ 1:3, J=3.3 Hz, each, 1H), 4.10, 4.13 (two singlets 0532. Less polar CD2-L15-R1-CI-A: HPLC analysis of in ratio of-3:1, 1 H), 4.55 (d. J–4.8 Hz, 1H), 4.94 (t, J=5.1 Hz, this isolatedless polar product showed single peak with reten 1H), 5.11 (distorted q, J=9.3, 3.9 HZ, 1H), 5.42 (d. J=3.0 Hz, tion time (T) of 4.546 min (HPLC Method: isocratic at 1:1 1H), 6.94 (q, J=5.7 Hz, 1H), 7.10 (dd, J=8.1, 0.6 Hz, 1H), 7.31 ACN/water): Obtained as a sticky solid. Yield: 0.6 g (42.4%); (dt, J=7.8, 0.9 Hz, 1H), 7.58 (dt, J–7.8, 1.5 Hz, 1H), 7.98 (dd, 'HNMR (CDC1,300 MHz): & 1.85 (d.J–24 Hz,3H), 2.35 (s, J=7.8, 1.5 Hz, 1H); MS m/z: 464.1 M+Nal". 3H), 3.85-4.18 (m, 4H), 4.57 (d. J–4.8 Hz, 1H), 4.95 (t, J–5.1 HZ, 1H), 5.14 (q, J=9.0, 4.5 Hz, 1H), 5.42 (d, J-3.0 Hz, 1H), Example 24 6.45 (q, J=11.4, 5.7 Hz, 1H), 7.10 (dd, J=8.1, 0.9 HZ, 1H), 7.31 (dt, J=7.5,0.9 Hz, 1H), 7.55 (dt, J=7.8, 1.5 Hz, 1H), 7.98 (2S)-2-(2-((1-(nitrooxy)ethoxy)carbonyloxy)ethyl (dd, J=8.1, 1.8 Hz, 1H); MS m/z: 437.0M+Na". sulfinyl)ethyl 2-(6-methoxy naphthalen-2-yl)pro 0533. More polar CD2-L15-R1-CI-B: HPLC analysis of panoate NO-Naproxen (I-CD1-L16-R1) this isolated more polar product showed single peak with 0536 The above compound was synthesized in 4 steps as retention time (T) of 4.317 min (HPLC Method: isocratic at shown in Scheme 6 and the experimental procedure is 1:1 ACN/water): Obtained as a sticky solid. Yield: 0.4 g described below: (32.7%); 'HNMR (CDC1, 300 MHz): & 1.84 (d. J=6.0 Hz, 3H), 2.35 (s.3H), 3.88-4.16 (m, 4H), 4.56 (d. J–4.8 Hz, 1H), Step 1: Preparation of (S)-2-(2-hydroxyethylthio) 4.95 (t, J=5.1 Hz, 1H), 5.14 (q, J=9.0, 4.5 Hz, 1H), 5.42 (d. ethyl 2-(6-methoxynaphthalen-2-yl)propanoate J=3.0 Hz, 1H), 6.43 (q, J=12.0, 6.0Hz, 1H), 7.10 (d. J=7.8 Hz, (CD1-L16S-OH) 1H), 7.31 (t, J–7.5 Hz, 1H), 7.58 (dt, J=7.8, 1.5 Hz, 1H), 7.99 (dd, J=7.8, 1.5 Hz, 1H); MS m/z: 437.0M+Na". 0537. A solution of freshly prepared naproxen acid chlo ride (CD1-CI, 16.0 g, 64.0 mmol) in DCM (-50 mL) was Step 4: Synthesis of (3S,6R)-6-((1-(nitrooxy)ethoxy) added to a stirred solution of 2,2'-thiodiethanol (HO-L16S carbonyloxy)hexahydrofuro3.2-bfuran-3-yl 2-ac OH, 26.0g, 256.0 mmol. 3.3 eqs.) in 100 mL of DCM at 0°C. etoxybenzoate (I-CD2-L15-R1-A or I-CD2-L15-R1 under nitrogen. To this stirred mixture was added triethy B) (Mixture of diastereomers) lamine (TEA, 13.0 mL. 92.9 mmol. 1.5 eqs.) drop-wise over 30 minutes and the mixture was stirred at RT under nitrogen 0534 Silver nitrate (0.3 g 1.7 mmol. 1.2 eqs.) was added for overnight. TLC analysis of the mixture indicated comple to a solution of (3S,6R)-6-(1-chloroethoxy)carbonyloxy) tion of the reaction. The mixture was washed with saturated hexahydrofuro3.2-bfuran-3-yl 2-acetoxybenzoate (CD2 sodium bicarbonate (3x100 mL) and brine (2x100 mL) to L15-R1-CI-A, Less polar product A, 0.6 g. 1.4 mmol. 1.0 eq.) remove the remaining un-reacted water-soluble linker. The in 15 mL of ACN and the mixture was refluxed at 85-90° C. organic layer was dried over anhydrous Na2SO4 and concen for 3 h when TLC analysis of the mixture indicated comple trated in vacuo to give 22.0 g of crude product which was tion of the reaction with the formation of the desired com purified by column chromatography (300.0 g of silica gel. pound I-CD2-L15-R1-A as the major product. The reaction 200-400 mesh). The expected bis-derivative was eluted with mixture was filtered and the filtrate was concentrated. The 10% EtOAc in petroleum ether. The desired compound was residue was diluted with 40 mL of DCM and washed with eluted with 15-25% EtOAc in petroleum ether. The pure title water (3x40 mL), brine (2x40 mL), dried over anhydrous compound (CD1-L16S-OH) was obtained as light yellow oil NaSO and concentrated to give a sticky solid residue which which solidified at low temperature (<0° C.). Yield: 17.4g was purified by column chromatography (25.0 g of silica gel. (81.3%); H NMR (CDC1, 300 MHz): & 1.60 (d. J=6.9 Hz, 200-400 mesh, eluted with 20-25% EtOAc in petroleum 3H), 2.63 (t, J=6.0 Hz, 2H), 2.70 (t, J=6.9 Hz, 2H), 3.62 (t, ether) to afford the title compound as a sticky solid. HPLC J=5.7 Hz, 2H), 3.88 (q, J–7.2 Hz, 1H), 3.93 (s.3H), 4.26 (t, analysis of this product has shown single peak with retention J=6.9 Hz, 2H), 7.10-7.20 (m, 2H), 7.41 (dd, J–8.4, 1.5 Hz, time (T) of 4.538 min (HPLC method: isocratic at 1:1 ACN/ 1H), 7.67-7.77 (m,3H); MS m/z:357.1 M+Na". This inter water); Yield: 0.3 g (43.3%); HNMR (CDC1, 300 MHz): 8 mediate was also synthesized in good yields by the reaction of 1.61 (d. J=5.7 Hz, 3H), 2.36 (s.3H), 3.87, 3.91 (two doublets naproxen with the corresponding diol in the presence of cou in ratio of ~ 1:2, J=5.4, 5.1 Hz, respectively, 1H), 3.95-4.17 pling agents such as DCC, DMAP in a suitable solvent such (m,3H), 4.54 (d. J–4.8 Hz, 1H), 4.94 (t, J=5.1 Hz, 1H), 5.00 as DCM or DMF. (q, J=9.3, 1.2 Hz, 1H), 5.42 (d, J-3.0 Hz, 1H), 6.94 (q, J=5.7 HZ, 1H), 7.10 (d. J=8.1 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.57 Step 2: Preparation of (2S)-2-(2-((1-chloroethoxy) (dt, J=7.8, 1.5 Hz, 1H), 8.00 (dd, J=7.8, 1.5 Hz, 1H); MS m/z: carbonyloxy)ethylthio)ethyl 2-(6-methoxynaphtha 464.0 M+Na". len-2-yl)propanoate (CD1-L16S-R1-CI) 0535. The other diastereomer isomer I-CD2-L15-R1-B was also obtained by following the same experimental pro 0538 C-Chloroethyl chloroformate (CI-R1-CI, 6.0 mL, cedure involving treatment of (3S,6R)-6-(1-chloroethoxy) 61.0 mmol) was added drop-wise to a solution of 2-(2-hy carbonyloxy)hexahydrofuro3.2-bifuran-3-yl 2-acetoxyben droxyethylthio)ethyl 2-(6-methoxynaphthalen-2-yl)pro Zoate (CD2-L15-R1-CI-B, the more polar product B, 0.4g, panoate (CD1-L16S-OH, 17.0g, 50.9 mmol) in 100 mL of 1.1 mmol. 1.0 eq.) with 0.2 g (1.2 mmol. 1.2 eqS.) of silver DCM at 0° C. under nitrogen. To this stirred mixture was nitrate. HPLC analysis of this product has shown single peak added a solution of pyridine (6.2 mL, 76.4 mmol) in 50 mL of with retention time (T) of 4.792 min (HPLC method: iso DCM over 5 minutes. The mixture was stirred at 0°C. under cratic at 1:1 ACN/water); this product was obtained as a sticky nitrogen for 1 h. TLC analysis of the mixture indicated solid. Yield: 0.3 g (59.8%); 'HNMR (CDC1, 300 MHz): 8 completion of the reaction. The mixture was washed with 1N US 2011/0263526 A1 Oct. 27, 2011

HCl (3x100 mL) and brine (2x100 mL). The organic layer M+Na"; HRMS ESI (m/z): M+Na" calculated for was dried over NaSO and concentrated in vacuo to afford CHNNaOS: 506. 1091: Found: 506.1109 (Mass the title compound (CD1-L16S-R1-CI) as yellow oil of suf Accuracy: -3.56 ppm). ficient purity to be used as such in the next step. Yield: 21.0 g (93.6%); H NMR (CDC1, 300 MHz): & 1.58 (d. J=6.6 Hz, Example 25 3H), 1.82 (d. J=6.0 Hz,3H), 2.64-2.77 (m, 4H), 3.86 (q, J–7.2 HZ, 1H), 3.91 (s.3H), 4.20 (t, J=6.9Hz, 2H), 4.24 (t, J=6.9Hz, (2S)-2-(2-((1-(nitrooxy)ethoxy)carbonyloxy)ethyl 2H), 6.40 (q, J=5.7 Hz, 1H), 7.10-7.18 (m, 2H), 7.39 (dd. sulfonyl)ethyl 2-(6-methoxy naphthalen-2-yl)pro J=8.4, 1.5 Hz, 1H), 7.65-7.74 (m, 3H); MS m/z: 463.1 panoate NO-Naproxen (I-CD1-L17-R1) M+Na. 0541. The title compound was synthesized as shown in Scheme 6 and the experimental procedure is described below: Step 3: Preparation of (2S)-2-(2-((1-(nitrooxy) 0542. A solution of oxone (4.7g, 7.7 mmol) in ~20 mL of ethoxy)carbonyloxy)ethylthio)ethyl 2-(6-methox water was added to a stirred solution of CD1-L16S-R1 (7.5 g. ynaphthalen-2-yl)propanoate (CD1-L16S-R1) 16.0 mmol) in 75 mL of 2:1 methanol/acetone at 0°C. over 10 0539 Silver nitrate (12.1 g, 71.3 mmol) was added to a minutes and the resulting turbid solution was stirred for over solution of 2-(2-(1-chloroethoxy)carbonyloxy)ethylthio) night when TLC analysis of the mixture indicated formation ethyl 2-(6-methoxynaphthalen-2-yl)-propanoate (CD1 of the intermediate sulfoxide. Additional 8.0 g (~13.0 mmol) of oxone as solution in water (-35 mL) was added to the L16S-R1-CI, 21.0 g, 47.6 mmol) in 175 mL of ACN and the mixture and the resulting turbid mixture was diluted with ~80 mixture was refluxed in dark at 85-90° C. for ~45 minutes mL of methanol and stirring was continued at RT for 1 h when when HPLC analysis of the mixture indicated complete con TLC analysis of the mixture indicated formation of the sul version. The mixture was cooled and filtered through celite. fone product. The mixture was concentrated on rotavap and The filtrate was concentrated and the residue was re-dissolved the residue thus obtained was dissolved in -300 mL of DCM in DCM (~100 mL) and filtered through celite to remove the and washed with water (3x100 mL) and brine (2x100 mL). precipitated silver chloride. The filtrate was concentrated in The organic layer was dried over anhydrous Na2SO4 and vacuo and the residue thus obtained was purified by column concentrated on rotavap to give -10.0 g of yellow oil which chromatography (400.0 g of silica gel, 200-400 mesh, eluted was purified by column chromatography (300.0 g of silica with 13% EtOAc in petroleum ether) to afford the title com gel, 200-400 mesh). The residual sulfide intermediate was pound as yellow oil. Yield: 20.0 g (89.8%); H NMR (CDC1, eluted with 10-15% EtOAc in petroleum ether. Elution with 300 MHz): 8 1.55-1.63 (m, 6H), 2.64-2.77 (m, 4H), 3.86 (q, 1:1 MeOH/DCM afforded the title compound as a slightly J–7.2 Hz, 1H), 3.91 (s, 3H), 4.19 (t, J=6.9 Hz, 2H), 4.24 (t, yellow colored solid. Mp: 98-100° C.; Yield: 5.0 g (62.5%); J=6.6 Hz, 2H), 6.90 (q, J=5.7 Hz, 1H), 7.10-7.18 (m, 2H), "H NMR (CDC1,300 MHz): & 1.55-1.63 (m, 6H), 2.43-2.74 7.39 (dd, J=8.4, 1.5 Hz, 1H), 7.65-7.74 (mor distortedt, 3H): (m. 2H), 3.10-3.33 (m, 2H), 3.82-3.95 (m, 2H), 3.92 (s.3H), CNMR (CDC1, 75.47 MHz): & 17.5, 18.6, 30.5, 30.8, 45.5, 4.05-4.16 (m. 1H), 4.38-4.48 (m. 1H), 4.51-4.62 (m. 1H), 55.4, 64.1, 67.4, 96.4, 105.7, 119.2, 126.1, 126.3, 127.3, 6.83-6.94 (m, 1H), 7.10 (d. J–2.1 Hz, 1H), 7.16 (dd, J=9.0, 2.4 129.0, 129.4, 133.8, 135.5, 152.6, 157.8, 174.5; MS m/z: HZ, 1H), 7.33 (dd, J–8.4, 1.2 Hz, 1H), 7.63 (s, 1H), 7.65-7.75 490.1 M+Na"; HRMS ESI (m/z): M+Na" calculated for (m. 2H); 'C NMR (CDC1, 75.47 MHz): & 16.9, 17.7, 44.9, CHNNaOS: 490.1142: Found: 490.1147 (Mass 52.0, 53.4, 54.9, 57.9, 58.0, 60.7, 96.0, 105.1, 119.2, 125.5, Accuracy: -1.02 ppm). 125.8, 127.1, 128.3, 128.7, 133.3, 134.5, 134.6, 1514, 157.6, 173.2: MS m/z: 498.8 M-H; HRMS ESI (m/z): M+Nat Step 4: Preparation of (2S)-2-(2-((1-(nitrooxy) calculated for CHNNaOS: 522.1041: Found: 522. ethoxy)carbonyloxy)ethylsulfinyl)ethyl 2-(6-methox 1063 (Mass Accuracy: -4.21 ppm). ynaphthalen-2-yl)propanoate (I-CD1-L16-R1) 0543. The compounds of the examples 26 and 27 were (0540. A solution of sodium periodate (NaIO 5.5g, 25.6 prepared by following the experimental procedure described mmol) in 25 mL of water was added drop-wise to a stirred for preparing the compound of example 25 except that 3,3'- solution of CD1-L16S-R1 (8.0 g, 17.0 mmol) in 100 mL of thiodipropanol CAS #: 10595-09-2 was used as the starting 3:1 methanol/acetone over 15 minutes and the resulting turbid diol linker. The characterization data of the compounds of mixture was stirred at RT for ~4h when TLC analysis of the examples 26 and 27 is provided below. mixture indicated >90% conversion. The mixture was con centrated and the residue thus obtained was diluted with 100 Example 26 mL of DCM and washed with water (3x100 mL) and brine (2S)-3-(3-((1-(nitrooxy)ethoxy)carbonyloxy)propy (1x100 mL). The organic layer was dried over anhydrous lthio)propyl 2-(6-methoxy naphthalen-2-yl)pro NaSO and concentrated to give a crude product (~9.0 g) panoate NO-Naproxen (I-CD1-L 18-R1) which was triturated and sonicated with 40% EtOAc in petro leum ether to afford the title compound (I-CD1-L16-R1) as a 0544 The title compound (I-CD1-L18-R1) was obtained white solid. Mp: 112-115° C.; Yield: 1.6 g (19.0%); H NMR as yellow oil. Yield (last step): 96.0%; H NMR (CDC1,300 (CDC1,300 MHz): 81.53-1.63 (m, 6H), 2.52-3.10 (m, 4H), MHz): & 1.60 (d. J=7.2 Hz, 3H), 1.61 (d. J=5.7 Hz, 3H), 3.87 (q, J–6.9 Hz, 1H), 3.91 (s, 3H), 4.09-4.67 (m, 4H), 1.75-1.91 (m, 4H), 2.40 (t, J=7.2 Hz, 2H), 2.43 (t, J–7.2 Hz, 6.86-6.94 (m, 1H), 7.12 (s, 1H), 7.15 (d. J=9.0 Hz, 1H), 7.37 2H), 3.87 (q, J–7.2 Hz, 1H), 3.94 (s.3H), 4.10-4.26 (m, 4H), (d. J=8.4 Hz, 1H), 7.65 (s, 1H), 7.71 (d. J=8.1 Hz, 2H); 'C 6.94 (q, J=5.7 Hz, 1H), 7.12-7.19 (m,2H), 7.41 (dd, J–8.4, 1.5 NMR (CDC1, 75.47 MHz): & 16.9, 17.7, 44.9, 50.2, 50.3, HZ, 1H), 7.68 (d. J=1.2 Hz, 1H), 7.72 (unsymmetricald, J–8.7 50.6, 50.8, 51.1, 54.9, 56.3, 56.4, 56.5, 60.5, 95.9, 96.0, 105.2, Hz, 2H); 'C NMR (CDC1, 75.47 MHz): & 16.9, 17.9, 27.6, 118.8, 118.9, 125.7, 126.9, 128.4, 128.8, 133.3, 134.62, 151. 27.7, 27.8, 28.1, 45.0, 54.8, 62.6, 66.7, 95.7, 105.1, 118.5, 7, 157.4, 1574, 173.6; MS m/z. 484.0 M+H", 506.0 125.4, 125.7, 126.6, 128.4,128.7, 133.2, 135.2, 152.1, 157.2, US 2011/0263526 A1 Oct. 27, 2011

174.0; MS m/z: 495.1.1 M+H", 518.1 M+Na; HRMS (t, J=6.0 Hz, 1H), 720-7.28 (m, 2H), 7.37 (d. J=4.5 Hz, 1H): ESI (m/z): M--Nal" calculated for CHNNaOS: 518. MS m/z: 628.2 M+H, 651.2 M+Na". 1455; Found: 518.1465 (Mass Accuracy: - 1.93 ppm). Step 2: Preparation of the title compound Example 27 NO-Amlodipine (I-AD1-L2-R1) (2S)-3-(3-((1-(nitrooxy)ethoxy)carbonyloxy)propyl Sulfinyl)propyl 2-(6-methoxynaphthalen-2-yl)pro 0549 Silver nitrate (0.6 g., 3.3 mmol) was added to a panoate NO-Naproxen (I-CD1-L19-R1) stirred solution of the intermediate AD1-L2-R1-CI (1.4g, 2.2 mmol) in 25 mL of ACN at RT and the mixture was stirred at (0545. The title compound (I-CD1-L19-R1) was obtained -90° C. for 1.5 h when HPLC analysis of the mixture indi as yellow oil. Yield (last step): 1.4 g (70.0%). "H NMR cated completion of the reaction. The mixture was cooled and (CDC1, 300 MHz) (Mixture of diastereomers): & 1.60 (dd. filtered through celite pad. The filtrate was concentrated and J=5.7, 1.5 Hz, 6H), 1.92-2.11 (m, 4H), 2.23-2.55 (m, 4H), the residue obtained was partitioned between EtOAc (75 mL) 3.87 (q, J–7.2 Hz, 1H), 3.93 (s.3H), 4.09-4.37 (m, 4H), 6.94 and water (75 mL). The EtOAc layer was separated, washed (q, J–5.7 Hz, 1H), 7.13 (distortedd, J-2.4 Hz, 1H), 7.18 (dd. with brine (1x75 mL), dried over anhydrous NaSO and J=8.7, 2.4 Hz, 1H), 7.40 (dd, J=7.2, 1.2 Hz, 1H), 7.67 (brs, concentrated in vacuo to give the crude product which was 1H), 7.71 (d, J=8.4 Hz, 2H); 'C NMR (CDC1, 75.47 MHz) purified by column chromatography on silica gel by eluting (Mixture of diastereomers): & 16.9, 17.6, 21.5, 21.6, 21.8, with 20% EtOAc in hexane to afford the title compound as 44.9, 47.8, 48.3, 54.8, 62.2, 62.3, 66.4, 66.5, 95.8, 105.1, yellow oil. Yield: 1.2g (81.0%): 'HNMR (CDC1,300MHz): 118.7, 125.4,125.7, 126.7, 128.3, 128.7, 133.2, 135.1, 135.2, & 1.20 (t, J–7.2 Hz, 3H), 1.60 (d. J=5.4 Hz, 2H), 2.38 (s. 2H), 152.0, 157.3, 173.9; MS m/z 512.2 M+H, 534.1 M+Na". 2.67 (s, 1H), 3.33-3.70 (m, 7H), 3.98-4.16 (m, 2H), 4.64-4.87 HRMS ESI (m/z): M+H" calculated for CHNOS: (m, 6H), 5.05 (bris, 0.7H), 5.32 (s, 0.37H), 5.42 (s, 0.7H), 512.1585; Found: 512.1598 (Mass Accuracy: -2.17 ppm). 5.55-5.63 (m, 0.25H), 5.70-5.90 (m, 2H), 6.94 (q, J=5.7 Hz, Purity by HPLC (a 210 nm: 96.39%. 1H), 7.02-7.47 (m, 5H); MS m/z. 654.2 M-HI. 0546. Examples of the compounds of formula I which are the prodrugs of the drugs containing an amino group: Example 29 Example 28 Ethyl 2-(1-(14-(nitrooxy)-3,12-dioxo-4,11,13-trioxa (Z)-3-ethyl 5-methyl 4-(2-chlorophenyl)-6-methyl-2- 7,8-dithia-2-azapentadecyl)cyclohexyl)acetate NO (15-(nitrooxy)-6,13-dioxo-2,7,12,14-tetraoxa-5-aza Gabapentin ethyl ester (I-AD2-L1-R1) hexadec-9-enyl)-1,4-dihydropyridine-3,5-dicarboxy 0550 This compound was synthesized in 4 steps as shown late NO-Amlodipine (I-AD1-L2-R1) in Scheme 9 and the experimental procedure is described 0547. This compound was synthesized in 2 steps as shown below: in Scheme 8 and the experimental procedure is described below: Step 1: Preparation of ethyl 2-(1-(3,12-dioxo-4, 11 dioxa-7,8-dithia-2-azamidecyl)cyclohexyl)acetate Step 1: Preparation of (Z)-3-ethyl 5-methyl 2-(15 (AD2-L1-OAc) chloro-6,13-dioxo-2,7,12,14-tetraoxa-5-azahexadec 9-enyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropy 0551. To a stirred solution of diphosgene (1.4 mL, 12.0 ridine-3,5-dicarboxylate (AD1-L2-R1-CI) mmol) in 4 mL of dry DCM at 0°C. under nitrogen was added a solution of 2-((2-hydroxyethyl)disulfanyl)ethyl acetate 0548. A solution of triphosgene (0.5g, 1.7 mmol) in 4 mL (HO-L1-OAc, 0.8 g. 4.0 mmol, freshly prepared by mono of DCM was added to a stirred solution of amlodipine besy acetylation of 2-hydroxyethyl disulfide (HO-L1-OH)) and late (2.9 g, 5.1 mmol) and triethylamine (1.5 mL, 10.1 mmol) diisopropylethylamine (DIPEA, 3.5 mL, 19.9 mmol) in 4 mL in 26 mL of DCM at RT and the mixture was stirred for 1.5h of DCM over 20 minutes and the mixture was stirred at the to get the crude isocyanate intermediate AD1-IM1. To this same temperature for 40 minutes. The mixture was concen stirred mixture was added a solution of (Z)-1-chloroethyl trated at RT to give the crude formyl chloride CI-L1-OAc. A 4-hydroxybut-2-enyl carbonate (HO-L2-R1-CI, 1.0 g, 5.1 mixture of gabapentin ethyl ester hydrochloride (0.9 g, 4.0 mmol, freshly prepared as described in Example 4) in 4 mL of mmol, freshly prepared from gabapentin using thionyl chlo DCM and the mixture was stirred at RT for 12 h when TLC ride/ethanol method) and DIPEA (1.4 mL, 8.0 mmol) in 4 mL analysis of the mixture indicated formation of a new product. of DCM was added to the intermediate formyl chloride The mixture was diluted with DCM (40 mL), washed with 0.5 CI-L1-OAc at 0° C. under nitrogen and the mixture was NHCl (1x40 mL) & brine (1x50 mL). The organic layer was stirred at RT for overnight (~12 h). The mixture was concen dried over MgSO and concentrated on rotavap to give a trated and the residue was re-dissolved in 25 mL of ethyl residue which was purified by column chromatography on acetate and washed with water (1x10 mL) and brine (1x10 silica gel by eluting with 30% EtOAc in hexane to afford the mL). The organic layer was dried over NaSO and concen title compound AD1-L2-R1-CI as yellow oil. Yield: 1.5 g. trated in vacuo to get 2.9 g of crude product as yellow oil (47.0%); H NMR (CDC1, 300 MHz): & 1.18 (t, J=4.2 Hz, which was purified by column chromatography (silica gel. 3H), 1.82 (d. J=3.6 Hz. 3H), 2.36 (s.3H), 3.42-3.51 (m, 2H), 90.0g, 200-400 mesh, eluted with 30% EtOAc in hexane) to 3.59-3.68 (m, 5H), 4.01-4.08 (m, 2H), 4.64-4.78 (m, 4H), afford the title compound as colorless oil. Yield: 1.2 g (73. 4.82 (d. J=3.6 Hz, 2H), 5.05 (brs, 1H), 5.40 (s, 1H), 5.74-5.87 0%); H NMR (CDC1, 300 MHz): & 1.22 (t, J=7.3 Hz, 3H), (m. 2H), 6.42(q, J=3.6 Hz, 1H), 7.04 (t, J–4.5 Hz, 1H), 7.14 1.27-1.68 (m, 10H), 2.06 (s.3H), 2.27 (s. 2H), 2.91 (t, J=6.6 US 2011/0263526 A1 Oct. 27, 2011

Hz, 4H), 3.19 (d. J=6.7 Hz, 2H), 4.12 (q, J–7.2 Hz, 2H), 4.31 2H), 4.31 (t, J–3.9 Hz, 2H), 4.45 (t, J=3.9 Hz, 2H), 5.37-5.48 (q, J=6.4 Hz, 4H), 5.40 (brs, 1H); MS m/z. 422 M+H, 444 (m. 1H), 6.93 (q, J=3.3 Hz, 1H); MS (ESI) m/z: 534.8 M+Na". M+Na". Step 2: Preparation of ethyl 2-(1-(((2-((2-hydroxy ethyl)disulfanyl)ethoxy)-carbonylamino)methyl) Example 30 cyclohexyl)acetate (AD2-L1-OH) 0555 (Z)-4-(1-(nitrooxy)ethoxy)carbonyloxy)but-2- 0552. To a stirred solution of AD2-L1-OAc (1.2g, 2.8 enyl (S)-2-(2-oxopyrrolidin-1-yl)butanoylcarbamate NO mmol) in 10 mL of methanol at 0°C. was added an ice-cold Levetiracetam (I-AD3-L2-R1) solution of KCO (0.6 g. 4.3 mmol) in 2 mL of water over a 0556. This compound was synthesized as shown in period of 30 minutes when TLC analysis of the mixture Scheme 8 and the experimental procedure is described below: indicated consumption of all the starting material. The mix 0557. Oxalyl chloride (1.2 mL, 14.0 mmol) was added to ture was filtered and the solid residue was washed with a solution of (S)-2-(2-oxopyrrolidin-1-yl)butanamide (AD3, methanol (10 mL). The filtrate was concentrated and the levetiracetam, 2.0 g, 11.7 mmol) in 10 mL of 3:1 mixture of residue was re-dissolved in 30 mL of ethyl acetate and DCE/DCM and the mixture was refluxed for 8 h to yield the washed with water (1x10 mL) and brine (1x10 mL). The corresponding isocyanate AD3-IM1. To this cooled and organic layer was dried over NaSO and concentrated to give stirred mixture was added drop-wise a solution of (Z)-4- 0.9 g of crude product which was purified by column chro hydroxybut-2-enyl 1-(nitrooxy)ethyl carbonate (HO-L2-R1, matography (silica gel, 30.0 g, 200-400 mesh, eluted with 2.5g, 11.7 mmol, freshly prepared as described in Example 4) DCM) to afford the title compound (AD2-L1-OH) as yellow in 10 mL of DCM over 5 minutes and the mixture was stirred oil. Yield: 0.4 g (32.0%); H NMR (CDC1,300 MHz): & 1.25 at RT for 12 h when TLC analysis of the mixture showed (t, J–7.2 Hz, 3H), 1.30-1.71 (m. 10H), 2.87-2.94 (m, 4H), completion of the reaction. The mixture was concentrated to 2.27 (s. 2H), 3.18 (d. J=6.6 Hz, 2H), 3.87 (t, J=5.7 Hz, 2H), give a residue which was purified by column chromatography 4.09-4.16 (q, J=7.1 Hz, 2H), 4.31 (t, J=6.6 Hz, 2H), 5.44 (br (silica gel 150-300 mesh, eluted with 40% EtOAc in petro s, 1H); MS m/z: 380 M+H, 402 M+Na". leum ether) to afford the title compound (I-AD3-L2-R1) as yellow oil. Yield: 1.5 g (30.6%); H NMR (CDC1,300 MHz): Step 3: Preparation of ethyl 2-(1-(14-chloro-312 8 0.90 (t, J–7.2 Hz, 2.25H), 0.94 (t, J=7.2 Hz, 0.75H), 1.61 (d. dioxo-4,11,13-trioxa-7,8-dithia-2-azapentadecyl) J=5.4 Hz, 3H), 1.80-2.15 (m, 4H), 2.38-2.50 (m, 2H), 3.03 cyclohexyl)acetate (AD2-L1-R1-CI) 3.15 (m, 0.75H), 3.31-3.41 (m, 0.25H), 3.48-3.58 (m, 0.25H), 0553 C.-Chloroethyl chloroformate (CI-R1-CI, 0.2 mL, 3.64-3.77 (m, 0.75H), 4.09 (m. 1H), 4.68-4.76 (m, 2H), 4.78 2.1 mmol) was added drop-wise to a stirred solution of AD2 4.86 (m, 2H), 5.73-5.92 (m, 2H), 6.94 (q, J=5.4 Hz, 5.7 Hz, L1-OH (0.4g, 1.1 mmol) and pyridine (0.2 mL, 2.1 mmol) in 1H), 8.04 (brs, 1H); MS m/z. 440.1 M+Na". 10 mL of DCM at 0°C. under nitrogen and the mixture was 0558. The compounds of examples 31-33 were prepared stirred at RT for 45 minutes when TLC analysis of the mixture by following the procedure as indicated in example 30. The indicated formation of the desired product. The mixture was characterization data for the compounds of examples 31-33 is washed with 0.5 NHCl (1x10 mL) and brine (1x10 mL), provided below: dried over MgSO and concentrated in vacuo to give a residue which was purified by column chromatography (silica gel. Example 31 15.0g, 200-400 mesh eluted with 20% EtOAc in hexane) to afford the title compound (AD2-L1-R1-CI) as yellow oil. (Z)-4-(1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl Yield: 0.4 g (83.0%); H NMR (CDC1,300 MHz): & 1.28 (t, (Z)-5H-dibenzob.fazepine-5-carbonylcarbamate J=7.2 Hz, 3H), 1.34-1.60 (m, 10H), 1.85 (d. J=6.0 Hz, 3H), NO-Carbamazepine (I-AD4-L2-R1) 2.30 (s. 2H), 2.92-3.03 (m, 4H), 3.22 (d. J=6.9 Hz, 2H), 4.15 (q, J–7.2 Hz, 2H), 4.30-4.38 (m, 2H), 4.48 (t, J–6.6 Hz, 2H), 0559 The title compound (I-AD4-L2-R1) was obtained as 5.42 (t, J–7.5 Hz, 1H), 6.44 (q, J=6.0Hz, 1H); MS m/z:508.1 an off-white gum. Yield: 0.6 g (55.4%); H NMR (CDC1,300 M+Na". MHz): & 1.59 (d. J=5.4 Hz, 3H), 4.72 (d. J=5.4 Hz, 2H), 4.77 (mixedd, J=5.1 Hz, 2H), 5.70-5.85 (m, 2H), 6.68 (brs, 1H), Step 4: Preparation of NO-Gabapentin ethyl ester/ 6.93 (q, J=5.4 Hz, 1H), 6.98 (s. 2H), 7.37-7.45 (m, 4H), Ethyl 2-(1-(14-(nitrooxy)-3,12-dioxo-4,11,13-trioxa 747-7.53 (m, 4H); MS (EI) m/z. 484.1 M+H", 506.1 7,8-dithia-2-azapentadecyl)cyclohexyl)acetate M+Na". (I-AD2-L1-R1) 0554 Silver nitrate (0.2g, 1.2 mmol) was added as a solid Example 32 to a stirred solution of AD2-L1-R1-CI (0.4g, 0.8 mmol) in 10 mL of ACN at RT and the mixture was stirred at 85-90° C. for (Z)-4-(1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl 1.5 h. The mixture was allowed to attain RT, filtered through 10-oxo-10,11-dihydro-5H-dibenzob.fazepine-5- celite, the celite bed was washed with fresh ACN (15 mL). carbonylcarbamate NO-Oxcarbazepine (I-AD5-L2 The filtrate and washings were combined and concentrated in R1) vacuo to get a residue which was purified by column chro matography (silica gel, 15.0g, 200-400 mesh, 20% EtOAc in 0560. The title compound (I-AD5-L2-R1) was obtained as hexane) to afford the title compound as yellow oil. Yield: 0.2 an off-white gum. Yield: 30.6%; H NMR (CDC1, 300 g (48.0%); H NMR (CDC1,300 MHz): & 1.26 (t, J=4.2 Hz, MHz): & 1.60 (d. J=5.7 Hz, 3H), 3.89 (d.J=14.7 Hz, 1H), 4.45 3H), 1.34-1.58 (m. 10H), 1.60 (d. J=3.3 Hz, 3H), 2.29 (s. 2H), (d. J=14.4 Hz, 1H), 4.75-4.79 (m, 4H), 5.76-5.83 (m, 2H), 2.90-2.99 (m, 4H), 3.20 (d. J–3.9 Hz, 2H), 4.13 (q, J–4.2 Hz, 6.92 (q, J=5.7 Hz, 1H), 7.07 (brs, 1H), 737-7.52 (m, 5H), US 2011/0263526 A1 Oct. 27, 2011 90

7.57-7.68 (m, 2H), 8.13 (d. J–7.5 Hz, 1H); MS (EI) m/z: mmol) in 3 mL of DCM was added drop-wise to a stirred 500.1 M+H, 522.1 M+Na". solution of diphosgene (0.1 mL, 0.9 mmol) in 1 mL of DCM at 0° C. under nitrogen over 10 minutes and the resulting Example 33 mixture was stirred for 45 minutes. The mixture was concen (Z)-5-((4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2- trated in vacuo and the corresponding dry formyl chloride, enyloxy)-carbonylcarbamoyl)-10,11-dihydro-5H CI-L2-R1, thus obtained was re-dissolved in 3 mL of DCM and cooled to 0°C. under nitrogen. To this stirred solution was dibenzob.fazepin-10-yl acetate NO O-Acetyl added drop-wise a solution of paclitaxel (0.08 g., 0.1 mmol) licarbazepine (1-AD6-L2-R1) and diisopropylethylamine (0.03 mL, 0.2 mmol) in 2 mL of 0561. The title compound (I-AD6-L2-R1) was obtained as DCM and the mixture was stirred for 2 h when TLC analysis an off-white gum. Yield: 48.8%; H NMR (CDC1, 300 of the mixture indicated completion of the reaction. The mix MHz): & 1.59, 1.60 (mixed doublets, J=5.4 Hz, 5.7 Hz, 3H), ture was diluted with 10 mL of DCM and washed with water 2.09 (d. J=12.6 Hz, 3H), 3.05-3.26 (m. 1H), 3.58-3.68 (m, (1x10 mL) and brine (1x10 mL). The organic layer was dried 1H), 4.65-4.87 (n, 4H), 5.72-6.07 (m, 3H), 6.38-6.45 (m, over MgSO and concentrated in vacuo to give a residue 0.5H), 6.92 (q, J=5.7 Hz, 1H), 7.00 (d. J=8.7 Hz, 1H), 7.22 which was purified by column chromatography on silica gel 7.54 (m, 8.5H); MS (ES") m/z: 544.2 M+H, 566.2 by eluting with 10% ACN in DCM to afford the title com M+Na". pound I-HD1-L2-R1 as a white solid. Mp: 141-143° C.; Yield: 0.07 g (75.0%); H NMR (CDC1,300 MHz): 81.16 (s, Example 34 3H), 1.31 (s.3H), 1.41-1.43 (m. 1H), 1.58-1.64 (m, 2H), 1.71 (s, 3H), 1.81-1.94 (m, 2H), 1.95 (s, 3H), 2.02-2.08 (m, 2H), (Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl 2.25 (s.3H), 2.37-2.65 (m, 3H), 2.49 (s.3H), 2.58-2.61 (m, 6-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) 1H), 3.83 (d. J–7.2 Hz, 1H), 4.04-4.19 (m, 1H), 4.22 (d. J=8.4 methylsulfinyl)-1H-benzodimidazole-1-carboxyla HZ, 1H), 4.34 (d. J–8.4 Hz, 1H), 4.42-4.52 (m, 1H), 4.62-4.84 |NO-Omeprazole (I-AD7-L2-R1) (m, 4H), 4.92-5.05 (m, 2H), 5.44 (s, 1H), 5.71 (d. J–7.2 Hz, 0562. This compound was synthesized as shown in 1H), 5.76-5.86 (m, 1H), 5.91 (s, 1H), 6.01 (d. J–8.7 Hz, 1H), Scheme 7 and the experimental procedure is described below: 6.26-6.36 (distorted torm, 2H), 6.50-6.68 (m, 2H), 7.35-7.68 0563 Diphosgene (0.2g, 1.3 mmol) was added drop-wise (m. 11H), 7.76 (d. J=7.5 Hz, 2H), 8.17 (d. J=7.2 Hz, 2H); MS to a stirred solution of (Z)-4-hydroxybut-2-enyl 1-(nitrooxy) m/Z: 1123.4 M+Na". ethyl carbonate (HO-L2-R1, 0.5g, 2.3 mmol, freshly pre pared as described in Example 4) and triethylamine (0.1 mL, Example 36 1.4 mmol) in 5 mL of dry DCM at 0°C. under nitrogen and the NO-Metronidazole Prodrug (I-HD2-L2-R1) mixture was stirred for 30 minutes. The reaction mixture was 0567 The title compound was synthesized in 3 steps as concentrated to get the corresponding formyl chloride, shown in Scheme 8 and the experimental procedure is CI-L2-R1, as yellow residue. This residue was re-dissolved in described below: DCM (5 mL) and the resulting solution was added to a stirred mixture of omeprazole (AD7, 0.4g, 1.1 mmol)) and DMAP Step 1: Synthesis of (Z)-4-hydroxybut-2-enyl 2-(2- (0.3g, 2.3 mmol) in DCM (5 mL) at 0°C. and the mixture was methyl-5-nitro-1H-imidazol-1-yl)ethyl carbonate stirred for 1 h when TLC analysis of the mixture indicated (HD2-L2-OH) formation of a major new product. The reaction mixture was 0568 CDI (3.1 g, 19.3 mmol) was added to a stirred sus diluted with DCM (15 mL), washed with water, dried over pension of metronidazole (3.0 g, 17.5 mmol) in 50 mL of anhydrous NaSO4, concentrated and purified by column DCM at RT under nitrogen and the mixture (after the addition chromatography on silica gel by eluting with methanol/ of CDI, the suspension slowly dissolved to form a clear solu dichloromethane gradient to afford the title compound tion in about 30 minutes) was stirred at RT for 2.5h when TLC I-AD7-L2-R1 as a brown gum. Yield: 0.3 g (45.0%); H NMR of the mixture indicated formation of a new product. The (CDC1, 300 MHz, mixture of diastereomers, -0.55:0.45): 8 mixture was cooled to 0°C. To this stirred mixture was added 1.61 (d. J=5.7, 3H), 2.21 (s.3H), 2.37 (s.3H), 3.76 (unsym a solution of 2-butene-1,4-diol (HO-L2-OH, 4.3 mL, 52.6 metrical d, J=1.2 Hz, 3H), 3.88, 3.92 (two singlets, 3H), mmol) in DCM (25 mL) and the mixture was stirred at RT for 4.65-4.94 (m, 4H), 5.02-5.21 (m, 2H), 5.90-6.10 (m, 2H), overnight and at 70° C. for 3 h when TLC analysis of the 6.93 (q, J=5.7 Hz, 1H), 7.03 (dd, J=2.4, 9.0 Hz, 0.5H), 7.09 mixture indicated formation of a new product. The mixture (dd, J=2.4, 9.0 Hz, 0.5H), 7.33 (d. J=2.4 Hz, 0.45H), 7.49 (d. was diluted with 50 mL of DCM, washed with water (2x30 J=1.8 Hz, 0.55H), 7.75 (d. J=9.0 Hz, 0.55H), 7.83 (dd, J=9.0, mL), dried over anhydrous NaSO and concentrated on 1.8 Hz, 0.45H), 8.06 (brs, 1H); MS (ES) m/z:593.2M+H", rotavap to give 5.0 g of crude product which was purified by 615.1 M+Na". column chromatography (50.0 g silica gel, 150-300 mesh, 0564) Examples of the compounds of formula I which are eluted with 2-5% MeOH in DCM to afford the title interme the prodruqs of the drugs containing hydroxyl group: diate HD2-L2-OH as greenish oil. Yield: 4.2 g (84.3%); H NMR (CDC1, 300 MHz): & 2.36 (t, J=3.6 Hz, 1H), 2.50 (s, Example 35 3H), 4.23 (t, J=3.6 Hz, 2H), 4.50 (t, J-3.0 Hz, 2H), 4.60 (t, NO-Paclitaxel Prodrug (I-HD1-L2-R1) J=3.0 Hz, 2H), 4.68 (d. J–4.2 Hz, 2H), 5.57-5.66 (m, 1H), 5.87-5.94 (m, 1H), 7.96 (s, 1H); MS m/z: 286.1 M+H", 0565. This compound was synthesized as shown in 308.1 M+Na". Scheme 7 and the experimental procedure is described below: 0566. A solution of (Z)-4-hydroxybut-2-enyl 1-(nitrooxy) Step 2: Synthesis of intermediate HD2-L2-R1-CI ethyl carbonate (HO-L2-R1, 0.1 g, 0.5 mmol, freshly pre 0569. C.-Chloroethyl chloroformate (CI-R1-C1, 0.8 mL, pared as described in Example 4) and DIPEA (0.3 mL, 1.8 7.7 mmol) was added drop-wise to a solution of the interme US 2011/0263526 A1 Oct. 27, 2011

diate HD2-L2-OH (2.0 g, 7.0 mmol) in 20 mL of DCM at 0° (mixed m, 2H), 6.23 (t, J=6.0Hz, 1H), 6.95 (q, J=5.7 Hz, 1H), C. under nitrogen. To this stirred mixture was added pyridine 7.36 (s, 1H), 8.40 (brs, 1H); MS (EI) m/z: 513.1 M-H. (0.8 mL, 9.6 mmol) over 5 minutes. The mixture was stirred 0573 The compound of example 38 was prepared by fol under nitrogen for 1 h while allowing it to attain RT. TLC lowing the experimental procedure described for preparing analysis of the mixture indicated completion of the reaction. the compound of example 37. The characterization data for The mixture was washed with water (1x20 mL) and dried the compound of example 38 is described below: over NaSO and concentrated on rotavap to afford 2.9 g of the crude product as red oil which was purified by column Example 38 chromatography (34.0 g of silica gel, 150-300 mesh, eluted NO-Budesonide prodrug (I-HD4-L2-R1) with DCM) to afford the title intermediate HD2-L2-R1-CI as red oil. Yield: 2.3 g (83.2%); H NMR (CDC1,300 MHz): 8 0574. The title compound (I-HD4-L2-R1) was obtained as 1.85 (d. J=5.7 Hz, 3H), 2.53 (s, 3H), 4.51 (t, J=4.8 Hz, 2H), yellow semisolid. Yield: 8.2%; H NMR (CDC1,300 MHz): 4.62 (t, J–4.8 Hz, 2H), 4.74 (d. J=5.7 Hz, 2H), 4.80 (s, 1H), 8 0.83-1.08 (mixed m, 7H), 1.09-121 (m, 2H), 1.23-1.33 (m, 4.82 (d. J=2.1 Hz, 1H), 5.75-5.93 (m, 2H), 6.43 (q, J=6.0 Hz, 2H), 1.36-1.50 (m, 5H), 1.62 (d. 3H), 1.74-1.86 (m, 2H), 1H), 7.99 (s, 1H); MS (EI) m/z: 392.1 M+H, 414.1 2.04-2.26 (mixed m, 4H), 2.32-2.38 (m. 1H), 2.53-2.64 (m, M+Na". 1H), 4.48-4.66 (mixed m, 2H), 4.71 (s.3H), 4.76-5.05 (mixed m,3H), 5.13-5.20 (m. 1H), 5.80-5.99 (mixed m, 2H), 6.04 (s, Step 3: Synthesis of NO-Metronidazole 1H), 6.29 (d. J=10.2 Hz, 1H), 6.95 (q, J=5.7 Hz, each, 1H), (I-HD2-L2-R1) 7.24 (d. J=3.6 Hz, 1H); MS m/z: 678.3 M+H", 700.3 0570 Silver nitrate (12.1 g, 71.3 mmol) was added to a M+Na" solution of the intermediate HD2-L2-R1-CI (1.5g, 3.8 mmol) Example 39 in 30 mL of ACN and the mixture was refluxed in dark at ~90° C. for 2 h and at RT for overnight. HPLC analysis of the NO-Budesonide Prodrug (I-HD4-L20-R1) mixture indicated complete conversion. The mixture was 0575. The above compound was synthesized in 4 steps as cooled and filtered through celite. The filtrate was concen shown in Scheme 10 and the experimental procedure is trated and the residue was re-dissolved in DCM (~100 mL) described below: and filtered through celite to remove the precipitated silver chloride. The filtrate was concentrated in vacuo and the resi Step 1: Synthesis of Intermediate HD4-L20-CHO due thus obtained was purified by column chromatography (50.0 g of silica gel, 150-300 mesh, eluted with 20-80% (0576 4-Formylbenzoic acid (HOC-L20-CHO, 0.2g, 1.4 EtOAc in petroleum ether) to afford the title compound mmol) followed by DCC (0.3g, 1.4 mmol) and DMAP (0.056 (I-HD2-L2-R1) as red oil. Yield: 1.0 g (63.1%); H NMR g, 0.5 mmol) were added to a stirred solution of budesonide (CDC1, 300 MHz): & 1.62 (d. J=5.7 Hz, 3H), 2.53 (s, 3H), (HD4, 0.5g, 1.2 mmol) in dichloromethane (30 mL) and the 4.51 (t, J–4.8 Hz, 2H), 4.63 (t, J–4.8 Hz, 2H), 4.73 (d. J–5.4 mixture was stirred at RT for overnight. The mixture was Hz, 2H), 4.79 (d. J=5.4 Hz, 2H), 5.75-5.95 (m, 2H), 6.94 (q, filtered and the filtrate was washed with water (1x2 mL), 1N J=5.7 Hz, 1H), 7.99 (s, 1H); MS (EI) m/z. 441.1 M+Na". HCl solution (1x2 mL), brine (1x2 mL), dried over anhydrous Na2SO and concentrated in vacuo to give 0.8 g of crude Example 37 product as a semisolid which was purified by column chro matography (40.0 g of silica gel, 200-400 mesh, eluted with NO-Zidovudine (I-HD3-L2-R1) 10-50% of ethyl acetate in petroleum ether) to afford the title 0571. The above compound was synthesized as shown in Intermediate HD4-L20-CHO as a white gum. Yield: 0.6 g. Scheme 7 and the experimental procedure is described below: (93.0%); H NMR (CDC1, 300 MHz): 8 0.97 (t, J–7.5 Hz, 0572 Diphosgene (0.1 g, 0.5 mmol) was added drop-wise 3H), 1.05 (d. J=12.0 Hz, 3H), 1.11-1.33 (m, 4H), 1.38-2.32 to a stirred solution of (Z)-4-hydroxybut-2-enyl 1-(nitrooxy) (m. 13H), 2.35 (d. J=2.7 Hz, -0.4H), 2.40 (d. J=2.7 Hz, ethyl carbonate (HO-L2-R1, 0.2 g, 0.9 mmol, freshly pre -0.6H), 2.60 (dt, J=13.5, 12.6, 5.1, 4.2 Hz, 1H), 4.56 (brs, pared as described in Example 4) and triethylamine (0.3 mL, 1H), 4.72 (t, J=4.5 Hz, 0.5H), 4.89 (d. J=4.5 Hz, 0.5H), 5.05 1.8 mmol) in 5 mL of DCM at 0°C. under nitrogen and the (d. J=13.2 Hz, -0.2H), 5.11 (d. J=12.9 Hz, -0.8H), 5.15-5.25 mixture was stirred for 30 minutes. The mixture was concen (m. 2H), 6.06 (brs, 1H), 6.30 (t, J–1.8 Hz, -0.5H), 6.33 (t, trated in vacuo and the crude and dry CI-L2-R1 thus obtained J=2.1 Hz, -0.5H), 7.29 (d. J=9.9 Hz, 1H), 8.00 (d. J=8.1 Hz, was re-dissolved in 5 mL of DCM and cooled to 0°C. under 2H), 8.26 (d. J–8.4 Hz, 2H), 10.14 (s, 1H). nitrogen. This cold solution was added to a stirred solution of zidovudine (0.2g, 0.9 mmol) and triethylamine (0.3 mL, 1.8 Step 2: Synthesis of intermediate HD4-L20-OH mmol) in 5 mL of DCM at 0°C. and the mixture was stirred (0577 Sodium borohydride (0.008g, 0.2 mmol) was added for 3 h when TLC analysis of the mixture indicated formation to a stirred solution of aldehyde intermediate HD4-L20-CHO of the product. The mixture was diluted with 10 mL of DCM (0.3 g, 0.5 mmol) in 3 mL of THF at 0°C. and the mixture was and washed with water (1x10 mL) and brine (1x10 mL). The stirred at 0° C. for 30 minutes. The reaction mixture was organic layer was dried over NaSO and concentrated in poured into 5 mL of ice cold 1N HCl solution (5 mL) and vacuo to give a residue which was purified by column chro extracted with ethyl acetate (2x5 mL). The organic layer was matography on silica gel by eluting with MeOH/DCM gra washed with brine (1x2 mL), dried over anhydrous NaSO dient to afford the title compound I-HD3-L2-R1 as yellow oil. and concentrated in vacuo to give 0.45g of crude product as Yield: 0.1 g (42.0%); H NMR (CDC1,300 MHz): & 1.63 (d yellow oil which was purified by column chromatography mixed with water peak, J=5.1 Hz, 3H), 1.93 (s.3H), 2.35-2.57 (25.0 g of silica gel, 150-300 mesh, eluted with 10-60% ethyl (m. 2H), 4.05-4.12 (m. 1H), 4.29 (q, J=5.7. 5.4 Hz, 1H), 4.44 acetate in petroleum ether) to afford the title HD4-L20-OH as (dq, J=12.0, 2.7 Hz, 2H), 4.65-4.88 (mixed m, 4H), 5.83-6.05 white gum. Yield: 0.3 g (94.0%); H NMR (CDC1, 300

US 2011/0263526 A1 Oct. 27, 2011 drugs of a drug containing a carboxylic acid functional group, by centrifugation for 5 min (1000xg) at 4°C. Each collected e.g. naproxen that is encompassed in the compounds of for plasma sample (50 ul) corresponding to naproxen and the mula (I), was selected. The release profile of naproxen from aforementioned nitric oxide releasing prodrugs of naproxen said nitric oxide releasing prodrugs was analysed using a was then transferred to a microcentrifuge tube containing HPLC system. acetonitrile (200 ul), mixed by vortex and centrifuged for 5 min (1000xg) at 4°C. The supernatant layer (150 ul) obtained Animals: after centrifugation was then transferred to HPLC vials. A (25 ul) volume of each sample solution was injected in to HPLC 0586 Male Sprague-Dawley rats weighing 150-220 g for analysis. The peak area values obtained for each of the were used in the study. The rats were fed normal standard plasma samples was compared with the naproxen standard laboratory chow and maintained understandard environmen curve to determine the plasma concentration of naproxen in tal conditions (room temperature of 22+2°C.; 50+10% rela rats after oral administration of naproxen and each of the tive humidity; 12 hrs light-dark cycle.). All experimental nitric oxide releasing prodrugs of naproxen. The plasma con procedures mentioned below were approved by the institu centration of naproxen in rats after oral administration of tional animal ethics committee and were performed in accor naproxen and each of the nitric oxide releasing prodrugs of dance with Standard guidelines of Committee for the purpose naproxen versus time intervals was plotted and the area under of control and supervision of experiments on animals (CPC the curve was determined by trapezoidal rule (Gibaldi, M. and SEA), Govt. of India for the experiment on animals. Perrier, D., Pharmacokinetics, Second edition, 15:445-447) HPLC Sample preparation and standard curve: for each of the samples corresponding to naproxen and nitric 0587 HPLC: Waters Alliance analytical HPLC equipped oxide releasing prodrugs of naproxen. The AUC values for the with 2996 PDA detector and Empower software were used nitric oxide releasing prodrugs of naproxen presented in to analyze the samples. Table 1 indicate that said prodrugs release a substantial 0588 HPLC Column: Waters X-Terra RP-18 reversed amount of naproxen parent drug in the rat plasma. phase column, 150x3.9 mm, 5um HPLC Method: TABLE 1 0589 Flow: 1 ml/min, Pharmacokinetic study data detector set at 210 nm and at Maxplot (210-400 nm range). Plasma Naproxen Compound' AUC (ughriml) + S.E.M Solvent A: Acetonitrile; Naproxen 2O2.77 13.95 (I-CD1-L1-R1) 133.0231.75 0590 Solvent B: 0.1% TFA in water. (I-CD1-L2-R1) 187.73 18.79 Injection volume: 20 ul (I-CD1-L3-R1) 65.13 - 11.36 Elution method: A linear gradient as specified below: (I-CD1-L4-R1) 122.95 - 14.35 (I-CD1-L6-R1) 12.88 - 3.85 (I-CD1-L7-R1) 9.850.77 (I-CD1-L16-R1) 118.47 8.01 (I-CD1-L17-R1) 93.85 S.S8 Time in min O-2 2-10 10-13 13-14 14-18 (I-CD1-L18-R1) 143.57 2.60 (I-CD1-L19-R1) 153.377.16 % A 2O 20-100 1OO 100-20 2O All the compounds were administered per oral at 10 mg/kg equivalent dose of naproxen, 0591 Blood samples were collected from the rats and the plasma was separated by centrifugation at 1000xg for 5 minat Example 44 4°C. A stock Solution of naproxen was prepared by dissolv ing it in acetonitrile and working solutions of various concen Estimation of Nitrate/Nitrite Release from the Com trations (0.625, 1.25, 2.5, 5, 10, 20 g/ml) were prepared by pounds of the Invention in Plasma spiking the blood plasma with the naproxen Stock solution. Each plasma sample (50 ul) was then transferred to a micro 0592 Male Sprague-Dawley rats (180–220 g) were accli centrifuge tube containing acetonitrile (200 ul), mixed by matized for a week and fasted 12-14 hours prior to the com vortex and centrifuged for 5 min (1000xg) at 4° C. The mencement of the experiment. The representative com Supernatant layer (150 ul) obtained after centrifugation was pounds of formula (I) i.e. the nitric oxide releasing prodrugs then transferred to HPLC vials. The sample solution (25 ul) of naproxen (I-CD1-L1-R1, I-CD1-L2-R1, I-CD1-L4-R1, was then injected into HPLC for analysis. A linear calibration and I-CD1-L18-R1) (at a dose of 10 mg/kg of naproxen) were curve between the naproxen concentration in plasma (0.625, administered orally to the rats. The blood sample was col 1.25, 2.5, 5, 10, 20 ug/ml) and the peak area ratio was lected from the rats administered with each of the aforemen obtained. The rats were divided in to six groups of three each. tioned nitric oxide releasing prodrugs of naproxen according Naproxen (10 mg/kg) was administered orally to one group of to a specific schedule (0.5, 1, 2, 4, 6 and 8 hours) and the rats and the representative compounds of formula (I) i.e. the plasma was separated by centrifugation (1000xg) for 5 minat nitric oxide releasing prodrugs of naproxen (I-CD1-L1-R1. 4°C. The release profile of the nitrate/nitrite in the blood I-CD1-L2-R1, I-CD1-L3-R1, I-CD1-L4-R1, I-CD1-L16-R1, plasma which is an indirect measure of the nitric oxide I-CD1-L17-R1 and I-CD1-L18-R1) (at a dose containing 10 released in the blood plasma was measured using Griess mg/kg of naproxen) were administered orally to the remain method by employing colorimetric nitrate/nitrite assay kit ing groups. Blood was collected from orbital plexus of the rats from Fluka. according to a specific schedule (0.25, 0.5, 1, 2, 4, 6 and 8 h 0593. The blood plasma samples were filtered using Mil after dosing) and the plasma was separated from each sample lipore ultra-filtration 96-well plate to remove the plasma pro US 2011/0263526 A1 Oct. 27, 2011 94 teins having particle size of >10 kDa. The assay was per orally to overnight fasted rats of different groups. One hour formed in a 96-well plate according to standard procedure later, carrageenan (100 ul, 1% w/v) was injected in to their described in the kit. The method comprised adding to the paws. The control group received PEG 400 (1 ml/kg). The well, standard (sodium nitrate) (80 ul) of various concentra paw Volume of the group of rats administered with naproxen tions (0, 20, 40, 60, 80 and 100 uM) followed by the reagents, and those administered with naproxen prodrug were mea nitrate reductase (10 ul) and enzyme co-factor (10 ul). The Sured before carrageenan injection and also at a time period of plasma sample (80 ul) obtained from the blood sample col 3 and 5 hours after the carrageenan was injected. The (%) lected at various time intervals from the rats (0.5, 1, 2, 4, 6 and inhibition of paw edema in rats administered with naproxen 8 hours) were added to separate wells, followed by the and the nitric oxide releasing prodrug of naproxen, I-CD1 reagents, nitrate reductase (10 ul) and enzyme co-factor (10 L2-R1 after 3 and 5 hours respectively were calculated as ul). The plate was incubated for 2 hat room temperature on compared to the control group and presented in Table 3. The orbital shaker (350-400 rpm). Griess reagent A (50 ul) was results indicate that the nitric oxide releasing prodrug of added to each well followed by incubation for 5 min and naproxen, I-CD1-L2-R1 exhibited anti-inflammatory activity subsequently, Griess reagent B (50 ul) was added to each well comparable to that of naproxen in the carrageenan-induced followed by incubation for 10 min. The absorbance of assay rat paw edema model. plate was measured by using a 96-well plate reader (Bio-Tek instruments) at 540 nm. This procedure was carried out for Ulcerogenic Activity each of the aforementioned nitric oxide releasing prodrugs of 0595. The ulcerogenic potential of the nitric oxide releas naproxen separately. A standard curve between the sodium ing prodrug of naproxen, I-CD1-L2-R1 in rats was assessed. nitrate concentration (LM) (0, 20, 40, 60, 80 and 100 uM) on Naproxen (100 mg/kg) and the nitric oxide releasing prodrug X-axis versus absorbance values on Y-axis was plotted. The of naproxen, I-CD1-L2-R1 (at a dose containing 100 mg/kg absorbance values of each of the plasma samples collected at of naproxen) was administered to overnight fasted rats of different time intervals corresponding to the aforementioned different groups. The animals were sacrificed after 5h of drug nitric oxide releasing prodrugs of naproxen from the rats was administration. The stomachs of the animals treated were compared with the standard curve to determine the plasma separated, perfused with 2% formalin (10 ml), and then a nitrate concentration in mice after oral administration of the large curvature was excised. The severity of the mucosal aforementioned nitric oxide releasing prodrugs of naproxen. damage was assessed on the basis of the size of the observed The plasma nitrate concentration in rats after oral adminis ulcer lesions in the images captured using a stereomicroscope tration of the aforementioned nitric oxide releasing prodrugs attached to a digital camera (Stemi 2000, Zeiss, Germany). of naproxen versus time intervals was plotted and the area The Image Pro Plus software (version 5.1) was used to quan under the curve was determined for each of the samples tify the hemorrhagic/ulcer lesions in pixels and converted into corresponding to the aforementioned nitric oxide releasing mm. The total area of lesions were calculated for each treat prodrugs of naproxen as presented in the following Table 2. ment group and the measure of gastric ulcers (MeantSEM) The results indicate that significant amounts of nitric oxide is (mm) presented in Table 3. The results indicate that none of released in the blood plasma by administering the aforemen the animals treated with the nitric oxide releasing prodrug of tioned nitric oxide releasing prodrugs of naproxen. naproxen, I-CD1-L2-R1 showed any signs of development of ulcers. However, severe haemorrhagic lesions were found in TABLE 2 rats administered with naproxen. Estimation of nitratefnitrite release from the compounds of the invention in plasma TABLE 3 Plasma Nitrate Nitrite Data: Anti-inflammatory and ulcerogenic Compound' AUC (M*h) activity of naproxen and I-CD1-L2-Rl Naproxen O Gastric ulcers (Mean it I-CD1-L1-R1 709 Anti-inflammatory activity' SEM) (mm.) I-CD1-L2-R1 60S %. Inhibition (a) 100 mg/kg eq. I-CD1-LA-R1 811.6 I-CD1-L18-R1 S81.2 Compound (a) 3 hours (a) 5 hours (a) 5 hours I-CD1-L19-R1 961.4 Naproxen 65.455.84 49.09 - 10.35 7S 13 All the compounds were administered per oral at 10 mg/kg equivalent dose of naproxen, I-CD1-L2-R1 54.275.31 36.61 - 8.92 OO Meant SEM, n = 8 Example 45 Determination of the Anti-Inflammatory Activity of Example 46 the Compounds of the Invention AMES Genotoxicity Assay 0594. The anti-inflammatory activity of naproxen and the nitric oxide releasing prodrug of naproxen, I-CD1-L2-R1 was 0596 AMES test or bacterial reverse mutation test uses assessed in carrageenan-induced rat paw edema model five mutant strains (i.e., TA98, TA100, TA1535, TA1537, according to the procedure described in Takeuchi et al., J. TA102) of Salmonella typhimurium to test the mutagenicity Pharmacol. Exp. Ther. 1998, 286 (1), 115-121). Male Spra of chemical substances (Kristien Mortelmans and Errol gue-Dawley rats were divided into three groups often each. Zeiger, The Ames Salmonella/microsome mutagenicity Naproxen (5 mg/kg) and the nitric oxide releasing prodrug of assay, Mutation Research 2000, 455, 29-60 and the relevant naproxen, I-CD1-L2-R1 (at a dose containing 5 mg/kg of reference cited therein). These mutants are called his mutants naproxen), were dissolved in PEG 400 and administered because of their dependence on an external Source of histidine US 2011/0263526 A1 Oct. 27, 2011

to grow. The test also uses one trp mutant strain WP2 uvra (which needs external supply of tryptophan for its growth) of TABLE 4-continued Escherichia coli (Kristein Mortelmans and Edward S. Riccio, The bacterial tryptophan reverse mutation assay with Genotoxicity data Escherichia coli WP2, Mutation Research 2000, 455, 61-69 Ames Test Results (up to 5000 Lig/plate and the relevant references cited therein). If the bacteria are Toxicity Genotoxicity incubated in the presence of a mutagen, a reverse mutation is Compound' to TA100 to 6 strains' induced, and the bacteria will grow. However, if the chemical I-CD1-L2-R1 Non-toxic Non-genotoxic Substance is not mutagenic, there will be no reversion and I-CD1-L4-R1 Non-toxic Non-genotoxic thus no growth. The result is thus obtained in the absence of I-CD1-L16-R1 Non-toxic Non-genotoxic metabolic activation. Because many chemicals that are poor I-CD1-L17-R1 Non-toxic Non-mutagenic with TA 1535 mutagens become potent mutagens after they have passed I-CD1-L18-R1 Non-toxic Non-genotoxic through the liver, homogenate of rat liver, called the S9 I-HD4-L2O-R1 Non-toxic Non-mutagenic with TA 1535 extract, are added to the bacteria before incubation. The bac All the compounds were administered per oral at 10 mg/kg equivalent dose of naproxen, teria/S9 mixture is then plated on a medium containing no *Salmonella strains TA100, TA98, TA1535, TA1537 and TA102 and Escherichia coistrain WP2 uvrA were used; histidine (use of tryptophan-deficient medium in case of E. NTD = NotDetermined. coli strain), and the test chemical is placed in the center of the plate. The result is thus obtained in the presence of metabolic activation. A second plate that contains a non-mutagenic Sol Example 47 vent as a negative control and a third plate that contains a known mutagen as a positive control are also run simulta In-Vitro Aspirin Release Study of No-Aspirin Pro neously. All the 3 types of plates (each type of plate, in fact, drugs run simultaneously in triplicate for obtaining statistically sig nificant data) are incubated for 48 hours at 37°C. The above 0598. The test compounds were dissolved in acetonitrile procedure is called the plate incorporation method. The pres ence of numerous colonies of revertants in the test disk indi to get a concentration of 200 mM which was used as stock cates a positive result: that is, the chemical Substance is a Solution. Blood samples were obtained from rats or humans in mutagen (i.e., mutagenic if the increase in revertants is >2 heparinized centrifuge tubes. Plasma was separated by cen fold for TA98, TA100, TA102 and WP2/uvra or >3 fold for trifugation of blood samples at 8000 rpm at 4°C. The plasma TA1535 and TA1537). Also, a positive result would be con samples collected were stored at -20° C. till use. Plasma sidered reliable when there is a dose-dependent increase in samples were incubated at 37°C. in an incubator-shaker. The revertants at any two consecutive non-toxic concentrations reaction mixture (2000 ul) consisted of the compound stock which can be in the range of 10-5000 ug/plate. The presence solution (10 ul) spiked into the plasma sample (1990 u) to of only a few spontaneous revertant colonies indicates a nega obtain a final compound concentration of 2 mM. Aspirin at tive result. If a negative or equivocal result is obtained, the concentration of 2 mM was used as Standard control. At pre-incubation method is performed in which the cells are different time points after addition of compound viz., 2, 5, 10. exposed to the test compounds for 30 min before plating. 20, 40 and 60 min, 60 ul of sample was removed from the Also, before Ames test is initiated, a toxicity test on the reaction mixture. The samples were added to 200 ul of aceto chemical substance is performed using TA100 strain in the nitrile and vortexed for 1 min followed by centrifuging at concentration range of 10-5000 ug/plate. The above Ames 12,000 rpm for 15 min. The supernatant obtained was sub mutagenicity test is initiated only when the test Substance is jected to HPLC analysis to determine the amount of aspirin non-toxic to TA100 in the concentration range of 10-5000 and salicylate in the samples. The HPLC analysis gave the ug/plate. When the test substance is found to be toxic at higher amount (LLM) of aspirin and salicylate present in the samples concentration range then the genotoxicity of that material is at their respective time-points. The percent release of aspirin tested only in the non-toxic lower concentration range. was calculated based on the initial concentration (2 mM) of 0597. When the nitric oxide releasing prodrugs of the compound in the reaction mixture versus the amount of naproxen, (I-CD1-L1-R1, I-CD1-L2-R1, I-CD1-L4-R1, aspirin released at different time-points. I-CD1-L16-R1 and I-CD1-L18-R1) were subjected to AMES test in AMES mutagenicity assay, said prodrugs were found TABLE 5 to be non-toxic to TA100 and non-mutagenic in all the afore mentioned six bacterial strains in the concentration range of In-vitro aspirin release data of NO-aspirin prodrugs 10-5000 ug/plate. The corresponding data is presented in the following Table 4. Compound Plasma sample % Release (max) Time I-CD2-L15-R1-A Rat 16.24 10 min TABLE 4 I-CD2-L15-R1-A Human 20.84 10 min I-CD2-L15-R1-B Rat 10.28 10 min Genotoxicity data I-CD2-L15-R1-B Human 12.53 20 min Ames Test Results (up to 5000 Lig/plate 0599 Having thus described in detail various embodi Toxicity Genotoxicity ments of the present invention, it is to be understood that the Compound' to TA100 to 6 strains' invention defined by the above paragraphs is not to be limited Naproxen ND ND to particular details set forth in the above description as many I-CD1-L1-R1 Non-toxic Non-genotoxic apparent variations thereof are possible without departing from the spirit or Scope of the present invention. US 2011/0263526 A1 Oct. 27, 2011 96

1. A compound of formula (I), all its stereoisomeric forms or a pharmaceutically acceptable salt thereof; -continued (Y) O

(I) N X X2 A O O O - D1 n 1 NZ11 NZ2 Y Sk Y NO, R2 O, O RI (Yg) O O, wherein, lu Dindependently represents a drug comprising of one or more d of the functional groups selected from a carboxylic acid, an (Y) amino, a hydroxyl or a sulfhydryl group that are capable of O O, forming a covalent bio-cleavable linkage with a bio-cleavable linker represented by the formula (IA): N-sul (Y) O CO2H O,

X2 A O O O (LA) -l N J 1n 1 N21 Sk SNO; H R2 (Y) O RI NHR7 H N wherein, Y X' is a bond, O, S, or NR; O O, X is a bond, O or NR; (Y) R is a bond or H: t RHN Y is C—O or a spacer group selected from: - ) \ O (Y) (Y) O, l It O HOC ) NH R4 O (Y)

I wherein: ls, R" is a bond, H, alkyl or a metalion; O, R is H. C. alkyl or phenyl: (Y) R is Hora group selected from: O —CH, —CH(CH), —CHCH(CH), —CH(CH) CHCH, -CHCOH, -CHCH-COH, -CHOH, CH(CH)OH, —CHSH, CHCH-SCH3, l —CH2CH2CHCH-NH2, —CHs —CH2CHs. R6 O, - CHCH-p-OH, -CHCHCH-NHC(=NH)NH, (Y) —CHC(=O)NH, -CHCHC(=O)NH, -CH indol-3-yl or —CH-imidazole; X is O, S, SO, SO, or NR; R’ is Hora group selected from: acetyl, benzoyl, alkyloxy carbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxy NHR7r Ö, carbonyl or its pharmaceutically acceptable ammonium (Y) salts; O R8 O, R is Hor C alkyl: c is an integer from 0 to 2: d is an integer from 1 to 5: sJ e is an integer from 1 to 4: NHR Z' represents (CH2): where a is an integer from 0 to 3: Z represents (CH), where b is an integer from 0 to 3: US 2011/0263526 A1 Oct. 27, 2011 97

A is selected from a bond, S, SO, SO, S. S, CH=CH, agents, anti-viral agents, anti-malarial agents, anti-diabetic 1.2-phenylene, 1.3-phenylene, 1.4-phenylene, 2.3-pyridine, agents, anti-ulcer agents, anti-oxidants or vitamins. 3,4-pyridine, 2.4-pyridine, 2.5-pyridine, 2.6-pyridine, 4. The compound according to claim 3, wherein the anti D-isosorbide skeleton, 1,4-anhydroerythritol skeleton, cycloalkylene, CRR', Co-Cio-arylene, a 5- or 6-membered inflammatory and analgesic agent is selected from opioids, heteroarylene or a 5- or 6-membered heterocyclylene steroids (glucocorticoids) or non-steroidal anti-inflammatory wherein, said arylene, heteroarylene and heterocyclylene drugs (NSAIDs). may be unsubstituted or substituted by one or more substitu 5. The compound according to claim 4, wherein the anti ent(s) independently selected from the group consisting of inflammatory and analgesic drug is selected from ace C. alkyl, C. alkoxy, hydroxyl, trifluoromethyl, cyano, clofenac, acemetacin, acetamidocaproic acid, acetylsalicyl amino and halogen; salicylic acid, actarit, alclofenac, 3-alminoprofen, amfenac, RandR'' are independently selected from: Hor C, alkyl: 3-amino-4-hydroxybutyric acid, aspirin (acetylsalycilic or Rand R' taken together with the carbon atom to which acid), balsalazide, bendazac, benoxaprofen, bromprofen, they are attached form a cycloalkyl or a heterocyclic ring; bromfenac, 5-bromosalicylic acid acetate, bucloxic acid, R" is H; and R is alkyl, cycloalkyl, aryl or aralkyl; or bumadizone, butibufen, carprofen, cinchophen, cinmetacin, R’ is H; and R' independently is alkyl, cycloalkyl, aryl or clidanac, clometacin, clonixin, clopirac, diacerein, aralkyl; diclofenac, diflunisal, dipyrocetyl, enfenamic acid, enox olone, etodolac, felbinac, fenbufen, fenclozic acid, fendosal, with the provisos that: fenoprofen, fentiazac, flufenamic acid, flunoxaprofen, fluo c) when A represents S, thena and b independently repre cortolone-21-acid, flurbiprofen, fosfosal, gentisic acid, sent 3; or ibufenac, ibuprofen, indomethacin, indoprofen, isofeZolac, d) when A represents D-isosorbide skeleton or 1,4-anhy isoxepac, ketoprofen, ketorolac, lonazolac, loxoprofen, droerythritol skeleton, then a and b independently rep meclofenamic acid, mefenamic acid, mesalamine, metiazinic resent 0. acid, mofeZolac, naproxen, niflumic acid, olsalazine, 2. The compound according to claim 1, wherein, oxaceprol, oxaprozin, piraZolac, pirprofen, pranoprofen, pro D is a drug containing a carboxylic acid group that is capable tizinic acid, salicy Sulfuric acid, Salicylamide o-acetic acid, of forming a bio-cleavable covalent linkage with the linker of Salsalate, Sulfasalazine, Sulindac, Suprofen, SuxibuZone, formula (IA); tiaprofenic acid, tolfenamic acid, tolmetin, tropesin, Ximo X is O: profen, Zaltoprofen or Zomepirac. R" is Hand R is C, alkyl; or 6. The compound according to claim 3, wherein the car R’ is Hand R' is C alkyl: diovascular agent is an anti-hypertensive agent selected from: X' is a bond; angiotensin converting enzyme (ACE) inhibitors, beta-block Y is C—O or a spacer group selected from: ers, Sartans (angiotensin II blockers), anti-thrombotic and vasoactive agents, anti-hyperlipidemic drugs (including HMG-CoA-reductase inhibitors i.e., statins), fibrates, anti (Y) anginal agents, anti-arrhythmic agents, anti-hypotensive O O agents, calcium channel blockers, cardiotonic agents, cardio protective agents, diuretics or vasodilators. l 7. The compound according to claim 6, wherein the car diovascular agent is selected from acifran, acipimox, acetyl R4 O salicylic acid, alacepril, gama-aminobutyric acid, angio (Yi) O R5 tensin, argatroban, atorvastatin, benazepril, benfurodil hemisuccinate, beraprost, beZafibrate, bumetanide, cande Sartan, capobenic acid, captopril, carmoxirole, ceronapril, l O cerivastatin, chromocarb, cilaZapril, ciprofibrate, clinofi brate, clofibric acid, dalteparin, daltroban, delapril, dex O; trothyroxine, eicosapentaenoic acid, eledoisin, enalapril, enalaprilat, enoxaparin, eprosartan, ethacrynic acid, fluvas where R is a bond, H, alkyl or a metalion; R is H. C. alkyl tatin, fosinopril, furosemide, gemfibrozil, iloprost, imidapril, or phenyl: indobufen, isbogrel, heparin, lamifiban, limaprost, lisinopril, A is selected from a bond, S, SO, SO, S. S, CH=CH, lotrafiban, meglutol, melagatran, mercamphamide, mercap 1.2-phenylene, 1.3-phenylene, 1.4-phenylene, 2.3-pyridine, tomerin Sodium, mercumallylic acid, mersalyl, methyldopa, 3,4-pyridine, 2.4-pyridine, 2.5-pyridine, 2.6-pyridine, moexipril, moveltipril, nadroparin, omapatrilat, oZagrel, D-isosorbide skeleton, 1,4-anhydroerythritol skeleton, oxiniacic acid, perindopril, piretanide, pitavastatin, pravasta cycloalkylene and CRR', where R and R' independently tin Sodium, prostaglandin E, quinapril, ramipril, ramiprilate, represent H or C. alkyl; with the provisos that: reviparin sodium salt, ridogrel, Sampatrilat, Saralasin, Sati e) when A is S, then a and b is 3; or grel, spirapril, taprostene, telmisartan, temocapril, thyro f) when A is D-isosorbide skeleton or 1,4-anhydroerythri propic acid, ticrynafen, tinzaparin, tirofiban, trandolapril, tri tol skeleton, thena and b is 0. flusal, Valsartan, Xanthinol niacinate or Xenbucin. 3. The compound according to claim 2, wherein D, the drug 8. The compound according to claim 3, wherein the anti containing a carboxylic acid group, is selected from anti allergic agent is selected from steroidal bronchodilators, mast inflammatory and analgesic agents, cardiovascular agents, cell stabilizers or anti-histamines. anti-allergic agents, anti-cancer agents, anti-depressants, 9. The compound according to claim 8, wherein the anti anti-convulsant agents, anti-bacterial agents, anti-fungal allergic agent is selected from acrivastine, amlexanox, bepo US 2011/0263526 A1 Oct. 27, 2011

tastine, cetirizine, fexofenadine, levocetirizine, lodoxamide, 17. The compound according to claim 3, wherein the anti montelukast Sodium, nedocromil, olopatadine, pentigetide or malarial agent is artesumate. tranilast. 18. The compound according to claim 3, wherein the 10. The compound according to claim3, wherein the anti antidiabetic agent is selected from mitiglinide, nateglinide or cancer agent is selected from: acitretin (etretin), aminole repaglinide. Vulinic acid, amsilarotene, butyric acid, eflornithine hydro 19. The compound according to claim3, wherein, the anti chloride, melphalan, methotrexate, minodronate (minodronic ulcer agent is selected from: acetoxolone, arbaprostil, car acid), retinoic acids (including 13-cis retinoic and all trans benoXolone, cetraxate, ecabet, 5-methylmethionine, proglu retinoic acids), Sulindac, tamibarotene or valproic acid. mide, rebamipide, rosaprostol, rotraxate, Sofalcone or 11. The compound according to claim3, wherein the anti trimoprostil. depressant is selected from anti-maniacs and anti-psychotics. 20. The compound according to claim 3, wherein the anti 12. The compound according to claim 11, wherein the oxidant is selected from: C-lipoic acid, L-Carnitine, N-acetyl antidepressant is selected from amineptine, gabapentin, 5-hy L-cysteine, N-acetyl carnosine, raxofelast, tetomilast or droxytryptophan (oxitriptan), pregabalin, tianeptine, Valproic SCMC-Lys (S-carboxymethyl-L-cysteine Lysine salt. HO). acid or vigabatrin. 21. The compound according to claim 3, wherein the vita 13. The compound according to claim3, wherein the anti min is selected from: biotin (vitamin H or coenzyme R), folic convulsant is selected from carbamazepine, felbamate, gaba acid (vitamin M), menadoxime, nicotinic acid (niacin), pan pentin, lamotrigine, levetiracetam, licarbazepine, Oxcarba tothenic acid or vitamin B (a member of the B complex Zepine, pregabalin, topiramate, Valpromide, vigabatrin, or Vitamins). Zonisamide. 22. The compound according to claim 1, wherein, 14. The compound according to claim3, wherein the anti D is a drug containing an amino group that is capable of bacterial is selected from: acediasulfone, amdinocillin, forming a bio-cleavable covalent linkage with the linker of p-aminosalicylic acid, amoxicillin, amphomycin, ampicillin, formula (IA); apalcillin, apicycline, aspoxicillin, azidocillin, azlocillin, X is O: aztreonam, bacitracin, balofloxacin, benzoylpas, benzylpeni R" is Hand R is C alkyl; or cillin, betamipron, biapenem, carbenicillin, carindacillin, R’ is Hand R' is C, alkyl: carumonam, cefaclor, cefadroxil, cefalexin, cefamandole, X is NR, where R is Hora bond; cefatiam, cefatrizine, cefazedone, cefazolin, cefbuperaZone, Y is C=O or a spacer group: cefclidin, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefnenoXime, cefimetazole, cefiminox, cefodizime, cefonicid, cefoperaZone, ceforanide, cefoselis, cefotaxime, (Y) cefotetan, cefotiam, cefoxitin, cefoZopran, cefpimizole, cef O O, piramide, cefpirome, cefroxadine, cefsulodin, ceftazidime, cefiteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cef l N prozil, cefuroxime, cefuZonam, cephacetrile sodium, cephal exin, cephaloglycin, cephaloridine, cephalosporin C, cepha R4 lothin, cephapirin Sodium, cephradine, cilastatin, cinoxacin, ciproflaxacin, clavulinic acid, clavulanate, clinafloxacin, wherein, R represents a bond, H or a metal ion; clometocillin, cyclacillin, dicloxacillin, difloxacin, enoxacin, A is selected from a bond, S, SO, SO, S. S, CH=CH, epicillin, ertapenem, fenbenicillin, fleroxacin, flomoxef, 1.2-phenylene, 1.3-phenylene, 1.4-phenylene, 2.3-pyridine, floxacillin, flumequine, fosfomycin, fropenem, fusidic acid, 3,4-pyridine, 2.4-pyridine, 2.5-pyridine, 2.6-pyridine, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, het D-isosorbide skeleton, 1,4-anhydroerythritol skeleton, acillin, hydnocarpic acid, imipenem, lomefloxacin, loracar cycloalkylene or CRR', where R and R' independently bef, lymecycline, merbromin, meropenem, metampicillin, represent H or C. alkyl with the provisos that: methicillin, mezlocillin, miloxacin, moxalactam, moxifloxa g) when A is S, then a and b is 3; or cin, nadifloxacin, nafcillin, nalidixic acid, negamycin, h) when A is D-isosorbide skeleton or 1,4-anhydroerythri noprysulfamide, norfloxacin, ofloxacin, opiniazide, oxacil tol skeleton, thena and b is 0. lin, oxolinic acid, panipenem, paZufloxacin, pefloxacin, peni 23. The compound according to claim 22 wherein D, the cillin(s), penimepicycline, phenethicillin, phthalylsulfaceta drug containing an amino group is selected from: anti-inflam mide, phthalylsulfathiazole, pipemidic acid, piperacillin, matory and analgesic agents, cardiovascular agents, anti-al piromidic acid, propicillin, prulifloxacin, quinacillin, riti lergic agents, anti-cancer agents, anti-depressants, anti-con penem, roSoxacin, rufloxacin, Salazosulfadimidine, salbac Vulsant agents, anti-bacterial agents, anti-fungal agents, anti tam, sitafloxacin, sparfloxacin, Succinylsulfathiazole, suc viral agents, anti-malarial agents, anti-diabetic agents, anti cisulfone, Sulbenicillin, Sulfachrysoidine, Sulfaloxic acid, ulcer agents, anti-oxidants or vitamins. 4-sulfanilamidosalicylic acid, Sulfanilic acid, taZobactam, 24. The compound according to claim 23, wherein, the teicoplanin, temocillin, ticarcillin, tigemonam, toSufloxacin, anti-inflammatory and analgesic drug is selected from: opio trovafloxacin, tyrocidine or Vancomycin. ids, steroids (glucocorticoids) or non-steroidal anti-inflam 15. The compound according to claim3, wherein the anti matory drugs (NSAIDs). fungal agent is selected from: amphotericin B, azaserine, 25. The compound according to claim 24, wherein the benzoic acid, candicidin, lucensomycin, natamycin, nystatin, anti-inflammatory and analgesic drug is selected from: ace propionic acid, Salicylic acid or undecylenic acid (10-unde clofenac, acetaminophen, acetaminosalol, actarit, alminopro cenoic acid). fen, amfenac, aminochlorthenoxazin, 3-amino-4-hydroxybu 16. The compound according to claim3, wherein the anti tyric acid, ampiroxicam, aminopropylon, anilleridine, viral agent is selected from foscarnet Sodium or Zanamivir. antrafenine, benorylate, benzpiperylon, p-bromoacetanilide,