Title of Invention

PRODRUGS CONTAINING NOVEL BIO-CLEAVABLE LINKERS

Abstract

The invention provides the compounds of formula (I) or pharmaceutically acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one more of pharmaceutically acceptable carriers, vehicles or diluents. The invention further provides methods of prepatation and methods of use of prodrugs including NO-releasing prodrugs, double prodrugs and mutual prodrugs comprising the compounds of formula I.

Full Text

FORM2 THE PATENTS ACT, 197O (39 of 197O) & The Patents Rules, 2OO3COMPLETE SPECIFICATION (See section 10; rule 13) 1. Title of the invention. - PRODRUGS CONTAINING NOVEL BIO- CLEAVABLE LINKERS 2. Applicant(s) (a) NAME :(b) NATIONALITY:(c) ADDRESS : NICHOLAS PIRAMAL INDIA LIMITED An Indian CompanyNicholas Piramal Tower, Peninsula Corporate Park, Ganpatrao Kadam Marg, 10wer Parel, Mumbai - 40O O13, State of Maharashtra, India AND (a) NAME:(b) NATIONALITY(a) ADDRESS : SATYAM, ApparaoA Citizen of United States of AmericaNicholas Piramal Research Centre, Nicholas Piramal IndiaLimited, 1, Nir10n Complex, Off Western ExpressHighway, Goregaon (East), Mumbai - 40O O63, State ofMaharashtra 3. PREAMBLE TO THE DESCRIPTION The fol10wing specification particularly describes the invention and the manner in which it is to be performed : This application takes priority from US Provisional Application USSN: 6O/6O4,632 filed 26 August 2004 and Indian Provisional Application 779/MUM/2OO5 filed O1 July 2OO5 and are herein incorporated in their entirety. Field of the Invention The present invention relates to compositions of prodrugs, including NO-releasing prodrugs, codrugs, double prodrugs and mutual prodrugs, containing bio-labile linkers and linkages, processes for their preparation and pharmaceutical compositions containing them and their use. Background of the Invention A prodrug is an active drug chemically transformed into a per se inactive derivative which by virtue of chemical or enzymatic attack is converted to the parent drug within the body before or after reaching the site of action. The process of converting an active drug into inactive form is called drug latentiation. Prodrugs can be carrier-linked-prodrugs and bioprecursors. The carrier-linked prodrug results from a temporary linkage of the active molecule with a transport molety. Such prodrugs are less active or inactive compared to the parent active drug. The transport molety will be chosen for its non-toxicity and its ability to ensure the release of the active principle with efficient kinetics. Whereas the bioprecursors result from a molecular modification of the active principle itself by generation of a new molecule that is capable of being a substrate to the metabolizing enzymes releasing the active principle as a metabolite. Prodrugs are prepared to alter the drug pharmacokinetics, improve stability and solubility, decrease toxicity, increase specificity, and increase duration of the pharmaco10gical effect of the drug. By altering pharmacokinetics the drug bioavailability is increased by increasing absorption, distribution, biotransformation, and excretion of the drug. Limited intestinal absorption, distribution, fast metabolism, and toxicity are some of the causes of failure of drug candidates during deve10pment. Avoidance of the foreseeable or proven pharmacokinetic defects thus assumes considerable significance in drug research. Accordingly, prodrugs play a significant role in drug research as well. 2 In designing the prodrugs, it is important to consider the fol10wing factors: a) the linkage between the carrier and the drug is usually a covalent bond, b) the prodrug is inactive or less active than the active principle, c) the prodrug synthesis should not be expensive, d) the prodrug has to be reversible or bioreversible derivative of the drug, and e) the carrier molety must be non-toxic and inactive when released. Prodrugs are usually prepared by: a) formation of ester, hemiesters, carbonate esters, nitrate esters, amides, hydroxamic acids, carbamates, imines, mannich bases, and enamines of the active drug, b) functionalizing the drug with azo, glycoside, peptide, and ether functional groups, c) use of polymers, salts, complexes, phosphoramides, acetals, hemiacetals, and ketal forms of the drug. For example, see Andrejus Korolkovas's, "Essentials of Medicinal Chemistry", pp. 97-118. The discovery and characterization of endothelium-derived nitric oxide (NO) was the subject of the 1998 Nobel Prize in Medicine and Physio10gy. NO is a major signaling molecule with important bio10gical roles. See, for example, Kerwin, Jr., J. F. et al., J. Med. Chem. 1995, 38, 4343, and Williams, R. J. P., Chem. Soc. Rev., 1996, 77. The major bio10gical functions of NO include controlling b10od pressure, smoothing muscle tone and inhibition of platelet adherence and aggregation, assisting the immune system in destroying tumor cells and intracellular pathogens and participating in neuronal synaptic transmission. See, for example, Moncada, S. et al., Pharmacol. Rev. 1991, 43, 109; Bredt, D.S. et al., Anuu. Rev. Biochem., 1994, 63, 175; Schmidt, H. H. W. et al., Cell 1994, 78, 919; Feldman, P. L. et al., Chem. and Eng. News. 1993, 71 (2Oth December issue), 26; and Wilsonm E. K., Chem. and Eng. News. 2004 (8th March issue), 39. Endogenously, NO is produced from arginine by the catalytic action of nitric oxide synthase. See, for example, Nathan, C. et al., Cell 1994, 78, 915, and Marietta, M. A., Cell 1994, 78, 927. NO is a free radical as well as a scavenger of free radicals. NO reacts quickly with ubiquitously generated reactive oxygen species (ROS) such as superoxide (O2") to generate a nefarious peroxynitrite (ONOO") molecule, which is implicated in many human diseases such as diabetes, heart disease, Alzheimer's disease and multiple sclerosis. In this setting, NO is often viewed as pathogenic. However, the chemistry of NO can also be a significant factor in lessening the injury mediated by reactive oxygen species (ROS) and reactive nitrogen oxide species (RNOS). There is a relationship 3 between NO and oxidation, nitrosation and nitration reactions. A number of factors determine whether NO promotes, abates or interconnects these chemistries. See, for example, Espay, et al., A chemical perspective on the interplay between NO, reactive oxygen species, and reactive nitrogen oxide species, Ann N. Y. Acad. Sci. 2OO2, 962, 195. Thus, by being a free radical, a10ng with the ability to scavenge other free radicals, NO is placed in a pivotal regulatory position. Insight into these pathophysio10gical processes and signaling are highly relevant to deve10p therapeutics. NO deficiency has been implicated in the genesis and evolution of several disease states. In patients with cardiovascular problems, the production of superoxide is increased and level or 10cation of NO synthesis is disrupted thereby causing cellular dysfunction as a result of vasoconstriction of b10od vessels, which can lead to, if pro10nged, cell damage or death. Agents that act to maintain the norma! balance between NO and superoxide in vascular endothelial cells may prove particularly useful in this regard. See, for example, Stokes, K., et al., Free Radic. Bio. Med., 2OO2, 33, 1026-1036. Nutritional and pharmaco10gical therapies that enhance the bioactivity or production of NO have been shown to improve endothelium-dependent vasodilation, reduce symptoms, and s10w the progression of atherosclerosis. Some of the strategies for NO modulation encompass anti-inflammatory, sexual dysfunction, and cardiovascular indications. Apart from newly deve10ped drugs, several commonly used cardiovascular drugs exert their beneficial action, at least in part, by modulating the NO pathway. Pharmaco10gical compounds that release NO have been useful tools for evaluating the pivotal role of NO in cardiovascular physio10gy and therapeutics. NO-DONORS: There are a wide variety of structurally dissimilar organic compounds that act as NO donors and release NO in solution. Some NO donors, such as isoamyl nitrite, nitroglycerine (GTN) and sodium nitroprusside, have been used in cardiovascular medicine 10ng before their biochemical mechanism was understood. The common mode of action for these drugs is liberation of NO, which evokes relaxation of smooth muscle through activation of guanylate cyclase with subsequent formation of cGMP. The relative importance of enzymatic versus non-enzymatic pathways for NO release, the identity of 4 the actual NO-generating enzymes and the existence of competing metabolic events are additional important determinants of the different NO donor classes. Pharmaco10gical compounds that release NO constitute two broad classes of compounds: those that release NO or one of its redox congeners spontaneously and those that require enzymatic metabolism to generate NO. See, for example, Ignarro, L. J. et al., Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide: an overview, Circ. Res. 2OO2, 90, 21-28. Nitroglycerine/glycerine trinitrate (GTN) and compounds referred to as nitrovasodilators or NO donors are frequently used in the treatment of ischemic heart disease. The common mode of action for these drugs is liberation of NO, which evokes relaxation of smooth muscle through activation of guanylate cyclase with subsequent formation of cGMP. However, early deve10pment of tolerance to nitrate therapy, particularly during acute myocardial infarction, has been the clinically significant drawback with GTN and some of the other available organic nitrates. This is a significant clinical problem and there exists a need for novel nitrate-based anti-anginal agents, which do not cause the problem of nitrate tolerance. There are a number of new examples of organic nitrates in which an alky! or aralkyl mononitrate is covalently linked to an existing drug molecule. Existing drugs from a large number of therapeutic areas such as anti-inflammatory, antiallergic, antibiotic, anticancer, antidiabetic, antiviral, antihypertensive, antianginal, anticonvulsant, analgesic, antiasthmatic, antidepressant, antidiarrheal, antiinfective, antimigraine, antipsychotic, antipyratic, antiulcerative, antithrombotic, etc., were made and evaluated. Some of Nicox's patents include: Synthesis and evaluation of nitrooxy derivatives of NSAIDs (WO 9412463, WO O230867, WO O292O72, WO O313499 and WO O384550), aspirin (WO 9716405, WO OO447O5 and WO O104082), paracetamol (WO O112584 and WO O230866), antiepileptic agents (WO O300642 and WO O300643), COX-2 inhibitors (WO O40O781 and WO O40O300), statins "(WO O4105754), ACE inhibitors (WO O4110432 and WO O4106300), and of known drugs used for the treatment of disease conditions resulting from oxidative stress and endothelial dysfunction (WO OO61537). 5 Most of these nitrate esters were shown to possess not only superior or equal efficacy when compared to the original drug but also exhibit much-reduced side effects. In fact, because of their superior efficacy combined with reduced toxicity, a few of such nitrate ester-containing drug conjugates are successfully passing through various stages of clinical trials. Some of Nicox's nitrooxy derivatives of drugs which are in clinical trials include: NCX 4016 (Phase II, peripheral vascular diseases). NCX 7O1 (Phase II, Acute pain), HCT 1026 (Phase I, Alzheimer's disease), HCT 3012 (Phase II, Osteoarthritis), NCX 285 (IND, Osteoarthritis), NCX 1022 (Phase I la completed, Dermatitis), NCX 102O (Phase 1, Asthma/COPD), NCX 100O (Phase I, Portal hypertension), and NCX 1510 (Phase II, Allergic rhinitis). US5767134 , and US2OO500O2942A1 disc10sed a few disulfide-containing prodrugs/folate-drug conjugates. WO 9842661, US 5807847, WO OO54756 and WO O149275 reported a few nitrooxy derivatives of organic molecules containing sulfahydryl or disulfide group which are called "SS-nitrates". These references are incorporated herein by reference. Representative examples from WO 9842661 have shown superior vasorelaxant activity and no tolerance was observed to the cGMP-increasing effects of those compounds under the same experimental conditions used for the induction of in vivo tolerance. WO O149275 reports drug conjugates where an anti-inflammatory drug is covalently linked to the ie/^-mercapto-nitrate via thioester bond. Biotransformation pathways proposed for NO release from GTN have largely been heme-dependent or sulfahydryl-dependent. See, for examples, Thatcher, G. R. J. et al., Chem.Soc. Rev. 1998, 27, 331 and reference cited therein, and Bennett, B M. et al., Trends Pharmacol, Sci. 1994, 15, 245. These references are incorporated herein by reference. A mutual prodrug is the association in a unique molecule of two drugs, usually synergistic, attached to each other, one drug being the carrier for the other and vice versa. The embodiments of the invention also provide mutual prodrugs, which are prodrugs of two or three therapeutic agents currently used/potential for use in combination therapy utilizing novel bio-cleavable linkers, water-soluble prodrugs of insoluble/sparingly-soluble therapeutic agents using the same linker techno10gy and water-soluble double and 6 triple prodrugs of sparingly-soluble therapeutic agents or any of the prodrugs linked to NO-releasing agent using the same linker techno10gy. Summary of the Invention Present invention relates to the compounds of formula (I) or pharmaceutically acceptable salts thereof: wherein, a is O-2; B independently represents a bond, (CH2)b, (CH2CH2O)c, S-S, S-SO, S-SO2 or S-S=NH; bis 1-6; c is 1-100O; A and A1 independently represent a bond, (CH2)d, 1,2-phenylene, 1,3-phenylene or 1,4- phenylene; d is 1-8; D represents a therapeutic agent comprising one or more of the functional groups selected from the group consisting of-OH, -SH, -NHR1, -CO2H, -CONHR1, - OC(=O)NHR\ -SO2NHRl, -OSO2NHR1, -N(R1)C(=O)NHR1 and -N(R,)SO2NHR1; D independently represents D , a peptide, protein, monoc10nal antibody, vitamin, R , R , R4, NO, NO2, a linkable nitric oxide-releasing group comprising a NONOate, a group comprising one or more of water-solubilizing functional groups, or a polymer; E independently represents CH2 or a bond; L and L independently represent a bond, O, S, NR , L, or a linkage selected from the group consisting of: 7 1 'J L is R or a group with bonding in any direction, independently selected from the group consisting of: X independently represents a bond, C, O, S, orNR1; Y independently represents a bond, OO, C=S, S=O, SO2, P(=O)XR', or (CH2)d; Z independently represents a bond, or (CH2)J; wherein, j is 1-4; R1 independently represents a bond, H, (C1-C8)alkyl, (C5-Ci4)aryl, aralkyl or Me+; R2 independently represents H, NH2, or NHAc; R3 independently represents H, CO2R5, CH2CO2R5, R4 independently represents H, OH, O-(C1-C8)alkyl, OMe+, or a group selected from the group consisting of: 8 M independently represents Na, K or a pharmaceutically acceptable metal ion, e=l-3, R5 independently represents at each occurrence H, Me+, (Ci-C8)alkyl, (C3-C8)cyc10alkyl, substituted (C5-C14)aryl, hetero(C2-C14)aryl, C(=O)(CH2)fCHR9CO2R5, CH2C(=O)OR5, P(=O)(OR5)2, 9 X2 independently represents O, S, SO, SO2, orNR5; R6 independently represents H, Na+, K+, any other pharmaceutically acceptable metal ion, (C1-C8)alkyl, or (C3-C8)cyc10alkyl, R7 independently represents at each occurrence same or different R5; R8 independently represents CH2, O, NR4, S, S=O or OSO; R9 independently represents H, (C1-C8)alkyl or an amino acid; f is O-6; g is O-1; h is 1-2OOO; , i is 1-4; R10and R11 independently represent H, (C]-C8)alkyl, (C3-C8)cyc10atkyl, or a group selected from the group consisting of: 10 with a proviso that when R is selected from the above group, R represents H or (C1- C8)alkyl, and when R11 is selected from the above group, R10 represents H or (C1- C8)alkyl; R1 independently represents a group selected from the group consisting of: 11 and X3 is independently O or NR7. 12 Another embodiment of the invention is a pharmaceutical composition comprising one or more compounds of formula I or intermediates thereof and one more of pharmaceutically acceptable carriers, vehicles or diluents. Further embodiments include methods of preparation and methods of use of prodrugs including NO-releasing prodrugs, double prodrugs and mutual prodrugs comprising the compounds of formula I. Detailed Description of the Invention The present invention characterizes compositions, methods of preparation and methods of use of prodrugs, NO-releasing prodrugs, mutual prodrugs, double prodrugs, and cod rugs. The compounds of the present invention are prodrugs or mutual prodrugs in which known therapeutic agents or potential therapeutic agents are linked covalently to novel biocleavable linkers. The compounds of the present invention also include NO-releasing prodrugs in which a therapeutic agent is linked covalently to nitrooxy (nitrate ester) group via a novel bio-cleavable linker containing a strategically placed disulfide group at p-position to the nitrate ester. The present invention also characterizes composition of NO-releasing prodrugs (i.e., nitrooxy ester or nitrate ester prodrugs), processes for their preparation, pharmaceutical composition containing them and their use. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention be10ngs. Listed be10w are definitions of various terms used to describe the compounds of the present invention. These definitions apply to the term as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or part of a larger group. The term "amino-containing" refers to drug/carrier molecule with NH functional groups such as amino (both primary and secondary), amide, urea, sulfonamide, carbamate, phosphoramadite, sulfamate, hydrazone, semicarbazone, thiosemicarbazone, hydrazide, carbazate and the like. This also includes NH-containing heterocylic compounds such as imidazoles, benzimidazoles, pyrazoles, benzpyrazols, pyrrols, indoles, triazoles, tetrazoles, benzotriazoles, benzotetrazoles and their derivatives. These NH-containing heterocyclic compounds can be sub-structures of more complex 13 drug/carrier molecules. Amino group of the candidate drug can be primary or secondary (both acyclic and cyclic) which include amide-NH, sulfonamide-NH, carbamate-NH, sulfamate-NH. hydrazide-NH, hydrazone-NH3 semicarbazone-NH, thiosemicarbazone-NH, urea-NH and also drugs containing indole, imidazole, benzimidazole, thiazole, oxozole, pyrrole, pyrazole, triazole, tetrazole, or similar NH-containing heterocylic substructures of a more complex drug molecule. The term "hydroxyl-containing" refers to drug/carrier molecules with hydroxyl groups (primary, secondary and tertiary) including hydroxyl groups of hydroxamic acids and ketoximes derived from keto-containing molecules. Hydroxyl group of drugs can be of primary, secondary or tertiary nature. The term "sulfahydryl-containing" refers to drug/carrier with free sulfahydryl (SH) group. The term "ha10" refers to fluoro, ch10ro, bromo, and iodo. The term "halide" refers to fluoride, ch10ride, bromide, and iodide. The term "alkyl" refers to acyclic alkyl chains. For example, the term "C|-Cs alkyl" refers to methyl, ethyl, propyl, isopropyl, butyl, cyc10butyl, s-butyl, and t-butyl, pentyl, hexyl, heptyl, octyl, and the like. The term "cyc10alkyl" refers to cyclic alkyl chains, e.g., the term "C3-C8 cyc10alkyl" refers to cyc10propyl, cyc10octyl, cyc10pentyl, cyc10hexyl, cyc10heptyl, cyc10octyl and the like. The term "aryl" refers to phenyl, naphthyl and the like. The term "aralkyl" refers to benzyl, phenethyl and the like. The term "alkoxy" refers to both acyclic and cyclic Cj-Cs alky10xy. For example, the term "Ci-Cs alky10xy" refers to methoxy, ethoxy, propoxy, isopropoxy, cyc10propoxy, butoxy, cyc10butoxy, s-butoxy, and t-butoxy, cyc10penty10xy, penty10xy, hexy10xy, cyc10hexy10xy, hepty10xy, cyc10hepty10xy, octy10xy, cyc10octy10xy and the like. The term "heterocyclic" and "heteroaryl" refers to both saturated and unsaturated 5- and 6-membered rings (including benzo-fused) containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. All of these rings may be substituted with up to three substituents independently selected from the group 14 consisting of amino, ha10, alkoxy, alkyl, cyano, nitro, hydroxyl, sulfahydryl, carboxyl and the like, Saturated rings include, for example, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuryl, oxazolidinyl, dioxanyl, pyranyl, and the like. Benzofused saturated rings include indolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl and the like. Unsaturated rings include furyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like. Benzofused unsaturated rings include isoquinolinyl, benzoxazolyl. benzthiazolyl, quinolinyl, benzofuranyl, thionaphthyl, indolyl and the like. The term "substituted alkyl" refers to acylic and cyclic alkyl groups substituted with one or more of groups such as alkyl, aryl, hydroxy, alkoxy, cyano, carboxyl, sulfahydryl, alkylthio, amino, nitro, ha10, carbonyl, carbamato, sulfamato, sulfonato, sulfato, and the like. The term "substituted aryl" refers to aryl groups substituted (including fused) with one or more of groups such as alkyl. aryl, hydroxy, alkoxy, cyano, carboxyl, sulfahydryl, alkylthio, amino, nitro, ha10, carbonyl, carbamato, sulfamato, sulfonato, sulfato, and the like. The term "amino acid" refers to molecules containing one or more amino and carboxyl groups. Examples of alfa-amino acids (D-, L- and DL- amino acids) -include natural alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, -threonine, tryptophan, tyrosine, and valine. Other examples include beta-amino acids and known unnatural amino acids. The term "amino acid ester" as used in this specification refers to an amino acid where the carboxyl group is substituted with a C1-C8 alkyl group. That is, the alkyl group when taken together with the carboxyl group forms a C1 –C6 alkyl ester. It is appreciated that some amino acids (e.g., aspartic acid and glutamic acid) have two carboxyl groups these may form mono- and di-esters. The term "protecting group" (PG) refers to an 'amino protecting group' or a 'hydroxyl protecting group' or a 'carboxyl protecting group' and the like. 15 The term "amino protecting group" refers to a group that selectively b10cks or protects the amino functionality in presence of other functional groups on the molecule. Examples of such ami no-protecting groups include the formyl group, the trityl group, the phthalimido group, the acetyl group, the trifluoroacetyl group, the ch10roacetyl, bromoacetyl, and iodoacetyl groups, urethane-type b10cking groups such as benzy10xycarbonyl ("CBZ"), 9-fluorenylmethoxycarbonyl ("FMOC"), tert-butoxycarbonyl ("BOC"), trich10roethylcarbonyl and the like. Additional examples of amino protecting groups are described by T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991. Molecules with two or more amino groups may form mono-, di-, tri-, poly-, protected derivatives depending on the reaction conditions used. The term "hydroxyl protecting group" refers to a group that selectively b10cks or protects hydroxyl functionality in presence of other reactive functional groups on the molecule. Examples of such hydroxyl-protecting groups include, for example, ether groups including methyl and substituted methyl ether groups such as methyl ether, methoxymethyl ether, methylthiomethyl ether, tert-buylthiomethyl ether, triphenylmethyl, tetrahydropuranyl (THP), (phenyldimethylsilyl)methoxy-methyl ether, benzy10xymethyl ether, p-methoxybenzy10xy-methyl ether, and tert-butoxymethyl ether; substituted ethyl ether groups such as ethoxyethyl ether, l-(2-ch10roethoxy)-ethyl ether, 2,2,2-trich10roethoxymethyl ether, and 2-(trimethylsilyl)ethyI ether; isopropyl ether groups; phenyl and substituted phenyl ether groups such as phenyl ether, p-ch10rophenyl ether, p-methoxyphenyl ether, and 2,4-dinitrophenyl ether; benzyl and substituted benzyl ether groups such as benzyl ether, p-methoxybenzyl ether, o-nitrobenzyl ether, and 2,6- dich10robenzyl ether; and alkylsilyl ether groups such as trimethyl-, triethyl- and triisopropylsilyl ethers, mixed alkylsilyl ether groups such as dimethylisopropylsilyl ether, tert-butyldimethylsilyl ether and diethylisopropylsilyl ether; and ester protecting groups such as acetate ester, formate ester, benzylformate ester, mono-, di-, and trich10roacetate esters, pivalate ester, phenoxyacetate ester, and p-ch10rophenoxyacetate, benzy10xycarbonate, 9-fluorenylmethoxycarbonate, tert-butoxycarbonate, trich10roethylcarbonate, carbamate, sulfamate and the like. Additional examples of hydroxyl protecting groups are described by T. W. Greene, "Protective Groups in 16 Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991. Molecules with two or more hydroxyl groups may form mono- and di-esters/ethers depending on the reaction condition. The term "carboxyl protecting group" refers to a group that selectively b10cks or protects carboxyl functionality in presence of other reactive functional groups on the molecule. Examples of such carboxyl-protecting groups include, for example (substituted) alkyl esters such methyl ester, ethyl ester, t-butyl ester, (substituted) benzyl ester, trich10roethyl ester, and the like. Additional examples of carboxylic acid protecting groups are described T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991. Molecules with two or more carboxylic acid groups may form mono-, di-, tri-, tetra-, poly- protected derivatives depending upon the reaction conditions used. The term "carbonyl activating group" refers to leaving group ("LG") of a carboxyl derivative that is easily replaced by an incoming nucleophile. Such "LG" groups include, but are not limited to, (substituted) alkoxy, ary10xy, nitrogen containing unsaturated heterocycles such as N-oxybenzotriazole, imidazoly!, o/p-nitrophenoxy, pentach10ro-phenoxy, N-oxysuccinimide, N,N'-dicyc10hexylisoure-O-yl, N-hydroxy-N-methoxyamino, and the like; acetates, formates, sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, or p-toluenesulfonate, and the like; and halides especially fluoride, ch10ride, bromide, or iodide. The term "carbonyl activating reagent" refers to a reagent that converts the carbonyl of a carboxylic acid group into one that is more susceptible to nucleophilic attack and includes, but is not limited to, such reagents as those found in "The Peptides", Gross and Meienhofer, Eds., Academic Press (1979), Ch. 2, and M. Bodanszky, "Principles of Peptide Synthesis", 2.sup.nd Ed., Springer-Verlag Berlin Heidelberg, 1993, hereafter referred to as "The Peptides" and "Peptide Synthesis" respectively. Carbonyl group (i.e., aldehyde or keto group) of candidate drugs may be converted first to aldoxime, ketoxime, hydrazone, semicarbazone and the like, before coupling to the linker. Specifically, carbonyl activating reagents include thionyl bromide, thionyl ch10ride, oxalyl ch10ride, and the like; esters of alcohols such as nitrophenol, pentach10rophenol, and the like; and compounds such as l,r-carbonyldiimidazole (CDI), 17 benzotriazole, imidazole, N-hydroxysuccinimide, dicyc10hexylcarbodiimide (DCC), EDC, phosgene or its equivalents, N, N-dimethylaminopyridine (DMAP) and the like. The terms "phosgene or its equivalents" refer to phosgene or it equivalents such as diphosgene, triphosgene, CDI, DSC, BTBC, alkoxycarbonyl ch10rides, o/p-nitrosubstituted phenoxycarbonyl ch10rides, and the like. In general, the term "pharmaceutical" when used as an adjective means substantially non-toxic to living organisms. The terms "pharmaceutically acceptable metal ions or salts" refer to salts of the compounds of this invention, which are substantially non-toxic to living organisms. See, e.g., Berge, S. M. et al., "Pharmaceutical Salts", J. Pharm. Sci., 66:1, 1977. Typical pharmaceutical salts include those salts prepared by reaction of the compounds of this invention with an inorganic or organic acid or base. Such salts are known as acid addition or base addition salts respectively. These pharmaceutical salts frequently have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions. Examples of pharmaceutically acceptable salts are those with inorganic bases such as sodium, potassium, calcium, magnesium, and hydroxides, and the like, or with organic bases such as lysine, arginine, triethylamine, dibenzylamine, piperidine, and the like. The term "suitable solvent" refers to a solvent that is inert to the ongoing reaction and sufficiently solubilizes the reactants to effect the desired reaction. Examples of suitable solvents include but are not limited to, dich10romethane, ch10roform, 1,2-dich10roethane, diethyl ether, tert-butylmethyl ether, acetonitrile, ethyl acetate, 1,3-dimethyl-2-imidazolidinone, tetrahydrofuran, dimethylformamide, benzene, toluene, xylene, N-dimethylacetamide, N-methylpyrrolidine, ch10robenzene, dimethylsulfoxide, dimethoxyethane, water, methanol, ethanol, isopropanol, pyridine, nitromethane, mixtures thereof, and the like. The term "suitable base" refers to a base, which acts as a proton trap for any protons, which may be produced as a byproduct of the desired reaction, or to a base, which provides a reversible deprotonation of an acidic proton from the substrate and is reactive enough to effect the desired reaction without significantly effecting any undesired reactions. Examples of such bases include, but are not limited to, carbonates, 18 bicarbonates, and hydroxides (e.g., lithium, sodium, potassium, magnesium, calcium and the like), sodium/potassium/calcium hydride, sodium/potassium alkoxide (i.e., methoxide, ethoxide, tert-butoxide and the like), triethylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, tetramethylguinidine, or aromatic nitrogen containing heterocycles such pyridine, 4-(dimethylamino)pyridine (DMAP), and the like. The term "NONOate" refers to a linkable nitric oxide-releasing group such as AcOCH2-O-N2-N(O')R7, OCHOCH2-O-N2-N(O") R7R7, CH2-O-N2-N(O)R7 R7 and the like. The term "therapeutic agent" refers to bio10gically active molecules such as drugs, vitamins, and other molecules, agents or substances concerned with or contributing to the treatment and cure of illness or contributing to the general well being of a mammal or human. The therapeutic agents can be both known and investigational drugs compiled in drug databases such as the Merck Index, IDdb, Prous Science's Integrity , Prous Science Drugs of the Future™, The Ensemble® and the like. The Merck Index is a one-volume encyc10pedia of chemicals, drugs and bio10gicals that contains more than 10,000 monographs. Each monograph in this authoritative reference source is a concise description" of a single substance or a small group of c10sely related compounds. Prous Science is an international health science publishing company, established in 1958 and headquartered in Barce10na, Spain. Prous Science Drugs of the Future™, produced by Prous Science Publishers, contains comprehensive drug monographs providing product information on new compounds, including the synthesis and corresponding schemes, pharmaco10gical action, pharmacokinetics and metabolism, toxicity, clinical studies, manufacturer, and references. Information on compounds is continuously updated as advances in deve10pment status are disc10sed worldwide. The Prous Science Integrity™ is a drug R&D portal where knowledge areas are coordinated to provide a harmonious and interrelated whole, which includes Drugs & Bio10gies, Targets, Organic Synthesis, Experimental Pharmaco10gy, Pharmacokinetics and Metabolism, Clinical Studies, Disease Briefings, Companies & Markets, Literature and Patents. The Investigational Drugs database (IDdb), deve10ped by Thomson Current Drugs, is a pharmaceutical competitor intelligence service. It covers all aspects of investigational drug deve10pment, from first patent to eventual launch or discontinuation. The Ensemble® on the Web 19 provides essential information, including chemical structures, on more than 140,OOO compounds with demonstrated bio10gical activity in the drug research and deve10pment pipeline. The term "vitamin" includes vitamin A, vitamin C, thiamine, folic acid, biotin, inositol, nicotinic acid, nicotinamide, riboflavin, pyridoxine, pyridoxal 5-phosphate, ergosterol, vitamin D2, vitamin D3, vitamin D4, vitamin E, menadoxime, menadiol, and vitamin K5. The term "peptide" includes large and small peptides, including, but not limited to, targetable small peptides such as a dipeptide, tripeptide, tetrapeptide, etc. The term "ligand" means a small molecule that binds to a larger macromolecule, whether or not the ligand actually binds at a metal site. Such ligands can be small peptides. One aspect of the invention is to provide mutual prodrugs of two or three therapeutic agents currently used for use in combination therapy utilizing novel bio-cleavable linkers, water-soluble prodrugs of insoluble and sparingly-soluble therapeutic agents using the same linker techno10gy, and water-soluble double and triple prodrugs of sparingly-soluble therapeutic agents using the same linker techno10gy. The embodiments of the invention may also comprise vitamins and targetable small peptides in addition to or in place of a promoeity to yield targetable prodrugs. The candidate drugs selected for mutual prodrug synthesis can be from one therapeutic category or from different therapeutic categories. Similarly, the constituent drugs of a mutual prodrug can act on the same bio10gical target with similar mechanism of action or act on different bio10gical targets with different mechanisms of action. To be considered for prodrug synthesis, the candidate drugs should contain one or more of the essential functional groups such as amino, hydroxyl, keto, or carboxyl groups in their structure. Amino group of the candidate drug can be primary or secondary (both acyclic and cyclic) which include amide-NH, sulfonamide-NH, carbamate-NH, sulfamate-NH, hydrazone-NH, semicarbazone-NH, thiosemicarbazone-NH and also drugs containing indole, imidazole, benzimidazole, thiazole, oxozole, pyrrole, pyrazole, triazole, tetrazole, or similar NH-containing heterocylic sub-structures of a more complex drug molecule. 20 Similarly, hydroxy I group of drugs can be of primary, secondary or tertiary nature. Keto group of candidate drugs may be converted first to ketoxime, hydrazone, semicarbazone and then like, before coupling to the linker. Obviously, hydroxyl or amino functions thus generated will be used to form covalent bond between the drug and the linker. The candidates for making mutual prodrugs can be the pairs of drugs that are currently used in combination therapy (including those combination studies at investigational stage) in various therapeutic areas provided each of those drugs possesses the requisite functional group(s). There are a number of therapeutic areas where such combination therapy is applied routinely and successfully. On the basis of the proposed sulfahydryl-dependent mechanism of NO-release from GTN, we have designed the compounds and prodrugs of the present invention where a suitable drug molecule is linked covalently to a nitrooxy (nitrate ester) group via a bio-labile linker containing strategically 10cated disulfide bond at 6e/a-position to nitrate ester. In vivo, the disulfide bond in the prodrug is expected to be reduced by endogenous sulfahydryf-containing species such as glutathione (GSH) to generate a reactive thiolate anion (i.e., &eta-mercapto-nitrate), which can trigger further break-down of the linker molety to release the free drug (via a mechanism as shown Scheme Ml) and NO simultaneously at the same 10cation. It is possible, as depicted in the mechanism Scheme Ml, the release of NO can go via a hypothetical cyclic transient intermediate 'b'. Similar hypothetical mechanism was proposed for NO release from SS-nitrates, which were also designed on the basis of a sulfahydryl-dependent NO release from GTN. See, for example, Zavorin, S. I. et al., Organic Letters, 2OO1, 3, 1113, incorporated herein in its entirety.Mutual prodrugs can be made by linking covalently any two of the fol10wing: an ami no-containing therapeutic agent to another amino-containing therapeutic agent; an amino-containing therapeutic agent to a hydroxyl-containing therapeutic agent; an amino-containing therapeutic agent to a carboxyl-containing therapeutic agent and its derivative; a hydroxyl-containing therapeutic agent to a carboxyl-containing therapeutic agent and its derivative; an amino-containing therapeutic agent to a carboxyl-containing therapeutic agent and its derivative; an amino-containing therapeutic agent to a keto-containing therapeutic agent or its hydazone, semicarbazone or oxime derivative and the likes; a 21 hydroxyl-containing therapeutic agent to a keto-containing therapeutic agent via its hydrazone, semicarbazone, or oxime derivative and the likes. Another aspect of the present invention is to provide new nitrate ester (NO-releasing) prodrugs of many types of existing drugs using novel biocleavable likers. Such prodrugs are expected to exhibit better efficacy and tolerability with reduced side effects compared to the corresponding original drugs. An embodiment of present invention relates to the compounds of formula (I) or pharmaceutically acceptable salts thereof: wherein, a is O-2; B independently represents a bond, (CH2)b, (CH2CH2O)c, S-S, S-S=O, S-SO2 or S-S-NH; bis 1-6; c is 1-100O; A and A1 independently represent a bond, (CH2)d, 1,2-phenylene, 1,3-phenylene or 1,4- phenylene; d is 1-8; D represents a therapeutic agent comprising one or more of the functional groups selected from the group consisting of-OH, -SH, -NHR1, -CO2H, -CONHR1, - OC(=O)NHR', -SO2NHR1, -OSO2NHR1, -NCR^CCO^HR1 and -N(R')SO2NHRl; D independently represents D , a peptide, protein, monoc10nal antibody, vitamin, R , R , R , NO, NO2, a linkable nitric oxide-releasing group comprising a NONOate, a group comprising one or more of water-solubilizing functional groups, or a polymer; E independently represents CH2 or a bond; L and L independently represent a bond, O, S, NR1, L, or a linkage selected from the group consisting of: 22 1 *} L is R or a group with bonding in any direction, independently selected from the group consisting of: X independently represents a bond, C, O, S, orNR1; Y independently represents a bond, C=O, C=S, SO, SO2, P(=O)XR', or (CH2)d; Z independently represents a bond, or (CH2)J; wherein, j is 1-4; R1 independently represents a bond, H, (C1-C8)alkyl, (C5-C]4)aryl, aralkyl or Me+; R2 independently represents H, NH2, or NHAc; R3 independently represents H, CO2R5, CH2CO2R5, R4 independently represents H, OH, O-(Ci-C8)alkyls OMe+, or a group selected from the group consisting of: 23 M independently represents Na, K or a pharmaceutically acceptable metal ion, e-1-3, R5 independently represents at each occurrence H, Me+, (C]-Cs)alkyl, (C3-C8)cyc10alkyI, substituted (C5-C14)aryl, hetero(C2-C14)aryl, C(=O)(CH2)fCHR9CO2R5, CH2C(=O)OR5, P(=O)(OR5)2, 24 X2 independently represents O, S, SO, SO2, orNR5; R6 independently represents H, Na+, K+, any other pharmaceutically acceptable metal ion, (C1-C8)alkyl, or (C3-C8)cyc10alkyl, R7 independently represents at each occurrence same or different R5; R8 independently represents CH2, O, NR4, S, S=O or O=SO; R independently represents H, (Ci-C8)alkyl or an amino acid; f is 0-6; | g is O-1; h is 1-2000; i is 1-4; Rl0and Rn independently represent H, (C1-C8)alkyl, (C3-C8)cyc10alkyl, or a group selected from the group consisting of: 25 with a proviso that when R is selected from the above group, R represents H or (C1- C8)alkyl, and when R11 is selected from the above group, R10 represents H or (C1- C8)alkyl; R12 independently represents a group selected from the group consisting of: 26 X is independently O or NR . 27 D1 and D2 of the present invention can be both known and investigational drugs compiled in drug databases such as the Merck Index, IDdb, Prous Science's Integrity®, Prous Science Drugs of the Future™, The Ensemble® and the like. In a double prodrug, D1 and D2 are the same drugs. In a mutual prodrug, D1 and D2 are different drugs. In some prodrugs, only Dl is a drug and D2 may not be a drug at all. The -OH, -SH, -Nth, -NHR1, -CO2H, -CONHR1, -OC(=O)NHR\ -SO2NHR1, -OSO2NHR1, -NfR'jCC^OJNHR1 and -N^^SChNHR1 functional groups in D1 and D2 of formula I participate in the formation of linkages between the drug and the linker. Accordingly, some of the atoms or groups in L and L may come from the corresponding D , D or linker. Another embodiment of the invention is the compound of formula I, wherein D" is an amino-, carboxyl- or hydroxyl- containing group or molecule comprising one or more water solubilizing functional groups selected from the group consisting of hydroxyl, amino, acylamino, carboxyl, sulphate, sulfonate, phosphate, phosphonate, N-acylsulfonamide, N-acylsulfamate, N-acylcarbamate, N-acylcarbamate metallic salts, and amino acids to give water-soluble prodrug. Another embodiment of the invention is the compound of formula I, wherein D is selected from the group of D, L and DL amino acids consisting of Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamine, Glutamic acid, Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, and Valine. Another embodiment of the invention is the compound of formula I, wherein D represents a polymer selected from the group consisting of arabinogalactan, polyamino acids, polyethylene glycol, polycaprolactone, polyglycolic acid, polylactic acid, polyacrylic acid, poly(2-hydroxyethyl 1-glutamine), dextran and modified dextrans such as dextran aldehyde, carboxymethyl dextran, arabinogalactane aldehyde, carboxymethyl arabinogalactane, and hyaluronic acid. Yet another embodiment of the invention is the compound of formula I, wherein D2 is a polyaminoacid selected from group consisting of poly(l-glutamic acid), poly(d-glutamic acid), poly(dl-glutamic acid), po!y(l-aspartic acid), poly(d-aspartic acid), poIy(dl- aspartic acid), copolymers of the polyaminoacids and polyethylene glycol, 28 Another embodiment of the invention is the compound of formula I, wherein the polymer has a molecular weight of about 5000 to about 100,000 Daltons. Yet another embodiment of the invention is the compound of formula I, wherein the polymer has a molecular weight of about 10,000 to about 50,000 Daltons. In a further embodiment D2 is a peptide, protein or monoc10nal antibody for achieving targeted delivery of prodrugs and drugs. Another embodiment of the invention is the compound of formula I, wherein D2 is a ligand or dipeptide or a dipeptide ligand. In a further embodiment D2 is a dipeptide ligand that is a substrate for intestinal transporters for selective intestinal absorption of the corresponding prodrugs thereby increasing the bioavailability of the prodrugs. In a further embodiment D is a targetable small peptide, i.e., dipeptide, tripeptide, tetrapeptide, etc. Another embodiment of the invention is the compound of formula I, wherein D2 is a vitamin. Such vitamin-conjugated prodrugs are expected to be taken up by the diseased cells via receptor-mediated endocytosis. In a further embodiment of the invention is a compound of formula I, wherein D2 is selected from the group of vitamins consisting of vitamin A, vitamin C, thiamine, folic acid, biotin, inositol, nicotinic acid, nicotinamide, riboflavin, pyridoxine, pyridoxal 5-phosphate, ergosterol, vitamin D2, vitamin D3, vitamin D4, vitamin E, menadoxime, menadiol, and vitamin K5. Another embodiment of the invention is the compound of formula I, wherein D1 and D2 represent the same therapeutic agent to give a symmetrical double prodrug. Another embodiment of the invention is the compound of formula I, wherein D and D represent different therapeutic agents to give a mutual prodrug. Another embodiment of the invention is the compound of formula (I), wherein D1 and D2 can be either from same or different therapeutic class. Another embodiment of the invention is the compound of formula (I), wherein D1 and D2 can be same or different therapeutic agents. Such therapeutic agents may have same or different mechanisms of action or they may work on different bio10gical targets or work on different disease conditions. Another embodiment of the invention is the compound of formula I, wherein D2 is R2, R3 or R4. Another embodiment of the invention is the compound of formula I, wherein a is O, B is S-S, S-S=O, S-SO2 or S-S=NH. Yet another embodiment of the invention is the compound of formula I, wherein a is O, B is S-S or S-S=O, S-SO2 and D2 29 is R2 or R3 or R4. A further embodiment of the invention is the compound of formula 1, wherein B is S-S, A and A1 are CH2-CH2, E is a bond and D2 is R2, R3 or R4. Another embodiment of the invention is the compound of formula I, wherein a is O; B is S-S or S-S=O, S-SO2; A and A1 are CH2-CH , E is a bond and D2 is R4. Another embodiment of the invention is the compound of formula I, wherein a is O; B is S-S; A and A1 are CH2-CH2j E is a bond and D2 is R4. Another embodiment of the invention is the compound of formula I, wherein a is O, B is a bond, (CH2)b, or (CH2CH2O)c; wherein b and c are as defined above. Another embodiment of the invention is the compound of formula I, wherein a is O, B is a bond, (CH2)b or (CH2CH2O)c and D2 is R2 or R3 or R4; wherein b and c are as defined above. Yet another embodiment of the invention is the compound of formula I, wherein a is O; B is S-S or S-SO, S-SO2; Dl and D2 are drug molecule or R2 or R4 containing carboxyl group; L1 and L2are independently selected from the fol10wing linkages: wherein, X, R , Z are as defined above; and Y is C=Q. In another embodiment, A and A1 are CH2-CH^ and E is a bond. In a further embodiment A and A1 are 1, 2-phenylene, 1, 3-phenylene or 1, 4-phenylene and E is CH2. Yet another embodiment of the invention is the compound of formula I, wherein a is O; B is S-S or S-S=O, S-SO2; A and A1 are CH2-GH2-E is a bond; D1 and D2 are drug molecule or R2 or R4 containing amino- or hydroxyl group; L1 and L2 are independently selected from the fol10wing linkages: wherein, X, R1, Z are as defined; and Y is C=Q.. In another embodiment, A and A1 are CH?-CH^ and E is a bond. In a further embodiment, A and A1 are 1, 2-phenylene, 1, 3-phenylene or 1, 4-phenylene_ and E is CH2. 30 Yet another embodiment of the invention is the compound of formula I, wherein a is O, B is S-S or S-S=O, S-SO2 and D is D . Another embodiment of the invention is the compound of formula I, wherein a is O; B is S-S or S-SO, S-SO2; A and A1 are CH2-CH2, E is a bond and D2 is D1. Another embodiment of the invention is the compound of formula I, wherein a is O; B is S-S or S-S=O, S-SO2; A and A1 are 1,2-phenylene, 1,3-phenylene or 1,4-phenylene; E is CH2 and D2 is D'or R2 or R3 or R4. Another embodiment of the invention is the compound of formula I, wherein a is O; B is S-S; A and A1 are 1,2-phenylene, 1,3-phenylene or 1,4-phenylene; E is CH2 and D2 is D'or R2 or R3 or R4. A further embodiment of the invention is the compound of formula I, wherein B is S-S, A and A1 are CH2-CH2, E is a bond and D2 is D1, Yet another embodiment of the invention is the compound of formula I, wherein a is O; B is S-S or S-SO, S-SO2; A and A1 are CH2-CH2, E is a bond and D2 is a dipeptide ligand. Yet another embodiment of the invention is the compound of formula I, wherein a is O; B is S-S; A and A1 are CH2-CH2, E is a bond and D2 is a dipeptide ligand. The peptide ligands used in the invention can be substrates for intestinal transporters for selective intestinal absorption of the corresponding prodrugs thereby increasing the bioavailability of the prodrugs. An embodiment of the present invention is the compounds of formula (I), wherein D1, L1 and L2 are as defined above; A and A are CH2; E is CH2; B is a bond or (CH2)b; b is 1-6; a is O; and D2 is D1 or R2 or R4. Another embodiment of the present invention is the compound of formula (1), wherein E, D1 and L1 are as defined; L2 is O; A and A1 are independently (CH2)d, 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene; d is 1-4; B is S-S, S-S=O, S-SO2 or S-S=NH; a is O; D2 is NO, NO2 or a nitric oxide releasing molecule such as NONOate. In a further embodiment, D2 is a NONOate selected from the group consisting of: In yet another embodiemnt, when D2 isone of the above NONOates, B is S-S. Another embodiment of the present invention is the compound of formula (I), L2 is O; A and A1 are independently (CH2)d, 1,2-phenylene, 1,3-phenylene, or 1,4- 31 phenylene; d is 1-4; B is S-S; a is O; D2 is NO2. In a further embodiment, when A and A1 CH2-CH2, E is a bond. In yet another embodiment, when E is CH2, A and A1 are independently 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene. Yet another embodiment of the present invention is the compound of formula (I), wherein D is a amino containing drug molecule having the fol10wing reactive functional groups which are involved in the formation of L1 linkages between the drug and the linker: -NH2,-NHR',-CONHR1 -O-C(=O)NHR1, -SO2NHR1, -OSO2NHR1, -NR'C(=O)NHR1 or -N(R1)SO2NHR1; L2 is O; E is bond; L1 is linkages selected from the group consisting of: wherein, X is independently a bond, O or NR , Y is C=O or SO2, A and A1 are CH2 CH2, BisS-S, aisOandD2isNO2. An embodiment of the present invention is the compound of formula (1), wherein D1 is a hydroxy! or sulfahydryl containing drug molecule such as Drug-OH or Drug-SH, wherein functional groups OH and SH are involved in the formation of L1 linkages between the drug and the linker; L is O; E is bond, L is a linkage selected from the group consisting of: wherein, X is independently a bond, O or NR1, Rl is not a bond, Y is C=O or SO2, A and A1 are CH2CH2; B is S-S; a is O; and D2 is NO2. An embodiment of the present invention is the compound of formula (I), wherein D1 is a drug molecule having carboxyl (-CO2H) as a reactive functional group such as -CO2H which is involved in the formation of L1 linkages between the drug and the linker; L2 is O; E is bond; L1 is O or NR1 or a linkage selected from the group consisting of: 32 wherein, X is independently a bond, O or NR1, R1 is not a bond; Y is C=O or SO2; A and A1 are CH2CH2; B is S-S; a is O and D2 is NO2. Another embodiment of the present invention is the compounds of formula (I), wherein D is an antioxidant or free radical scavenger such as a hydroxyl-containing stable radical such a4-hydroxy-2,2,6,6-tetramethylpiperidin-l-oxyl (4-hydroxy-TEMPO), 4-carboxy -2,2,6,6-tetramethylpiperidin-l-oxyl (4-carboxy-TEMPO) or any other amino-/carboxyl-/hydroxyl-containing antioxidants or radical/super oxide scavengers, and D is NO2. The amino-/carboxyl-/hydroxyl-containing antioxidants and radical/super oxide scavengers can be known or investigational. An embodiment of the present invention is the compound of formula (I), wherein OO * A * ■ XANAX L'is x x or R1 ; wherein, X is a bond, O, S orNR1; L2 is O, E is a bond; A and A1 are CH2CH2; B is S-S; a is O; and D2 is NO2. An embodiment of the present invention is the compounds of formula (I), wherein D1 and L1 are as defined above; L is O; A is 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene; A1 is CH2; E is CH2; B is S-S; a is O and D2 is NO2. An embodiment of the present invention is the compounds of formula (1), wherein L2 is O; A and A1 are CH2; E is CH2; B is a bond or (CH2)b; b is 1-6; a is O; D2 is NO2 and L1 is a group selected from wherein, X is O, S or NR1; Rl is as defined. An embodiment of the invention is the compound of formula I selected from the groups consisting of: A. Prodrugs: 33 34 35 (c) From hydroxy 1-containing drugs: 37 38 A PRODRUG OF ISOTAXEL I-S23-PD1 Y = O, NR1 (R1 = H, Alkyl, Aralkyl, Cyc10alkyl), (CH2)nC(=O) (n=l-6), (CH2)nCO2- Z = C=O, S O2, P(=O)YR3 (R3 = H or a metal ion) R2 = H, a bond, CH2CH2N(CH3)2. HC1, an Amino acid, or any molecule containing solubilizing groups such as carboxylic acid, sulphonic acid, hydroxyl, amino groups, polyethyleneglycol (PEG), a metal ion such a Na+, Ca2+, etc. 39 B. NO-releasing Prodrugs (a) From carboxyl-containing drugs 41 (b) From amino-containing drugs 43 C. Mutual or Double Prudrugs (a) From two amino-containing drugs 44 45 46 (b) From two carboxyl-containing drugs 47 (c) From two hydroxyl-containing drugs 48 49 50 (d) From an amino-containing drug and a carboxyl-containing drug: 51 (e) Mutual prodrugs of one carboxy I -containing and one hydroxyl-containing drugs CO2H I-CH-MPD6 55 56 60 An embodiment of the invention is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, or a pharmaceutical salt thereof and one or more pharmaceutically acceptable carriers, vehicles or diluents. Another embodiment of the invention is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I selected from the group consisting of I-C1-PD1,1-C1-PD2,1-C1-PD3,1-C1-PD4,1-Cl-PD4a, I-Cl-PD4b5I-C1-PD5,I-C1-PD6,1-C1-PD7,1-CI-PD8,1-C1-PD9, T-C1-PD10,1-Cl-PD11,1-C1-PD12,1-C1-PD13,I-C1-PD14,1-Cl-PD15a, I-Cl-PD15b, I-Al-PDl, I-Al-PD2,1-A1-PD3,1-A1-PD4,I-A1-PD5,I-A1-PD6,1-A1-PD7,1-A1-PD8,1-A1-PD9,1-Al-PD10,1-A1-PD11,I-A1-PD12,I-AI-PD13,1-A1-PD14,1-A1-PD15A, I-A1-PD15Aa, I-A1-PD15B, I-Al-PD15Bb, I-A1-PD16,1-A1-PD17,1-A2-PD1,1-A2-PD2,I-A2-PD2b, I-A2-PD3a, I-A2-PD3b, I-A2-PD4,1-A2-PD5,I-A3-PD1,I-A3-PD2a, I-A3-PD2b, 1-A3-PD3a, I-A3-PD3b, I-A3-PD4,1-A3-PD5,1-A3-PD6,I-A3-PD7b, I-H1-PD1,1-H1-PD2,1-H1-PD3,1- H1-PD4,1- H1-PD5,1- H1-PD6,1- H1-PD7,1- H1-PD8,1- H1-PD9,1- Hl-PD10,1-Hl-PDll,I-Hl-PD12)I-Hl-PD13,I-Taxol-PDl,I-Taxol-PD2)T-Taxol-PD3) I-Taxol-PD4,I-Taxol-PD5,1-Taxol-PD6,I-S23-PD1,1-C1-NOPDI, I-C1-NOPD2,1-CI-NOPD3a, I-Cl-NOPD3b, I-C1-NOPD4,1-Cl-NOPD5a, I-Cl-NOPD5b, I-C1-NOPD6,1-C1-NOPD7,I-Cl-NOPD8a, I-Cl-NOPD8b, I-C1-NOPD9,I-C1-NOPD10,1-Cl-NOPD1 la, I-C1-NOPD13,1-Cl-NOPD14a, I-CI-NOPD14b, I-Cl-NOPD15b, I-Cl-NOPD16,I-Cl-NOPD17a, I-Cl-NOPD17b, I-C1-NOPDI8,1-C1-NOPD19,1-Cl-NOPD2Oa, I-C1-NOPD2Ob, I-C1-NOPD21,1-C1-NOPD22, l-Cl-NOPD23b, I-Cl-NOPD24,1-C1-NOPD25,1-C1-NOPD26,I-A1-NOPD1,1-A1-NOPD2,1-A1-NOPD3A, I-AI-NOPD3B, I-A1-NOPD4,1-A1-NOPD5,1-A1-NOPD6,1-A1-NOPD7,T-Al-NOPD8,I-A1-NOPD9,1-AI-NOPD10a, I-Al-NOPD10b, I-A2-NOPDla, I-A2-NOPDlb, I-A2-NOPD2a51-A2-NOPD2b, I-A3-NOPDla, I-A3-NOPDlb, I-A3-NOPD2a, I-A3-NOPD2b, I-H1-NOPD1,1-Hl-NOPD2a, I-Hl-NOPD2b, I-H1-NOPD3, l-H1-NOPD4,1-Hl-NOPD5b,I-Hl-NOPD63I-Hl-NOPD7,I-HI-NOPD8,I-Hl-NOPD9, I-H1-NOPD10,I-AA-MPD1,I-AA-MPD2,1-AA-MPD3a, I-AA-MPD4,1-AA-MPD5, I-AA-MPD6,1-AA-MPD7,1-AA-MPD8,1-AA-MPD9,1-AA-MPDIO, I-AA-MPD11,1-AA-MPD12,1-AA-MPD13,I-AA-MPD14,1-AA-MPD15,I-AA-MPD16,1-AA-MPD17, I-AA-MPD18,1-AA-MPD19,1-AA-MPD2O,I-AA-MPD21,1-AA-MPD22,1-AA- 61 MPD23,1-AA-MPD24,I-AA-MPD25,I-AA-MPD26,I-AA-MPD27,I-CC-MPD1,1-CC-MPD2,I-CC-MPD3,1-CC-MPD4,I-CC-MPD5,1-CC-MPD6,1-HH-MPD1,1-HH-MPD2,1-HH-MPD3,1-HH-MPD4,1-HH-MPD5,1-HH-MPD6,1-HH-MPD7,1-HH-MPD8,I-HH-MPD9,I-HH-MPD10,1-HH-MPD11,I-HH-MPD12,I-HH-MPD13, l-HH-MPD14,I-HH-MPD15,1-HH-MPDI6,1-HH-MPD17,1-HH-MPD18,1-HHAH-TMPD1, I-CA-MPD1,1-CA-MPD2,I-CA-MPD3,I-CA-MPD4,I-CA-MPD5,I-CA-MPD6,I-CA-MPD7,1-CA-MPD8,1-CA-MPD9,I-CA-MPDIO, I-CA-MPD11,1-CA-MPD12,1-CA-MPD13,I-CA-MPD14,I-CA-MPD15,I-CA-MPD16,I-CA-MPD17,I-CA-MPD18,1-CA-MPD19,1-CA-MPD2O,1-CA-MPD21,1-CA-MPD22,1-CA-MPD23,I-CA-MPD24, I-CA-MPD25,I-CA-MPD26,I-CA-MPD27,1-CA-MPD28,I-CA-MPD29,1-CA-MPD30,I-AH-MPD1,1-AH-MPD2,I-AH-MPD3,I-AH-MPD4,1-AH-MPD5,1-AH-MPD6,1-AH-MPD7,1-AH-MPD8,1-AH-MPD9,I-AH-MPDIO, 1-AH-MPD11,1-AH-MPD12,1-AH-MPD13,1-AH-MPD14,I-AH-MPD15,I-AH-MPD16,I-AH-MPD17,1-AH-MPD18,I-AH-MPD19,1-AH-MPD2O,I-AH-MPD21,I-AH-MPD22,I-AH-MPD23, I-AH-MPD24,I-AH-MPD25,I-AH-MPD26,1-CH-MPD1,1-CH-MPD2,I-CH-MPD3,1-CH-MPD4,1-CH-MPD5, and I-CH-MPD6 or a pharmaceutical salt thereof and one or more pharmaceutically acceptable carriers, vehicles or diluents. An embodiment of the invention is a method of treating a mammal or human in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition comprising the compound of formula I. 62 Another embodiment of the invention is the be10w listed novel intermediates: 63 Another embodiment of the invention is use of the above listed novel intermediates in the processes for the preparation of compounds of formula I; Further embodiments include methods of preparation and methods of use of compounds of formula (I) or pharmaceutically acceptable salts thereof. Another embodiment of the invention is process for the preparation of compounds of formula I, or pharmaceutically acceptable salts thereof, wherein the process comprises of: monoprotection of Bis-(2-hydroxyethyl)disulphide (SL-1) with an appropriate hydroxyl protecting group to give a corresponding monoprotected intermediate, 65 conversion of the corresponding monoprotected intermediate to an activated formyl intermediate by treating with phosgene or its equivalent, and reaction of the activated formyl intermediate with an appropriate amino- or hydroxy containing D1 to give the corresponding compound of formula 1. Another embodiment of the invention is a process for the preparation of compounds of formula I, or pharmaceutically acceptable salts thereof, wherein the process comprises of: -converting carboxy containing Dl into an activated intermediate comprising acyl halide, imidazolide or isocyanate, and -reacting the activated intermediate with a linker intermediate to obtain the compound of formula I. In another embodiment, the invention is a process in which the monoprotected intermediate is Lllx, and the activated formyl intermediate is Lllxy. Another embodiment of the invention is a process for preparation of compounds of formula (I), wherein D2 is NO2 or pharmaceutically acceptable salts thereof, wherein the process comprises, mixing a selectively protected and activated Dl with a solution of 2-((2-hydroxyethyl)dithio)ethyl nitrate (LI-2b) in a suitable solvent in presence of a suitable coupling agent. Another embodiment of the invention is a process for preparation of compounds of formula (I), wherein D2 is NO2 or pharmaceutically acceptable salts thereof, wherein a process comprises, converting 2-((2-hydroxyethyl)dithio)ethyl nitrate (LI-2b) into its formyl halide or imidazolide (LI-4x) by using a phosgene or its equivalent reagent and mixing/reacting the resulting reactive intermediate with a suitable amino- or hydroxy-contain'mg drug in suitable solvent in presence of a suitable base. Another embodiment of the invention is a process for preparation of compounds of formula (I), wherein D2 is NO2 or pharmaceutically acceptable salt thereof, wherein the process comprises, mixing/reacting a selectively protected and activated drug with a solution of 2-((2-aminoethyl)dithio)ethyl nitrate (LI-5) in a suitable solvent in presence of a suitable coupling agent and/or base. 66 Another embodiment of the invention is a process for preparation of mutual prodrugs of compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein a process comprises, A ) monoprotection of Bis-(2-hydroxyethyl)disulphide (SL-1) with an appropriate hydroxyl protecting group to give the corresponding monoprotected intermediate LI-lx, B) reaction of formyl linker intermediate Ll-lxy with amino or hydroxyl containing drug (D ) to obtain the prodrug of formula I with free hydroxyl group on the linker, C) conversion of the intermediate obtained in the step B into activated formyl halide or imidazolide derivative, and D) reaction of the intermediate obtained in the step C with the drug D2 to obtain the mutual prodrug of formula I. Further embodiments of the invention are processes for the preparation of compounds of formula I, or pharmaceutically acceptable salts thereof, wherein the processes comprise of the steps that are generally depicted in the schemes 1-23. Further embodiments include the pharmaceutical composition comprising a therapeutically effective amount of novel intermediates or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, vehicles or diluents. Another embodiment of the invention is use of compounds of formula (I) or pharmaceutically acceptable salt thereof, in the treatment of disease conditions originally treatable by the corresponding free drug(s). It should be understood that while this invention has been described herein in terms of specific embodiments set forth in detail, such embodiments are presented by way of illustration of the general principles of the invention, and the invention is not necessarily limited thereto. Certain modifications and variations in any given material, process step or chemical formula will be readily apparent to those skilled in the art without departing from the true spirit and scope of the present invention, and all such modifications and variations should be considered within the scope of the claims that fol10w. The contents of the articles, patents, and patent applications, and all other documents mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. 67 Yet another embodiment of the invention is a compound of formula f containing an amino-containing therapeutic agent selected from the group consisiting of: I-AA-MPD1,1-AA-MPD2,1-AA-MPD3, and I-AA-MPD4. Another embodiment of the invention is double prodrug of formula (I) selected from the group consisting of: I-AA-MPD5,1-AA-MPD6,1-AA-MPD7, and I-AA-MPD8. The present invention also provides mutual prodrugs of formula (I) selected from the group consisiting of: I-CA-MPD1, I-CA-MPD2, I-CA-MPD3, I-CA-MPD4, I-CA-MPD5, I-CA-MPD6, I-CA-MPD7, I-CA-MPD8, I-CA-MPD9, I-CA-MPD10, I-CA-MPD11, I-CA-MPD12, I-CA-MPDI3, I-CA-MPD14, I-CA-MPD15, I-CA-MPD16, 1-CA-MPD17, I-CA-MPD18, I-CA-MPD19, I-CA-MPD2O, I-CA-MPD21, I-CA-MPD22, I-CA-MPD23, I-CA-MPD24, I-CA-MPD25, I-CA-MPD26, I-CA-MPD27, I-CA-MPD28,I-CA-MPD29, and I-CA-MPD30. In another embodiment, the invention provides compounds of formula (I) selected from the group of mutual prodrugs made from amino-containing therapeutic agent and a hydroxyl-containing therapeutic agent such as: I-AH-MPD1, I-AH-MPD2, I-AH-MPD3, I-AH-MPD4, I-AH-MPD5, I-AH-MPD6, I-AH-MPD7, I-AH-MPD8, I-AH-MPD9, I-AH-MPD10, I-AH-MPD11, I-AH-MPD12, I-AH-MPD13,1-AH-MPD14, I-AH-MPD15, I-AH-MPD16, I-AH-MPD17, 1-AH-MPD18, I-AH-MPD19, I-AH-MPD2O, I-AH-MPD21,I-AH-MPD22,I-AH-MPD23,I-AH-MPD24, [-AH-MPD25, and I-AH-MPD26. Yet another embodiment of the invention relates to compounds of formula (I) of mutual prodrugs made from a hydroxyl-containing therapeutic agent and a hydroxyl-containing therapeutic agent such as: I-HH-MPD1, I-HH-MPD2, I-HH-MPD3, I-HH-MPD4, I-HH-MPD5, I-HH-MPD6, I-HH-MPD7, I-HH-MPD8, I-HH-MPD9, I-HH-MPD10, I-HH-MPD11, I-HH-MPDI2, I-HH-MPD13, I-HH-MPD14, I-HH-MPD15, I-HH-MPD16,I-HH-MPD17,and I-HH-MPD18. The present invention also provides compounds of formula (I) containing water-soluble prodrugs of insoluble or sparingly-soluble therapeutic agents such as: I-H1-PD1, I-HI-PD2,I-H1-PD3, I-HI-PD4, I-H1-PD5, I-H1-PD6, J-H1-PD7, I-H1-PD8, I-H1-PD9, I-H1-PD10, I-H1-PD11, I-H1-PD12,1-H1-PD13, I-A1-PDI, I-A1-PD2, I-A1-PD3, l-Al-PD43 I-A1-PD5, I-A1-PD6, I-A1-PD7, I-A1-PD8,1-A1-PD9, I-A1-PD10, I-A1-PD11, I-A1-PD12, I-AI-PD13, I-A1-PD14, I-AI-PD15A, I-Al-PDIAa, I-A1-PD15B, I-AI- 68 PD15Bb, 1-A1-PD16, 1-A1-PD17, I-A2-PDI, I-A2-PD2, I-A2-PD2b, I-A2-PD3a, I-A2-PD3b, I-A2-PD4,1-A2-PD5,1-A3-PD1,1-A3-PD2a, I-A3-PD2b, I-A3-PD3a, I-A3-PD3b, 1-A3-PD4, I-A3-PD5, I-A3-PD6, I-A3-PD7b, I-H1-PD1, I-H1-PD2, I- H1-PD3, I- Hl-PD4, I- H1-PD5, I- H1-PD6, I- H1-PD7, I- H1-PD8, I- H1-PD9, I- H1-PD10, I- Hl-PD11, I- H1-PD12, J- H1-PD13,I-Taxol-PDl, I-Taxol-PD2,1-Taxol-PD3,I-Taxol-PD4, I-Taxol-PD5,1-Taxol-PD6, and I-S23-PD1. Another embodiment of the invention relates to the compounds of formula (I), selected from the group of NO-releasing prodrugs consisting of: I-C1-NOPD1, I-Cl-NOPD2,I-Cl-NOPD3a, I-Cl-NOPD3b, I-C1-NOPD4,1-Cl-NOPD5a, I-Cl-NOPD5b, I-C1-NOPD6,I-C1-NOPD7,I-Cl-NOPD8a, I-Cl-NOPD8b, I-C1-NOPD9,I-C1-NOPD10, I-C1-NOPD1 la, I-C1-NOPD13,1-Cl-NOPD14a, I-Cl-NOPD14b, I-C1-NOPD15b, I-Cl-NOPD16, I-Cl-NOPD17a, I-Cl-NOPD17b, I-C1-NOPD18, I-C1-NOPD19, I-Cl-NOPD2Oa, I-Cl-NOPD2Ob, I-C1-NOPD21, 1-C1-NOPD22, I-Cl-NOPD23b, I-Cl-NOPD24, I-C1-NOPD25, I-C1-NOPD26, I-A1-NOPD1, 1-A1-NOPD2, I-A1-NOPD3A, I-A1-NOPD3B, I-A1-NOPD4, I-A1-NOPD5, T-A1-NOPD6, I-A1-NOPD7, I-Al-NOPD8, J-A1-NOPD9, I-A1 -NOPD1 Oa, I-Al-NOPD10b, I-A2-NOPDla, I-A2-NOPDlb, I-A2-NOPD2a, I-A2-NOPD2b5 I-A3-NOPDla, l-A3-NOPDlb, 1-A3-NOPD2a, I-A3-NOPD2b, I-H1-NOPD1,1-Hl-NOPD2a, I-Hl-NOPD2b, I-H1-NOPD3,1-H1-NOPD4, I-Hl-NOPD5b, I-H1-NOPD6, I-H1-NOPD7, I-H1-NOPD8, I-H1-NOPD9, I-H1-NOPD10. Another aspect of the invention provides the use of the compounds of formula (I) in combination with a compound used to treat cardiovascular diseases selected from the group consisting of: beta adrenergic b10ckers, calcium channel b10ckers, angiotensin II receptor antagonists, antithrombotics, HMGCoA reductase inhibitors, aspirin or nitrooxy derivatives of aspirin, nitrosated beta b10ckers, nitrosated or nitrosilated calcium channel b10ckers. Suitable drugs are described in the literature such as the Merck Index, IDdb, Prous Science's Integrity®, Prous Science Drugs of the Future™, The Ensemble® and the like. Another aspect of the invention provides the use of the pharmaceutical compositions containing compounds of formula (I) in combination with a compound, used to treat other diseases such as cardiovascular diseases, selected from beta adrenergic 69 b10ckers, calcium channel b10ckers, angiotensin II receptor antagonists, antithrombotics, HMGCoA reductase inhibitors, aspirin or nitrooxy derivatives of aspirin, nitrosated beta b10ckers, nitrosated or nitrosilated calcium channel b10ckers. Pharmaceutical compositions containing two or more of compounds of the invention can be used for the purpose of combination therapy. These pairs of compounds of invention can be from the same therapeutic area or from different therapeutic areas for treating one or more diseases or conditions. The compounds of the invention, which have one or more asymmetric carbon atoms, can exist as the optically pure enantiomers, pure diastereomers, enantiomer racemic mixtures, diastereomer racemic mixtures, racemates or racemate mixtures. Within the scope of the invention are also all the possible isomers, stereoisomers and their mixtures of the compounds of formula (I). Another embodiment of the invention relates to the pharmaceutical composition comprising one or more compounds of formula (I) or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, vehicles or diluents. Another embodiment of the invention relates to the pharmaceutical composition comprising one or more compounds of formula (I) or pharmaceutically acceptable salts thereof and at least another pharmaceutically active compound. The pharmaceutically active compound can be from the same or different therapeutic areas for treating one or more disease condition(s) together with one or more pharmaceutically acceptable carriers, vehicles or diluents. Further embodiments include methods of use of compounds of formula (I) or pharmaceutically acceptable salts thereof. Another embodiment of the invention is a process for preparation of compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the process comprises, mixing a selectively protected and activated drug with a solution of 2-((2-hydroxyethyl)dithio)ethyl nitrate in a suitable solvent in presence of a suitable coupling agent. Another embodiment of the invention is a compound or intermediate generated in the above methods and processes. Another embodiment of the invention is a process for preparation of compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein a process comprises, 70 converting 2-((2-hydroxyethyl)dithio)ethyl nitrate into its formyl halide or imidazolide by using a phosgene or its equivalent reagent and mixing/reacting the resulting reactive intermediate with a suitable drug in suitable solvent in presence of a suitable base. Another embodiment of the invention is a process for preparation of compounds of formula (I) or pharmaceutically acceptable salt thereof, wherein the process comprises, mixing/reacting a selectively protected and activated drug with a solution of 2-((2-aminoethyl)dithio)ethyl nitrate (or its acid salt) in a suitable solvent in presence of a suitable coupling agent and/or base. Another embodiment of the invention comprises the novel intermediates formed in the preparation of present invention. Further embodiments include a pharmaceutical composition comprising a therapeutically effective amount of novel intermediates or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, vehicles or diluents. Another embodiment of the invention is processes for the preparation of compounds of formula (I) or pharmaceutically acceptable salt thereof, as well as the starting materials and intermediates involved as depicted in schemes 1-23. Another embodiment of the invention the novel intermediates obtained in the preparation of compounds of formula I, wherein the intermediates are selected from: 71 Another embodiment of the invention is use of compounds of formula ([) or pharmaceutically acceptable salts thereof, in the treatment of disease conditions originally treatable by the corresponding free drugs. Another embodiment of the invention includes but not limited to a pharmaceutical composition comprising the compounds of formula (1), or pharmaceutically acceptable salt thereof, selected from the group of NO-releasing prodrugs described herein, or more pharmaceutically acceptable carriers, vehicles or diluents. It should be understood that while this invention has been described herein in terms of specific embodiments set forth in detail, such embodiments are presented by way of illustration of the general principles of the invention, and the invention is not necessarily limited thereto. Certain modifications and variations in any given material, 73 process step or chemical formula will be readily apparent to those skilled in the art without departing from the true spirit and scope of the present invention, and all such modifications and variations should be considered within the scope of the claims that fol10w. The contents of the articles, patents, and patent applications, and all other documents mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. POTENTIAL EXAMPLES OF MUTUAL PRODRUGS/CODRUGS: Mutual prodrugs made from an amino-containing therapeutic agent and another amino-containing therapeutic agent: A Mutual Prodrug of des10ratadine and pseudoephedrine (I-AA-MPD1) is proposed as a potential treatment option for seasonal allergic rhinitis (SAR). Des10ratadine (an active metabolite of 10ratadine) is a new, non-sedating, 10ng-acting histamine antagonist and has been shown effective in the treatment of nasal and non-nasal symptoms associated with SAR. Pseudoephedrine is an oral decongestant. A Mutual Prodrug of am10dipine (Pfizer's Norvasc®) and lisinopril (Zeneca's Zestrir) (I-AA-MPD2) is proposed as a potential treatment option for hypertension and congestive heart failure. Am10dipine is a calcium channel b10cker and is used as an antihypertensive and antianginal agent. Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor and is used for the treatment of hypertension and congestive heart failure. A combination therapy using these two drugs has been proven to be more effective treatment option than monotherapy using either of these drugs. A Mutual Prodrug of am10dipine (Pfizer's Norvasc®) and 10sartan (Merck's Cozaar®) (I-AA-MPD3a) is proposed as a potential treatment option for mild to moderate hypertension. Am10dipine is a calcium channel b10cker and is used as an antihypertensive and antianginal agent. 10sartan potassium is an angiotensin II b10cker and is used for the treatment of hypertension. A combination therapy using these two drugs has been proven to be more effective treatment option than monotherapy using either of these drugs. Examples of mutual prodrugs and double prodrugs of valdecoxib and celecoxib containing a disulfide linker are: 1-AA-MPD4 and I-AA-MPD5. 74 Examples of double prodrugs of valdecoxib or celecoxib containing non-disulfide [inkers: I-AA-MPD6,1-AA-MPD7, [-AA-MPD8. A Mutual Prodrug of fluoxetine (Lilly's Prozac®) and olanzapine (Lilly's Zyprexa® (I-AA-MPD9) is proposed for potential treatment of patients with Bipolar disorder. Fluoxetine and Olanzapine are used in combination to treat patients with bipolar disorder while being spared the treatment-emergent mania that such patients often get on antidepressant monotherapy. Example of double prodrug of gabapentin is proposed as potential antiepileptic agent: I-AA-MPD10. Mutual prodrugs made from an amino-containing therapeutic agent and a carboxyl-containing therapeutic agent: A mutual prodrug of cetirizine and pseudoephedrine (J-CA-MPD1) is proposed for treatment of rhinitis. Cetirizine is an antihistamine and pseudoephedrine is a nasal decongestant. Mutual prodrugs of gabapentin and valproic acid are potential antiepileptic agents. This same kind of prodrug may be a potential treatment option for patients with bipolar disorder and other mental illnesses. The fol10wing are some of the examples: 75 Other illustrative examples of mutual prodrugs under this category include the fol10wing: Mutual prodrugs of valproic acid and other carboxyl-, hydroxyl-, and amino-containing (including amide-, and sulfonamide-containing) anticonvulsant agents such as levetiracetam, lamotrigine, pregabalin, carbamazepine, oxcarbamazepine, licarbazepine. felbamate, topiramate and the like. (Structures are given be10w). The list also includes investigational antiepileptic agents such as antipamezole, licarbazepine, Eslicarbazepine Acetate (BIA 2-O93), fluorofelbamate, isovaleramide (NPS 1776), retigabine (D-23129), saflnamide (NW-1015), stiripentol (STP), talampanel (TLP), (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl]butanamide 83alpha (ucb 34714), valrocemide (TV 1901), and the like. Mutual Prodrugs can be made from combination of any two anti-convulsant agents listed above or any other suitable anticonvulsant agents. Mutual prodrug of gabapentin and naproxen (I-CA-MPD22) is proposed for potential treatment option for neuro10gical pain and inflammation. 77 Mutual prodrugs made from an amino-containing therapeutic agent and a hydroxyl-containing therapeutic agent: Mutual prodrugs of norf10xacin and metronidazole (I-AH-MPD1,1-AH-MPD2, I-AH-MPD3) are proposed for potential treatment of diarrhea and dysentery of bacterial, amoebic and mixed origin. Metronidazole is an antianaerobic agent and used in combination with antibiotics such as norf10xacin, ciprof10xacin, etc. for the treatment of patients with diarrhea and dysentery of bacterial, amoebic and mixed origin. A mutual prodrug of 10peramide and norflaxacin (1-AH-MPD4) is proposed for potential treatment of diarrhea and dysentery. A mutual prodrug of valdecoxib and tramadol (I-AH-MPD5 and I-AH-MPD6) as a potential therapy in postoperative pain management. A mutual prodrug of gabapentin and tramadol (I-AH-MPD7) is proposed for potential treatment of neuropathic pain after spinal cord injury. A mutual prodrug of venlafaxine and paroxetine (I-AH-MPD8) is proposed for potential treatment of neuro10gical and depression related disorders. Mutual prodrugs made from a hydroxyl-containing therapeutic agent and another hydroxyl-containing therapeutic agent: Mutual prodrugs of zidovudine (AZT/Retrovir) and lamivudine (3TC/Epivir) (I-HH-MPD1,1-HH-MPD2) are proposed as a potential treatment option for HIV and other viral infections. POTENTIAL EXAMPLES OF WATER-SULUBLE PRODRUGS: Water-soluble prodrugs of insoluble/sparingly-soluble therapeutic agents can be prepared using the same linker techno10gy. Water-soluble prodrugs of metronidazole include: I-H1-PD-2, I-H1-PD-3, I-Hl-PD-4. Water-soluble prodrugs of valdecoxib include: I-A3-PD1, I-A3-PD2a, I-A3-PD2b, I-A3-PD3a, I-A3-PD3b, I-A3-PD4,1-A3-PD5,1-A3-PD6, and I-A3-PD7b. Water-soluble prodrugs of paclitaxel include: I-Taxol-PDl, I-Taxol-PD2,1-Taxol-PD3,1-Taxol-PD4,1-Taxol-PD5,1-Taxol-PD6, and I-S23-PD1. POTENTIAL EXAMPLES OF NO-RELEASING PRODRUGS: 78 79 In the fol10wing potential examples, X is O, NR1 (Rl= H, alkyl) or a bond; Y is CO, SO2, P(=O)XR1 or bond; R1 is H, alkyl, aralkyl, or a metal ion; A is a bond, 1,4-/1,3-/1,2-phenylene or (CH2)O (o = O-6) and m is 1-2 unless otherwise stated; ADDITIONAL POTENTIAL EXAMPLES: In the fol10wing additional potential examples, X is O, NR1 (R1=: H, alkyl) or a bond; Y is CO, SO2, P(=O)XR: or bond; R1 is H, alkyl, aralkyl, or a metal ion; A is a bond, l,4-/l,3-/l,2-phenylene or (CH2)O (o = O-6) and m is 1-2 unless otherwise stated; 80 84 NO-Releasing Prodrug of Ursodeoxycholic Acid 85 86 NO-Releasing Prodrugs of Antioxidants and /or Free Radical Scavengers: NO-Releasing Prodrugs of Antibiotics: 87 88 Plausible Mechanisms of Drug Release from Prodrugs Drugs can be released form the prodrugs and mutual prodrugs via cleavage of bio-labile linker(s) in vivo (cleavage can be either chemical or enzymatic or both) by illustrative mechanisms as shown in Schemes Ml through M5. Plausible mechanisms for concomitant release of nitric oxide (NO) and free drug from NO-releasing prodrug(s) of amino-, hydroxyl-, or carboxyl-containing drug(s) are illustratively shown in Schemes Ml. Thus, the attack of thiolate ion (from GSH or any other sulfahydryl-containing species) on nitrooxy-containing prodrug would release carboxylic acid-containing free drug, episulfide (d) and the intermediate conjugate (a) according to path 1. If the prodrugs are made from amino-, or hydroxyl-containing drugs, then the prodrug would be cleaved via path 2 to release the corresponding free drug, the cyclic thiocarbonate intermediate (c) and the intermediate conjugate (a). The cyclic thiocarbonate intermediate may further breakdown into episulfide (d) and carbon dioxide. The reactive episulfide (d) would be further neutralized by glutathione. The nitrate ester-containing intermediate conjugate can further break down in the presence of GSH to glutathione dimer (GS-SG) and transient intermediate (b). which can break down via path 3 to release NO. It is also possible the same transient intermediate can break down via path 4 to yield episulfide (d) and a relatively innocuous nitrate anion (NO3). 89 Plausible mechanisms of drug release from mutual prodrugs of one carboxyl-containing and one amino-/hydroxy!-containing drug is shown in Scheme M2. 90 Plausible mechanism of drug release from prodrugs (including mutual and NO-releasing prodrugs of amino-, hydroxyl-and carboxyl-containing drugs) containing modified bio-labile linkers is shown in Scheme M3. Thus, the thiolate anion derived from the attack of glutathione on disulfide of the prodrug may trigger cyclization to release the free drug (Dl-XmlH) and a stable six-membered (or five-membered, if Xm2 is a bond) thio-lactone intermediate. 91 Plausible mechanisms of drug release from double/mutual prodrugs containing additional linkages to couple two hydroxyl-containing drugs are shown in Scheme M4. Thus, the thiolate anion generated by the attack of glutathione on disulfide bond of the prodrug triggers further cleavage as shown to release the free drug (D1-OH) and a five-membered 2-imidazolidone. Through in vitro decomposition studies, we have found that the drug release from this type of prodrug is more facile when R group is an alkyl group. 92 This invention also covers novel bio-labile linkers containing 1,4-phenylene group and 1,2-phenylene group as shown in Schemes 5 and 6, respectively. As depicted in Scheme M5, the linker is expected to release the free Drug upon glutathione-assisted cleavage and may generate 1,4-quinonemethid (ea) as a byproduct via 1,6-elimination process. Similarly, the free Drug is expected to be released from the intermediate conjugate (a) as shown in the scheme. As depicted in Scheme M6, the 1,2-phenylene-containing linker is also expected to release free drugs upon glutathione assisted cleavage and genereate 1,2-quinonemethid (eb) as a byproduct via 1,4-elimination process (via pathway 'b'). However, this linker can also cleave via pathway 4a' to generate benzo-monothiocarbonate as a byproduct. Although the generated byproducts seem to be toxic, they are likely to be quickly neutralized by detoxification enzymes in the body. 94 95 Scheme M7: Plausible mechanism of diazepam formation from an acyclic prodrug of diazepam Diazepam, a benzodiazepine tranquilizer, is very sparingly water-soluble drug and a water-soluble acyclic prodrug of diazepam can be made by using our linker techno10gy. As shown in the Scheme M7, reduction of disulfide bond in the prodrug triggers release of open-chain intermediate of diazepam which spontaneously cyclizes to diazepam in vivo. Where GSH is glutathione (reduced) or any other in vivo bioreductive agent that can reduce the disulfide bond. As illustrated, cleavage of disulfide bond triggers further breakage of the remaining portion of the linker to release the free drugs. In the process, some byproducts are generated and these are either eliminated or further degraded by some bio10gical process. For clarity, the mechanism of cleavage of the linker is shown as occurring in stepwise manner. However, both the steps can possibly occur in a concomitant fashion to release both the drugs simultaneously. As illustrated in Scheme M3 and M4, Linkers may have additional spacer groups between one side (or both sides) of the linkers and the drug molecule and some of these spacer groups may be cleaved independently by a chemical or enzymatic process to release the drugs prematurely before the cleavage of disulfide linkage. The prodrugs and mutual prodrugs containing such spacer groups may be useful when faster release of drug(s) is desired. 96 LISTS OF CANDIDATE DRUGS USEFUL FOR PRODRUG SYNTHESIS: Drugs listed in the fol10wing list can be converted to NO- releasing prodrugs. This list is in no way limiting the scope of drugs covered in this invention, but given as representative examples. All the amino- (including amide-NH and sulfonamide-NH, carbamate-NH, sulfamate-NH, hydrazone-NH, semicarbazone-NH, thiosemicarbazone-NH, urea-NH, phosphoramide-NH and the like. See above, for the description of "amino-containing drugs"), carboxyl-, hydroxyl-(including oxime-OH), and carbonyl (both aldehyde and keto groups)-containing drugs under various therapeutic categories as listed in Merck Index (13th editions) and other data bases such as prous science's ensemble, integrity, and the like and also all the qualified (i.e:, amino-, and /or hydroxyl-, and/or carboxyl-, and/or carbonyl-containing) investigational drugs as listed in databases such Merck Index (13th editions), iddb, ensemble, integrity, and the like, are covered under this invention without any limitation. ANTI-INFLAMMATORY DRUGS: Amino-containing (including Amide NH and Sulphonamide NH and Phosphomide NH, etc.): Ampiroxicam, Buco10me, Celecoxib, Difenpiramide, Mofebutazone, Nimesulide, Paranyline, Parecoxib, Parsalmide, Piketoprofen, Talniflumate, Tenidap, Terofenamate, and Valdecoxib. Hydroxyl-containing: 21-Acetoxypregneno10ne, Alc10metasone, alfa-Bisabo10l, Budesonide, Deflazacort, Dif10rasone, Desonide, Desoximetasone, Dif10rasone, Diflucorto10ne, Difluprednate, Ditazol, Fluazacort, Fluocinonide, Fluocortin Butyl, Fluprednidene Acetate, Glucametacin, Halcinonide, Ha10betasol Propionate, Ha10metasone, Ha10predone Acetate, Ibuproxam, 10teprednol Etabonate, Mazipredone, Mometasone Furoate, Oxyphenbutazone, Perisoxal, Rimexo10ne, Hydroxyl-, and Amino-containing (including Amide NH and Sulphonamide NH and Phosphomide NH, etc.): Bufexamac, Etofenamate, Fepradinol, Ibuproxam, Isoxicam, 10rnoxicam, Me10xicam, Oxametacine, Piroxicam, and Tenoxicam. Hydroxyl- and sulphahydryl-containing: Tixocortol, Carboxyl- and Amino-containing (including amide NH and sulphonamide NH and phosphomide NH, etc.): Acec10fenac, Alminoprofen, Amfenac, 3-Amino-4- 97 hydroxybutyric Acid, Carprofen, Dic10fenac, Enfenamic Acid, Etodolac, Flufenamic Acid, Mec10fenamic Acid, Mefenamic Acid, Niflumic Acid, and Tolfenamic Acid. Carboxyl-containing: Acemetacin, Acetamidocaproic Acid, Bendazac. Benoxaprofen, Bermoprofen, Buc10xic Acid , Butibufen, Cinmetacin, Clidanac, C10pirac, Felbinac, Fenbufen, Fenc10zic Acid, Fenoprofen, Fentiazac, Flunoxaprofen, Flurbiprofen, Ibuprofen, Indomethacin, Isofezolac, Isoxepac, Ketoprofen, 10nazolac, 10xoprofen, Metiazinic Acid, Mofezolac, Naproxen. Oxaprozin, Pirazolac, Pirprofen, Pranoprofen, Protizinic Acid, Sulindac, Suprofen, Suxibuzone, Tiaprofenic Acid, Tolmetin, and Tropesin. Carboxyl- and Hydroxyl-containing: Balsalazide, Enoxo10ne, Fendosal, Olsalazine, Oxaceprol, and Ximoprofen. Amino-, Carboxyl- and Hydroxyl-containing: 3-Amino-4-hydroxybutyric Acid, Mesalamine, and Sulfasalazine. Keto-containing: Nabumetone, and Piketoprofen. Carboxyl- and keto-contianing: Bermoprofen, Buc10xic Acid, Isoxepac, Ketoprofen, 10xoprofen, and Zaltoprofen. ANALGESIC AND/OR ANTIPYRETIC DRUGS: Amino-containing: Aminoch10rthenoxazin, Aminopropy10n, Anileridine, Antrafenine, Benorylate, Benzpipery10n, p-Bromoacetanilide, Butacetin, Carsalam, Difenamizole, Etersalate, Ethenzamide, Ethoxazene, Flipirtine, Isonixin, Nifenazone, Phenacetin, Phenazopyridine, Phenocoll, Phenopyrazone, Piminodine, Piritramide, Propacetamol, Ramifenazone, Pipery10ne, Salverine, and Tinoridine. Hydroxyl-containing: Aluminum bis(acetylsalicylate), Benzylmorphine, Buprenorphine, Butorphanol, Ch10robutanol, Ciramadol, Codeine, Desomorphine, Dihydrocodeine, Dihydromorphine, Dihydroxyaluminum acetylsalicylate, Dimepheptanol, Eptazocine, Ethylmorphine, Eugenol, Hydroxypethidine, Levorphanol, Meptazinol, Metazocine, Morphine, Nalbuphine, Pentazocine, Phenazocine, Phenoperidine, Phenylsalicylate, Salicin, Tramadol, and Viminol. Carboxyl-containing: Acetylsalicylsalicylic acid, Alc10fenac, Aspirin, Benoxaprofen, 5-Bromosalicylic acid acetate, Cinchophen, Diacerein, Dipyrocetyl, Fosfosal, Ibufenac, Indoprofen, and Salicysulfuric acid. 98 Amino- and Hydroxyl-containing: Acetaminophen, Acetaminosa10l, Bucetin, Capsaicine, Dezocine, F10ctafenine, Glafenine, Isoladol, p-Lactophenetide, Norlevorphanol, Normorphine, Phenyl ram idol, Salacetamide, and Salicylamide. Amino- and Carboxyl-containing: Actarit, Bumadizone, C10nixin, and Salicylamide O-acetic acid. Carboxyl- and Hydroxyl-containing: Diflunisal, Gentisic acid, and Salsalate. Keto-containing: Amtolmetin, Dipipanone, Hydrocodone, Isomethadone, Methadone, Norpipanone, and Phenadoxone. Hydroxy- and Keto-containing: Hydromorphone, Ketobemidone, Metopon, Oxycodone, and Oxymorphone. Carboxyl- and Keto-containing: C10metacin, Ketorolac, and Zomepirac. Amino- Carboxyl- and Keto-containing: Bromfenac. ANTIHYPERTENSIVE DRUGS: Amino-containing: Alfuzosin, Benzylhydroch10rothiazide, Bethanidine, Bopindo10l, Budralazine, Bunazosin, Cic10sidomine, C10nidine, C10pamide, Cyc10penthiazide, Debrisoquin, Edeserpidine, Diazoxide, Dihydralazine, Doxazosin, Endralazine, Guanabenz, Guanacline, Guanazodine, Guanethidine, Guanoch10r, Guanadrel, Guanfacine, Guanoxan, Hydracarbazine, Hydralazine, Hydroflumethiazide, Indapamide, Indoramin, Irbesartan, Ketanserin, 10fexidine, Mebutamate, Mecamylamine, Methyl 4-pridyl ketone thiosemicarbazone, Mibefradil, Minoxidil, Monatepil, Moxonidine, Pheniprazine, Pinacidil, Prazosin, Raubasine, Rescinnamine, Reserpiline, Reserpine, Rilmenidine, Syrosingopine, Tasosartan, Terazosin, Tiamenidine, Todralazine, To10nidine, Tripamide, and Urapidil. Hydroxy-containing: Ajmaline, Cicletanine, Levcromakafim, Naftopidil, Phenactropinium ch10ride, and Protoveratrines. Carboxyl-containing: Eprosartan, Fosinopril, and Telmisartan, Amino- and Carboxyl-containing: Alacepril, gama-Aminobutyric acid, Benazepril, Candesartan, Carmoxirole, Caronapril, Cilazapril, Delapril, Enalapril, Enalaprilat, Imidapril, Lisinopril, Moexipril, Moveltipril, Perindopril, Quinapril, Ramipril, Saralasin, Spirapril, Temocapril, Trandolapril, and Valsartan. 99 Amino- and Hydroxyl-containing: Acebuto10l, Alpreno10l, Amosula10l, Arotino10l, Ateno10l, Betaxo10l, Bisopro10l, Bosentan, Bucindo10l, Bufeniode, Bunitro10l, Buprano10l, Butofi1010l, Cadralazine, Celipro10l, Carazo10l, Carteo10l, Cetamo10l, Carvedi10l, Epano10l, Indeno10l, Nado10l, Dileva10l, Fenoldopam, Guanoxabenz, Labeta10l, 10sartan, Mepindo10l, Metiprano10l, Metopro10l, Mopro10l, Nebivo10l, Olmesartan, Oxpreno10l, Penbuto10l, Phentolamine, Pildralazine, Pindo10l, Proprano10l, Rescimetol, Sulfina10l, Talino10l, Tertato10l. Timo10l, and Trimazosin. Amino-, Hydroxy!- and Carboxyl-containing: Methyldopa, and Sampatrilat, Sulfahydryl-and Carboxyl-containing: Captopril, and Omapatrilat, Carbonyl-containing: Aranidipine, and Eplerenone, ANTIBIOTICS: All the known amino-, hydroxyl-, and carboxyl-containing antibiotics such as Amoxicillin, Ampicillin, Olivanic acid, Metronidazole, and the like as listed in Merck Index. 13th edition and other drug databases integrity, ensemble, iddb, and the like. These antibiotics can be used in combination with beta-lactamase inhibitor such as clavulanic acid, penicillinic acid sulfone and the like. The fol10wing lists of antibacterial and antifungal agnets are given for clarity. ANTIBACTERIAL AGENTS: Amino-containing: Acedapsone, Acetosulfone sodium, Ambazone, Bacampicillin, Benzylsulfamide, Brodimoprim, Cefcapene pivoxil, Cefpodoxime proxetil, Ch10ramine- B, Ch10ramine-T, Capreomycin, C10fazimine, Cyacetacide, Cyc10serine, Dapsone, Ethionamide, Furazolium ch10ride, N2-Formylsulfisomidine, Furonazide, Isoniazid, Lenampicillin, Linezolide, Mafenide, 4’-(Methylsulfamoyl)sulfanilanilide, Morphazinamide, Nifuradene, Nitrofurantoin, Penamecillin, Penethamate hydriodide, Pexiganan, Pivampicillin, Pivcefalexin, Pic10xydine, Protionamide, Pyrazinamide, Solasulfone, Subathizone, 4,4'-Sulfinyldianiline, Sulfoxone sodium, 4'- Sulfanilylsulfanilamide, Sulfoniazide, Sulfabenzamide, Sulfacetamide, Sulfach10rpyridazine, Sulfacytine, Sulfadiazine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sulfaethidole, Sulfaguanidine, Sulfaguanole, Sulfalene, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole, Sulfamethomidine, Sulfamethoxazole, Sulfamethoxypyridazine, Sulfamethylthiazole, Sulfametrole, Sulfamidochrysoidine, 100 Sulfamoxole, Sulfanilamide, p-Sulfanilylbenzylamine, Sulfanilylurea, N-Sulfanilyl-3,4-xylamide, Sulfaperine, Sulfaphenazole, Sulfaproxyline, Sulfapyrazine, Sulfasomizole, Sulfasymazine, Sulfathiazole, Sulfathiourea, Sulfisomidine, Sulfisoxazole, Sultamicillin, Sulfatolamide, Talampicillin, Taurolidine, Tetroxoprim, Thiazosulfone, Thiacetazone, Tiocarlide, and Trimethoprim. Hydroxyl-containing: Azithromycin, Ch10roxylenol, Ch10rquinadol, C10foctol, C10xyquin, Diathymosulfone, Glucosulfone sodium, Nifurpirinol, Nifurtoinol, Nitroxoline, Roxarsone, Roxithromycin, Xanthocillin, and Xibornol. Carboxyl-containing (including sulfate, phosphate and phosphonate-containing): Amdinocillin, Cinoxacin, Dif10xacin, Fosfomycin, and Hydnocarpic acid. Amino- and Carboxyl-containing (including sulfate-, sulfonic acid-, phosphate and phosphonate-containing): Acediasulfone, Amphomycin, Ampicillin, Azidocillin, Az10cillin, Aztreonam, Bacitracin, Ba10f10xacin, Betamipron, Carbenicillin, Carindacillin, Carumonam, Cefac10r, Cefazedone, Cefazolin, Cefclidin, Cefditoren, Cefepime, Cefetamet, Cefixime, Cefrhenoxime, Cefmetazole, Cefodizime, Ceforanide, Cefotaxime, Cefotetan, Cefotiam, Cefoxitin, Cefozopran, Cefpimizole, Cefpirome, Cefroxadine, Cefsu10din, Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Cefuzonam, Cephacetrile sodium, Cephalexin, Cepha10glycin, Cepha10ridine, Cepha10sporin C, Cepha10thin, Cephapirin sodium, Cephradine, Cilastatin, Ciproflaxacin, Clinaf10xacin, C10metocillin, Cyclacillin, Dic10xacillin, Enoxacin, Epicillin, Fenbenicillin, F10xacillin, Hetacillin, 10racarbef, Metampicillin, Methicillin, Mez10cillin, Nafcillin, Noprysulfamide, Opiniazide, Oxacillin, Penicillin(s), Penimepicycline, Phenethicillin, Phthalylsulfacetamide, Phthalylsulfathiazole, Piperacillin, Propicillin, Quinacillin, Succinylsulfathiazole, Succisulfone, Sulbenicillin, Sulfachrysoidine, Sulfanilic acid, Temocillin, Ticarcillin, and Tigemonam. Amino- and Hydroxyl-containing: Amikacin, p-Aminosalicylic acid hydrazide, Arbekacin, Azidamfenicol, Bambermycins, 5-Bromosalicylhydroxamic acid, Butirosin, Clindamycin, C10mocycline, Ch10ramphenicol, C10xacillin, Colistin, Demec10cycline, Deoxydihydrostreptomycin, Dibekacin, Dihydrostreptomycin, Dirithromycin, Doxycycline, Enviomycin, Ethambutol, Forimicins, Gentamycin, Glyconiazide, N4-beta-D-Glucosylsulfanilamide, Gramicidin(s), Isepamicin, Kanamycin(s), Lincomycin, 101 Mec10cycline, Methacycline, Micronomicin, Neomycin, Netilmicin, Novobiocin, Paromomycin, Phenyl aminosalicylate, Pipacycline, Polymyxin, Primycin, Ramoplanin, Ribostamycin, Rifabutin, Rifalazil, Rifamide, Rifamycin SV, Rifampin, Rifapentine, Rifaximin, Ristocetin, Salinazid, Sancycline, Sisomicin, Streptolydigin, Streptomycin, Streptonicozid, 2-p-Sulfanilylanilinoethanol, Thiamphenicol, Thiostrepton, Tobramycin, Tuberactinomycin, Viomycin, and Virginiamycin. Hydroxyl- and Carboxyl-containing (including sulfate, phosphate and phosphonate-containing): Fropenem, Nadif10xacin, Biapenem, Fusidic acid, and Merbromin. Hydroxyl- and Aldehyde-containing: Josamycin, Leucomycins, Midecamycins, Miokamycin, Rokitamycin, and Spiramycin. Amino-, Hydroxyl-, and Carboxyl-containing (including sulfate, phosphate and phosphonate-containing): p-Aminosalicylic acid, Apicycline, Amoxicillin, Apaicillin, Aspoxicillin, Benzoylpas, Cefadroxil, Cefamandole, Cefatrizine, Cefbuperazone, Cefdinir, Cefminox, Cefonicid, Cefoperazone, Cefoselis, Cefpiramide, Cefprozil, Ertapenem, F10moxef, Imipenem, Lymecycline, Meropenem, Moxalactam, Negamycin, Panipenem, Ritipenem, Salazosulfadimidine, Sulfa10xic acid, 4-SuIfanilamidosalicylic acid, Teicoplanin, Tyrocidine, and Vancomycin. Keto-containing: Troleandomycin. Hydroxy- and Keto-containing: Carbomycin, Clarithromycin, Erythromycin, all erythromycin ester derivatives, Oleandomycin, and Telithromycin. Hydroxy-, Aldehyde-, and Keto-containing: Rosaramicin. Amino- and Keto-containing: Porfiromycin. Carboxyl- and Keto-containing: Fleroxacin, Flumequine, Mi10xacin, Nalidixic acid, Of10xacin, Oxolinic acid, Pef10xacin, Piromidic acid, Prulif10xacin, Rosoxacin, and Ruf10xacin. Amino-, hydroxyl-, and Keto-containing: Ch10rtetracycline, Dalfopristin, Guamecycline, Mikamycin, Minocycline, Oxytetracycline, Pristinamycin, Quinupristin, Rolitetracycline, Spectinomycin, and Trospectomycin. 102 Amino-, carboxyl-,and keto-contianing: Garenoxacin, Gatif10xacin, Gemif10xacin, Grepaf10xacin, 10mef10xacin, Moxif10xacin, Norf10xacin, Pazuf10xacin, Pipemidic acid, Sitaf10xacin, Sparf10xacin, Tosuf10xacin, and Trovaf10xacin. Sulfahydryl-containing: Pyrithione. ANTIFUNGAL AGENTS: Amino-containing; Ch10rdantoin, Exalamide, Flucytosine, 10flucarban, Magenta 1, and Pyrrolnitrin. Hydroxy-containing: Ch10rphenesin, Cic10pirox, Dermostatin, Filipin, Fluconazole, Fungichromin, Peci10cin, Posaconazole, Ravuconazole, Rubijervine, Siccanin, 2,4,6-Tribromo-m-cresol and Voriconazole. Carboxyl-containing; Undecylenic acid (10-undecenoic acid), and Propionic acid, Amino- and Carboxyl-containing: Azaserine. Amino- and Hydroxyl-containing: Salicylanilide, Acrisorcin (9-Aminoacrindine compound with 4-Hexylresorcinol (1:1)), Anidulafungin, Bromosalicylch10ranilide, Buc10samide, Caspofungin, Micafungin, and Tubercidin. Amino-, Carboxyl- and Hydroxyl-containing; Natamycin, Amphotericin B, Lucensomycin, and Nystatin. Carbonyl-containing: sodium propionate and griseofulvin. Hydroxy- and carbonyl-containing: Viridin. Amino-, hydroxyl-, and carbonyl-containing: Perimycin and Mepartricin. Amino-, carboxyl-, hydroxyl-, and carbonyl-containing: Candicidin. ANTIVIRAL DRUGS: Hydroxy-containing: Edoxudine, F10xuridine, Idoxuridine, Kethoxal, Podophyl10toxin, Sorivudine, Stavudine, Trifluridine, and Zidovudine. Amino-containihg: Amantadine, Amidinomycin, Atevirdine, Capravirine, Delavirdine, Efavirenz, Famcic10vir, Imiquimod, Lamivudine, Methisazone, Moroxydine, Nevirapine, Oseltamivir, Rimantadine, Stallimycin, mantadine, and Valacyc10vir. Amino- and Hydroxyl-containing: Abacavir, Acyc10vir, Adefovir, Amprenavir, Atazanavir, Cidofovir, Didanosine, Dideoxyadenosine, Emtricitabine, Entecavir, Indinavir, Lamivudine, 10pinavir, 5-(methylamino)-2-deoxyuridine (MADU), Nelfinavir, 103 Pencic10vir, Resiquimod, Ribavirin, Ritonavir, Saquinavir, Tenofovir, Tipranavir, Valgancic10vir, Vidarabine, and Zalcitabine. Carboxyl- and Hydroxyl-containing: Foscarnet sodium, and Gancic10vir. Amino-, Carboxyl- and Hydroxyl-containing: Zanamivir. ANTIMALARIAL: Amino-containing: Ch10rguanide, Ch10roquine, Ch10rproguanil, Cyc10guanil, Pamaquine, Plasmocid, Primaquine, Quinocide, and Tafenoquine. Hydroxyl-containing: Artemisinin alcohol, Bebeerines, Cinchonidine, Cinchonine, Dihydroartemisinin, Ha10fantrine, Lumefantrine, Quinine and Yingzhaosu A. Carboxyl-containing: Arteflene and Artesunate. Amino-, and Hydroxyl-containing: Amodiaquin, Hydroxych10roquine, Mef10quine, and Pyronaridine. Hydroxyl, and carbonyl-containing: Fosmidomycin. Carbonyl-containing: Arteflene. ANTINEOPLASTIC DRUGS: Hydroxy-containing: Aclacinomycins, Arzoxifene, Batimastat, Broxuridine, Calusterone, Capecitabine, CC-1065, Chromomycins, Diethylstilbestrol, Docetaxel, Doxifluridine, Dro10xifene, Dromostano10ne, Enocitabine, Epitiostanol, Estramustine, Etanidazole, Etoposide, Fenretinide, Flavopiridol, Formestane, Fosfestrol, Fulvestrant, Gemcitabine, Irinotecan, Melengestrol, Menogaril, Miltefosine, Mitobronitol, Mitolactol, Mopidamol, Nitracrine, Nogalamycin, Nordihydroguaiaretic Acid, Olivomycins, Paclitaxel and other known paclitaxel ana10gs, Plicamycin, Podophyl10toxin, Retinoic acid (including all trans-retinioc acid), Roquinimex, Rubitecan, Seocalcitol, Temoporfin, Teniposide, Tenuazonic Acid, Topotecan, Valrubicin, Vinblastine, Vincristine, and Zosuquidar. Amino-containing (including Amide-NH and Sulphonamide-NH, Carbamate-NH, Sulfamate-NH, and Phosphomide-NH): 9-Aminocamptothecin, Aminolevulinic Acid, Amsacrine, Bisantrene, Cactinomycin, Carboquone, Carmofur, Carmustine, Cyc10phosphamide, Dacarbazine, Dactinomycin, Demecolcine, Diaziquone, 6-Diazo-5-oxo-L-norleucine (DON), Edatrexate, Efaproxiral, Ef10rnithine, Eniluracil, Er10tinib, 104 Fluorouracil, Gefitinib, Gemcitabine, Goserelin, Histamine, Ifosfamide, Imatinib, Improsulfan, Lanreotide, Leuprolide, Liarozole, 10baplatin, Cisplatin, Carboplatin, 10mustine, 10nafarnib, Mannomustine, Melphalan, Methotrexate, Methyl Aminolevulinate, Miboplatin, Mitoguazone, Mitoxantrone, Nilutamide, Nimustine, Nolatrexed, Oxaliplatin, Pemetrexed, Phenamet, Piritrexim, Procarbazine, Raltitrexed, Tariquidar, Temozo10mide, Thiamiprine, Thioguanine, Tipifarnib, Tirapazamine, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP)/ 3-Aminopyridine-4-methyl-2-carboxaldehyde thiosemicarbazone (3-AMP/Triapine /OCX-191/OCX-O191), Trimetrexate, Uracil Mustard, Uredepa ([Bis(l-aziridinyl)phosphinyl]carbamic acid ethyl ester, ethyl carbamate and Meturedepa. Both Hydroxy- & Amino- containing (including Amide-NH and Sulphonamide-NH, Carbamate-NH, Sulfamate-NH, and Phosphomide-NH): Ancitabine, Anthramycin, Azacitidine, Bleomycins, Bropirimine, Buserelin, Carubicin, Ch10rozotocin, Cladribine, Cytarabine, Daunorubicin, Decitabine, Defosfamide, Docetaxel, Doxorubicin, Ecteinascidins, Epirubicin, Gemcitabine, Hydroxyurea, Idarubicin, Marimastat, 6-Mercaptopurine, Pentostatin, Pep10mycin, Perfosfamide, Pirarubicin, Prinomastat, Puromycin, Ranimustine, Streptonigrin, Streptozocin, Tiazofurin, Troxacitabine, Vindesine and Zorubicin. Carboxyl-containing: Butyric acid. ANTIOXIDANTS/FREE RADICAL SCAVENGERS: Amino-containing (including some investigational drugs): BTX-51072 (4,4-dimethyl-3,4-dihydro-2H-l,2-benzoselenazine), Carnosine, Melatonin, (+)-R-Pramipexole, and Stobadine. Hydroxy I-containing (including some investigational drugs): Ascorbic acid, Curcumin, Dexanabinol, Edaravon, (-) Epigal10catechin Gallate, Emoxipin, Hydroxytyrosol, Idebenone, Luteolin, Nicanartine, NZ-419, Oxyresveratrol, Probucol (including probucol prodrugs such as AGI-1067 and AGI-1096), Quercetin, Reductic acid, Silybin, Tempol (4-Hydroxy-TEMPO), and alfa-Tocopherol (Vitamin E). Carboxyl-containing (including some investigational drugs): N-Acetyl L-cysteine, Alfa-Lipoic acid, Raxofelast, and Tetomilast. 105 Amino-/Hydroxyl-, and Carboxyl-containing (including some investigational drugs): N-Acetyl carnosine, L-Carnitine, and SCMC-Lys (S-carboxymethyl-L-cysteine Lysine salt H2O). Amino- and Hydroxyl-containing (including some investigational drugs): BN-82451, and Zeatin. BENZODIAZEPINE TRANQUILIZERS AND HYPNOTICS: Diazepam, Triazolam, Alprazolam, and the like. ANTIULCER AGENTS: Amino-containing (^including Amide NH and Sulphonamide NH and Phosphomide NH, etc.): Aldioxa, Benexate HC1, Cimetidine, Ebrotidine, Ecabapide, Esaprazole, Esomeprazole, Famotidine, Irsogladine, Lafutidine, Lansoprazole, Omeprazole, Pantoprazole, Pirenzepine, Polaprezinc, Rabeprazole, Ranitidine, Roxatidine, and Troxipide. Hydroxyl (and Keto and Keto and/or Carboxyl) -containing: Enprostil, Misoprostol, Ornoprostil, Plaunotol, Rioprostil, Trimoprostil, and Oryzanol A. Carboxyl-containing: Acetoxo10ne, Carbenoxo10ne, Rebamipide, and Sofalcone. Amino (or Hydroxyl) - and Carboxyl-containing: Cetraxate, Ecabet, S-Methylmethionine, Rosaprostol, and Rotraxate. Carbonyl-containing: Spizofurone, and Teprenone. ANTICONVULSANTS: Amino-containing (including Amide NH and Sulphonamide NH and Phosphomide NH, etc.): Acetylpheneturide, Albutoin, JV-benzyl-3-ch10ropropionamide, Carbamazepine, Cinromide, C10nazepam, Decimemide, Dimethadione, Doxenitoin, Ethosuximide, Ethotoin, Felbamate, Fosphenytoin, Lamotrigine, Levetiracetam, Mephenytoin, Mephobarbital, Metharbital, Methetoin, Nitrazepam, Oxcarbazepine, Oxicarbamazepine, Phenacemide, Phenetharbital, Pheneturide, Phenobarbital, Phenylmethylbarbituric Acid, Phenytoin, Phethenylate Sodium, Primidone, Progabide, Remacemide, Rufinamide, Suc10fenide, Sulthiame, Talampanel, Tetrantoin, Topiramate, Valpromide, Zonisamide, 5-Methyl-5-(3-phenanthryl)hydantoin, and 3-Methyl-5-phenylhydantoin. Hydroxyl-containing: Ganaxo10ne. 106 Hydroxyl-, and Amino-containing (including Amide NH and Sulphonamide NH and Phosphomide NH): 4-Amino-3-hydroxybutyric Acid, Atrolactamide, and Buramate. Carboxyl- and Amino-Containing (including Amide NH and Sulphonamide NH and Phosphomide NH): Gabapentin, Pregabalin, and Vigabatrin. Carboxyl-containing: Tiagabine, and Valproic Acid. ANTIPARKINSON'S: Levodopa & Carbidopa. ANTIDEPRESSANT: Amino-containing (including Amide NH and Sulphonamide NH and Phosphomide NH, etc.): Amoxapine, Caroxazone, Demexiptiline, Desipramine, Du10xetine, Fluoxetine, Fluvoxamine, Indalpine, Tnde10xazine Hydroch10ride, Iproc10zide, Iproniazid, Isocarboxazid, Levophacetoperane, Maprotiline, Metapramine, Milnacipran, Minaprine, Moc10bemide, Nialamide, Nomifensine, Nortriptyline, Octamoxin, Oxypertine, Paroxetine, Protriptyline, Reboxetine, Rolipram, Sertraline, Tofenacin, Tranylcypromine, Vi10xazine, Benmoxine, and Rolicyprine. Hydroxyl-containing: Bef10xatone, Bupropion, Fenpentadiol, Hypericin, Opipramol, Pyrisuccideanol, To10xatone, and Venlafaxine. Hydroxyl-, and Amino-containing (including Amide NH and Sulphonamide NH and Phosphomide NH): S-Adenosylmethionine, 5-Hydroxytryptophan, and Roxindole. Carboxyl- and Amino-Containing (including Amide NH and Sulphonamide NH and Phosphomide NH): Amineptine, and Tianeptine. ANTIHISTAMINE Amino-containing (including Amide NH and Sulphonamide NH and Phosphomide NH, etc.): Antazoline, Astemizole, C10benzepam, Des10ratadine, Epinastine, Metron S, Mizolastine, and Tritoqualine. Hydroxyl-containing: Terfenadine, and A^-Hydroxyethylpromethazine Ch10ride. Hydroxyl-, and Amino-containing (including Amide NH and Sulphonamide NH and Phosphomide NH, etc.): Cetoxime. Carboxyl-containing: Acrivastine, Bepotastine, Cetirizine, and Levocabastine, Carboxyl- and Hydroxyl-containing: Fexofenadine. 107 ANTICANCER, ANTIOXIDATIVE, ANTIINFLAMMATORY, AND CARDIOPROTECTIVE AGENT: Trans-Resveratrol [(E)-3,4\5-trihydroxystilbene). ANTIDIABETIC: Metformin, and Nateglinide/Glipizide/GIibencIamide (Glyburide). It should be understood that while the lists of names of various categories of drugs have been included above, such lists are presented in a way of illustration of the structural features of the qualifying drugs in this invention and therefore, the number and types of listed drugs are not necessarily limited thereto. In principal, any amino-, and /or carboxyl, and/or carbonyl-, and/or hydroxyl-containing drug (from both known and investigational drugs), irrespective of its therapeutic category and their mechanism of action, as listed in drug databases such as Merck Index, prous science's ensemble, integrity, iddb, and the like, are generally covered within the true spirit and scope of the present invention. For clarity, in addition to the above lists of drugs, any amino-, and/or carboxyl-, and/or carbonyl-, and/or hydroxyl-containing drug(s) (both known and investigational drugs) from the fol10wing therapeutic areas are covered without any limitation: CENTRAL NERVOUS SYSTEM: Sedatives, Hypnotics, Antidepressants, Antipsychotics and Antimanics, Analgesics & Antipyretics, Antimigraine agents, Anticonvulsants, Drugs used in parkinsonism and movement disorders, Drug for dementia, Antiemtics, drugs for Vertigo, CNS Stimulants & activators. EYE: Antiinfective eye preparations, Antiinflammatory and antiallergic preparations, antiglucoma drugs and other preparations to cure eye diseases. EAR, NOSE and OROPHARYNX: Drugs used aural, nasal and oropharyngeal preparation. CARDIOVASCULAR SYSTEM: Antiarrhythemic drugs, Antihypertensives (including alfa/beta-b10ckers, channel b10ckers, ACE inhibitors, Angiotensin II receptor antagonists, diuretics, etc.), Antianginals (includinig nitrates, calcium channel b10ckers, etc.), Drugs for cardiac failure and shock, Vasodilators, Coagulants, Anticoagulants, Thrombolytics and antiplatelet drugs. RESPIRATORY SYSTEM: Respiratory stimulants, Antitussives, Expectorants, Mucolytics and Decongestants, Antihistamine agents, and antiasthmatics. GASTRO INTESTINAL TRACT: Antiulcer and Antisecretory drugs (including H2 receptor antagonists, Proton Pump linhibitors, Prostaglandin ana10gues, etc.), 108 Antacids, Antispasmodics and drugs modifying intestinal motility, Antidiarrhoeals (including antimotility and antimicrobial drugs) and drugs acting on gall bladder. GENITO URINARY SYSTEM; Urinary antiinfectives, Diuretics, Urinary analgesics & antispasmodics, Antiinfective drugs acting on urethra and vagina, drugs acting on uterus, Drugs for prostatic hypertrophy (including alfa b10ckers and antiandrogens), Drugs for erectile dysfunction, and Spermicidal & nonhormonal contraceptives. SKIN: Emollients and keratolyses, topical antiinfectives, topical antifungals, topical parasiticidals, topical steroids, topical drugs for acne vulgaris, drugs for psoriasis, pigmentation disorders, and Antiseborrhoeics. MUSCU10SKELETAL DISORDERS: Non Steroidal Anti Inflammatory Drugs (NSAIDs) including COX-2 inhibitors, Antiarthritic agents, Immunosuppressants, Topical analgesics, Muscle relaxants and Neuromuscular Drugs. INFECTIONS AND INFESTATIONS: Penicillin antibiotics, Cepha10sporin antibiotics, Quino10ne & Fluoroquino10ne antibiotics, Macrolide antibiotics, Ch10ramphenicol, Tetracycline antibiotics, Sulfonamides, Antianaerobics such as Metronidazole, Antitubercular drugs, Antileprosy drugs, Antifungals, Antiprotozoals, Anthelminthics & Antiinfestive Drugs, Antimalarials and Antivirals. ENDOCRINE SYSTEM: Anabolic and androgenic steroids, Corticosteroids, Oestrogens, Progestogens and Hormonal contraceptives, Fertility Agents, Trophic hormones and related drugs, Thyroid and antithyroid drugs, Antidiabetics and hyperglycaemics. NUTRITION: Vitamins, Amino acids, Anti-obesity drugs METABOLISM: Hypolipidaemic drugs (including fibric acid derivatives, statins [(i.e., HMG CoA reductase inhibitors), nicotinic acid group, etc.], Drugs used for Gout and Drugs affecting bone metabolism (including bisphosphonates). NEOPLASTIC DISORDERS: Anticancer drugs such as alkylating agents, cytotoxic antibiotics, antimetabolites such as cytarbine, Fludarbine, 5-Fluorouracil, Mercaptopurine, Thioguanine, etc., Vinca alka10ids and Etoposide, Taxanes, Topoisomerase I inhibitors, Cytotoxic immunosuppressants, Immunostmulants, 109 Cytoprotectives such as Amifostine, Oestrogens, Progestogens, hormon antagonists and other antineoplastic drugs. ALLERGY AND IMMUNO10GY: Antiallurgics such as non-sedative antihistamins (e.g., Cetirizine, Des10ratadine, Terfenadine, Fexofenadine, etc.), sedative histamines and histamine receptor b10ckers. ANAESTHETICS & SURGICALS: 10cal anaesthetics, intravenous anaesthetics, inhalation anaesthetics and muscle relaxants. DRUG COMBINATIONS: It is appreciated that NO-releasing prodrugs of any two or more drugs from the above lists of potential drugs can be used in combination depending on the medical application/need. While a combination formulation may occassionally consist of more than two drugs (depending on the medical need), the fol10wing pairs of drugs are covered in this invention as illustrative pairs of candidate drugs for combination therapy. ANTICANCER: Paclitaxel and Doxorubicin, Paclitaxel and Mitomycin C; Paclitaxel and 9-aminocamptothecin, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP)/ 3-Aminopyridine-4-methyl-2-carboxaldehyde thiosemicarbazone (3-AMP) and another known anticancer drug such as Paclitaxel, Doxorubicin, Mitomycin C and the like; CC-1065 and another known anticancer drug such as Paclitaxel, Doxorubicin, Mitomycin C and the like; Trans-Resveratrol [(E)-3,4',5-trihydroxystilbene) and another known anticancer drug such as Paclitaxel, Doxorubicin, Mitomycin C and the like; Retinoic acid (including all trans-retinoic acid) and Butyric acid. Paclitaxef and Captopril, Doxorubicin and Biotin. 5-Fluorouracil and Cytarabine. Edatrexate and Paclitaxel; Cepha10sporanic acid and Paclitaxel; Cepha10sporin and Paclitaxel; and Paclitaxel and Gemcitabine, ANTIPERKINSON'S: Levodopa and Carbidopa. ANTIBIOTICS: Amoxicillin and Clavulanic acid; Ampiciltin and Clavulanic acid, Amoxicillin and Pencilling acid sulfone; Ampicillin and Pencillinic acid sulfone; Olivanic acid (or any carbapenem antbiotic) and a renal dipeptidase (dehydropeptidase I) inhibitor such as 3-substituted Z-2-acylaminopropionic acid and the like 110 ANTILIP1DEM1C AND HYPERTENSION: Lifibrol and 10vastatin/Pravastatin/Fluvastatin/Atorvastatin/Simvastatin; Ezetimibe and 10vastatin/ Pravastatin/Fluvastatin/Atorvastatin/Simvastatin; Am10dipineand10vastatin/Pravastatin/Fluvastatin/Atorvastatin/Simvastatin. ANTIDIABETIC: Metformin and Nateglinide/Glipizide/Glibenclamide (Glyburide) ANTIDIABETIC AND HYPERTENSION: Metformin and 10vastatin/Pravastatin/FIuvastatin/Atorvastatin/Simvastatin. ANTIASTHMATIC, ALLERGIC RHINITIS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD): Pseudoephedrine and Fexofenadine/Cetirizine/Des10ratadine/Epinastine; Salbutamol and Ipratropium bromide; Mometasone and Formoterol/SalmeteYol; Fluticasone and Formoterol/Salmeterol; Budesonide and Formoterol/Salmeterol. ANTIARTHRITIS, INFLAMMATION AND ULCERS: Dic10fenac (any known NSAID) and Misoprostol; Dic10fenac (any known NSAID) and a proton pump inhibitor such as Omeprazole, Lansoprazol, Rabeprazole, Leminoprazole, Pantoprazole, and the like; A known antibacterial agent and a proton pump inhibitor such as Omeprazole, Lansoprazol, Rabeprazole, Leminoprazole, Pantoprazole, and the like; Naproxen (or any known NSAID) and Prophenazone; Acetaminophen and ch10rzoxazone/metaxa10ne/mephenoxa10ne. ANTIVIRAL (HIV/AIDS, PEPATITIS B AND OTHER VIRAL INFECTIONS): Zidovudine and Lamivudine; Triple prodrug of Zidovudine; Lamivudine and Abacavir (Ziagen); 10pinavir and Ritonavir; Lamivudine and Adefovir or its prodrug adefovir dipivoxil; Amprenavir and Zidovudine; Nelfinavir and a nucleoside reverse transcriptase inhibitor such as Zidovudine, Lamivudine, and the like; Stavudine and an antiretroviral agent such as Zidovudine, Lamivudine, and the like; Dideoxyinosme and an antiretroviral agent such as Zidovudine, Lamivudine, and the like; Emtricitabine and Pencic10vir/Famcic10vir; Acyc10vir (or any other known antiviral compound) and a bile acid such as cholate, deoxycholate, chenodeoxycholate, and ursodeoxycholate (for targeting bile acid transporters for enhanced oral bioavailability of the drug; Triple and prodrug of Zidovudine, Lamivudine and Efavirenz. 111 In addition to the above list of drugs, the the present invention also covers newer drugs with the above mentioned active functional groups as listed in the Merck index (13th edition) and other drug databases such as Prous Science's ensemble, integrity and the investigational drugs as listed in databases such as iddb, ensemble, integrity, and the like without any limitation. It shoud be understood that either or both of any selected pair of drugs (in any proportion) can be in the form of nitrate ester (NO-releasing) prodrug(s) of formula (I) or pharmaceutically acceptable salts thereof and the other drug can be in its native form. For clarity, let us assume that Ibuprofen and Paracetamol are present as active principles in a pharmaceutical compoisition. Then, either or both of these drugs can be in their NO-releasing prodrug form (i.e., NO-Paracetamol and Ibuprofen/ Paracetamol and NO-Ibuprofen/ NO-Paracetamol and NO-Ibuprofen, etc.) and they can be present in any proportion. It should also be understood that a pharmaceutical composition consisting of two or more of the above listed/qualified drugs, one of the drugs can be in the form of NO-releasing (nitrooxy derivative) prodrug and the other drug(s) in the combination can be in the form another type of prodrug(s). It should also be understood that a pharmaceutical composition containing a combination of one of the above listed/qualified drug(s) and its own prodrug is also covered (i.e., a pharmaceutical composition consisting of NO-Paracetamol and Paracetamol in any proportion). In such pharmaceutical combinations, the free drug will be useful for faster onset of action and the prodrug will be useful for extension of the duration of action as it releases the drug in a controlled fashion over a 10nger period of time. Such combination drug therapy may also minimize the toxicity and other side effects due to excessive plasma concentration of free drug. It should also be understood that a pharmaceutical combination may contain a prodrug of one of the above listed/qualified drugs and an another type of prodrug of the same drug (i.e., NO prodrug of pracetamol and mutual prodrug of paracetamol with another drug) and these can be present in any therapeutic proportion depending on the medical need. 112 EXPERIMENTAL ABBREVIATIONS USED: BOP: Benzotriazol-l-yI-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate DMF: N,N-Dimethylformamide DSC: N,N'-Disuccinimidyl carbonate CDI: N,N'-Carbonyldiimidazole DTE: Dithioerythritol DTT: Dithiothreitol DCC:N,N'-Dicyc10hexylcarbodiimide EDAC. HCI: l-Ethyl-(3rdimethylaminopropyl)carbodiimide hydroch10ride HBTU: O-(Benzotriazol-l-yO-N,N,N'-tetramethyluronium hexafluorophosphate TBTU: O-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate EtOH: Ethanol Et2O: Diethyl ether THF: Tetrahydrofuran DMSO: Dimethyl sulfoxide TEA: Triethylamine D1PEA: N,N-Diisopropylethylamine DCM: Dich10romethane EtOAc: Ethyl acetate DME: Dimethoxyethane MeOH: Methanol PE: Petroleum ether RT: Room temperature TFA: Trifluoroacetic acid HOBT: N-Hydroxybenzotriazole SYNTHETIC METHODS: The prodrugs described herein can be prepared by any number of methods known/obvious to those skilled in the art. The synthetic approaches and the linkages are chosen depending upon the functional groups such as carboxyl, hydroxyl, amino or carbonyl groups present in the drug molecules to be used. The fol10wing illustrative 113 methods, as shown in Schemes 1 through 9, can be utilized to make carbonate, urethane, amide, ester, N-acyl carbamate, N-acyl amide, N-acyl sulfamate, and N-acyl sulfonamide, N-acyl phosphoramide, N-oxycarbonylsulfonamide, N- oxycarbonylcarbamate linkages, etc., between drug(s) and linker(s). Methodfs) of making carbonate linkage(s): As depicted in the scheme I, the carbonate linkage between the drug and the linker can be made by reacting the hydroxyl-containing drug (alternatively, hydroxy! group of the linker) with phosgene or its equivalents such as diphosgene, triphosgene, N,N'-carbonyldiimidazole (CDI), N,N'-disuccinimidyl carbonate (DSC), 4-nitrophenyl ch10roformate and the like, to give a reactive alkoxycarbonyl derivative, where LG is suitable leaving group such as a halide, imidazole, O-succinimide, 4-nitrophenoxide and the like, which can be reacted with hydroxy! group of the linker (alternatively, hydroxy! group of drug if the linker is converted to active alkoxycarbonyl derivative) in the presence of a suitable base and solvent. Phosgene or its equivalent O p., nu/Q->\ O Rx—OH > Rx A — ' R*^ ^k /R* S1 A suitable base and solvent O LG O O IPi P| Rx and Ry are any monovalent organic radicals; Scheme 1 Bases such as triethylamine, diisopropylethylamine, 4-(dimethyIamino)pyridine (DMAP), and the like, can be used. Suitable solvents include CH2CI2, CHC13, DMF, THF, ACN, ethyl acetate, ethyl ether and the like. Method of making urethane linkage(s): As shown in scheme 2, the urethane linkage between the drug and the linker can be made by reacting the hydroxyl-containing linker with phosgene or its equivalents (defined above) to give a reactive alkoxycarbonyl derivative, which can be reacted with amino-containing drug in the presence of a suitable base and solvent. Alternatively, a urethane linkage can be made by adding an alcohol to an isocyanate. 114 Scheme 2 Suitable bases and solvents are same as defined above. Method(s) of making amide or ester linkageCs): As shown in the Scheme 3, an amide or ester linkage between the drug and the linker can be made by reacting a carboxyl-containing drug with an amino- or hydroxyl-containing linker in the presence of a suitable coupling agent, base and solvent. Alternatively, the carboxyl-containing compound can be first converted to reactive carbonyl derivative such as an acid halide, a succinimide ester, a pentafluorophenyl ester, an imidazolide and the like, which can be treated with amino-containing or hydroxyl-containing linker in the presence of a suitable base and solvent to afford the corresponding amide or ester linkage(s), respectively (see, Bodanszky, M. and Bodanszkv. A.. The Practice of Peptide Synthesis, Springer-Verlaa. New York, 1984) scheme 3 Suitable coupling agents include DCC, EDCLHC1, BOP, HBTU, TBTU, DCC/HOBT, EDC/HOBT, and the like. Suitable bases and solvents are same as defined above. Method(s) of making N-acyl carbamate and N-acyl urea linkage: The linkage such as N-acyl carbamate linkage between the linker and drug can be made as shown in Scheme 4. Thus, treatment of an alcohol with phosgene or its 115 equivalent can yield the corresponding carbonoch10ridate, which upon treatment with ammonia gas can give the corresponding carbamate intermediate. The carbamate nitrogen can be acylated by a suitable carboxylic acid derivatives such as anhydride or acid halide, a succinimide ester, a pentafluorophenyl ester, an imidazolide, and the like, in the presence of a suitable base to yield the corresponding N-acyl carbamate. Alternatively, N-acyl carbamate can be made by the reaction of an alcohol with N-acyl isocyanate, which can be prepared either by the reaction of the corresponding amide with oxalyl ch10ride (See, Speziale, A. J. et al., J. Org. Chem. 1962, 27, 3742; Speziale, A. J. et al., J. Org. Chem. 1963, 28, 1805-1811) or by the reaction of the corresponding acid ch10ride with silver cyanate. (See, Hill, A.J. et. al., J. Am. Chem. Soc, 1940, 62, 1595; Kim, D.K. J. Heterocyclic Chem. 1995, 32, 1625). Scheme 4 Suitable bases and solvents are same as defined above. Method(s) of making N-acyl amide linkage: The N-acyl amide linkage between the linker and drug can be made as shown in Scheme 5. Thus, the amide nitrogen can be acylated by a suitable carboxylic acid derivatives such as anhydride or acid halide, a succinimide ester, a pentafluorophenyl ester, an imidazolide, and the like, in the presence of a suitable base to yield the corresponding N-acyl amide. 116 Scheme 5 Suitable bases and solvents are same as defined above. Method(s) of making N-acyl sulfamate linkage: The linkage such as N-acyl sulfamate between the linker and drug can be made as shown in Scheme 6. Thus, treatment of an alcohol with sulfuryl ch10ride in the presence of suitable base gives the intermediate sulfoch10ridate, which can be converted to the corresponding sulfamate. Acylation of sulfamate nitrogen with a suitable carboxylic acid derivatives such as anhydride or acid halide, a succinimide ester, a pentafluorophenyl ester, an imidazolide, and the like, can yield the corresponding N-acy! sulfamate. Scheme 6 Suitable bases and solvents are same as defined above. Method(s) of making N-acyl/oxycarbonyl sulfonamide linkages: The N-acyl/oxycarbonyl sulfonamide linkage between the linker and drug can be made as shown in Scheme 7. Thus, a sulfonamide nitrogen can be acylated by a suitable carboxylic acid derivatives such as anhydride or acid halide, a succinimide ester, a pentafluorophenyl ester, an imidazolide, and the like, to yield the corresponding N-acylsulfonamide, which can me metallated using an inorganic base. Similarly, the 117 sulfonamide nitrogen can be acylated by a suitable formyl ch10ride derivative such as alky10xycarbonyl ch10ride, imidazolide and the like, to yield the corresponding N-alky10xycarbonyl sulfonamide as shown in the scheme. Alternatively, the same linkage can be made by the reaction of an alcohol with sulfonyl isocyanate which can be prepared by known methods such by treatment of sulfonamide with oxalyl ch10ride (see, Hans Krzikalla et al., US2666787 or Smith, J. et al., J. Org. Chem. 1965, 30, 126O-1262)"or by treatment of sulfonyl ch10ride with silver cyanate (See, Smith, J. et al., J. Org. Chem. 1965,30, 126O-1262). Rx, and Ry are any monovalent organic radicals; M is a metal ion; x is 1-4 Scheme 7 Suitable bases and solvents are same as defined above. Method(s) of making N-oxycarbonylcarbamate and N-oxycarbonylurea linkages: The N-oxycarbonylcarbamate (or N-oxycarbonylurea) linkage between the linker and drug can be made as shown in Scheme 8. Thus, carbamate nitrogen can be acylated by suitable formyl ch10ride derivatives such as alky10xycarbonyl ch10ride, 118 imidazolide and the like, to yield the corresponding N-alky10xycarbonylcarbamate as shown in the scheme. Alternatively, the N-oxycarbonyl carbamate (or N-oxycarbonylurea) linkage between the linker and drug can be made by the reaction of an alcohol (or an amine) with carbamoyl isocyanate (IP15A), which can be prepared by known methods such by treatment of carbamate with oxalyl ch10ride (See, Grehn L, et al., Synthesis, 1988, 922-994) or by treatment of a formyl ch10ride with silver cyanate (See, Kim, D.K. et al., J. Heterocyclic Chem. 1995, 32, 1625). Alternatively, N-oxycarbonylcarbamate (or N-oxycarbonylurea) can be prepared in two steps. Step 1: reaction of an alcohol or phenol with ch10rocarbonyl isocyanate to give N-oxycarbonyl carbamoyl ch10ride intermediate (IP15B). Step 2: reaction of the intermediate IP15B with the same or another alcohol or phenol or an amine. (For a review on chemistry of ch10rocarbonyl isocyanate, see, Gorbatenko, V. I. Tetrahedron, 1993, 49, 3227). Scheme 8 Suitable bases and solvents are same as defined above. Method(s) of making Nitrate (nitrooxy") or Nitrite (nitrosy10xy) esters: The nitrate or nitrite esters can be made as shown in Scheme 9. Thus, a nitrate or nitrite ester can be made by treating an alcohol with HNO3/H2SO4 (or HNO3/AC2O) or nitrosyl ch10ride, respectively. Alternatively, a nitrate ester can be made by treating a halide (bromide or iodide is preferred) with silver nitrate in a polar aprotic solvent such as acetonitrile. 119 Scheme 9 Compounds (Prodrugs) of the formula (I) containing bio-cleavable linkers and linkages can be synthesized by various methods obvious to those skilled in the art. As a matter of illustration, any of the approaches shown in the fol10wing schemes can be used to make such prodrugs of the formula (I) described herein. Monoprotection of diol or aminoalcohol or diamino compounds [i.e., linker(s)] with suitable protecting groups and their selective removal at appropriate stage of the synthesis are carried out as described in Theodora W. Greene and Peter G.M. Wuts, "Protective Groups in Organic Synthesis", 3r edition, John Wiley and Sons, Inc. New York (1999), the disc10sures of which are incorporated herein by reference. Suitable protecting groups (PGs) include, but not limited to, acetyl, Boc, Fmoc, benzoyl, piva10yl, trityl, tetrahydropyranyl (THP), and silyl (TBDMS, TMS, etc.). Obviously, selection of a suitable protecting group is very crucial for the success of a chosen method for the synthesis of prodrugs described in this invention. Synthesis of appropriately derivatized/modified bio-labile linker is shown in Scheme 10. 120 121 122 Some of the methods for the synthesis of prodrugs (including NO-releasing prodrugs) of carboxyl-, amino-, and hydroxyl-containing drugs are shown in Schemes 11 through 14. Scheme 11: Synthesis of Prodrugs of Carboxyl-containing Drugs 123 Scheme 12: Synthesis of Prodrugs of Amino-containing Drugs Scheme 14: Synthesis of Prodrugs of Hydroxy 1-containing Drugs A) Prodrugs with carbonate and carbamate linkages: Some of the methods for the synthesis of prodrugs (including NO-releasing prodrugs and water-soluble prodrugs) are shown in Schemes 15 and 16. 124 125 Scheme 15: Synthesis of Water-soluble Prodrug(s) using a bio-cleavable linker(s) and spacer linker (s) 126 Scheme 16: Synthesis of Prodrugs containing a biocleavable linker and various types linkages 127 Double/Mutual prodrugs described in this invention can be synthesized by any of the approaches depicted in Schemes 17 through 19. Scheme 17: Synthesis of Mutual Prodrug(s) using a bio-cleavable linker(s) and spacer linker (s) 128 Scheme 18: Synthesis of Double/Mutual Prodrug(s) with additional linkers 129 Scheme 19: Synthesis of Mutual Prodrug(s) using modified bio-cleavable linkers) 130 Scheme 2O: Synthesis of Mutual Prodrug(s) using modified bio-cleavable linker(s) 131 As a matter of illustration, mutual prodrug of des10ratadine and pseudoephidrine was synthesized as depicted in Scheme 21. 132 Scheme 22: Synthesis of a water-soluble prodrug of paclitaxel 133 Scheme 23: Generation of Paclitaxel from a Prodrug of Isotaxel Scheme 24: An alternative method for the synthesis of Linker Intermediates LI-2b and LI-5 Example 1 Synthesis of 2-[(2-hydroxyethyl)dithio]ethyl acetate (Li-la): Acetic anhydride (5.67 ml, 56.87 mmol) and pyridine (40.4 ml, 499 mmol) were added to a solution of 2-(hydroxyethyl)disulflde (SL-1, 15.39 g, 99.78 mmol) in DCM (350 mL) at RT and the mixture was stirred at RT for 16 h. The mixture was concentrated and the residue, after usual aqueous work-up and chromatographic purification, afforded 8.16 g (42%) of Li-la as a pale yel10w oil. 'H-NMR (300 MHz, CDCI3): 6 2.00 (bs, 1H), 2.08(s, 3H), 2.80-2.95 (m, 4H), 3.89 (t, 2H, J = 6 Hz), 4.35 (t, 2H, J = 6 Hz), MS: (m/z) 219 [M]+. Example 2 Synthesis of 2-{[2-(tetrahydro-2H-pyran-2-y10xy)ethyl]dithio}ethanol (Li-lb): This compound was synthesized by a method described by K. F. Bernady et al., J. Org. Chem., 1979, 44, 1438. Dihydropyran (8.41 g, 100 mmol) was added to a solution of SL- 1 (15.4 g, 100 mmol) in DCM (200 mL) at O-5 °C, fol10wed by PTSA (-5%) and stirred at RT for 5 h. The mixture, after usual aqueous work-up and chromatographic purification, afforded 14.5 g (50%) of Li-lb. ' H-NMR (300 MHz, CDC13): □ 1.5-1.9 (m, 6H), 2.88 (t, 2H, J = 6 Hz), 2.94 (t, 2H, J = 6 Hz), 3.45-3.57 (m, 1H), 3.67-3.78 (m,lH), 3.85-4.05 (m, 2H), 3.90 (t, 2H, J = 6 Hz), 4.65 (s, 1H). Example 3 Synthesis of 2-{[2-(Trity10xy)ethyl]dithio}ethanol (LI-lc): 134 This compound was synthesized by a method described by O. Hernandez et aL, Tetrahedron Letters, 1981, 22, 1491-1494. Thus, 8.58 g (21.4 mmol) of 4-dimethylamino-N-triphenylmethylpyridinium ch10ride (A.V. Bhatia et aL Organic Synthesis, 1997, 75, 184-185) was added to a solution of SL-1 (3.0 g, 19.45 mmol) in DCM (90 mL) and stirred at RT for 24 h. The mixture, after usual aqueous work-up and chromatographic purification, afforded 2.86 g (37%) of LI-lc. ]H-NMR (300 MHz, CDCI3): 8 2.70 (t, 2H, J = 6.0 Hz), 2.88 (t, 2H, J = 6.0 Hz), 3.39 (t, 2H, J = 6.0 Hz), 3.80 (q, 2H, J = 6.0 Hz), 7.24-7.33 (m, 10H), 7.44-7.46 (m, 5H). MS (m/z): 396 [M]+. Example 4 Synthesis of ch10roacetic acid 2-(2-hydroxyethyldisulfanyl)ethyl ester (Ll-ld): To a solution of SL-1 (23 g, 150 mmol) in DCM (250 mL) at O °C were added TEA (10.12 g, 100 mmol) and ch10roacetyl ch10ride (11.3 g, 100 mmol) and stirred overnight at RT. The reaction mixture was concentrated and purified by column chromatography to afford 8.3 g (37%) of Ll-ld. 'H-NMR (300 MHz, CDCb): 8 2.88 (t, 2H, J = 5.7 Hz), 2.95 (t, 2H, J = 6.6 Hz), 3.89 (t, 2H, J - 5.7 Hz), 4.09 (s, 2H), 4.47 (t, 2H, J = 6.6 Hz). Example 5 Synthesis of 2-((2-hydroxyethyl)dithio)ethyl nitrate (LI-2b) and 2,2'-bis(ethyl nitrate)disulfide (LI-3b): These intermediates were synthesized in two steps as shown in Scheme 10. Step 1: Synthesis of 2-((2-bromoethyI)dithio)ethanol (LI-2a) and bis(2-bromoethyl)disulfide (LI-3a): These compounds can be synthesized via bromination of SL-1 by a known bromination method.(For a suitable bromination method, see Fruniss, B.S. et aL, Vogel's Text Book of Practical Organic Chemistry, 5th edition, Pearson Education, Singapore, 1989; pp 559-579). The fol10wing methods were exp10red: Method 1: To a solution of SL-1 (15g, 97.4 mmol) in DMF (50 mL) was added PPh3 (25.5g, 97.4 mmol) and cooled to O °C. Bromine (3.33 mL, 64.9 mmol) was added drop-wise and stirred at RT for 18 h. TLC of the mixture showed the mono-bromo derivative LI-2a as the major product with only trace amounts of dibromide LI-3a. The mixture was diluted with water and extracted with EtOAc. After usual aqueous work-up and chromatographic purification, 3.65 g (26%) of LI-2a were obtained. ]H-NMR (300 MHz, 135 CDCI3): δ 1.82 (s, 1H), 2.88 (t, 2H, J = 5.8 Hz), 3.08 (t, 2H, J = 7.90 H), 3.63 (t, 2H, J = 7.90 Hz), 3.90 (t,2H, J = 5.8 Hz). Method 2: To a solution of SL-1 (40 g, O.26 mol) in DCM (40O mL) at O °C was added a solution of PBr3 (24.62 mL, O.26 mol) in DCM (50 mL) and the mixture was stirred at RT for 15 h. TLC indicated formation of LI-3a as the major product with trace amounts of LI-2a. The reaction was quenched by the addition of water and extracted with DCM. After usual aqueous work-up and chromatographic purification, 33 g (45.3%) of LI-3a were obtained. 'H-NMR (500 MHz, CDCI3): 5 3.1-3.15 (m, 4H), 3.6O-3.66 (m, 4H). MS (Cl)+ m/z: 277.69 [M+H]+, 279.66. An alternative synthesis of LI-3a has been reported. (Sharma, M. etal., Bioorg. Med Chem. Lett., 2004,14, 5347-5350). Method 3: To a cold suspension of SL-1 (2O g, 129 mmol) in DCM (400 mL) was added CBr4 (42 g, 129 mmol) and stirred for 10 min. PPh3 (34 g, 129 mmol) was then added and stirred at RT for 14 h. The reaction mixture was concentrated and the residue purified by column chromatography to give 13.5 g (52.3%) of LI-2a and 13.0 g (36%) of LI-3a. These compounds were identical (by TLC, NMR and MS) to those obtained in Methods 1 and 2 described above. Synthesis of 2-((2-hydroxyethyl)dithio)ethyl nitrate (LI-2b): To a solution of LI-2a (2g, 9.21 mmol) in acetonitrile (15 mL) was added AgNO3 (1.88g, 11.05 mmol) portion-wise and the mixture was stirred at RT in the dark for 45 min. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue, after usual aqueous work-up and chromatographic purification gave 1.46 g (74%) crude LI-2b which was used for the next reaction without further purification. An analytical sample was obtained by chromatographic purification. 'H-NMR (300 MHz, CDC13): 5 2.89 (t, 2H, J = 6.0 Hz), 2.98 (t, 2H, J = 7.5 Hz), 3.90 (t, 2H, J - 6.0 Hz), 4.74 (t, 2H, J = 7.5 Hz); MS (EI)+ (m/z): 199 [M]+. Synthesis of 2,2'-bis(ethyl nitrate)disulfide (LI-3b): AgNO3 (8.O1 g, 47.12 mmol) was added portion-wise to a solution of LI-3a (6.0 g, 21.42 mmol) in acetonitrile (40 mL) at RT in the dark and stirred for 30 min. The mixture was filtered through celite and the filtrate was concentrated in vacuo at 35 °C to afford 4.6 g (88%) of LI-3b, which was used without further purification. An analytical sample was obtained by chromatographic 136 purification (3-15% EtOAc in petroleum ether). 'H-NMR (300 MHz, CDC13): 6 3.10 (t, 4H, J = 6.7 Hz), 4.71 (t, 4H, J = 6.7 Hz). MS (EI)+m/z: 244 [M]+. Example 6 Synthesis of tert-butyl 2-[(2-hydroxyethyl)dithio]ethylcarbamate (LI-2c): To a solution of cysteamine hydroch10ride (15 g, 132 mmol) in MeOH (130 mL) at O-5 °C was added TEA (37 mL, 264 mmol), fol10wed by a solution of SL-1 (20.4 g, 132 mmol) in DCM (50 mL) and stirred at RT for 6 h. The mixture, which contained the intermediate SL-2, was cooled and (Boc)2O (63.4 g, 290.4 mmol) was added and stirred overnight. MeOH was removed under vacuum. After usual aqueous work-up and chromatographic purification, LI-2c was obtained as a co10rless oil (14.6 g, 44%). The above linker intermediate can also be prepared by the fol10wing method: Step 1: TEA (37 ml, 264 mmol) and a solution of (Boc)2O (48 g, 220 mmol) in DCM (100 mL) were added to a suspension of cystamine dihydroch10ride (20 g, 88.8 mmol) in of DCM (300 mL) and stirred at RT for 15 h. The mixture was concentrated and the residue, after usual aqueous work-up and chromatographic purification, gave 30 g (96%) of tert-butyl 2-({2-[(tet-butoxycarbonyl)amino]ethyl}dithio)ethylcarbamate as a white solid. 'H-NMR (300 MHz, CDC13): 6 1.43 (s, 18H), 2.78 (t, 4H, J = 6.3Hz), 3.44 (q, 4H, J = 6.0 Hz), 5.00 (bs,lH). MS (m/z): 353.18 [M+H]+, 375.24 [M+Na]+. Step 2: A solution of 2-mercaptoethanol (1.44 g, 18.5 mmol) in DCM (10 mL) was added to a mixture of tert-butyl 2-({2-[(tert-butoxycarbonyl)amino]ethyl}dithio)ethyl carbamate (5.O g, 14.2 mmol) and TEA (3.87 ml, 27.7 mmol) in DCM (30 mL) and stirred overnight at RT. After usual aqueous work-up and chromatographic purification, 2.0 g (56%) of LI-2c was obtained. 'H-NMR (300MHZ, CDC13): 6 1.43 (s, 9H ), 2.79 (t, 2H, J = 6.5Hz ), 2.87 (t, 2H, J = 5.7Hz ), 3.48 (q, 2H, J = 6Hz ), 3.88 (t, 2H, J = 5.5 Hz), 4.8 (bs,lH). MS (m/z): 254 [M+H]4, 276.13 [M+Na]+. Removal of the Boc group of LI-2c was accomplished as described in Example 10 to afford the TFA salt, LI-2c.TFA. Obviously, the linker intermediates LI-2b and LI-2c can also be synthesized by fol10wing the method outlined in Scheme 24. 137 Example 7 Synthesis of 2-Boc-aminoethyl-2'-methansulfonyIoxyethyl disulfide (LI-2d): To an ice-cold solution of LI-2c (9 g, 35.52 mmol) in DCM (80 mL) and TEA (9.9 mL, 70.7064 mmol) was added methanesulfonyl ch10ride (4.2 mL, 53.28 mmol). The reaction mixture was stirred at O-5 °C for 45 min, then diluted with DCM. After usual aqueous work-up and chromatographic purification, 13.38 g of LI-2d were obtained, which was pure enough for further use. 'H-NMR (300 MHz, CDC13): δ 1.43 (s, 9H), 2.80 (t, 2H, J - 6.4 Hz), 2.98 (t, 2H, 5.7 Hz), 3.05 (s, 3H), 3.35-3.45 (m, 2H), 4.45 (t, 2H, J = 6.7 Hz), 4.78 (br s, 1H). Example 8 Synthesis of 2-Boc-aminoethyl-2'-bromoethyl disulfide (LI-2e): To a solution of LI-2d (13 g, 39.27 mmol) in acetone (100 mL) at RT was added LiBr (6.82 g, 78.54 mmol) and stirred under reflux for 1 h. The reaction mixture was concentrated and the residue, after usual aqueous work-up and chromatographic purification, afforded 8.8 g (78%) of LI-2e. 'H-NMR (300 MHz, CDCb): δ 1.44 (s, 9H), 2.80 (t, 2H, J = 6.32 Hz), 3.06 (t, 2H, J = 6.73 Hz), 3.44 (q, 2H), 3.61 (t, 2H, J = 7.62 Hz), 4.87 (br s, 1H). MS (EI)+ m/z: 317 [M+H]4. Example 9 Synthesis of 2-((2-Boc-aminoethyl)dithio)ethyl nitrate (LI-21): To a solution of LI-2e (8 g, 25.3 mmol) in acetonitrile (80 mL) was added AgNO3 (5.16 g, 30.36 mmol) portion-wise and stirred at RT for 1 h in the dark. The mixture was filtered through celite and the filtrate was concentrated. The residue obtained was purified by column chromatography to afford 6.34 g (84%) of LI-2f. 'H-NMR (300 MHz, CDC13): 6 1.44 (s, 9H), 2.80 (t, 2H, J = 6.32 Hz), 3.06 (t, 2H, J = 6.73 Hz), 3.44 (q, 2H), 4.7O (t, 2H, J = 7.62 Hz), 4.87 (br s, 1H). MS ( El)+ m/z: 299 [M+H]+ The above linker intermediate was also prepared by the fol10wing method: TEA (3.56 g, 35.2 mmol) was added to a solution of cysteamine hydroch10ride (2g, 17.60 mmol) and LI-3b (4.29g, l7.6mmol) in methanol (25mL) at 0 °C and stirred at RT for 4 h. To the mixture, which contained the intermediate free amine (LI-5), a solution of (Boc)2O (7.68 g, 35.2 mmol) and TEA (3.56 g, 35.2 mmol) in MeOH (10mL) was added and the mixture was stirred overnight. The reaction mixture was filtered through celite 138 and evaporated to dryness. The residue was purified by column chromatography to afford 0.380g(7%)ofLI-2f. Example 10 Synthesis of 2-((2-Aminoethyl)dithio)ethyl nitrate.TFA salt (LI-5.TFA): To an ice- cold solution of LI-2f (2 g, 6.7 mmol) in DCM (2O mL) was added TFA (5 mL) and stirred at room temperature for 1 h. The mixture was concentrated, the residue was triturated with ether and concentrated to remove traces of TFA and finally dried to afford LI-5.TFA, which was used as such in further reactions. The above linker intermediate LI-5.TFA was also synthesized as described be10w: TEA (3.56 g, 35.2mmol) was added drop-wise to a solution of cysteamine hydroch10ride (2g, 17.60mmol) and LI-3b (4.29g, 17.6mmol) in MeOH (25mL) at O °C and stirred at RT for 4 h. The mixture was cooled to O °C and a solution of (Boc)2O (7.68 g, 35.2mmol) in MeOH (10 mL) was added, fol10wed by TEA (3.56 g, 35.2mmol), and stirred overnight at RT. The reaction mixture was filtered through celite and the filtrate concentrated. The residue was purified by column chromatography to afford 0.38 g (7.25%) of LI-2f, which was identical (TLC and 'H-NMR) to that obtained in Example 9. Removal of the Boc group from LI-2f to give LI-5.TFA was accomplished as described in Example 10. Example 11 Synthesis of methyl [(2-hvdroxyethyl)dithio]acetate [L3I2a]: Methyl mercaptoacetate (10.32 g, 97.4 mmol) was added to a solution of SL-1 (10.O g, 64.93 mmol) in DCM (150 mL) at RT, fol10wed by TEA (18 mL, 129 mmol) and the mixture was stirred overnight at RT. After usual aqueous work-up and chromatographic purification, 2.7 g (22.9 %) of L3I2a were obtained. 'H-NMR (300 MHz, CDC13): 5 2.95 (t, 2H3 J = 2.5 Hz), 3.49 (s, 2H), 3.76 (s, 3H), 3.86 (q, 2H, J - 5.64). MS (m/z): 182 [M+H]+. Example 12 Synthesis of prodrug I-C1-PD10; This prodrug was synthesized as described in Scheme 11, Method B. Thus, TEA (O.73 mL, 10 mmol) was added to a suspension of cetirizine dihydroch10rtde (2.0 g, 4.68 mmol) in DCM (50 mL), fol10wed by a solution of SL-1 (O.72 g, 4.67 mmol), DCC (1.13 g, 5.47 mmol) and DMAP (O.112g, 1 mmol) and stirred at RT for 15 h. The mixture was concentrated and the residue, after usual aqueous work- 139 up and chromatographic purification, gave 0.44 g (19%) of I-C1-PD10. lH-NMR (300 MHz, CDCl3): □ 2.50 (bs, 4H), 2.80 (bs, 6H), 2.87 (t, 2H, J = 6.09 Hz), 2.94 (t, 2H, J = 7.32 Hz), 3.75 (m, 2H), 3.86 (t, 2H, J = 6.12 Hz), 4.13 (s, 2H), 4.24 (s, JH), 4.40 (t, 2H, J = 6.09 Hz) and 7.22-7.35 (m, 9H). MS (m/z): 527 [M+H]+. Example 13 Synthesis of prodrug I-C1-PD6: Step 1: To a suspension of aspirin (3 g, 16.65 mmol) in benzene (25 mL) and DMF (2 drops) at O-5 °C was added oxalyl ch10ride (1.7 mL, 19.98 mmol) in benzene (5 mL). The reaction mixture was refluxed at 85 °C for 2 h, cooled to RTe and concentrated to give a yel10w oil. Step 2: The yel10w oil was dissolved in benzene (30 mL), silver cyanate (2.99 g, 19.98 mmol) was added and the mixture was refluxed for 1h in the dark. Step 3: The reaction mixture was cooled to RT, and a solution of SL-1 (2.56 g, 16.65 mmol) in benzene (5 mL). The reaction mixture was stirred for 1h, filtered through celite, concentrated and purified by column chromatography to afford 2.24 g (54%) of I-Cl- PD6. lH NMR (CDCl3, 300 MHz): δ 2.12 (s, 3H), 2.83-2.91 (m, 4H), 3.84 (t, J = 5.9 Hz, 2H), 4.27 (t, J = 5.16 Hz, 2H), 6.20 (br s, IH), 7.O6 (d, J = 8.21 Hz, IH), 7.19 (t, J = 7.55 Hz, IH), 7.59 (t, J = 7.24 Hz, IH), 7.97 (d, J = 6.82 Hz, IH). MS: m/z 36O.O6 [M+H]+, 377.05 [M+NH4]+, 382.01 [M+Na], 357.96 [M-H]+ Example 14 Synthesis of prodrug I-Cl-PD11:To a solution of SL-1 (7g, 45.45 mmol) and valproic acid (7.85 g, 54.5 mmol) in DCM (80 mL) was added DCC (11.26 g, 54.5 mmol), fol10wed by DMAP (6.65 g, 54.5 mmol), and the resulting suspension was stirred at RT for 18 h. After usual aqueous work-up and chromatographic purification, 2.82 g (22 %) of I-C1-PD11 were obtained as a co10rless oil. ]H NMR (CDCI3, 300 MHz): 6 O.86-0.93 (m, 6H), 1.22-1.29 (m, 8H), 1.32-1.59 (m,4H), 2.37 (m,1H), 3.89 (t, 2H, J = 5.7 Hz), 4.35(t, 2H, J = 6.5 Hz). Example 15 Synthesis of prodrug I-C1-PD13: To a solution of valpromide (5 g, 34.9 mmol) in DCE (50 mL) was added oxalyl ch10ride (3.7 mL, 41.88 mmol) at 0 °C and refluxed for 16 h. The mixture was added to a solution of SL-1 (10.76 g, 69.8 mmol) in DCE (80 mL) and stirred overnight at RT. After usual aqueous work-up and chromatographic purification, 140 5.O1 g (44%) of I-C1-PD13 were obtained as a co10rless oil. 'H NMR (CDC13, 300 MHz): δ O.89 (t, 6H, J = 7.21 Hz), 1.23-1.66 (m, 9H), 2.90 (t, 2H, 5.82 Hz), 2.97 (t, 2H, J= 6.46Hz), 3.90 (t, 2H, J= 5.82Hz), 4.44 (t, 2H, J= 6.48 Hz), 7. 61 (br s, 1H) Example 16 Synthesis of prodrug I-C1-PD14: To a cold solution of diphosgene (O.9 mL, 7.14 mmol) in DCM (5 mL) was added a solution of I-C1-PD11 (I g, 3.57 mmol) and DIPEA (1.9 mL, 10.71 mmol) in DCM (5 mL). The reaction mixture was stirred at RT for 30 min. DCM and excess phosgene were removed under vacuum and the resulting solid was dissolved in DCM (5 mL). To it was added a suspension of methanesulfonamide (0.41 g, 4.284 mmol) and DIPEA (1.9 mL, 10.71 mmol) in DCM (5 mL) at 0-5 °C and the mixture was stirred overnight at RT. After usual aqueous work-up and chromatographic purification, 1.1 g (77%) of I-C1-PD14 were obtained as a white solid. 'H NMR (CDCl3, 300 MHz): 5 O.89 (t, 6H, J = 7.22 Hz), 1.27-1.63 (m, 8H), 2.34-2.43 (m, 1H), 2.90 (t, 2H, J = 7.O Hz), 2.96 (t, 2H, J - 6.13 Hz), 3.30 (s, 3H), 4.36 (t, 2H, J - 6.98 Hz), 4.45 (t, 2H, J = 6.14 Hz). MS: (ES+) m/z 402 [M+H]+, 419 [M+NH4]+, 424 [M+Na]+, 440 [M+K]+; (ES')401 [M-H]. Example 17 Synthesis of prodrug I-A1-PD1: This prodrug was synthesized as shown in Scheme 14, Method B. Thus, to a solution of am10dipine (18.75 g, 45.86 mmol) in DCM (100 mL) at O °C was added triphosgene (4.62 g, 15.59 mmol) fol10wed by TEA (7.71 g, 76.35 mmol) in DCM (10 mL) and stirred at RT for 3 h. To this was added a solution of Li-la (9.0 g, 48.86 mmol) and TEA (4.63 g, 45.86 mmol) in DCM (10 mL) at 0 °C and stirred at RT for 3 d. The mixture was concentrated and the residue purified by column chromatography to yield 23 g (79.5%) of I-A1-PD1. 'H-NMR (300 MHz, CDC13): 6 1.16 (t, 3H, J = 7.5 Hz), 2.05 (s, 3H), 2.34 (s, 3H), 2.86-2.94 (m, 4H), 3.43-3.45 (m, 2H), 3.59-3.62 (m, 5H), 4.0-4.35 (m, 4H), 4.30-4.35 (m, 4H), 4.69 (q, 2H, J = 15 Hz), 5.20 (bs, 1H), 5.38 (s, 1H), 7.01-7.34 (m,4H). MS (m/z): 631 [M+H]+, 653 [M+Naf. Example 18 Synthesis of prodrug I-A1-PD2: To a solution of I-A1-PD1 (23.0 g, 36.45 mmol) in MeOH (250 mL) at 0 °C was added a solution of K2CO3 (7.54 g, 54.67 mmol) in water 141 (55 mL) and stirred for 10 min. The mixture was concentrated and purified by column chromatography to afford 18 g (83.8%) of the intermediate I-A1-PD2. 'H-NMR (300 MHz, CDCI3): 5 1.16 (t, 3H, J = 6 Hz), 2.35 (s, 3H), 2.84-2.88 (t, 2H, J = 6 Hz), 2.90-2.94 (t, 2H, J = 6 Hz), 3.44 (bs, 2H), 3.59-3.61 (bs, 5H), 3.84-3.91 (m, 2H), 4.O-4.O3 (q, 2H, J = 3.11 Hz), 4.33 (bs, 2H), 4.69 (q, 2H, J = 15 Hz), 5.28 (bs, 1H), 5.37 (s, 1H), 7.12-7.36 (m, 4H). MS (ES4): m/z 589 [M+], 611 [M+Na]+. Example 19 Synthesis of prodrug I-Al-PD3:To a suspension of lamotrigine (13.09 g, 50.7062 mmol) in toluene (100 mL) at 110 °C was added a solution of Ll-1xy (synthesized from Li-la and CDI, as described in Scheme 10) (16.27 g, 56.12 mmol) in THF (50 mL) and stirred at 110 °C overnight. The reaction mixture was purified by column chromatography to give 6.0 g (24%) of I-A1-PD3 as a white solid. 'H NMR (CD30D, 300 MHz) 6 2.04, (s, 3H), 2.96-3.02 (m, 4H), 4.30-4.35 (m, 2H), 4.45 (t, 2H), 7.38-7.45 (m, 2H), 7.67-7.69 (m, 1H). MS: (ES*) m/z 477.9 (M+H)+, 499.9 (M+Na)+. Example 2O Synthesis of prodrug I-Al-PD4o a solution of I-A1-PD3 (2 g, 4.18 mmol) in MeOH (15 mL) and THF (5mL) at 0°C was added a solution of K2CO3 (O.886 g, 6.276 mmol) in water (5 mL) and stirred at 0°C for 3 h. After usual aqueous work-up and chromatographic purification, 1.1 g (6O%) of I-A1-PD4 were obtained as a white solid. lH NMR (DMSO d6, 300 MHz): 8 2.75-2.82 (m, 2H), 2.96-3.0 (m, 2H), 3.0 (s, 1H), 3.6 (t, 2H, J = 6.3Hz), 4.30 (t, 2H, J = 6.6 Hz) 7.38-7.49 (m, 2H), 7.72-7.75 (m, 1H). MS: (ES +) m/z 436 (M+H)+, 457 (M +Na)+. Example 21 Syntheis of prodrug I-A1-PD5: To a solution of diphosgene (O.99 mL, 8.24 mmol) in DCM (3 mL) at O °C was added a solution of L3I2a (0.5 g, 2.74 mmol) and Htinig's base (2.39 mL, 13.73 mmol) in DCM (3 mL). The mixture was stirred at O °C for 30 min and concentrated to yield the intermediate L3I3a as a light-yel10w semi-solid. A solution of a mixture of gabapentin ethyl ester hydroch10ride (O.77g, 3.29 mmol) and Htinig's base (1.7 mL, 9.79 mmol) in DCM (6 mL) was added to the intermediate L3I3a at RT and stirred for 15 h. After usual aqueous work-up and chromatographic purification, 0.34 g (30 %) of I-A1-PD5 were obtained as a yel10w oil. ]H NMR (CDCI3, 300 MHz): 8 1.26 142 (t, 3H, J = 6 Hz), 1.22-1.51 (m, 10 H), 2.26 (s, 2H), 2.96 (t, 2H, J= 6 Hz), 3.18 (d, 2H, J= 6 Hz), 3.49 (s, 2H), 3.82 (s, 3H), 4.O9 (q, 2H, J = 6 Hz), 4.29 (t, 2H, J = 6 Hz), 5.39 (bs 1H). MS:(ES+)m/z408(M+H)+)430(M+Na)+;(ES") m/z 406 (M-H)Example 22 Synthesis of prodrug I-A1-PD6: To a solution of I-A1-PD8 (0.706 g, 2.63 mmol) in DCM (3 mL) at RT was added CDI (O.46 g, 2.89 mmol) and stirred for 15 h. A suspension of serine methyl ester hydroch10ride (0.61 g, 3.95 mmol) in DCM (4 mL) and TEA (1.1 mL, 7.90 mmol) was added and stirring continued for 15 h. After usual aqueous work-up and chromatographic purification, 0.706g (51%) of I-A1-PD6 were obtained as a co10rless oil. 'HNMR(CDCl3s300MHz):5 1.25 (t, 3H, J = 7.1 Hz), 1.35-1.51 (m, 10H),2.28(s, 2H), 2.91-2.98 (m, 4H), 3.16 (d, 2H, J = 9Hz), 3.78 (s, 3H), 3.94-4.38 (m, 9H), 5.5 (bs, 1H), 6.0 (bs, 1H). MS: (ES)+: m/z 525 (M+H)+, 547 (M+Na)+. (ES)': m/z 523 (M-H)+. Example 23 Synthesis of prodrug I-A1-PD7: To a solution of I-A1-PD8 (86 mg, O.22 mmol) in DCM (9 mL) at RT was added CDI (40 mg, O.24 mmol) and stirred for 15 h, after which a solution of dimethyl glutamate (80 mg3 O.45 mmol) and TEA (O.O6 mL, O.45 mmol) was added and stirred for 2 d. After usual aqueous work-up and chromatographic purification, 97 mg (74 %) of I-A1-PD7 were obtained as a co10urless oil. 'H NMR (CDC13J 300 MHz): 5 1.25 (t, 3H, J=7.13 Hz), 1.36-2.5 (m, 16H), 2.93(t, 4H, J = 6.46 Hz), 3.19 (d, 2H, J = 6.67), 3.67 (s, 3H), 3.74 (s, 3H), 4.12 (q, 2H, J = 7.13 Hz), 4.25-4.44 (m, 5H), 5.4 (bs, 1H), 5.65 (bs, 1H). MS: (ES+) m/z 581 (M+H)+, 6O3 (M+Na)+; (ES') m/z571(M-H)~. Example 24 Synthesis of prodrug I-A1-PD9: To a suspension of gabapentin (10 g, 58.4 mmol) in THF (100 mL) at 0°C was added IN NaOH (70 mL), fol10wed by (Boc)2O. The mixture was stirred at RT for 15 h. After washing with diethyl ether (100 mL x 2), the aqueous layer was acidified with solid KHSO4 and extracted with EtOAc (100 mL x 2). Organic extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated to afford 10.41g (68 %) of boc-protected gabapentin as a white solid. A mixture of boc-protected gabapentin (5.0 g, 18.45 mmol) and CDI (3.59 g, 22.14 mmol) in DCM (75 mL) was stirred for 15 h. The mixture was concentrated and 143 dissolved in acetonitrile (50 mL), fol10wed by the addition of 30 % aqueous solution of ammonia (50 mL) and stirred for 1.5 h at RT. After usual aqueous work-up, 4.5 g (90 %) of boc-protected gabapentin-amide were obtained as a white solid. To a solution of boc-protected gabapentin-amide (2.59 g, 9.61 mmol) in DCM (12 mL) at O °C was added solution of TFA (4mL) in DCM (4 mL) and stirred for 2.5 h at RT. The mixture was concentrated and dissolved in DCM (2O mL). This was treated successively with Hunig's base (6.7 mL, 38.46 mmol) and Li-la (1.45g, 7.39 mmol), and stirred at RT for 3 h. After usual aqueous work-up and chromatographic purification, 1.19 g (41 %) of I-A1-PD9 were obtained as a yel10w oil. 1H NMR (CDCI3, 300 MHz): 6 1.28-1.48 (m, 10H), 2.06 (s, 3H), 2.15 (s, 2H), 2.91 (t, 4H, J = 6.0 Hz), 3.23 (d, 2H, J = 6.0 Hz), 4.28-4.38(m, 4H), 5.7(bs, 1H). MS: (ES)+ m/z 393(M+H)+; (ES)' m/z 392(M- H) Example 25 Synthesis of prodrug I-A1-PD10 : A mixture of I-A1-PD8 (l.0g, 2.63 mmol) and CDI (O.469 g, 2.89 mmol) in DMF (3 mL) was stirred for 12 h, after which N,N dimethylethylenediamine (0.56mL, 5.26 mmol) and DMAP (0.32 g, 2.63 mmol) was added. The mixture was stirred for 4 h. After usual aqueous work-up and chromatographic purification, 0.763 g (59 %) of were obtained as a yel10w oil. '.H NMR (CDCl3s 300 MHz): 5 1.25 (t, 3H, J = 6.0 Hz), 1.28-1.53 (m, 10H), 2.24 (s, 6H), 2.29 (s, 2H), 2.42 (t, 2H, J = 6.0 Hz), 2.92 (t, 4H, J = 6.0 Hz), 3.20(d, 2H, J - 6.0 Hz), 3.26 (q, 4H, J = 6.0 Hz), 4.13 (q, 2H, J - 7.O Hz), 4.31 (t, 4H, J = 6.0Hz), 7.26 (bs, -1H). MS: (ES)+ m/z 494 (M+H)+, 516 (M+Na)+; (ES)" m/z 492 (M-H)". Example 26 Synthesis of prodrug I-A1-PD11: A mixture of Li-la (2.0 g, 10.2O mmol) and CDI (1.98 g, 12.24 mmol) in DCM (12 mL) was stirred for 2 h and concentrated. The residue was dissolved in acetonitrile, and a suspension of gabapentin (2.62 g, 15.30 mmol) in saturated NaHCO3 (15 mL) was added. The mixture was stirred at RT for 15 h. Acetonitrile was removed by distillation and the basic aqueous portion was washed with diethyl ether (100 mL x 2). The aqueous layer was acidified using 2N HCI and extracted in EtOAc (6O mL x 3). The organic layer was concentrated and the residue was purified by chromatographic purification, 1.76 g (43 %) of I-A1-PD11 were obtained as a 144 co10rless oil. 1H NMR (CDC13, 300 MHz): δ 1.27-1.68 (m, 10H), 2.07 (s, 3H); 2.31 (s, 2H), 2.92 (t, 4H, J = 6.0 Hz), 3.22 (d, 2H, J = 9.O Hz), 4.31-4.35 (m, 4H), 5.43 (bs, IH). MS:(ES)" m/z 392 (M-H)'. Example 27 Synthesis of prodrug I-A1-PD13: This prodrug was synthesized as shown in Scheme 12, Method B. Thus, to a solution of diphosgene (7.02 mL, 58.18 mmol) in DCM (20 mL) at 0 °C was added a solution of Li-la (5.71 g, 29.09 mmol) and Hunig's base (25.3 mL, 145.45 mmol) in DCM (30 mL) and stirred at RT for 40 min. The mixture was concentrated and a mixture of gabapentin ethyl ester hydroch10ride (7.546 g, 32 mmol) and Hunig's base (11.15 mL, 64 mmol) in DCM (50 mL) was added and stirred overnight. Reaction mixture was concentrated and, after usual aqueous work-up and column chromatography, 8.42 g (67 %) of I-A1-PD13 were obtained. ]H NMR (CDCI3, 300 MHz): 8 1.22 (t, 3H, J = 7.3 Hz), 1.27-1.68 (m, 10H), 2.06 (s, 3H), 2.27 (s, 2H), 2.91 (t, 4H, J - 6.6 Hz), 3.19 (d, 2H, J = 6.7 Hz), 4.O8-4.15 (q, 2H, J = 7.1 Hz), 4.27^1.34 (q, 4H, J = 6.4 Hz), 5.4 (bs, IH). MS: m/z422 [M+H]+, 444 [M+Na]+. Example 28 Synthesis of prodrug I-A1-PD8: To an ice-cold solution of I-A1-PD13 (8.O g, 18.98 mmol) in MeOH (30 mL) was added a solution of K2CO3 (5.24 g, 37.96 mmol) in water (38 mL). After 15 min, the mixture was concentrated. After usual aqueous work-up, 5.O g (69 %) of I-A1-PD8 were obtained. 'H NMR (CDC13, 300 MHz): 5 1.25 (t, 3H, J = 7.11 Hz), 1.30-1.71 (m, 10H), 2.87-2.94 (m, 4H), 2.27 (s, 2H), 3.18 (d, 2H, J = 6.6 Hz), 3.87 (t, 2H, J = 5.7 Hz), 4.O9-4.16 (q, 2H, J = 7.12 Hz), 4.31 (t, 2H, J = 6.51 Hz), 5.44 (bs, IH). MS: m/z 380 [M+H]+, 402 [M+Naf. Example 2 9 Synthesis of prodrug I-A1-PD12: To a solution of diphosgene (1.91 mL, 15.81 mmol) in DCM (2O mL) at O °C was added a solution of I-A1-PO8 (4 g, 10.54 mmol) and Hunig's base (5.5 mL, 31.62 mmol) in DCM (30 mL). The mixture was stirred at RT for 40 min, cooled to O-5 °C, and dry ammonia gas was passed through it for 30 min. Reaction mixture was concentrated and, after usual aqueous work-up, 5.3 g (91 %) of I-A1-PD12 were obtained. ]H NMR (CDCI3, 300 MHz): 8 1.23 (t, 3H, J - 7.1 Hz), 1.27-1.79 (m, 145 10H), 2.28 (s, 2H), 2.91-3.03 (m, 4H), 3.19 (d, 2H, J = 6.7 Hz), 4.12 (q, 2H, J = 7.1 Hz), 4.31 (t, 4H, J = 6.4 Hz), 5.4 (t, 1H, J = 6.0 Hz). MS: m/z 423 [M+H]+, 446 [M+Na]+. Example 30 Synthesis of prodrug I-A1-PD14: Ethyl ch10roformate (O.86 g, 7.9 mmol) was added to a solution of 3-carbamoylmethyl-5-methylhexanoic acid (M. S. Hoekstra et al., Org. Proc. Res. Dev. 1991, 7, 26-38) (0.706 g, 5.3 mmol) in THF (6 mL) at -10 °C, fol10wed by TEA (2.4 mL, 17.O mmol) and the mixture was stirred at -10 °C for 30 min. A solution of NaN3 (1.73 g, 26.6 mmol) in water (10 mL) was added and stirred for 2h at -10 °C. The reaction mixture was brought to RT and extracted with EtOAc (3 x 25 mL), washed with water (2 x 25 mL), dried over Na2SO4 and concentrated. Toluene (20 mL) was added to the residue and refluxed for 6 h. After cooling to RT, a solution of and SL-1 (825 mg, 5.3 mmol) in DCM (10 mL) was added and stirred at RT for 14 h. After usual aqueous work-up and chromatographic purification, 318 mg (17 %) of I-A1-PD14 were obtained as a co10rless oil. *H NMR (300 MHz, CDC13): 5 O.89-O.95 (m, 6H), 1.25-1.29 (m, 2H), 1.62-1.71 (m, 1H), 2.04-2.1 (m, 1 H), 2.38 (d, J = 5.2 Hz, 2H), 2.87-2.95 (m, 4H), 3.05-3.36 (m, 2H), 3.88 (t, J = 5.7 Hz, 2H), 4.34 (t, J = 6.2 Hz, 2H), 5.O6 (br s, 1H). MS: m/z 338 [M]+. Example 31 Synthesis of prodrug I-Al-PD15Ba: To a solution of I-A1-PD4 (0.350 g, O.802 mmol) in DMF (3 mL) at RT was added CD [0.195g, 1.204 mmol) and stirred at RT for 3 h. This mixture was added to a suspension of methanesulphonamide (0.304 g, 3.2 mmol) in DMF (4 mL) and NaH (O.153 g 3.2 mmol) at 0 °C and stirred at RT for 4 h. The reaction was quenched with ice and, after usual aqueous work-up and chromatographic purification, 0.12 g (26%) of I-Al-PD15Ba were obtained as a white solid. 'H NMR (CDCI3+ CD3OD, 300MHz): 5 2.83- 2.90 (m, 4H), 3.10 (s, 3H), 4.26-4.36 (m, 4H), 7.19-7.28 (m, 2H), 7.48-7.51 (m, 1H). MS: (ES +) m/e 556.96 (M+H)+, 578.92 (M +Na)+. Example 32 Synthesis of prodrug I-A1-PD16: CDI (4 g, 24.7 mmol) was added to a solution of LI-2c (4 g, 15.8 mmol) in THF (30 mL) and stirred at RT for 2 h. Then, a solution of gabapentin (4 g, 23.4 mmol) in 2O % NaHCO3 solution (10 mL) was added and stirred overnight at RT. The reaction mixture was neutralized with 0.5N HC1 (pH ~ 4), extracted 146 with EtOAc (4 x 40 mL), dried over Na2SO4, concentrated and purified by column chromatography to afford 4.7 g (66 %) of I-S12-PD2 as a co10rless oil. 1H NMR (300 MHz, CDC13): 5 1.45-1.49 (br s, 19H), 2.35 (s, 2H), 2.80-2.97 (m, 4H), 3.24 (d, J = 5.7 Hz, 2H), 3.46 (m, 2H) 4.33 (t, J = 5.7 Hz, 2H), 5.0 (br s, 1H), 5.71 (br s, 1H). MS: (m/z) [ES]" 449.1 [M-H]+; [ES]+451.2 [M+H]+. EtOAc saturated with HCI gas (5mL) was added to I-S12-PD2 (0.55 g, 1.22 mmol) and stirred at RT for 10 h. Solvent was removed under reduced pressure and purified by preparative HPLC to give 425 mg (90 %) of I-A1-PD16 as a co10rless liquid. 1H NMR (300 MHz, CD30D): 5 1.52 (br s, 10H), 2.4 (s, 2H), 2.98-3.09 (m, 4H), 3.27-3.34 (m, 2H), 3.61 (s, 2H), 4.5 (t, J = 6.0 Hz, 2H). MS: [ES] m/z 350.706 [M+H]+. Example 33 Synthesis of prodrug I-A2-PD1: To a solution of levetiracetam (0.706 g, 5.87 mmol) in DCE (20 mL) and DCM (4 mL) was added oxalyl ch10ride (0.61 mL, 7.05 mmol), and heated at 70 °C for 8h. Reaction mixture was cooled and added to a solution of SL-1 (1.81 g, 11.75 mmol) in DCM (15 mL) and stirred at RT overnight. After chromatographic purification, 1.13 g (41%) of I-A2-PD1 were obtained. 'H NMR (CDCI3, 300 MHz): 8 (ppm): O.87 (t, J = 7.3 Hz, 3H), 1.84-2.04 (m, 4H,), 2.41 (t, J = 6.9 Hz, 2H,), 2.69 (bs, 1H), 2.87-2.95 (m, 4H), 3.02-3.11 (m, 1H), 3.65-3.75 (m, 1H), 3.85-3.95 (m,2H), 4.O6-4.12 (m, 1H), 4.34-4.41 (m, 2H), 8.69 (bs, 1H).MS: (ES+): m/z 350.706 [M+H]+; 372.9 [M+Na]+. Example 34 Synthesis of prodrug I-A3-PD1: To a solution of I-S13-PD1 (which was synthesized as described in Example 37, Step 2) (215 mg, O.292 mmol) and triisopropylsilane (6O DL) in 0.75 mL of DCM was added 20 % TFA in DCM (0.5 mL) and stirred at RT for 90 min. The mixture was concentrated and the residue purified by column chromatography to give 65 mg (46%) of I-A3-PD1. 'H-NMR (300 MHz, CDCI3): 8 2.51 (s, 3H), 2.85-2.92 (m, 4H), 3.87 (t, 2H, J = 4.5 Hz), 4.37 (t, 2H, J = 6.0 Hz), 7.25-7.43 (m, 7H), 8.01 (d, 2H, J = 3.0 Hz). MS (m/z): 493 [M-H]", 517 [M+Na]+. Example 35 Synthesis of prodrugs I-A3-PD3a and I-A3-PD3b: Step 1: DSC (210 mg, O.824 mmol) and TEA (O.230 mL, 1.64 mmol) were added to a solution of methyl [(2- 147 hydroxyethyl)dithio]acetate (100mg, 0.549 mmol) in acetonitrile (1 mL) at 0 °C and stirred at RT for 3h. The mixture was concentrated and the residue dissolved DCM. Usual aqueous work-up and chromatographic purification gave the crude intermediate. Step 2: TEA (24mg, 0.236 mmol) and DMAP (13 mg) were added to a mixture of valdecoxib (62mg, 0.195 mmol) and the product obtained from step 1 above in THF (1 mL) and stirred at RT for 3 d. The mixture was concentrated and the residue dissolved in EtOAc. After usual aqueous work-up and chromatographic purification, 53 mg (52%) of I-A3-PD3a obtained. !H- NMR (300 MHz, CDC13): 5 2.51 (s, 3H), 2.97 (t, 2H, J = 6.0 Hz), 3.48 (s, 2H), 3.76 (s, 3H), 4.37 (t, 2H, J = 6.0 Hz), 7.33-7.40 (m, 7H), 8.O3-8.12 (m, 2H).MS(m/z):521 [M-H] Step 3: The above material was converted to the corresponding mono-, and/or di-sodium salt forms I-A3-PD3b by using standard methods. Thus, to a cold solution of the above compound (150 mg, 0.287 mmol) in THF (1 mL) was added 1M LiOH solution (28 mg in ImL water) and stirred overnight at RT. The mixture was concentrated, the residue diluted with water, acidified with IN HC1 (~3 ml, pH -3) and extracted with EtOAc. After usual aqueous work-up and chromatographic purification, 20 mg (13%) of product were obtained. 'H- NMR (300 MHz, CDCb): 5 2.49 (s, 3H), 2.70-2.89 (m, 4H), 4.23- 4.33 (m, 2H), 7.28-7.38 (m, 7H), 8.01-8.O3 (m, 2H). Example 36 Synthesis of prodrug I-A3-PD4: This prodrug was synthesized as described in Scheme 13, Method B. Step I: Synthesis of intermediate LI-8: CDI (1.65 g, 10.19 mmol) was added to a solution of LMa (2.0 g, 10.19 mmol) in DMF (10 mL) and stirred at RT for 3 h. N,N-Dimethylethylenediamine (1.2 mL, 11.12 mmol) was added and stirred for 2 h. The mixture was concentrated and the residue taken up in EtOAc. After usual aqueous work-up and chromatographic purification, 1.3 g (41%) LI-8 were obtained. 'H-NMR (300 MHz, CDCI3): 5 2.07 (s, 3H), 2.31 (bs, 6H), 2.51 (t, 2H, J = 6.0 Hz), 2.91 (t, 4H, J = 6.0 Hz), 3.31 (q, 2H, J = 6.0 Hz), 4.28-4.34 (m, 4H), 5.52 (bs, lH).MS(m/z):333[M+Na]+. Step 2: Synthesis of intermediate LI-9: To a solution of LI-8 (1.3 g, 4.18 mmol) in MeOH (7 mL) was added a 1.25M solution of K2CO3 (5 mL) and stirred at RT for 1h. 148 The mixture was concentrated and the residue was taken up in DCM. After usual aqueous work-up, 0.7062 g (91 %) of product were obtained. 'H-NMR (300 MHz, CDCI3): 5 2.29 (s, 6H), 2.54 (t, 2H, J = 6.0 Hz), 2.86-2.99 (m, 4H), 3.33 (q, 2H, J = 5.0 Hz), 3.86 (t, 2H, J = 6.0 Hz), 4.31 (t, 2H, J = 6.0 Hz), 5.71 (bs, 1H). MS (m/z): 269 [M+H]+. This product was used as such in the next step. Step 3: Synthesis of intermediate LI-10: A solution of LI-9 (0.7062 g, 3.80 mmol) in acetonitrile (10 mL) was added to a cold solution of DSC (1.46 g, 5.7O mmol) in acetonitrile (50 mL) fol10wed by TEA (1.58 ml, 11.40 mmol), and stirred overnight at RT. The mixture was concentrated and the residue was taken up in DCM. After usual aqueous work-up, 1.33 g (85%) of LI-10 were obtained. Step 4: Synthesis of I-A3-PD4: TEA (O.194 mL, 1.39 mmol) and DMAP (73 mg, O.6 mmol) were added to a solution of LI-10 (1.33 g, 3.24 mmol) and valdecoxib (364 mg, 1.16 mmol) in THF (6 mL) and stirred at RT for 5 d. The mixture was concentrated and the residue was taken up in DCM. After usual aqueous work-up and chromatographic purification, 177 mg (12 %) of LI-10 were obtained. *H-NMR (300 MHz, CDCI3): 6 2.46 (s, 3H), 2.85-2.95 (m, 10H), 3.28 (t, 2H, J = 6.0 Hz), 3.65 (q, 2H, J = 3.0 Hz), 4.22- 4.28 (m, 4H), 7.22-7.41 (m, 7H), 7.94 (d, 2H J = 9.O Hz). MS (m/z): 6O9 [M+H]+. This product was converted to water-soluble hydroch10ride salt form using standard methods. Example 37 Synthesis of prodrug I-A3-PD5: This prodrug was synthesized as shown in Scheme 13, Method B. 149 Step 1: Synthesis of prodrug intermediate Ll-lxy: A solution of LI-lc (0.706 g, 2.52 mmol) in acetonitrile (10 mL) was added to a solution of DSC (O.96 g, 3.78 mmol) in acetonitrile (2O mL) and stirred for 10 min. After cooling to O °C, TEA (1 ml, 7.57 mmol) was added and stirred at RT for 3.5 h. The solution was concentrated and the residue was taken up in DCM. After usual aqueous work-up, the crude product obtained was used as such in the next step. Step 2: Synthesis of prodrug intermediate I-S13-PD1: A mixture of valdecoxib (280 mg, O.892 mmol), DMAP (56 mg, 0.5 mmol) and TEA (150 DL, 0.7066 mmol) in THF (5 mL) was stirred at RT for 4.5 d. The mixture was concentrated and the residue dissolved in EtOAc. After usual aqueous work-up and chromatographic purification, 354 mg (54 %) of I-S13-PD1 were obtained. !H-NMR (300 MHz, CDC13): 5 2.47 (s, 3H), 3.32-3.41 (m, 4H), 4.28 (t, 2H, J = 6.0 Hz), 4.47 (t, 2H, J = 6.0 Hz), 7.20-7.61 (m, 22H), 8.00 (d, 2H, J = 9.0 Hz). MS (m/z): 736 [M-H]. Step 3: Synthesis of intermediate I-A3-PD1: To a solution of I-S13-PD1 (215 mg, 0.292 mmol) and triisopropylsilane (60 DL) in 0.75 ml of DCM was added 2O%TFA in DCM (0.5 mL) and stirred at RT for 90 min. The mixture was concentrated and the residue purified by column chromatography to give 65 mg (46%) of I-A3-PD1. 'H-NMR (300 MHz, CDCb): 5 2.51 (s, 3H), 2.85-2.92 (m, 4H), 3.87 (t, 2H, J - 4.5 Hz), 4.37 (t, 2H, J = 4.5 Hz), 7.25-7.43 (m, 7H), 8.01 (d, 2H, J = 3.0 Hz). MS (m/z): 493 [M-H]", 517 [M+Na]+. Step 4: Synthesis of I-A3-PD5-Me-ester: CDI (40mg, O.243 mmol) was added to a solution of I-A3-PD1 (10Omg, O.2O2 mmol) in DMF (0.5 mL) and stirred at RT for 2.5 h. To this were added a solution of dimethyl glutamate (53 mg, 0.303 mmol) in DMF (0.3 mL) and DMAP (37 mg, 0.303 mmol) and stirred overnight at RT. The mixture was dissolved in EtOAc and, after usual aqueous work-up and chromatographic purification, 110 mg (78%) of I-A3-PD5-Me-ester were obtained ]H- NMR (300 MHz, CDC13): 5 1.71-1.91 (m, 2H), 2.38-2.42 (m, 2H), 2.44 (s, 3H), 2.84-2.95 (m, 4H), 3.66 (s, 3H), 3.67 (s, 3H), 4.31-4.34 (m, 4H), 4.43^.52 (m, 1H), 7.31-7.41 (m, 7H), 8.O2 (d, 2H, J -9.O Hz). MS (m/z): 694 [M-H]". Step 5: Synthesis of prodrug I-A3-PD5: IN Lithium hydroxide (1.2 mL, 1.2 mmol) was added to a solution of I-A3-PD5-Me-ester (100 mg, O.144 mmol) in THF (O.4 mL) at O °C and the mixture al10wed to attain ambient temperature. After 30 min, the mixture was 150 concentrated and the residue diluted with water. Acidification with IN HC1, fol10wed by extraction with EtOAc, usual aqueous work-up and chromatographic purification gave 26 mg (26%) of I-A3-PD5. 'H-NMR (300 MHz, CD30D): 8 1.82-1.97 (m, 1H), 2.05-2.13 (m, 1H), 2.30-2.40 (m, 2H), 2.48 (s, 3H), 2.84 - 2.94 (m, 4H), 4.O6 - 4.O8 (m, 1H), 4.15 -4.22 (m, 4H), 7.30 (d, 2H, J = 9 Hz), 7.35 - 7.41 (m, 5H)5 7.92 (d, 2H, J = 9.O Hz). MS (m/z): 666 [M-H]. Example 38 Synthesis of prodrug I-H1-PD1: This prodrug was synthesized as shown in Scheme 14, Method B. Step 1: A solution of metronidazole (5.O g, 29.22 mmol) and CDI (5.21 g, 32.2 mmol) in DCM (100 mL) was stirred overnight at RT. After usual aqueous work-up, 7.32 g of the imidazolide of metronidazole were obtained, which was used as such in the next step. Step 2: A solution of the imidazolide of metronidazole (7.32 g) in DMF (30 mL) was added to a solution of SL-1 (6.39 g, 41.43 mmol) in DMF (10 mL) and stirred at 6O °C for 2.5 h. The mixture was concentrated and the residue was taken up in DCM. After usual aqueous work-up and chromatographic purification, 6.32 g (65%) of I-H1-PD1 were obtained. 'H-NMR (300 MHz, CDCI3): 5 2.15 (bs, 1H), 2.52 (s, 3H), 2.83-2.92 (m, 4H), 3.84-3.92 (m, 2H), 4.34 (t, 2H5 J = 6.0 Hz), 4.51 (t, 2H, J = 3.0 Hz), 4.53-4.62 (m, 2H),7.96(s, 1H). Example 39 Synthesis of I-H1-PD14: This prodrug was synthesized as described in Scheme 14, Method C. Thus, TEA (O.915 mL, 6.56 mmol) and DMAP (cat.) were added to a solution of LI-2C.TFA (541 mg, 3.94 mmol) and the imidazolide of metronidazole (synthesis described in Example 114) (87O mg, 3.28 mmol) in DMF (2 mL) and the mixture was heated at 6O °C for 3.5 h. The mixture was concentrated and the residue, after usual aqueous work-up and chromatographic purification, gave 546 mg (48%) of I-H1-PD14. 'H-NMR (300 MHz, CDCI3): 5 2.48 (s, 3H),2.76-2.96 (m, 4H), 3.46 (q, 2H, J = 6.0 Hz), 3.87 (t, 2H, J = 6.0 Hz), 4.41 (t, 2H, J = 6.0 Hz), 4.57 (t, 2H, J = 4.5 Hz), 7.90 (s, 1H).MS(m/z):351[M+H]+. Example 40 151 Synthesis of prodrug I-H1-PD2: This prodrug was synthesized as described in Scheme 14, Method C. Thus, CDI (180 mg, 1.1 mmol) was added to a solution of I-H1-PD14 (350 mg, 0.706 mmol) in DMF (2 mL) and stirred at RT for 4 h. N,N-Dimethylethylenediamine (88 mg, 0.706 mmol) was added and stirred for 3 h. The mixture was concentrated and the residue purified by column chromatography to afford 175 mg (38%) of I-H1-PD2. 'H-NMR (300 MHz, CDC13): 8 2.28 (s, 3H),2.49 (s, 6H), 2.51-2.55 (m, 2H), 2.81 (t, 2H, J = 6.0 Hz), 2.89 (t, 2H, J = 6.0 Hz), 3.27-3.33 (m, 2H), 3.46 (q, 2H, J = 6.0 Hz), 4.29 (t, 2H, J = 6.0 Hz), 4.40 (t, 2H, J = 4.5 Hz), 4.57 (t, 2H, J = 4.5 Hz), 5.55 (bs, IH), 7.94 (s, 1H). MS (m/z): 465[M+H]+. This product was converted to water-soluble hydroch10ride salt form using a standard method. Example 41 Synthesis of prodrug I-H1-PD5: This prodrug was synthesized as described in Scheme 14, Method A. Step 1: Synthesis of Intermediate I-S14-PD1: A solution of the imidazolide of LI-lc (1.6 g, 2.98 mmol) in acetonitrile (10 mL) was added to a solution of zudovudine (0.706 g, 3.74 mmol) in acetonitrile (2O mL) at RT, fol10wed by DMAP (O.914 g, 7.48 mmol) and stirred for 24 h. The mixture was concentrated and the residue, after usual aqueous workup and chromatographic purification, gave 1.62 g (79%) of intermediate I-S14-PD1. 1H-NMR (300 MHz, CDCI3): □ 1.95 (s, 3H), 2.35-2.45 (m, 2H), 2.78 (t, 2H, J= 6.6 Hz), 2.87 (t, 2H, J- 6.33 Hz), 3.38 (t, 2H, J= 6.33 Hz), 4.O5 (m, IH), 4.25 (m, 1H), 4.35-4.41 (m, 4H), 6.2O (t, IH, J= 6.16), 7.21- 7.33 (m, 9H), 7.42-7.48 (m, 6H) and 8.49 (s, IH). MS(m/z):712[M+Na]+. Step 2: Synthesis of I-H1-PD5: To a solution of I-S14-PD1 in DCM (15 mL) were added triisopropylsilane (0.446 ml, 2.17 mmol), fol10wed by 10% TFA in DCM (15 mL) and stirred at RT for 30 min. The mixture was concentrated and purified by column chromatography to afford O.68 g (7O%) of prodrug I-H1-PD5. 'H-NMR (300 MHz, CDCI3): □ 1.93 (s, 3H), 2.30 (bs, IH), 2.41-2.48 (m, 2H), 2.88 (t, 2H, J= 6.1 Hz), 2.96 (t, 2H, J= 6.6 Hz), 3.88 (t, 2H, J= 5.8 Hz), 4.O5 (m, IH), 4.29 (m, IH), 4.30-4.48 (m, 4H), 6.18 (t, IH, J= 6.3 Hz), 7.34 (s, IH) and 9.11 (s, IH). MS (m/z): 448 [M+H]+, 47O [M+Na]+. 152 Example 42 Synthesis of prodrug I-S22-PD1: This prodrug was synthesized in two steps as shown in Scheme 22. Step 1; To a solution of diphosgene (0.35 mL, 2.93 mmol) in DCM (3mL) was added a solution of Ll-ld (O.404 mg, 1.75 mmol), Hunig's base (O.765 mL, 4.39 mmol) and the resulting mixture was stirred at RT for 45 min. The mixture was concentrated, the residue dissolved in DCM (5 mL), cooled in an ice-bath and treated with a solution of paclitaxel (500 mg, 0.585 mmol), Hunig's base (O.765 mL, 4.39 mmol) and DMAP (cat.) in DCM (5 mL) over 5 min and the resulting mixture was stirred at RT for 2 h. The mixture was purified by column chromatography to give 519 mg (78%) of the protected intermediate S22-I2 as an off-white solid. 'H NMR (500 MHz, CDCI3): 6 1.14 (s, 3H), 1.28 (s, 3H), 1.68 (s, 3H), 2.04 (s, 3H), 2.23 (s, 3H), 2.37 - 2.45 (m, 2H), 2.46 (s, 3H), 2.50 - 2.52 (m, 2H), 2.90 - 2.95 (m, 4H), 3.82 (d, 1H, J - 7.O Hz), 4.O5 (s, 2H), 4.21 (d, 1H, J = 8.5 Hz), 4.32 (d, 1H, J = 8.O Hz), 4.40 - 4.42 (m, 5H), 4.97 (d, 1H, J = 9.5 Hz), 5.29 (s, 1H), 5.43 (d, 1H, J = 2.5 Hz), 5.69 (d, 1H, J = 7.O Hz), 6.0O (dd, 1H, J = 9.5 Hz, 2.5 Hz), 6.26-6.29 (m, 2H), 7.O2 (d, 1H, J = 9.5 Hz), 7.38 - 7.61 (m, 11H), 7.75 (d, 2H, J = 7.5 Hz), 8.15 (d, 2H, J = 7.5 Hz). Step 2; To an ice-cold solution of S22-I2 (6O mg, O.O532 mmol) in MeOH (1 mL) was added 2 drops of methanol saturated with ammonia gas and the resulting mixture was stirred for 1 h. The reaction mixture was purified by column chromatography to give 38 mg (69%) of I-S22-PD1 as an off white solid. lH NMR (500 MHz, CDCI3): 6 1.14 (s, 3H), 1.23 (s, 3H), 1.68 (s, 3H), 1.91 (s, 3H), 2.23 (s, 3H), 2.38 - 2.42 (m, 2H), 2.46 (s, 3H), 2.50 - 2.58 (m, 2H), 2.84 (t, 2H, J = 5.4 Hz), 2.94 (t, 2H, J = 6.5 Hz), 3.82 (t, 3H, J = 6.0 Hz), 4.2O (d, 1H, J = 8.5 Hz), 4.31 (d, 1H, J = 8.5 Hz), 4.35 - 4.41 (m, 3H), 4.97 (d, 1H, J = 7.5 Hz), 5.44 (d, 1H, J = 2.5 Hz), 5.69 (d, 1H, 7.O Hz), 6.0 (dd, 1H, J = 9.25 Hz, 2.25 Hz), 6.22-6.29 (m, 2H), 7.O8 (d, 1H, J = 9.5 Hz), 7.36-7.6O (m, 11H), 7.78 (d, 2H, J = 7.5 Hz), 8.14(d,2H,J = 7.5Hz). Example 43 Synthesis of prodrug I-S22-PD2: To a solution of I-S22-PD1 (38 mg, O.O367 mmol) in acetonitrile (O.6 mL) was added succinic anhydride (5 mg, O.O44 mmol) and DMAP (cat.). The resulting mixture was stirred overnight at RT and purified by column 153 chromatography to give 12 mg (29%) of prodrug I-S22-PD2 as an off white solid. ]H NMR (500 MHz, CDCI3): 5 1.14 (s, 3H), 1.25 (s, 3H), 1.68 (s, 3H), 1.91 (s, 3H), 2.22 (s, 3H), 2.36 - 2.41 (m, 1H), 2.49 (s, 3H), 2.57 - 2.63 (m, 5H), 2.86 - 2.89 (m, 2H), 2.93 (t, 2H, J - 6.5 Hz), 3.79 (d, 1H, J = 7.O Hz), 4.20 - 4.44 (m, 7H), 4.98 (d, 1H, J = 8.0 Hz), 5.53 (d, 1H, 3.0 Hz), 5.69 (d, 1H, J = 7.O Hz), 6.02 (dd, 1H, J = 9.5 Hz, J - 3.0 Hz), 6.26- 6.29 (m, 2H), 7.20 (d, 1H, J = 9.0 Hz), 7.33 - 7.62 (m, 1IH), 7.74 (d, 2H, J = 7.5 Hz), 8.14(d,2H,J = 7.5Hz).MS(ES+)/w/z: 1134.44 [M+H]+; 1156.56 [M+Na]+. Water solubility: Paclitaxel and its prodrug I-S22-PD2 (2 mg each) were suspended in 1 mL water or PBS-buffer (pH 7.4). The suspensions were sonicated for 15 min and centrifuged (13,000 g) for 10 min. The supernatant was analyzed using HPLC. HPLC: Waters RP18 column (150 x 3.9 mM, X-Terra); DAD-HP Agilent (Model 1100); eluent: CH3CN:H2O (gradient 0-100% acetonitrile in 0-15 min). The uv-detector was set at 210 nM. The concentrations were determined by measuring the relative area of paclitaxel or I-S22-PD2. It was observed that the solubility of I-S22-PD2 was 2O times more than that of paclitaxel. (i.e, -0.2 mg/mL). The fol10wing double/mutual prodrugs (Examples 44 - 80) were synthesized by the methods depicted in Schemes 17-21, using appropriate therapeutic agents and obvious modifications: Example 44 Synthesis of mutual prodrug of des10ratidine and pseudoephedrine (I-AA-MPD1): This mutual prodrug was synthesized as depicted in Scheme 21. The compound I-AA-MPD1 was obtained as a co10rless gum. 'H-NMR (300 MHz, CDCI3): 5 0.706O (d, 3H, J = 6.9 Hz), 2.27-2.51 (m, 4H), 2.74-2.97 (m, 9H), 3.28-3.41 (m, 4H), 3.79 (bs, 2H), 4.28- 4.30 (m, 4H), 4.57 (m, 1H), 7.O4-7.44 (m, 9H), 8.26-8.33 (m, 2H). MS (m/z): 682 [M+H]+. Example 45 Synthesis of mutual prodrug of am10dipine and lisinopril (I-AA-MPD2): Step 1: Synthesis of diethyl ester of lisinopril: To a suspension of lisinopril (10.0 g, 22.62 mmol) in ethanol (150 mL) was added SOCI2 (4.95 mL, 67.94 mmol) and refluxed for 1.5 h. An additional 1 mL of SOCl2 was added to the mixture every hour for 4 h. The mixture was concentrated and azeotroped with 154 benzene. The resulting hydroch10ride was basified with saturated NaHCO3 and extracted with EtOAc. Usual aqueous work-up gave 12.86 g of lisinopril diethyl ester, which was used without purification. 'H-NMR (300 MHz, CDCl3): 5 1.23-1.64 (m, 10H), 1.89-2.3 (m, 6H), 2.63-2.66 (m, 2H), 2.80 (bs, 2H), 3.19 (t, 2H, J = 7.5 Hz), 3.36-3.59 (m, 6H), 4.12-4.19 (m, 4H), 4.4-4.5 (m, 1H), 7.14-7.28 (m, 5H). MS [m/z]: 462.4 [M+H]+. Step 2: Synthesis of I-AA-MPD2: CD1 (1.23 g, 7.64 mmol) was added to a solution of I-A1-PD2 (Example 18) (3.0 g, 5.09 mmol) in DMF (10 mL) and stirred RT for 3.5 h. A solution of lisinopril diethyl ester (2.34 g, 5.09 mmol) in DMF (5 mL) was added and stirred at 65 °C for 8 h. The reaction was quenched with brine and taken up in EtOAc. After usual aqueous work-up and chromatographic purification, 2.5 g (45%) of I-AA-MPD2 were obtained. 'H-NMR (300 MHz, CDC13): 8 1.17 (t, 3H, J = 7.5 Hz), 1.24-1.30 (m, 7H), 1.45-1.80 (m, 7H), 1.90-2.30 (m, 7H), 2.36 (s, 3H), 2.70 (bs, 2H), 2.89-2.95 (m, 4H), 3.10-3.200(bs, 3H), 3.40-3.70 (m, 9H), 4.00-4.40 (m, 10H), 4.47-4.53 (m, 1H), 4.68-4.73 (q, 2H, J = 13 Hz), 5.30 (bs, 1H), 5.39 (s, 1H), 5.65 (bs,lH), 7.15-7.36 (m, 9H). MS (m/z): 1076 [M+H]+, 1098 [M+Naf. Example 46 Synthesis of mutual prodrug of am10dipine and 10sartan (I-AA-MPD3a): This mutual prodrug was synthesized as described in Example 34, with obvious modifications, using the appropriate amino containing therapeutic agents. The product I-AA-MPD3a was obtained as a cream co10r solid. 'H-NMR (300 MHz, CDCI3): 8 O.86 (t, 3H,J = 6.6Hz), 1.16(t,3H,J = 7.1 Hz), 1.31 (m, 2H), 1.6O (m, 2H), 2.31 (s, 3H), 2.48 (t, 2H, J = 7.9 Hz), 2.80-2.92 (m, 4H), 3.40 (m, 4H), 3.56 (s, 3H), 4.O1 (m, 2H), 4.32 (m, 4H), 4.68 (q, 2H, J = 6.5 Hz), 5.00 (s, 2H), 5.14 (s, 2H), 5.37 (s, 1H), 6.90 (d, 1H, J = 7.8 Hz), 7.O2- 7.22 (m, 5H), 7.33-7.43 (m, 3H), 7.50-7.6O (m, 2H). MS (m/z): 1037 [M-H] Example 47 Synthesis of mutual prodrug of celecoxib and valdecoxib (I-AA-MPD4): This mutual prodrug was synthesized by reacting the imidazolide intermediate of I-A3-PD1 with valdecoxib according to method described in Scheme 17 with appropriate modifications. This mutual prodrug I-AA-MPD4 was obtained as a white solid. 'H-NMR (300 MHz, CDCI3): 8 2.16 (s, 3H), 2.29 (s, 3H), 2.71 (bs, 4H), 4.14 (bs, 4H), 6.69 (s, 2H), 7.O2-7.33 (m, 14H), 7.97 (d, 3H, J = 9.O Hz). MS (m/z): 90O [M-H] 155 Example 48 Synthesis of double prodrug of valdecoxib (I-AA-MPD5): This double prodrug was synthesized by reacting I-A3-PD1 and valdecoxib using the method B described in Scheme 13. The double prodrug I-AA-MPD5 was obtained as an off white solid. 'H-NMR (300 MHz, CDC13): 8 2.40 (s, 6H), 2.82 (bs, 4H), 4.2O (bs, 4H), 7.2O-7.35 (m, 14H), 7.97 (d, 4H, J = 9.O Hz). MS (m/z): 833[M-H] Example 49 Synthesis of double prodrug of valdecoxib (I-AA-MPD8a): This mutual prodrug was synthesized using succinic anhydride and valdecoxib according to method B described in Scheme 13 with appropriate modifications. This double prodrug I-AA-MPD8a was obtained as an off-white solid. 'H-NMR (300 MHz, CDC13): 5 2.46 (s, 6H), 2.58 (s, 4H), 7.25-7.37 (m, 16H), 7.95 (d, 2H J = 9.O Hz). MS (m/z): 7O9 [M-H]Example 50 Synthesis of double prodrug of valdecoxib (I-AA-MPD8b): This mutual prodrug was synthesized using glutaric anhydride and valdecoxib according to method B described in Scheme 13 with appropriate modifications. This double prodrug I-AA-MPD8b was obtained as a co10rless gum. ' H-NMR (300MHz, CDCI3 + CD30D): D 1.68-1.74 (m, 2H), 2.15 (t, 4H, J = 4.5 Hz), 2.38 (s, 6H), 7.O1 (bs, 1H), 7.17-7.30 (m, 14H), 7.50 (bs, 1H), 7.88 (d, 4H, J = 8.58 Hz). MS (m/z): 723 [M-H]Example 51 Synthesis of mutual prodrug of olanzapine and fluoxetine (I-AA-MPD9): This mutual prodrug was made according to Scheme 17 with appropriate modifications. This mutual prodrug I-AA-MPD9 was obtained as a yel10w gum. !H-NMR (300 MHz, CDCI3): 8 2.05-2.2O (m, 2H), 2.40 (s, 3H), 2.44 (s, 3H), 2.50-2.90 (m, 12H), 3.30-3.80 (m, 4H), 4.10-4.50 (m, 4H), 5.2O (bs, 1H), 6.42 (s, 1H), 6.87 (d, 2H3 J = 8.52 Hz), 7.O4- 7.36 (m, 9H), 7.42 (d, 2H, J = 8.67 Hz). MS (m/z): 828 [M+H]+. Example 52 Synthesis of double prodrug of gabapentin (I-AA-MPD10a): This double prodrug was synthesized as described be10w: 156 Step 1: A solution of SL-1 (3.0 g, 19.4 mmol) in DMF (5 mL) was added to a suspension of CDI (9.46 g, 5.83 mmol) in DMF (15 mL) and stirred at RT for 20 h. The mixture was concentrated and the residue purified by column chromatography. The bis-imidazolide obtained was used as such in the next step. Step 2: A solution of the bis-imidazolide (0.706 g, 2.91 mmol) in acetonitrile (3 mL) was added to a dispersion of gabapentin (1.49 g, 8.75 mmol) in 1N NaHCO3 (8 mL) and stirred at RT for 3 d. The mixture was diluted with water, acidified with 2N HC1 and extracted with EtOAc. After usual aqueous work-up and chromatographic purification, 0.7064 g (65%) of pure I-AA-MPD10 was obtained. 1H-NMR (300 MHz, CDC13): δ 1.20- 1.47 (m, 20H), 2.33 (s, 4H), 2.96 (t, 4H, J = 5.48 Hz), 3.23 (d, 4H, J = 6.5 Hz), 4.31 (t, 4H, J = 6.0 Hz), 5.55 (t, 2H, J = 6.6 Hz),. ESI - MS (m/z): 547 [M-H] Example 53 Synthesis of double prodrug of gabapentin ethyl ester (I-AA-MPD10b): A mixture of I-A1-PD8 (2.0 g, 5.26 mmol) and Hunig's base (2.75 mL, 15.8 mmol) in DCM (8 mL) was added to a solution of diphosgene (1.27 mL, 10.53 mmol) in DCM (4 mL) at O °C and stirred for 30 min. The mixture was concentrated, dissolved in DCM (10 mL) and treated with a solution of gabapentin ethyl ester hydroch10ride (1.86 g, 7.88 mmol) and Hunig's base (2.74 mL, 15.77 mmol) in DCM (10 mL). The mixture was stirred for 3 h. After usual aqueous work-up, the crude material was purified by preparative HPLC to afford 2.2 g (69 %) of I-AA-MPD10b as a co10rless oil. 'H-NMR (300 MHz, CDCb): 8 1.25 (t, 6H, J - 6.0 Hz), 1.35-1.67 (m, 2OH), 2.33 (s, 4H), 2.91 (t, 4H, J = 6.0 Hz), 3.18 (d, 4H, J = 6.0 Hz), 4.12 (q, 4H, J = 6.0 Hz), 4.29 (t, 4 H, J = 6.0 Hz) 5.42 (bs, 2H). MS : ES+ m/z 6O5 [M+H]+, 627 [M+Na]+. Example 54 Synthesis of mutual prodrug of lamotrigine and gabapentin (I-AA-MPD11): To a solution of I-A1-PD4 (4.5 g, 10.32 mmol) in acetonitrile (40 mL) at RT was added CDI (2.0 g, 12.38 mmol) and stirred for 3 h. To this was added a solution of gabapentin (2.12 g, 12.38 mmol) in 10 ml of 1% NaHCO3 solution and the mixture was stirred at RT for 24 h. After usual aqueous work-up and chromatographic purification, 2.6 g (40 %) of I-AA-MPD11 was obtained as an off white solid. 'H NMR (CD30D, 300 MHz): 5 1.14- 1.48 (m, 10H), 2.28 (s, 2H), 2.99 (t, 2H, J = 6.0 Hz), 3.06 (t, 2H, J = 6.3Hz), 3.22 (s, 2H), 157 4.31 (t, 2H, J = 6.0 Hz), 4.46 (t, 2H, J = 6.3 Hz), 7.39-7.49 (m, 2H), 7.69-7.71 (m, 1H). MS: (ES+)m/z 633.1 (M+H)\ 655.1 (M+Na)+. Example 55 Synthesis of mutual prodrug of gabapentin ethyl ester and lamotrigine (I-AA-MPD12): To a suspension of lamotrigine (2.70 g, 10.55 mmol) and DMAP (1.28 g, 10.55 mmol) in toluene (40 mL) at 110 °C was added a solution of the imidazolide of I-A1-PD4 (4.99 g, 10.55 mmol) THF (20 mL) and stirred overnight at 110 °C. The reaction mixture was purified by column chromatography to afford O.85 g (12 %) of I-AA-MPD12 as a white solid. l HNMR (CDC13, 300 MHz) 5 1.24 (t, 2H, J = 7.2 Hz), 1.36- 1.77 (m, 10H), 2.29 (s, 2H), 2.93-3.03 (m, 4H), 3.22 (d, 2H, J = 6.6 Hz), 4.11 (q, 2H, J - 7.2 Hz), 4.34 (t, 2H, J = 6.6 Hz), 4.47 (t, 2H, J= 6.3 Hz), 5.65 (t, 1H ), 7.34-7.41 (m, 2H), 7.6O-7.63 (m, 1H). MS: ES+ m/z 661 (M+H)+, 682 (M+Na)+. Example 56 Synthesis of mutual prodrug of gabapentin ethyl ester and levetiracetam (I-AA-MPD13): To a solution of levetiracetam (0.706 g, 5.87 mmol) in DCE (25 mL) and DCM (5 mL) at RT was added oxalyl ch10ride (895 mg, 7.05 mmol). The reaction mixture was refluxed for 8 h, after which it was cooled to RT and a solution of I-A1-PD8 (2.67 g, 7.05 mmol) in DCE (2O mL) was added drop-wise. The resulting mixture was stirred at RT for 18 h. After usual aqueous work-up and chromatographic purification, 1.63 g (48%) of I-AA-MPD13 was obtained as a yel10w oil. 'H NMR (CDC13, 300 MHz): 8 O.87 (t, 3H, J = 7.4 Hz), 1.25&3H, J = 7.1 Hz), 1.34-1.52 (m, 10H), 1.82-2.01 (m, 4H), 2.28 (s, 2H), 2.40 (t, 2H, J = 7.O Hz), 2.89-2.94 (m, 4H), 3.04-3.11 (m, 1H), 3.19 (d, 2H3 J = 6.6 Hz), 3.66-3.75 (m, 1H), 4.O7-4.16 (m, 3H), 4.27-4.35 (m, 4H), 5.48 (t, 1H, J = 6.5 Hz), 8.18 (bs, 1H). MS: (ES*): m/z 576.1 [M+H]+; 598.1 [M+Na]+. (£$'): m/z 574.2 [M-H]+. Example 57 Synthesis of mutual prodrug of gabapentin ethyl ester and valproic acid (I-AA-MPD14): This mutual prodrug was synthesized according method outlined in Scheme 18. This mutual prodrug I-AA-MPD14 was obtained as oil. MS (m/z): 592 [M+H]+. Example 58 Synthesis of mutual prodrug of gabapentin ethyl ester and valproic acid (I-AA-MPD15): 158 This mutual prodrug was synthesized according method outlined in Scheme 18. The mutual prodrug I-AA-MPD15 was obtained as a yel10w oil. MS (m/z): 62O [M+H]+. Example 59 Synthesis of mutual prodrug of gabapentin ethyl ester and valproic acid (I-AA-MPD16): To a suspension of valpromide (750 mg, 5.24 mmol) in DCE (15 mL) at O-5 °C was added oxalyl ch10ride (0.5 mL, 6.29 mmol) and refluxed overnight. The reaction mixture was cooled to RT, treated with a solution of I-A1-PD8 (2.18 g, 5.76 mmol) in DCE (2 mL) and stirred at RT for 2 h. The reaction mixture was purified by column chromatography to afford 1.61 g (51%) of I-AA-MPD16 as a co10rless oil. ]H NMR (CDCI3, 300 MHz): 8 0.89 (t, 6H, J = 7.O9 Hz), 1.25 (t, 3H, J = 6.96 Hz), 1.31-1.69 (m, 18H), 2.29 (s, 3H), 2.89-2.99 (m, 4H), 3.20 (d, 2H, J = 6.47 Hz), 4.13 (q, 2H), 4.33 (t, 2H, J = 6.71 Hz), 4.40 (t, 2H, J = 5.97 Hz), 5.54 (t, 1H), 8.29 (br s, 1H). MS: ES+ m/z 549[M+H]+, 571 [M+Na]+. Example 60 Synthesis of double prodrug of valproic acid (I-AA-MPD22): To a suspension of valpromide (3.0 g, 2O.95 mmol) in DCE (30 mL) at O-5 °C was added oxalyl ch10ride (1.3 mL, 15.O8 mmol) and refluxed overnight. The reaction mixture was cooled to RT, a solution of SL-1 (O.808 g, 5.24 mmol) in DCE (3 mL) was added and stirred overnight. After usual work-up and chromatographic purification, 1.97 g (43%) of I-AA-MPD22 were obtained as a white solid. lH NMR (CDCI3, 300 MHz): 5 O.89 (t, 12H, J = 7.18 Hz), 1.28-1.66 (m, 16H), 2.94-2.95 (m, 2H), 3.02 (t, 6H, J = 6.51 Hz), 4.42 (t, 4H, J = 6.47 Hz). MS: m/z 493.2 [M+H]+, 510.O [M+NH4]+, 515.10 [M+Naf. Example 61 Synthesis of mutual prodrug of gabapentin ethyl ester and valproic acid (I-AA-MPD27): Step 1: To a solution of I-A1-PD8 (4.O g, 10.54 mmol) in THF (25 mL) was added CD1 (2.22g, 13.7 mmol) and stirred at RT for 90 min. To this was added t-butyl carbazate (1.39 g, 10.54 mmol) and DMAP (1.288 g, 10.54 mmol), and stirred overnight at RT. After usual aqueous work-up and chromatographic purification, 4.O g (91%) of the intermediate boc-hydrazide was obtained as a co10rless gummy material. 'H NMR (CDCI3, 300 MHz): δ 1.25 (t, 3H, J = 7.1 Hz), 1.43 (s, 9H), 1.31-1.74 (m, 10H), 2.30 (s, 159 2H), 2.90-3.01 (m, 4H), 3.20 (d, 2H, J - 6.6 Hz), 4.17 (q, 2H, J = 7.1 Hz), 4.32 (t, 2H, J = 6.5 Hz), 4.39 (t, 2H, J = 6.5 Hz), 5.42 (br s, 1H), 6.04 (br s, IH), 6.98 (br s, 1H). Step 2: To a solution of the above boc-hydrazide (4.0 g, 7.44 mmol) in DCM (2O mL) was added 50% TFA/DCM (10 mL) and stirred at RT for Ih. DCM was removed under vacuum, the resulting residue triturated with diethyl ether (2 x 20 mL) and dried to give a co10rless oil, which was dissolved in THF (20 mL). To the above solution at 0-5 °C was added TEA (2.1 mL, 14.88 mmol), valproic acid (1.18 g, 8.184 mmol), DCC (2.3 g, 11.16 mmol) and DMAP (0.909 g, 7.44 mmol) and the mixture was stirred overnight at RT. The mixture was filtered, concentrated and purified by column chromatography to afford 2.59 g (51 %) of I-AA-MPD27 as a co10rless gummy material. *H NMR (CDC13, 300 MHz): 6 0.85 (t, 6H, J = 7.2 Hz), 1.3 (t, 6H, J = 7.11 Hz), 1.21-1.80 (m, 26H), 2.2-2.3 (m, IH), 2.35 (s, 2H), 2.81-2.94 (m, 4H), 3.21 (d, 2H, J = 6.6 Hz), 3.65-3.68 (m, IH), 4.19 (q, 2H, J = 7.11 Hz), 4.36 (t, 2H, J = 6.51 Hz), 4.39 (t, 2H, J = 6.51 Hz), 5.51 (t, IH), 8.17 (s, IH). MS: m/z 712 [M+Na]+, 728 [M+K]+, 688 [M-H] Example 62 Synthesis of mutual prodrug of valproic acid and nicotinic acid (I-CC-MPD1): Step 1: To a solution of nicotinyl ch10ride hydroch10ride (3.16 g, 17.76 mmol) and LI-2c (3 g, 11.84 mmol) in THF (50 mL) was added TEA (8.3 mL, 59.2 mmol) and stirred overnight at RT. After usual aqueous work-up and chromatographic purification, 4.14 g (97%) of LI-2c-nicotinate ester was obtained as a co10rless oil. 'H NMR (CDCI3, 300 MHz): 5 1.43 (s, 9H), 2.82 (t, 2H, J = 6.31 Hz), 3.42-3.48 (q, 2H), 4.62 (t, 2H, J = 6.59 Hz), 7.29-7.33 (m, IH), 8.30 (d, IH, J = 7.95 Hz), 8.78 (dd, IH, J = 4.86, 1.72 Hz), 9.23 (d, IH, J = 2.13 Hz). MS: m/z 358 [M+H]+, 381 [M+Naf, 739 [2M+Na]+. Step 2: To a solution of LI-2c-nicotinate ester (0.92 g, 2.50 mmol) in DCM (5 mL) was added 50% TFA/DCM (5 mL) and stirred for lh. Reaction mixture was concentrated and the residual TFA salt was used as such in Step 3. Step 3: To a solution of valproic acid (0.37 g, 2.56 mmol) in THF (5 mL) was added CD1 (0.5 g, 3.08 mmol) and stirred for 2h. This was treated with a solution of the above TFA salt, TEA (0.7 mL, 5.13 mmol) and DMAP (50 mg, 0.41 mmol) in THF (10 mL) and the mixture was stirred overnight at RT, After usual aqueous work-up and chromatographic purification, 0.7 g (71%) of I-CC-MPD1 was obtained as a white solid. 'H NMR 160 (CDCI3, 500 MHz): δ 0.88 (t, 6H, J = 7 Hz), 1.25-1.59 (m, 8H), 2.06-2.08 (m, 1H), 2.86 (t, 2H, J = 6 Hz), 3.05 (t, 2H, J = 7 Hz), 3.58-3.61 (q, 2H, J = 9.O Hz), 4.63 (t, 2H, J = 6.5 Hz), 7.40-7.42 (m, 1H), 8.30 (dt, 1H, J = 8.O, 2.0 Hz), 8.79 (dd, 1H, J = 5.O, 2.0 Hz), 9.23 (d, 1H, J = 0.5 Hz). MS: m/z 385 [M+H]+, 407 [M+Naf, 423 [M+K]+. Example 63 Synthesis of mutual prodrug of valproic acid and nicotinic acid (I-CC-MPD2): This mutual prodrug was synthesized as described in Example 62, with obvious modifications. 0.612 g (41%) of I-CC-MPD2 was obtained as a white solid. !H NMR (CDC13, 300 MHz): 6 O.89 (t, 6H, J = 7.23 Hz), 1.24-1.62 (m, 8H), 2.34-2.42 (m, 1H), 2.92 (t, 2H, J = 6.83 Hz), 2.98 (t, 2H, J = 6.04 Hz), 3.78-3.84 (q, 2H), 4.37 (t, 2H, J = 6.79 Hz), 7.36-7.41 (m, 1H), 8.15 (d, 1H, J = 7.92 Hz), 8.73 (d, 1H, J = 4.78 Hz), 9.O2 (s, 1H). MS: m/z 385 [M+H]+, 419 [M+HC1]+, 383 [M-H]Example 64 Synthesis of mutual prodrug of zidovudine and lamivudine (I-HH-MPD1): Step 1: Synthesis of intermediate I-S17-PDI1: 4-Nitrophenyl ch10roformate (0.27 g, 1.34 mmol) was added to a solution of the I-Hl- PD5 (0.4 g, 0.89 mmol) and pyridine (76 DL, 1 mmol) in DCM (10 mL) and stirred at RT for 15 h. The mixture was concentrated and the residue purified by column chromatography to give 0.29 g (53%) of I-S17-PDI1. 'H-NMR (300 MHz, CDC13): D 1.93 (s, 3H), 2.45 (m, 2H), 2.97-3.06 (m, 4H), 4.O5 (m, 1H), 4.41 (m, 1H), 4.40-4.49 (m, 4H), 4,54 (t, 2H, J = 6.5 Hz), 6.17 (t, 1H, J = 6.0 Hz), 7.33 (s, 1H), 7.39 (d, 2H,-J= 4.8 Hz), 8.28 (d, 2H, J = 4.8 Hz) and 8.50 (s, 1H). MS (m/z): 635 [M+Na]+. Step 2: Synthesis of I-HH-MPD1: Lamivudine (45 mg, O.196 mmol) and DMAP (48 mg, 0.39 mmol) were added to a solution of I-S17-PDI1 (80 mg, O.13 mmol) in DMF (1.5 mL) and stirred at RT for 30 min. The mixture was concentrated and purified by column chromatography to give 40 mg (43%) of product I-HH-MPD1. 'H-NMR (300 MHz, CDCb): D 1.90 (s, 3H), 2.45 (t, 2H, J = 6.1 Hz), 3.05 (t, 4H, J = 6.2 Hz), 3.20 (m, 1H), 3.53 (m, 1H), 4.O8 (m, 1H), 4.30-4.80 (m, 8H), 5.45 (t, 1H, J = 3.0 Hz), 5.90 (d, 1H, J = 7.5 Hz), 6.17 (t, 1H), 6.30 (t, 1H), 7.55 (s, 1H) and 7.90 (d, 1H, J = 7.50 Hz). MS (m/z): 725 [M+Na]+. 161 Example 65 Synthesis of mutual prodrug of zidovudine and lamivudine (I-HH-MPD2b): This mutual prodrug was synthesized according to the method outlined in Scheme 18. The mutual prodrug I-HH-MPD2b was obtained as a white solid. ' H-NMR (300 MHz, CDCI3): □ 1.97 (s, 3H), 2.42 (m, 2H), 2.90-2.94 (m, 16H), 3.06 (m, 1H), 3.40-3.44 (m, 8H), 3.50-3.56 (m, 1H), 3.71-3.73 (m, 1H), 4.95 (m, 1H), 4.27-4.30 (m, 4H), 4.37-4.49 (m, 4h), 5.32 (t, 1H, J = 5.1 Hz), 5.83 (d, 1H, J = 6.6 Hz), 6.07 (m, 1H), 6.33 (bs, 1H), 7.2O-7.25 (m, 1H), 7.74 (m, 1H). MS (m/z): 954 [M+Na]+. Example 66 Synthesis of mutual prodrug of cetirizine and pseudoephedrine (I-CA-MPD1): Step 1: Synthesis of intermediate I-S17-PDI1: This intermediate was prepared by reacting I-C1-PD10 with p-nitrophenyl ch10roformate by a procedure similar to that described in Example 64. The desired intermediate I-S17-PDI1 was obtained as a gum. 'H-NMR (300 MHz, CDC13): D 2.49-2.71 (m, 10H), 2.95 (t, 2H, J = 6.6Hz), 3.01 (t, 2H, J = 6.5 Hz), 3.73 (bs, 2H), 4.13 (s, 2H), 4.22 (s, 1H), 4.41 (t, 2H, J = 6.6 Hz), 4.53 (t, 2H, J = 6.6 Hz), 7.18-7.40 (m, 11 H), 8.28 (d, 2H, J = 7.1 Hz). Step 2: The mutual prodrug I-CA-MPD1 was synthesized by reacting intermediate I-S17-PDI1 with pseudoephidrine by a procedure similar to that described in Example 64, Step 2. The desired mutual prodrug I-CA-MPD1 was obtained as a co10rless gummy material. ]H-NMR (300 MHz, CDC13): D O.99-0.7069 (d, 3H, J = 6.6 Hz), 2.45 (bs, 4H), 2.68 (bs, 6H), 2.90 (s, 3H), 2.91-2.94 (m, 4H), 3.71 (bs, 3H), 4.11 (s, 2H), 4.18 (s, 1H), 4.26-4.41 (m, 4H), 4.56 (m, 2H), 7.17- 7.35 (m, 12H). MS (m/z): 716 [M+ H]+. Example 67 Synthesis of mutual prodrug of gabapentin ethyl ester and naproxen (I-CA-MPD5): This mutual prodrug was synthesized by reacting I-A1-PD8 and Naproxen using Scheme 11, Method B. This mutual prodrug was obtained as co10rless oil. lH-NMR (300 MHz, CDCI3): □ 1.25(t, 3H,J = 7.1 Hz), 1.30-1.55 (m, 10H), 1.57 (d, 3H, J = 7.1 Hz), 2.27 (s, 2H), 2.84 (q, 4H, J = 6.4 Hz), 3.18 (d, 2H, J = 6.7 Hz), 3.80-3.88 (m, 1H), 3.91 (s, 3H), 4.12 (q, 2H, J = 7.1 Hz), 4.2O-4.40 (m, 4H), 5.35 (bt, 1H), 7.05-7.2O (m, 2H), 7.39 (dd, 1H, J = 1.8 Hz, 8.4 Hz), 7.6O-7.73 (m, 3H). MS (m/z): 592 [M+H]+, 614 [M+Na]+. 162 Example 68 Synthesis of mutual prodrug of valproic acid and nicotinic acid (I-CA-MPD14); This mutual prodrug was synthesized using valpromide and nicotinyl ch10ride hydroch10ride, according to the methods described in Scheme 13 and Scheme 17, with obvious modifications. 0.706 g of the mutual prodrug I-CA-MPD14 was obtained as a yel10w oil. 'H NMR (CD30D, 300 MHz): 8 O.87 (t, 6H, J = 6 Hz), 1.26-1.75 (m, 9H), 2.83 (s, 1H), 2.95-3.0 (m, 4H), 3.81 (t, 2H, J = 6 Hz), 4.44 (t, 2H, J = 6 Hz), 7.O (s, 1H), 7.4 (bs, 1H), 7.42 (m, 1H), 8.2O (d, 1H), 8.65-8.74 (bs, 2H), 9.O (s, 1H). MS: ES+ m/z 428.1 [M+H]+, 450.1 [M+Na]+. Example 69 Synthesis of mutual prodrug of valproic acid and nicotinic acid (I-CA-MPD15): To a solution of I-C1-PD13 (1.5 g, 4.63 mmol) and nicotinyl ch10ride hydroch10ride (O.99 g, 5.56 mmol) in THF (25 mL) was added TEA (2 mL, 13.89 mmol) at O °C and stirred for 2O h at RT. After usual aqueous work-up and chromatographic purification, 0.706 g (83%) of I-CA-MPD15 was obtained as a yel10w viscous liquid. *H NMR (CD30D, 500 MHz): 6 O.89 (t, 6H, J = 5.O Hz), 1.29-1.33 (m, 8H), 1.64 (bs, 2H), 3 (t, 2H, J = 5.O Hz), 3.07 (t, 2H, J = 5.O Hz), 4.42 (t, 2H, J = 5.O Hz), 4.63 (t, 2H, J - 5.O Hz), 7.41-7.43 (m, 1H), 8.31 (bs, 1H), 8.78 (bs, 1H), 9.26 (s, 1H). MS: ES+ m/z 429 [M+H]+, 451[M+Na]+,467[M+K]+. Example 70 Synthesis of mutual prodrug of gabapentin ethyl ester and nicotinic acid (I-CA-MPD18): To a solution of I-S12-PD2 (synthesized as described in Scheme 12, Method C) (3.76 g, 7.64 mmol) in THF (30 mL) was added nicotinyl ch10ride hydroch10ride (1.5 g, 8.40 mmol), fol10wed by TEA (4.26 mL, 30.56 mmol) and stirred overnight at RT. After usual aqueous work-up and chromatographic purification, O.87 g (23 %) of I-CA-MPD18 was obtained as a yel10w oil. ]H NMR (CDC13, 300 MHz): 5 1.24 (t, 3H, J = 6.0 Hz), 1.27-1.47 (m, 10H), 2.27 (s, 2H), 2.90-3.17 (m, 4H), 3.16 (d, 2H, J = 6.0 Hz), 3.79 (q, 2H, J = 6.0 Hz), 4.10 (q, 2H, J = 6.0 Hz), 4.36 (t, 2H, J = 6.0 Hz), 5.56 (bt, 1H, J = 6.0 Hz), 7.32-7.38 (m, 1H),8.17(d, 1H, J = 9.O Hz), 8.71 (d, 1H, J = 6.0 Hz), 9.O7 (s, 1H). MS: (ES)+ m/z 484 (M+H)+, 506 (M+Na)+; (ES)' m/z 482 (M-H)+. 163 Example 71 Synthesis of mutual prodrug of levetiracetam and valproic acid (I-CA-MPD19): To a solution of levetiracetam (0.706 g, 5.87 mmol) in DCE (2OmL) and DCM (4mL) was added oxalyl ch10ride (894 mg, 7.05 mmol) and heated at 80 °C for 7h. The reaction mixture was cooled to RT, a solution of I-C1-PD11 (1.97 g, 7.05 mmol) in DCE (10mL) was added and stirred at RT for 18 h. After usual aqueous work-up and chromatographic purification, 1.73 g (61 %) of I-CA-MPD19 was obtained as a yel10w oil. 'H NMR (CDC13, 300 MHz): 5 0.85-0.91 (m, 9H), 1.24-1.62 (m, 8H), 1.80-2.05 (m, 4H), 2.34-2.44 (m, 3H), 2.91 (t, 4H, J = 6.0 Hz), 3.03-3.12 (m, 1H), 4.06-4.O9 (m, 1H), 4.31^1.36 (m, 4H), 8.32 (bs, 1H). MS: (ES*) m/z 477.1 [M+H]+, 498.9 [M+Na]+ (ES)" m/z 475.O [M-H]'. Example 72 Synthesis of mutual prodrug of gabapentin ethyl ester and valproic acid (I-CA-MPD21): This mutual prodrug was synthesized by fol10wing a route depicted in Scheme 19, with obvious modifications. The mutual prodrug I-CA-MPD21 was obtained as a co10rless oil. 'H-NMR (CDCI3, 300 MHz): □ O.81 (t, 6H, J = 7.19 Hz), 1.15-1.6O (m, 21H), 2.2O (s, 2H)3 2.25-2.35 (m, 1H), 2.84 (t, 4H, J = 6.6 Hz), 3.11 (d, 2H, J = 6.7 Hz), 4.O5 (q, 2H3 J = 7.16 Hz and 17.3 Hz), 4.15-4.25 (m, 4H), 5.43 (bt, 1H). MS (m/z): 506 [M+H]+, 528 [M+Na]+. Example 73 Synthesis of mutual prodrug of gabapentin ethyl ester and nicotinic acid (I-CA-MPD22): To a suspension of nicotinyl ch10ride hydroch10ride (0.35 g, 1.97 mmol) in THF (3 mL) at O °C was added TEA (O.82 mL, 5.91 mmol). After 5 min, a solution of I-A1-PD8 (0.5g, 1.31 mmol) and TEA (O.27 mL, 1.97 mmol) in THF (4 mL) was added and stirred overnight at RT. The mixture was purified by column chromatography to afford 0.573 g (90 %) of I-CA-MPD22 as a yel10w oil. *H NMR (CDC13, 300 MHz): 5 1.24 (t, 3H, J = 6.0 Hz), 1.27-1.47 (m, 10H), 2.27 (s, 2H), 2.94 (t, 2H, J = 6.0 Hz), 3.07 (t, 2H, J = 6.0 Hz), 3.19 (d, 2H, J = 6.0 Hz), 4.12 (q, 2H, J = 6.0 Hz), 4.32 (t, 2H, J = 6.0 Hz), 4.62 (t, 2H, J = 6.0 Hz), 5.29 (bs, 1H), 7.36-7.42 (m, 1H), 8.30 (t, 1H, J = 3.0 Hz), 8.78 (dd, 1H, J = 1.69 Hz), 9.24(s, 1H). MS: (ES)+ m/z 485 (M+H)+, 507 (M+Na)+. 164 Example 74 Synthesis of mutual prodrug of lamotrigine and valproic acid (I-CA-MPD23): To a suspension of lamotrigine (O.455 g, 1.78 mmol) and DMAP (O.217 g, 1.78 mmol) in toluene (10 mL) at 110 °C was added a solution of the imidazolide of I-C1-PD11 (O.665 g, 1.78 mmol) in THF (5 mL). The reaction was stirred at 110 °C overnight and purified by column chromatography to afford O.2O g (2O%) of I-CA-MPD23 as a white solid. *H NMR (300 MHz, CDCI3): 5 O.86-O.90 (m, 6H), 1.2O-1.44 (m, 6H), 1.53-1.62 (m, 2H)5 2.36-2.39 (m, IH), 2.90-3.0 (m, 4H), 4.34 (t, 2H, J = 6.3 Hz), 4.46 (t, 2H J = 6.6 Hz), 7.36-7.38 (m,2H), 7.6O-7.63 (m, 1H). MS: (ES+) m/z 562 (M+H)+, 585 (M+Na)+. Example 75 Synthesis of mutual prodrug of lamotrigine and nicotinic acid (I-CA-MPD24): A solution of I-A1-PD4 (0.5 g, 1.14 mmol) and TEA (0.5 mL, 2.87 mmol) in THF (5 mL) was added to a suspension of nicotinyl ch10ride (0.305 g, 1.71 mmol) and 0.5 mL TEA in THF (5 mL). The mixture was stirred at RT for 24 h. After usual aqueous workup and chromatographic purification, O.15 g (14%) of I-CA-MPD24 were obtained as a white solid. JHNMR (CDC13, 500MHz): 5 3.06 (t, 2H, J = 6.5Hz), 3.10 (t, 2H, J = 6.5 Hz), 4.49 (t, 2H, J = 6.5 Hz), 4.65 (t, 2H, J = 6.5 Hz), 7.38-7.43 (m, 3H)5 7.6O-7.62 (m, 1H), 8.33-8.36 (m, 1H), 8.81 (m, 1H), 9.35 (bs, 1H). MS: (ES +) m/z 540.9 (M+H)+. Example 76 Synthesis of mutual prodrug of lamotrigine and nicotinic acid (I-CA-MPD25): This mutual prodrug was synthesized using lamotrigine and nicotinyl ch10ride hydroch10ride, according to the methods outlined in Scheme 12 and Scheme 17. O.8 g (44%) of I-CA-MPD25.HC1 were obtained as an off white solid. ]H NMR (D2O, 500MHz): 8 2.93 (t, 2H, J = 6.5 Hz), 3.10 (t, 2H, J = 6.0Hz), 3.69 (t, 2H, J = 6.5Hz),"4.49 (m, 2H), 7.37-7.43 (m, 3H), 7.69-7.71 (m, 1H), 8.O5-8.O7 (m, 1H), 8.78-8.79 (m, 1H), 9.30 (bs, 1H). MS: (ES+) m/z 539.9 (M+H)+, 561.8 (M+Na)+. Example 77 Synthesis of mutual prodrug of metronidazole and norf10xacin (I-AH-MPD1): Step 1: Synthesis of imidazolide of I-H1-PD1: CDl(3l9mg, 1.97 mmol) was added to a solution of I-H1-PD1 (577 mg, 1.64 mmol) in DMF (8 mL) and stirred at RT for 4 h. The mixture was concentrated and the residue 165 purified by column chromatography to give 395 mg (54%) of the imidazolide of I-Hl-PD1. 'H-NMR (300 MHz, CDC13): 6 2.50 (s, 3H), 2.92 (t, 2H, J = 6.0 Hz), 3.0O-3.10 (m, 2H), 4.36 (t, 2H, J = 3.0 Hz), 4.47-4.51 (m, 2H), 4.57-4.7O (m, 4H),7.O7 (s, 1H), 7.43 (s, 1H), 7.95 (s, 1H), 8.15 (s, 1H). MS (m/z): 446 [M+H]+. Step 2: Synthesis of I-AH-MPD1: A solution of the imidazolide of I-H1-PD1 (100 mg, O.224 mmol) in DMF (1 mL) was added to a suspension of norf10xacin (86 mg, O.269 mmol) in DMF (2 mL) and stirred at RT for 6O h. The mixture was concentrated and the residue purified by column chromatography to give 35 mg (22%) of I-AH-MPD1. !H-NMR (300 MHz, CDC13): 5 1.59 (t, 3H J = 7.5 Hz), 2.53 (s, 3H), 2.86-2.97 (m, 4H), 3.27-3.30 (m, 4H), 3.72 (t, 4H, J = 4.5 Hz), 4.32-4.40 (m, 6H), 4.48-4.52 (m, 2H), 4.59-4.63 (m, 2H), 6.85 (d, 1H, J = 6.0 Hz), 7.96 (s, 1H), 8.O9 (d, 1H J = 12.0 Hz), 8.68 (s, 1H). MS (m/z): 697 [M+H]+. The fol10wing mutual prodrugs (Examples 78 - 80) were obtained according to procedures similar to those described in Example 77, with the substitution of the appropriate pairs of amino-containing and hydroxyl-containing therapeutic agents: Example 78 Synthesis of mutual prodrug of metronidazole and norf10xacin (I-AH-MPD3b): The mutual prodrug I-AH-MPD3b was obtained as a yel10w solid. *H-NMR (300MHz, CDCb): 8 1.59 (t, 3H, J = 7.1 Hz), 2.49 (s, 3H), 2.82-2.98 (m, 10H), 3.30 (t, 4H, J = 4.5 Hz), 3.39 (bs, 4H), 3.72 (t, 4H, J = 4.8 Hz), 4.38 (dt, 8H, J = 26.2, 6.4 Hz), 4.61 (t, 2H, J = 4.8 Hz), 6.86 (d, 1H, J = 6.4 Hz), 7.95 (s, 1H), 8.O7 (bd, 1H, J= 12.8 Hz,), 8.67 (s, 1H), 14.9 (s, 1H). MS (m/z): 811.26 [M+H]+. Example 79 Synthesis of mutual prodrug of gabapentin and tramadol (I-AH-MPD7): The mutual prodrug was synthesized according to the method in Scheme 15 with obvious modifications. The mutual prodrug I-AH-MPD7 was obtained as a co10rless gummy material. 'H-NMR (300 MHz, CDCI3): 8 1.25 (t, 3H, J = 7.1 Hz), 1.32-2.45 (m, 30H), 2.91-2.99 (m, 4H), 3.16 (t, 2H, J = 7.3 Hz), 3.80 (s, 3H), 4.O8-4.15 (q, 2H, J - 7.1 Hz), 4.28-4.40 (m, 4H), 5.4 (t, 1H), 6.74-6.81 (m, 3H), 7.23-7.29 (t, 1H, J = 8 Hz),MS (m/z): 669.30 [M+H]+. Example 80 166 Synthesis of mutual prodrug of venlafaxine and paroxetine (I-AH-MPD8) The mutual prodrug was synthesized according to the method outlined in Scheme 15 with obvious modifications. The mutual prodrug I-AH-MPD8 was obtained as a white sticky solid. 1H-NMR was consistent with the expected structure. MS: m/z 812 [M]+. Example 81 Synthesis of NO-releasing prodrug of Valproic acid (I-C1-NOPD1): This prodrug was synthesized as shown in Scheme 11, Method B using as reagents valproic acid (725 mg, 5.O3 mmol), LI-2b (1 g, 5.O3 mmol), TEA (611 mg, 6.04 mmol), DCC (1.25 g, 6.04 mmol) and DMAP (100 mg). Yield: 832 mg (51%). 'H-NMR (300 MHz, CDC13): 6 O.89 (t, 6H, J = 7.O9 Hz), 1.22-1.77 (m, 8H), 2.36-2.40 (m, 1H), 2.93- 3.0O (m, 4H), 4.34 (t, 2H, J = 6.8 Hz), 4.7O (t, 2H, J = 6.35 Hz). MS (CI)+ m/z: 326 [M+H]+. Example 82 Synthesis of NO-releasing prodrug of valproic acid (I-Cl-NOPD3a): This prodrug was prepared as shown in Scheme 13, Method A. Thus, to a stirred mixture of valproyl isocyanate, which was freshly prepared from valpromide (O.7 g, 4.90 mmol [valpromide was synthesized from valproic acid by using known methods as shown in Scheme 11, Method I) using a known method (see J. Org. Chem., 1962, 27, 3742) in DCM (20 mL) at RT was added a solution of LI-2b (0.976 g, 4.90 mmol) in DCM (5 mL) drop-wise and stirred at RT for 2 h. The mixture was concentrated and the residue, after usual aqueous work-up and chromatographic purification, afforded O.6 g (33%) of prodrug I-Cl-NOPD3a. ' H-NMR- data is consistent with the expected structure. MS: [ES]+ m/z 391[M+Na]+, 407.2 [M+K]+; [EI]+ m/z 368 [M + H]+. Example 83 Synthesis of NO-releasing prodrug of aspirin (I-C1-NOPD4): This prodrug was synthesized as shown in Scheme 11, Method D. Thus, to a solution of aspirin (3.0 g, 16.65 mmol) in THF (30 mL) at O °C was added oxalyl ch10ride (1.86 mL, 21.64 mmol) and heated at 7O °C for 2 h. The mixture was concentrated, the residue was dissolved in THF (30 mL) and treated with a solution of LI-2a (3.61 g, 16.65 mmol), TEA (3.48 mL, 24.97 mmol) and DMAP (361 mg) in THF (2O mL). The resulting mixture was stirred at RT for 2 h and filtered through celite. The filtrate was concentrated 167 and the residue purified by column chromatography to afford 3.06 g (48%) of the bromide S11-Il. 'H-NMR (300 MHz, CDC13): 5 2.35 (s, 3H), 3.01-3.12 (m, 4H), 3.61 (t, 2H, J = 6.5 Hz), 4.53 (t, 2H, J = 6.0 Hz), 7.11 (dd, 1H, J = 8 Hz, 1 Hz), 7.32 (t, 1H, J = 7.6 Hz), 7.57 (t, 1H, J = 7.6 Hz), 8.O3 (dd, 1H, J = 7.8 Hz, 1.6 Hz). MS (ES+) m/z: 403.92 (M+Na)+. To a solution of S11-Il (2.0 g, 5.27 mmol) in acetonitrile (20 mL) at 0 °C was added AgNO3 (0.7067 g, 6.32 mmol) in the dark. The mixture was stirred at RT for 1.5 h, filtered through celite and concentrated. The residue, after usual aqueous work-up and chromatographic purification, afforded 0.965 g (50%) pure I-C1-NOPD4. ]H-NMR (300 MHz, CDCI3): δ 2.36 (s, 3H), 2.98 (t, 2H, J = 6.8 Hz), 3.05 (t, 2H, J = 6.4 Hz), 4.54 (t, 2H, J = 6.4 Hz), 4.70 (t, 2H, J = 6.8 Hz), 7.12 (d, 1H, J = 8 Hz), 7.33 (t, 1H, J = 7.6 Hz), 7.59 (t, 1H, J = 7.5 Hz), 8.03 (dd, 1H, J = 7.8 Hz, 1 Hz). MS (ES)+ m/z: 379.11 (M+NH4)+, 383.98 (M+Na)+. Example 84 Synthesis of NO-releasing prodrug of aspirin (l-Cl-NOPD5a): As shown in Scheme 11, Method H, this prodrug was synthesized in three steps: Step 1: To a suspension of aspirin (1 g, 5.55 mmol) in benzene (15 mL) and DMF (1 drop) at 0-5 °C was added a solution of oxalyl ch10ride (0.6 mL, 6.66 mmol) in benzene (5 mL) and stirred at 85 °C for 2 h. The reaction mixture was concentrated, and the crude acid ch10ride was used immediately in the next step. Step 2: To a solution of the above acid ch10ride in benzene (30 mL) was added silver cyanate (998 mg, 6.66 mmol) and refluxed in the dark for 1 h. The mixture, containing 2- acetoxybenzoyl isocyanate, was cooled to RT and used in the next step. Step 3:-To the above mixture was added a solution of LI-2b (1.33 g, 6.66 mmol) in benzene (5 mL) and stirred at RT for 1h. The mixture was filtered through celite and concentrated, and the residue was purified by column chromatography to afford 1.2 g (54%) of pure I-Cl-NOPD5a. ]H-NMR data is consistent with the expected structure. MS (ES*) m/z: 404.98 [M+H]+, 426.94 [M+Na]+, 442.97 [M+K]+, (ES) m/z: 403.01 [M- H]. Example 85 Synthesis of sodium salt of NO-releasing prodrug of aspirin (I-Cl-NOPD5b): 168 To a suspension of 6O% sodium hydride (45 mg, 1.3 mmol) in THF (0.5 mL) was added solution of I-Cl-NOPD5a (500 mg, 1.24 mmol) in THF (1.5 mL). After stirring for 5 min, THF was removed under vacuum, the residue was washed with dry Et2O (4x3 mL) to remove unreacted starting material and dried in vacuum to afford 410 mg (78%) of I-Cl-NOPD5b as an off-white solid. lH NMR (D2O, 500 MHz): 8 2.28 (s, 3H), 2.93-2.97 (m, 4H), 4.33 (t, 2H, J = 6.0 Hz), 4.68 (t, 2H, J = 7.2 Hz), 7.O7 (d, 1H, J = 8.O Hz), 7.26 (t, 1H, J = 7.5 Hz), 7.41 (t, 1H, J = 9.O Hz), 7.57 (d, 1H, J = 7.5 Hz). MS: m/z 427.O [M+H], 449.O [M+Na]+. Example 86 Synthesis of NO-releasing prodrug of aspirin (I-C1-NOPD6): This prodrug was synthesized as shown in Scheme 11, Method E. Thus, to a solution of aspirin (1.20g, 6.70 mmol) in DCM (15 mL) at 0 °C was added oxalyl ch10ride (O.74 mL, 8.65 mmol) and stirred at RT for 1.5 h. The mixture was concentrated and the residual acid ch10ride was treated with LI-5.TFA (6.7O mmol) in DCM (14 mL), fol10wed by drop-wise addition of TEA (3.73 mL, 26.81 mmol) at O °C. The mixture was stirred at RT for 4 h and concentrated. The residue, after usual aqueous work-up and chromatographic purification, gave O.822g (34 %) of I-C1-NOPD6. 'H-NMR (300 MHz, CDCI3): 8 2.35 (s, 3H), 2.92 (t, 2H, J = 6.11 Hz), 2.98 (t, 2H, J = 6.0Hz), 3.76 (q, 2H, J - 6.0 Hz), 4.71 (t 2H, J = 6.0 Hz), 6.7O (bs, 1H), 7.10 (d, IH, J = 9.O Hz), 7.31-7.33 (m, 1H), 7.48-7.50 (m, 1H), 7.78 (d, IH, J = 6.0 Hz). MS (El)+ m/z: 361 (M+H)+. Example 87 Synthesis of NO-releasing prodrug of nicotinic acid (I-C1-NOPD7): This prodrug was synthesized as shown in Scheme 11, Method C. Thus, to a suspension of nicotinyl ch10ride hydroch10ride (2.68 g, 15.O7 mmol) in THF (10 mL) at O °C was added a solution of LI-2b (2.0g, 10.O5 mmol) and TEA (5.6 mL, 40.2 mmol) in THF (7 mL) and stirred at RT for 15 h. The mixture was filtered, concentrated and the residue purified by column chromatography to afford 2.23 g (73%) of pure I-C1-NOPD7. 'H-NMR (300 MHz, CDC13): S 3.01 (t, 2H, J = 4.75 Hz), 3.09 (t, 2H, J =6.5 Hz), 4.63 (t, 2H, J = 5.25 Hz), 4.7O (t, 2H, J =4.75 Hz), 7.39-7.42 (m, IH), 8.29-8.31 (dt, IH, J = 8 Hz, 2 Hz), 8.78-8.80 (dd, IH, J = 2 Hz), 9.23 (d, IH, J = 2Hz). MS (ES)+m/z: 305 (M+H)+ 169 Example 88 Synthesis of NO-releasing prodrug of nicotinamide (I-Cl-NOPD8a): This prodrug was synthesized from nicotinamide (1 g, 8.18 mmol) according to the procedure described in Example 77 (see Scheme 11, Method I or Scheme 13, Method A). After usual workup, the crude product was purified by column chromatography to afford O.1 g (3.5%) of prodrug I-Cl-NOPD8a. !H-NMR (300 MHz, CDC13): 6 2.97-3.0 (m, 4H), 4.51 (t, 2H, J = 6.3 Hz), 4.73 (t, 2H, J = 6.7 Hz), 7.38-7.48 (m, 1H), 8.16-8.22 (m, 1H), 8.71-8.79 (m, 2H), 9.O4 (s, 1H). MS [ESf m/z: 348 [M+H]+, 37O [M+Na]+. Example 89 Synthesis of NO-releasing prodrug of nicotinic acid (I-C1-NOPD9): This prodrug was synthesized as shown in Scheme 11, Method F. Thus, TEA (6.92 mL, 50.55 mmol) was added to a suspension of nicotinyl ch10ride hydroch10ride (3.0 g, 16.85 mmol) and cysteamine hydroch10ride (2.11 g, 18.53 mmol) in DCM (30 mL) at O °C and stirred at RT for 4 h. The mixture was concentrated and the residue dissolved in MeOH (2O mL). To this solution at O °C was added a solution of LI-3b (4.11 g, 16.85 mmol) in MeOH (5 mL), fol10wed by TEA (4.61 mL, 33.7O mmol) and stirred overnight at RT. The mixture was filtered through celite, concentrated and the residue was purified by column chromatography to afford 3 g (58%) of pure I-C1-NOPD9. 'H-NMR (300 MHz, DMSO-d6): 2.94 (t, 2H, J = 6.7 Hz), 3.09 (t, 2H, J = 6.3 Hz), 3.56 (q, 2H, J = 6.3 Hz), 4.73 (t, 2H, J = 6.3 Hz), 7.49-7.53 (m,lH), 8.16-8.19 (m, 1H), 8.69-8.7O (m, 1H), 8.87 (br t, 1H), 8.98 (s,lH). MS (ES"*) m/z: 304 (M+H)+, 326 (M+Na)+. Example 90 Synthesis of NO-releasing prodrug of naproxen (I-C1-NOPD10): This prodrug was synthesized as shown in Scheme 11, Method B. Thus, to a solution of naproxen (2.23 g, 9.7 mmol) and LI-2b (1.93 g, 9.7 mmol) in THF (7O mL) at RT were added DCC (3 g, 14.55 mmol) and DMAP (1.78 g, 14.55 mmol) and stirred overnight. The mixture was filtered and concentrated, and the residue purified by column chromatography to afford 0.7063 g (25%) of pure I-C1-NOPD10. 'H-NMR (300 MHz, CDCI3): 5 1.59 (d, 3H, J = 7.16 Hz), 2.81 (t, 2H, J = 6.77 Hz), 2.87 (t, 2H, J - 6.42 Hz), 3.85-3.88 (m, 1H), 3.91 (s, 3H), 4.33 (t, 2H, J - 5.26 Hz), 4.53 (t, 2H, J - 6.79 Hz), 7.10-7.16 (m, 2H), 7.41 (d, 1H, J = 1.7Hz), 7.69 (t, 3H, J = 8.55 Hz). 17O Example 91 Synthesis of NO-releasing prodrug of naproxen (I-C1-NOPD12): This prodrug was synthesized as shown in Scheme 11, Method E. Thus, to a solution of naproxen (1.698 g, 7.37 mmol) in ch10roform (2O mL) at O-5 °C was added oxalyl ch10ride (O.8 mL, 8.844 mmol), fol10wed by 2-3 drops of DMF. The mixture was stirred at RT for 90 min and concentrated. This acid ch10ride (-7.37 mmol) was treated with LI- 5.TFA (6.7 mmol) in THF (2O mL) and cooled to O °C. To this was added TEA (5.6 mL, 40 mmol) and stirred at RT for 3 h. The mixture was concentrated and the residue, after usual aqueous work-up and chromatographic purification, afforded O.409 g (14%) of pure I-C1-NOPD12. 'H-NMR (CDC13, 300 MHz): 6 1.24 (d, 3H), 2.87 (t, 2H, J = 6.5 Hz), 2.93 (t, 2H, J = 6.7 Hz), 3.64 (q, 2H, 7.5 Hz), 3.76 (m, 1H), 3.88 (s, 3H), 4.7O (t, 2H, J = 6.6 Hz), 4.79 (br s, 1H), 6.97-7.O8 (m, 3H), 7.35-7.46 (m, 3H). Example 92 Synthesis of NO-releasing prodrug of flurbiprofen (I-C1-NOPD13): This prodrug was synthesized as shown in Scheme 11, Method A, using as reagents flurbiprofen (4.O g, 16.37 mmol), CDI (3.97 g, 24.56 mmol) and LI-2b (3.25 g, 16.37 mmol). Yield: 3 g (43%). lH-NMR (300 MHz, CDCI3): 5 1.56 (d, 3H, J = 7.2 Hz), 2.80- 3.0 (m, 4H, J = 5.67 Hz), 3.78 (q, 1H, J = 7.10 Hz), 4.36 (m, 2H), 4.66 (t, 2H, J = 6.78), 7.11-7.54 (m,8H). Example 93 Synthesis of NO-releasing prodrug of flurbiprofen (I-Cl-NOPD14a): This prodrug was synthesized as shown in Scheme 11, Method I. Thus, to a solution of flurbiprofen (5.0 g, 20.46 mmol) in benzene (50 mL), was added oxalyl ch10ride (3.11 g, 24.55 mmol) at 0 °C and 2 drops of DMF and stirred at RT for 20 hrs. Benzene was removed under vacuum and the residue was diluted with DCM (50mL). The reaction mixture was cooled to 0 °C and dry ammonia was passed for 30 min. The reaction mixture was concentrated and, after usual aqueous work-up, 4.5 g of flurbiprofen amide was obtained as a white solid. To a solution of flurbiprofen amide (3.0 g, 12.33 mmol) in DCM (7O mL) was added oxalyl ch10ride (1.87g, 14.79mmol) at 0 °C and refluxed for 16 h. Reaction mixture 171 was cooled to RT and treated with LI-2b (2.45 g, 12.33 mmol) in DCE (10mL) and stirred overnight. After usual aqueous work-up and chromatographic purification, 0.5 g of I-Cl-NOPD14a were obtained. ]H NMR (CDCI3, 300 MHz): 5 1.55 (d, 3H, J= 6.9 Hz), 2.94-2.97 (bs, 4H), 4.38-1.47 (bs, 3H), 4.68 (t, 2H, J = 6.6 Hz), 7.13-7.55 (bs, 8H) MS: ES+m/z 469.O3[M+H]+, 467.16 [M-H]+. Example 94 Synthesis of NO-releasing prodrug of flurbiprofen (I-Cl-NOPD15b): This prodrug was synthesized as shown in Scheme 11, Method A. Thus, to a solution of flurbiprofen (2.5 g, 10.23 mmol) in THF (30 mL) was added CDI (3.31 g, 2O.46 mmol) and stirred at RT for 16 h. To this was added LI-5.TFA (3.64 g, 10.23 mmol) in THF (15 mL), fol10wed by TEA (2.85 mL, 2O.46 mmol) and stirred for 16 h. After usual work-up and chromatographic purification, 1.5 g (91%) of I-Cl-NOPD15b were obtained. ]H NMR (CDCI3, 300 MHz): 5 1.5 (d, 3H, J = 6.9 Hz), 2.82 (t, 2H, J = 6.3 Hz), 2.92 (t, 2H, J = 6.9 Hz), 3.50 (m, 3H), 4.6 (t, 2H, J = 6.6 Hz), 5.8 (s, 1H), 7.11-7.55 (bs, 8H). MS:ES+m/z 425.21 [M+H]+, 423.11 [M-H]+. Example 95 Synthesis of NO-releasing prodrug of indomethacin (I-C1-NOPD16): This prodrug was synthesized as shown in Scheme 11, Method A. Thus, to a solution of indomethacin (2.0 g, 5.59 mmol) in ch10roform (25 mL) was added CDI (0.7069 g, 6.71 mmol) and stirred for 2h. A solution of LI-2b (1.22 g, 6.15 mmol) and DMAP (751 mg, 6.15 mmol) in ch10roform (5 mL) was added, and the mixture was stirred at RT for 16 h. After usual aqueous work-up and chromatographic purification, 2.02 g (67%) of pure I- C1-NOPD16 was obtained. 'H-NMR (300 MHz, CDCI3): 5 2.39 (s, 3H), 2.88-2.95 (m, 4H), 3.69 (s, 2H), 3.84 (s, 3H), 4.38 (t, 2H, J = 6.3 Hz), 4.63 (t, 2H, J = 6.6 Hz), 6.67 (dd, 1H, J = 2.4, 8.7 Hz), 6.87 (d, IH, J = 8.7 Hz), 6.96 (d, 1H, J = 2.1 Hz), 7.47 (d, 2H, J = 8.4 Hz), 7.67 (d, 2H, J = 8.4 Hz). MS (ES4) m/z: 539.2 [M+H]+, 56O.79 [M+Na]+. Example 96 Synthesis of NO-releasing prodrug of indomethacin (I-C1-NOPD18): This prodrug was synthesized as shown in Scheme 11, Method A. Thus, to a solution of indomethacin (3.01 g, 8.42 mmol) in THF (50 mL) at RT was added CDI (1.64 g, 10.10 mmol). After 1 h, LI-5.TFA (3 g, 8.42 mmol) was added at O °C, fol10wed by TEA (5.9 172 mL, 42.1 mmol) and DMAP (O.6 g, 4.91 mmol). The reaction mixture was stirred at RT for 2 d. After usual aqueous work-up and chromatographic purification, 3.16 g (7O%) of I-C1-NOPD18 were obtained as yel10w solid. ]H NMR (CDC13, 300 MHz): δ 2.38 (s, 3H), 2.79 (t, 2H, J = 6.3 Hz), 2.86 (t, 2H, J = 6.9 Hz), 3.54 (q, 2H, J - 6.0 Hz), 3.66 (s, 2H), 3.83 (s, 3H), 4.61 (t, 2H, J = 6.6 Hz), 6.01 (bs, 1H), 6.71 (dd, 1H, J = 2.1, 9.O Hz), 6.9 (dd, 2H, J = 3.3, 8.1 Hz), 7.49 (d, 2H, J = 8.4 Hz, 2H), 7.66 (d, 2H, J = 8.4 Hz). MS: m/z 538.10 [M+H]+, 56O.1 [M+Na]+. Example 97 Synthesis of NO-releasing prodrug of ketoprofen (I-C1-NOPD19): This prodrug was synthesized as shown in Scheme 11, Method A according to the method described in Example 90, using as reagents ketoprofen (1.27 g, 5 mmol), CD1 (1.21 g, 7.5 mmol) and LI-2b (1 g, 5 mmol). Yield: 0.6 g (51%). *H-NMR (300 MHz, CDCI3): δ 1.55 (d, 3H, J - 7.O Hz), 2.80-2.95 (m, 4H), 3.82 (q, 1H, J = 6.7 Hz), 4.35 (t, 2H, J = 6.1 Hz), 4.64 (t, 2H, J = 6.5 Hz), 7.40-7.85 (m, 9H). MS (ES+) m/z: 436.06 [M+H]+, 458.O2 [M+Na]+. Example 98 Synthesis of NO-releasing prodrug of ketoprofen (I-Cl-NOPD2Oa): This prodrug was synthesized as shown in Scheme 11, Method I. Thus, to a solution of the amide of ketoprofen (1.78 g, 7 mmol) in DCE (70 mL) was added oxalyl ch10ride (0.706 g, 8.4 mmol) at 0 °C and refluxed for 16 h. After cooling to RT, a solution of LI-2B (1.4 g, 7 mmol) in DCE (10 mL) was added and stirred for 20 h. After usual aqueous work-up and chromatographic purification, 0.6 g (17 %) of I-Cl-NOPD2Oa was obtained as a pale yel10w gum. 1H NMR (CDC13, 300 MHz): 8 1.47 (d, 3H, J = 6.96 Hz), 3.00 (bs, 4H), 4.00 (q, 1H, J - 6.81 Hz), 4.39 (t, 2H, J = 6.21 Hz), 4.68 (bs, 2H), 7.47-7.77 (bs, 9H). MS: ES+ m/z 478[M+H]+, 477.I5[M-H]+. Example 99 Synthesis of NO-releasing prodrug of dic10fenac (I-C1-NOPD22): This prodrug was synthesized as shown in Scheme II, Method B, using as reagents dic10fenac (0.706 g, 3.378 mmol), LI-2b (O.68 g, 3.37 mmol), DMF (8 mL), DCC (O.835 g, 4.O54 mmol) and DMAP (O.O82 g, O.675 mmol). Yield: 0.35 g (22 %). 'H-NMR (300 MHz, CDCI3): 8 2.91-3.04 (m, 4H), 3.85 (s, 2H), 4.42 (t, 2H, J = 6.6 Hz), 4.72 (t, 2H, J = 173 6.6 Hz), 6.56 (d, 1H, J= 8.1 Hz), 6.82 (s,1H), 6.94-7.O3 (m, 2H), 7.12-7.27 (m,2H), 7.35 (d, 1H, J= 8.1Hz). MS (ES+) m/z: 476.90 [M+H]+, 498.86 [M+Na]+. Example 100 Synthesis of NO-releasing prodrug of flurbiprofen (I-C1-NOPD26): This prodrug was synthesized as outlined in Scheme 20. Thus, to a solution of S2O-I1 (0.8 g, 2.90 mmol) in THF (10 mL) and DMF (10 mL) was added the cesium salt of flurbiprofen (1.2 g, 3.19 mmol) and stirred at RT for 2 h. After usual aqueous work-up and chromatographic purification, 1.13 g (80 %) of I-C1-NOPD26 was obtained as a light yel10w semi solid. !H NMR (500 MHz, CDC13): 6 1.58 (d, 3H, J = 7.5 Hz), 2.88-2.94 (m, 4H), 3.88 (q, 1H, J= 7.O Hz), 4.40 (t, 2H, J = 6.5 Hz), 4.64-4.68 (m, 4H), 7.14-7.54 (m,8H). MS: m/z 501.1 [M+NH4]+, 506.1 [M+Na]+. Example 101 Synthesis of NO-releasing prodrug of gabapentin ethyl ester (I-A1-NOPD1): This prodrug was synthesized as shown in Scheme 12, Method A. Thus, to a stirred solution of diphosgene (O.88 mL, 7.37 mmol) in DCM (3 mL) at O °C was added drop-wise a solution of LI-2a (O.80 g, 3.68 mmol) & Hunig's base (1.92 mL, 11.85 mmol) in DCM (1 mL). The mixture was stirred at O °C for 30 min and concentrated. The residue was dissolved in DCM (4 mL) and treated with gabapentin ethyl ester hydroch10ride (O.95 g, 4.O5 mmol) & Hunig's base (1.39 mL, 8.O5 mmol). The mixture was stirred at RT for 3 h and concentrated. The residue, after usual aqueous work-up, gave 1.6 g (98 %) of I-S12-I1. 'H-NMR data is consistent with the expected structure. MS (ES+) m/z: 444 [M+H]+, 465.9 [M+Na]+. To a stirred solution of I-S12-I1 (1.3 g, 2.94 mmol) in acetonitrile (8 mL) at RT was added silver nitrate (O.6 g, 3.52 mmol) portion-wise and stirred at RT for 2.5 h. After filtration through celite, the filtrate was concentrated and the residue purified by column chromatography to afford 0.561 g (45 %) of prodrug I-A1-NOPD1. 'H-NMR data is consistent with the expected structure. MS (ES+) m/z: 425 (M+H)+, 447 (M+Na)+. Example 102 Synthesis of NO-releasing prodrug of lamotrigine (I-Al-NOPD3a and I-Al-NOPD3b): This prodrug was synthesized as shown in Scheme 12, Method B. Thus, to a suspension of lamotrigine (1 g, 3.90 mmol) in toluene (20 mL) at 120 °C was added drop-wise a 174 solution of the imidazolide of LI-2b (1.4 g, 4.70 mmol) in THF (10mL) and refluxed for 6 h. After usual aqueous work-up and chromatographic purification, 340 mg (20%) of I- Al-NOPD-3a/b was obtained. 'H-NMR data is consistent with the expected structure. MS(ES)+m/z: 481 (M+H)+. Example 103 Synthesis of NO-releasing prodrug of nicotinic hydrazide (I-A1-NOPD4): This prodrug was synthesized from nicotinic hydrazide (235 mg, 1.70 mmol) according to the procedure described in Example 109 (see Scheme 13, Method B). After usual workup, the crude product was purified by column chromatography to afford 0.21 g (34%) of prodrug I-A1-NOPD4. !H-NMR (300 MHz, DMSO-d6): 6 3.02 (t, 2H, J - 5.8 Hz), 3.10 (t, 2H, J = 6.1 Hz), 4.28 (t, 2H, J = 5.8 Hz), 4.76 (t, 2H, J = 6.1 Hz), 7.51-7.55 (dd, 1H, J = 4.8 Hz, 7.7 Hz), 8.17 (d, 1H, J = 7.8 Hz), 8.74 (d, 1H, J = 3.8 Hz), 8.98 (s, 1H), 9.44 (bs, 1H), 10.54 (bs, 1H). MS (EI)+m/z: 363 [M+H]+. Example 104 Synthesis of NO-releasing prodrug of lisinopril dimethyl ester (I-A1-NOPD5): This prodrug was synthesized from lisinopril dimethyl ester hydroch10ride (1.10 g, 2.56 mmol) according to the procedure described in Example 101 (see Scheme 12, Method B). After usual workup, the crude product was purified by column chromatography to afford 0.76 g (67%) of prodrug I-A1-NOPD5. !H-NMR (300 MHz, CDC13): 5 1.49-1.54 (m, 2H), 1.93-2.07 (m, 8H), 2.12-2.28 (m, 1H), 2.64-2.68 (m, 2H), 2.91-3.0 (m, 4H), 3.18- 3.25 (m, 3H), 3.42-3.47 (m, 1H), 3.52-3.55 (m, 2H)S 3.69 (s, 3H), 3.73 (s, 3H), 4.28 (t, J = 6.3 Hz, 2H), 4.47-5.05 (m, 1H), 4.69 (t, J - 6.8 Hz, 2H), 5.22 (bt, 1H), 7.14-7.19 (m, 3H), 7.23-7.28 (m, 2H). MS (EI)+m/z: 659 [M+H]+. Example 105 Synthesis of NO-releasing prodrug of omeprazole (I-A1-NOPD6): This prodrug was synthesized as shown in Scheme 12, Method B. To an ice-cold solution of diphosgene (0.3 mL, 2.48 mmol) in toluene at 0 °C, was added a mixture of LI-2b (0.5 g, 2.51 mmol) and TEA (0.42 mL, 3.0 mmol) in toluene (3 mL) and stirred for 2 h. In a separate flask, omeprazole (O.867 g, 2.50 mmol) was dissolved in THF (5 mL), cooled to 0 °C and NaH (0.059 g, 2.5 mmol) was added. The mixture was stirred for 30 min, the above reaction mixture was added dropwise to it and stirred for 2 h. After usual aqueous 175 work-up and chromatographic purification, O.23 g (2O %) of I-A1-NOPD6 was obtained as a reddish-yel10w gum. 'H-NMR; (CDC13, 300 MHz): 2.21 (s, 3H), 2.36 (s, 3H), 2.93- 3.05 (m, 2H), 3.19-3.28 (m, 2H), 3.88 (s, 3H), 3.92 (s, 3H), 4.7O-4.87 (m, 6H), 7.10-7.80 (m, 3H), 8.10 (s, 1H). MS: ES+ m/z 571 (M+H)+, 593 (M+Na)+. Example 106 Synthesis of NO-releasing prodrug hydralazine (I-A1-NOPD7): This prodrug was synthesized from hydralazine hydroch10ride (0.99g, 5.01 mmol) according to the procedure described in Example 109 (see Scheme 13, Method B). After usual workup, the crude product was purified by column chromatography to afford 0.8 g (41%) of prodrug I-A1-NOPD7. 'H-NMR (300 MHz, CDC13): 8 2.95-3.06 (m, 4H), 4.43 (t, 2H, J = 6.35Hz), 4.69 (t, 2H, J - 6.7 Hz), 7.57 (m, 1H), 7.63-7.71(m, 2H), 8.16 (s, 1H), 8.29 (d, 1H, J = 7.6 Hz). MS (ES4) m/z: 386.05 (M+H)+. Example 107 Synthesis of NO-releasing prodrug of am10dipine (I-A1-NOPD8): This prodrug was synthesized from am10dipine (1.67 g, 4.09 mmol) according to the procedure described in Example 109 (see Scheme 12, Method B). After usual workup, the crude product was purified by column chromatography to afford 1.33 g (61%) of I- A1-NOPD8. 'H-NMR (300 MHz, CDCI3): 8 1.18 (t, 3H, J = 7.1 Hz), 2.36 (s, 3H), 2.93- 2.99 (m, 4H), 3.47 (bs, 2H), 3.61-3.64 (m, 5H), 4.04 (q, 2H, J = 7.1 Hz), 4.35 (bt, 2H), 4.68-4.74 (m, 4H), 5.0 (bs, 1H), 7.13-7.36 (m, 4H). MS (ES*) m/z: 634.14 (M+H)+, 656.83 (M+Na)+; (ES") m/z: 631.94 (M-H)+. Example 108 Synthesis of NO-releasing prodrug of levetiracetam (I-A2-NOPDla): This prodrug was synthesized from levetiracetam (0.706 g} 5.87 mmol) according to the procedure generally described in Example 82 (see Scheme 13, Method A). After usual workup and chromatographic purification, the product was further purified by preparative HPLC to afford 728 mg (31%) of prodrug I-A2-NOPDla. 'H-NMR was consistent with the expected structure. MS (ES)+m/z: 396.1 [M+H]+, 418.1 [M+Na]+, (ES) m/z: 394.1 [M-H] Example 109 Synthesis of NO-releasing prodrug of valdecoxib (I-A3-NOPDla): 176 This prodrug was synthesized as shown in Scheme 13, Method B. Thus, to a cold suspension of sodium hydride (271 mg, 6.81 mmol) in THF (7 mL) was added drop-wise a solution of valdecoxib (1.78 g, 5.68 mmol) in THF (15 mL) and stirred at RT for 2 h. A solution of the imidazolide of LI-2b (2.0 g, 6.81 mmol) in THF (15 mL) was added and stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue, after usual aqueous work-up and chromatographic purification, afforded 976 mg (32 %) of prodrug I-A3-NOPDla. ]H-NMR data is consistent with the expected structure. MS (ES)"m/z: 538 [M-H] Example 110 Synthesis of NO-releasing prodrug of celecoxib (I-A3-NOPD2a): This prodrug was synthesized from celecoxib (6.62 g, 17.35 mmol) according to the procedure described in Example 109 (see Scheme 13, Method B). After usual workup, the crude product was purified by column chromatography to afford 1.55 g (15%) of prodrug I-A3-NOPD2a. 'H-NMR (300 MHz, CDC13): 6 2.38 (s, 3H), 2.84-2.98 (m, 4H), 4.34 (t, 2H, J = 6.45 Hz), 4.63-4.71 (m, 2H), 6.74 (s, 1H), 7.O9-7.25 (m, 4 H), 7.51 (d, 2H, J - 6.8 Hz), 8.O2 (d, 2H, J = 6.8 Hz). MS (ES)+ m/z: 6O6.87 [M + H]+, 628.93 [M + Na]+; (ES)* m/z: 6O4.88 [M-H] Example 111 Synthesis of NO-releasing prodrug of paracetamol (I-H1-NOPD1): This prodrug was synthesized as shown in Scheme 14, Method B. Thus, to a solution of paracetamol (2.0 g, 13.24 mmol) in THF (20 mL) was added CDI (2.36 g, 14.57 mmol) and the mixture was stirred at RT for 3 h. To this was added a solution of LI-2b (1.21 g, 6.62 mmol), fol10wed by DMAP (0.802 g, 6.622 mmol) and stirred overnight at RT. The mixture was quenched with water and extracted with EtOAc. After usual aqueous workup and chromatographic purification, 0.3 g (6%) of prodrug I-H1-NOPD1. 'H-NMR data is consistent with the expected structure. MS (Cl)+ m/z: 376 [M+H]+. Example 112 Synthesis of NO-releasing prodrug of paracetamol (I-Hl-NOPD2a): This prodrug was synthesized as shown in Scheme 14, Method D. Thus, to a solution of ch10rocarbonyl isocyanate (0.70 lg, 6.622 mmol) in benzene (5 mL) at 0 °C was added a solution of paracetamol (1 g, 6.622 mmol) and stirred at 0 °C for 1 h. To this was added a 177 solution of LI-2b (1.21 g, 6.622 mmol) and TEA (1 mL) in THF (5 mL), and stirred overnight at RT. After usual aqueous work-up and chromatographic purification, 90 mg (3%) of prodrug I-Hl-NOPD2a was obtained. 'H-NMR data was consistent with the expected structure. MS: (ES)" m/z: 418 [M-H]". Example 113 Synthesis of NO-releasing prodrug of paracetamol (I-H1-NOPD3): This prodrug was synthesized from paracetamol (2.0 g, 13.24 mmol) according to the procedure described in Example 122 (see Scheme 14, Method C). After usual workup, the crude product was purified by column chromatography to afford 0.706 g (2O%) of prodrug I-H1-NOPD3. 'H-NMR (500 MHz, CDC13): 5 2.11 (s, 3H), 2.91 (t, 2H, J = 6.5 Hz), 3.06 (t, 2H, J = 6.5Hz), 3.49 (t, 2H, J = 6.5 Hz), 4.75 (t, 2H, J = 6.5 Hz), 7.05 (d, 2H, J = 9.O Hz), 7.54 (d, 2H, J = 9.O Hz). MS (ES)+ m/z: 376 [M+H]+, 393 [M+NH4f, 397 [M+K]+. Example 114 Synthesis of NO-releasing prodrug of metronidazole (I-H1-NOPD6): This prodrug was synthesized in two steps as shown in Scheme 14, Method C. Step 1; To a suspension of metronidazole (5 g, 29.22 mmol) in ch10roform (100 mL) was added CDI (5.21 g, 32.2 mmol) and stirred overnight at RT. The reaction mixture, after usual aqueous work-up, gave 7.66 g (98 %) of the imidazolide intermediate. 'H-NMR data was consistent with the expected structure. MS (ES)+ m/z: 266.1 [M + H]+. Step 2: To a mixture of LI-5.TFA (2.68 mmol) and TEA (0.7068 g, 10.72 mmol) in DCM (10 mL) at 0 °C was added the imidazolide of metronidazole (0.78 g, 2.95 mmol) and stirred at RT for 48 h. The reaction mixture was quenched with water and extracted with DCM. After usual aqueous work-up and chromatographic purification, 50 mg (4.3%) of I-H1-NOPD6 was obtained. 'H-NMR (500 MHz, CDCU): 8 2.50 (s, 3H), 2.80 (t, 2H, J = 6.3 Hz), 2.96 (t, 2H , J = 6.6Hz), 3.47-3.50 (m, 2H), 4.41 (t, 2H, J = 5.1Hz), 4.58 (t, 2H, J = 5.1Hz), 4.70 (t, 2H, J = 6.6Hz), 7.96 (s, IH). MS (ES)+ m/z: 395.99 [M+H]+. Example 115 Synthesis of NO-releasing prodrug of budesonide (I-H1-NOPD9): This prodrug was synthesized from budesonide (0.5 g, 1.16 mmol) according to the procedure described in Example 122 (see Scheme 14, Method C). After usual workup, 178 the crude product was purified by column chromatography to afford 0.25 g (33%) of prodrug I-H1-NOPD9. 'H-NMR data was consistent with the expected structure. MS (ES)+ m/z: 655 [M+H]+. Example 116 Synthesis of NO-releasing prodrug of 4-Hydroxy-TEMPO (I-H1-NOPD10): A solution of LI-2b (0.20 g, 1.20 mmol) and CD1 (0.195 g, 1.20 mmol) in ch10roform (5 mL) was stirred at RT for 2 h, which was fol10wed by the addition of 4-hydroxy-TEMPO (0.173 g, 0.7060 mmol) and DMAP (0.122 g, 0.7060 mmol). The mixture was refluxed for 2 d, then purified by column chromatography to afford 110 mg (27 %) of I-H1-NOPD10 as a red oil. MS: EI+ m/z 398 [M+H]+, 42O [M+Na]+. Example 117 Synthesis of NO-releasing prodrug of edaravone (I-H1-NOPD11): To a solution of edaravone (0.87 g, 5 mmol) in acetonitrile was added KF-AI2O3 (66 g) and, under thorough mixing, LI-3a (2.8 g, 10 mmol) was added. The mixture was agitated for 20 h. After usual aqueous work-up and chromatographic purification, 70 mg (4%) of the intermediate bromide was obtained as a reddish-yel10w oil. ]H NMR (CDCI3, 500 MHz): 5 2.28 (s, 3H), 3.00-3.10 (m, 4H), 3.59 (t, 2H, J = 8 Hz), 4.34 (t, 2H, J = 6.5 Hz), 5.5 (s, 1H), 7.4 (t, 2H, J = 1 Hz), 7.69 (t, 3H, J = 1 Hz). MS: ES+ m/z 375 [M+H]+, 397.O [M-t-Na]*. To a solution of the above bromide (0.05 g, 0.134 mmol) in acetonitrile (1.5 mL) was added AgNO3 (0.027 g, 0.160 mmol) and stirred for 2O h. After usual aqueous workup and purification, 0.025 g (53 %) of I-H1-NOPD11 was obtained as a brown gum. 'H NMR (CDCI3, 500 MHz): 5 2.28 (s, 3H), 2.90 (t, 2H, J = 6.5 Hz), 3.10 (t, 2H, J = 6.5 Hz), 4.33 (t, 2H, J = 6.0 Hz), 4.63 (t, 2H, J= 6.5 Hz), 5.5 (s, 1H), 7.60-7.63 (bs, 2H), 7.65-7.67 (bs, 3H). MS: ES+ m/z 356 [M+H]+. Bio10gical Example 1: Screening of prodrugs and mutual prodrugs of anticonvulsants: Most of the prodrugs and mutual prodrugs of anticonvulsants described in this invention were evaluated at National Institute of Neuro10gical Disorders and Stroke (NINDS), National Institute of Health (NIH), under their Antiepileptic Screening Program (ASP). 179 Test 1 is an initial screening for anticonvulsant activity in the Maximal Electroshock Test (MES) and Subcutaneous Metrazol Seizure Threshold Test (scMET) models combined with an initial assessment of toxicity (TOX) in mice via i.p. injection (see further explanation be10w). The data for each condition is presented as N/F, where N = number of animals protected from seizure and F = number of animals tested. For test of toxicity, N = number of animals displaying toxic effects and F = number of animals tested. Any deaths occurring during the test were recorded. Maximal Electroshock Test (MES): The MES is a model for generalized tonic-c10nic seizure and provides an indication of a compound's ability to prevent seizure spread when all neuronal circuits in the brain are maximally active. These seizures are highly reproducible and electro-physio10gically consistent with human seizures. For all tests based on MES convulsions, 60 Hz of alternating current (50 mA in mice) is delivered for 2s by corneal electrodes, which have been primed with an electrolyte solution containing an anesthetic agent (0.5% tetracaine hydroch10ride). Mice were tested at various intervals fol10wing doses of 30, 100 and 300 mg/kg of test compound given by i.p. injection of a volume of 0.01 mL/g. Other doses can be used if indicated by previously known pharmaco10gy. An animal is considered "protected" from MES-induced seizures upon abolition of the hind-limb tonic extensor component of the seizure. Subcutaneous Metrazol Seizure Threshold Test (scMET): Subcutaneous injection of the convulsant metrazol produces clonic seizures in laboratory animals. The scMET test detects the ability of the test compound to raise the seizure threshold of an animal and thus protect it from exhibiting a c10nic seizure. Animals were pretreated with various doses of the test compound given by i.p. injection. At the previously determined Time to Peak Effect (TPE) of the test compound, the dose of metrazol which will produce convulsions in 97% of animals (CD97: 85 mg/kg in mice) was injected into a 10ose fold of skin in the midline of the neck. The animals were placed in isolation cages to minimize stress and observed for the next 30 minutes for the presence or absence of a seizure. An episode of c10nic spasms, approximately 305 seconds, of the fore and/or hind limbs, jaws, or vibrissae is taken as the end point. Animals which do not meet this criterion were considered protected. 180 Acute Toxicity - Minimal Motor Impairment (MMI): To assess a compound's undesirable side effects (toxicity), animals were monitored for overt signs of impaired neuro10gical or muscular function. In mice, the rotorod procedure is used to disc10se minimal muscular or neuro10gical impairment. When a mouse is placed on a rod that rotates at a speed of 6 rpm, the animal can maintain its equilibrium for 10ng periods of time. The compound is considered toxic if the animal falls off this rotating rod three times during a 1-min period. In addition to MMI, animals may exhibit a circular or zigzag gait, abnormal body posture and spread of the legs, tremors, hyperactivity, lack of exp10ratory behavior, somnolence, stupor, catalepsy, 10ss of placing response and changes in muscle tone. Compounds that were active in Test 1 (mice i.p.) were further screened in Test 2 (rat p.o.). Compounds retaining activity in Test 2 (rat p.o.) were selected for secondary evaluation (i.e., Test 3, Rat P.O. quantification) as explained be10w: Secondary Evaluation: All quantitative in vivo anticonvulsant/toxicity evaluations of the active compounds were conducted at compound's time of peak pharmacodynamic activity (TPE). Groups of at least 8 rats received various doses of the candidate compound until at least two points were established between the limits of 100 percent protection or toxicity and zero percent protection or minimal toxicity. The 95 percent confidence limits, s10pes of the regression lines and standard errors of the s10pes were calculated for each quantitative determination. Rats received test compounds orally. Test 1 screening results are presented in Table 1. Compound I-CA-MPD24 was active in both MES and scMET models and was shown to be non-toxic. However, some compounds were active in both MES and scMET models and were also shown to be toxic. The compounds (i.e., I-A1-PD4,1-AA-MPD12,1-CA-MPD23,1-A1-PD5,1-Al-NOPD3, I-CA-MPD24,I-A1-PD15,1-CA-MPD25, and I-AA-MPD11) that are shown to be active in MES but showed no or mild toxicity were selected for Test 2 screening and those results are presented in Table 2. Three of the compounds (i.e., I-A1-PD4,1-AA-MPD12, and I-A1-NOPD3) were considered for secondary evaluation, where quantification of their antiepileptic activity and neurotoxicity in rats (p.o.) was carried out. This secondary evaluation determines the time to peak effect (TPE), neurotoxicity, median effective dose (ED50) and bio10gical 181 response. The 95% confidence interval, the s10pe of the regression line, and the standard error are then calculated. The results of secondary evaluation (Test 3) are presented in Tables 3A and 3B. Table 1: Primary Screening (Test 1) data for Anticonvulsant Activity and Neurotoxicity in Mice (test compound administered i.p.) Compd MESa,b ScMETa,c Rotorod Toxicitya,d 0.5 h 4.0 h 0.5 h 4.0 h 0.5 h 4.0 h 1-A1-PD7 + (1/1) - + (l/l)e - + (2/4)d - I-A1-PD8 ++ (2/3) + (1/1) + (1/1) + (1/1) - + (4/4)f - 1-A1-PD4 ++(1/7) + (2/5) +++(1/1)++ (3/3)+ (1/1) - - - - I-AA-MPD12 nd ++ (3/3) ++ (l/3)g+ O/1) nd nd nd nd I-CA-MPD23 - ++(l/3)h + (1/3) - - - - I-A1-PD13 +(1/1) - +(I/D - + (1/4) - I-A1-PD5 +(1/1) - + (3/5) - + (3/4)' - I-A1-PD6 +(1/1) - + (1/1) - + (4/4)1 - I-A1-PD10 - - - - ++ (8/8) nd I-AA-MPD13 +(1/1) + (4/4) I-A1-NOPD1 ++ (l/3)k + (1/1) - +(1/1) - + (4/4)i - I-A1-NOPD3 - ++(1/3) + (1/1) ++ (1/1)1 - +++(1/4) - 182 - I-CA-MPD24 - ++ (3/3)++ (3/3)h ++ (3/3)m - --+ (l/l)1 - - I-A1-PD15 ' + (1/1) ++ (2/3) + (1/0 - - - - 1-CA-MPD25 + (1/1) ++ (2/3) + (1/1) - - - - I-AA-MPDI1 + (1/1) ++ (3/3) + (1/1) - - + (1/4) - aKey: +++ = activity or toxicity at 30.mg/kg, ++ = activity or toxicity at 100 mg/kg, + = activity or toxicity at 300 mg/kg, - = no activity or no toxicity at 300 mg/kg. bMaximal electroshock seizure test. cSubcutaneous pentylenetetrazole seizure test. dNeuro10gical toxicity (number of animals exhibiting toxicity/number of animals tested). e(number of animal protected/number of animal tested), nd = not determined, toss of righting reflux. gAt 6 hours after dosing. hAt 2 hours after dosing. 'Unable to grasp rotorod. jDeath. kAt 0.25 hours after dosing. 'Myoc10nic jerks. mAt 6 hours after dosing. Table 2: Screening (Test 2) data for Anticonvulsant Activity and Neurotoxicity in Rats (test compound administered p.o.) Compd Dose (mg/kg) Time (h) MESa,b Toxicityc'd I-Al-PD4 30 0.50 0.7060 2.0 4.00 0/4 1/4 3/4 4/4 0/4 0/4 0/4 0/4 T-AA- 30 0.50 0/4 0/4 183 MPD12 1.002.00 4.00 0/4 1/43/4 0/4 0/4 0/4 I-CA-MPD23 150 2.00 4.00 6.00 8.00 4/44/4 4/4 4/4 0/4 0/4 0/4 0/4 I-Al-PD5 50 0.50 1.00 2.00 4.00 0/4 O/4 1/4 1/4 0/4 0/4 0/4 0/4 1-A1-NOPD3 30 0.50 1.00 2.00 4.00 O/4 2/4 1/4 4/4 0/4 0/4 0/4 0/4 I-CA-MPD24 30 0.50 1.00 2.004.00 O/4 2/4 3/4 4/4 0/4 0/4 0/4 0/4 I-Al-PD15 30 0.50 1.002.00 4.00 O/4 1/43/4 4/4 0/4 0/4 0/4 0/4 I-CA-MPD25 30 0.50 1.002.004.00 O/43/4 4/4 2/4 0/4 0/4 0/4 0/4 I-AA-MPD11 30 0.50 1.002.002.00 4.OO O/42/4 1/44/4 0/4 0/4 0/4 0/4 184 aMaximal electroshock seizure test, (number of animal protected/number of animal tested). ‘Neuro10gical toxicity. d(number of animals exhibiting toxicity (i.e., atoxia)/number of animals tested). Table 3A: Screening (Test 3) data for Anticonvulsant Activity (Time to Peak Effect) and Neurotoxicity in Rats (test compound administered p.o.) Compd Dose(mg/kg) Time (h) Time to Peak Effect 1 Toxicityd,e (mg/kg) MESa'b ScMETb'c(50mg/kg) I-Al-PD4 10 4.0 6.0 8.0 24 4/4 3/4 2/4 O/4 30 0.250.50.7062.04.0 2/4 2/4 2/4'2/4 4/4 1/4*0/42/41/48O/4 0/4(100) 0/4(100) 0/4(100) 0/4(100) I-AA-MPD12 15 6.0 8.0 2/41/4 30 0.51.02.04.06.08.0248.0 0/4 0/4 1/4 3/44/4 4/4 2/4 1/4 O/4 O/4 1/4 2/4 O/4 0/4 (50) 0/4 (50) 0/4 (50) 0/4 (50) 0/4 (50) 0/4 (50) 1/8 (100)h 185 I-Al- 30 O.25 0/8 (500) NOPD3 0.5 0.706 0/8 (500) 0/8 (500) 2.0 1/4 0/4 0/8 (500) 4.O 3/4 0/4 0/8 (500) 6.0 3/4 1/4 1/8 (500) 8.O 4/4 3/4 0/8 (500) 24 3/4 1/4 aMaximal electroshock seizure test. b(number of animal protected/number of animal tested). cSubcutaneous pentylenetetrazole seizure test. ivleuro10gical toxicity. e(number of animals exhibiting toxicity (i.e., atoxia)/number of animals tested). Death fol10wing continueous seizure. sPopcorn effect and continuous seizure activity. Mild ataxia only. Table 3B: Screening (Test 3) data for Anticonvulsant Activity (ED50 and Bio10gical Response and ED50) in Rats (test compound administered p.o.) Compd ED 50 Values and Bio10gical Response Time (h) Dose (mg/kg) MESa'b ED50 95%ConfidenceInterval10w/High S10pe/Std. Er I-Al-PD4 4 1.9 3.87.5 15 30 0/8 4/8 4/8 7/8 7/8 6.55 3.56/10.72- 2.27/O.63 186 I-AA- 6 7.5 0/8 MPD12 15 30 60 5/8 7/8 7/8 17.1 9.98/25.8 3.2/0.95 I-Al- 8 3.8 3/8 NOPD3 7.5 3/8 15 30 60 4/89/128/8 10.1 2.99/17/44 1.61/3.15 aMaximal electroshock seizure test.. (number of animal protected/number of animal tested). I-A1-PD4 is a simple prodrug of lamotrigine. For this prodrug, ED50 for the MES model was determined to be 6.55 mg/kg and the time to peak effect was found to be 4.O h after drug administration at doses of 10 as well as 30 mg/kg. This compound has shown moderate protection in scMET models where one out of four animals were protected at O.25 h and 2.0 h period and two out of four animals were protected at 0.706 h after administration of the drug at a dose of 50 mg/kg. For the toxicity analysis, none of the animals given 100 mg/kg showed signs of toxicity. I-AA-MPD12 is a mutual prodrug of lamotrigine and gabapentin ethyl ester. For this compound, ED50 for the MES model was found to be 17 mg/kg and the time to peak effect was found to be 6.0-8.O h at a dose of 30 mg/kg and indicated a significant extension protection (2 out of 4 animals were still protected) at 24 h after drug administration. Surprisingly, this compound, although less potent than lamotrigine, has exhibited significant extension in the duration of protection. At 50 mg/kg, none of the animals exhibited toxicity. However, at 100 mg/kg, one of eight animals exhibited mild ataxia. I-A1-NOPD3 is a NO-releasing prodrug of lamotrigine. For this prodrug, ED50 for the MES model was determined to be 10.1 mg/kg and the time to peak effect was found be at 8.O h at a dose of 30 mg/kg and revealed a significant extension of protection (3 out 4 animals were still protected) even at 24 h after drug administration. Surprisingly, this prodrug, although less potent than its parent drug, has exhibited significant extension 187 in the duration of protection. At 50 mg/kg, this compound has also exhibited significant protection (3 out of 4 animals were protected at 8 h after drug administration) in scMET rat model. For the toxicity analysis, only one in eight animals exhibited toxicity at 6.0 h time point at a dose of 500 mg/kg. At other time points (i.e., O.25 h, 0.5 h, 0.706 h, 2.0 h, 4.O h, 8.O h after drug administration), none of the animals (O/8) exhibited any significant toxicity at the high dose of 500 mg/kg. Bio10gical Example 2: The pharmaco10gical experiments on NO-releasing aspirin prodrugs were carried out by fol10wing the procedures described herein: Animals and Procedures: Male or female Sprague-Dawley rats weighing 150-2OO g were used in the study. The rats were fed normal standard laboratory chow and maintained under standard conditions (room temperature of 22 ± 2 °C; 50 ± 10 % relative humidity; artificial light O6:OO to 18:OO). All experimental procedures mentioned be10w are approved by institutional animal research committees and were performed in accordance with standard guidelines for the treatment of animals. Sample preparation and standard curve: HPLC: Waters Allience analytical HPLC equipped with 2996 PDA detector and Empower software were used to analyze the samples. HPLC Column: WatersX-TerraRP-18 analytical column, 150X3.9 mm, 5 D. HPLC Method: F10w: 1 mL/min, detecter set at 210 nm and at Maxp10t (210-40O nm range). Solvent A: Acetonitrile; Solvent B: O.1% TFA in water. Elution method: A linear gradient of 0-100% A. Plasma samples were processed by transferring 75 u.1 quantity of b10od into a test tube containing 250 µl acetonitrile, vortex-mixed and centrifuged at 1000 g for 5 min. 200 µl of supernatant was then taken and diluted to 2 times with acetonitrile. 100 µl of the sample was injected into HPLC for analysis. Salicylate standard curves were generated using acetonitrile as solvent in the working range of 1-100 ng/ml. 188 Pharmacokinetic parameters were calculated using WinNonlin software (4.1 version). Cmax, Tmax, AUC O-24, AUC O-infinity, and T|# characterized and each curve generated fol10wing oral treatment In Vitro Plasma stability: The rationale is that the prodrugs would be hydrolyzed in-vivo before, during or after absorption to release the corresponding free drugs. Therefore, we tested whether the test compounds (I-C1-NOPD6,1-C1-NOPD4,1-C1-NOPD5A) released parent drug in rat plasma at 37 ° C after 30 minutes incubation. The compounds were extracted back into acetonitrile with rigorous vortex. The results suggested that all prodrugs tested except I-C1-NOPD6 were found to be converting to the expected metabolite (salicylate) of the parent drug (aspirin) as revealed by HPLC analysis. Even aspirin was completely metabolized to salicylate after 30 minutes of incubation with rat plasma indicating that all the test compounds released aspirin, which in turn converted into salicylate. Pharmacokinetic studies: The oral pharmacokinetics of the test compounds, I-C1-NOPD6, I-C1-NOPD4,1-C1-NOPD5A and I-C1-NOPD5B was done in rats and the release profiles of salicylate from these compounds were analyzed by HPLC and the results were presented in Figure 1 and Table 4. Overnight fasted rats were fed with 35 mg/kg equivalent doses of aspirin and test compounds. B10od was collected from orbital plexus of test animals at various time points up to 24 hrs. As shown in Figure 1, the test compounds I-C1-NOPD4 and I-C1-NOPD5B indicated unexpected drug release profiles wherein the salicylate is released in a sustained and controlled manner starting from 1 hour through 12 hours. For I-Ci-NOPD5B, the plasma salicylate concentration was maintained between 50 and 75 g/ml during this extended period of over 11 hours. This kind of plasma concentrations of the drug can result in significant extension of duration of action. For I-C1-NOPD4 also, the plasma salicylate concentration was maintained between 35 and 50 g/mL during an extended period of over 11 hours. Although aspirin absorption (Figure 1) was highest during 0.5 - 6.0 hrs (during which period much of the damage to the gastrointestinal tract of the subject occurs due to high concentrations of the drug), plasma salicylate concentration for aspirin and I-C1-NOPD4 were comparable during the period from 8 through 24 hours. Such sustained release profile of active drug from the prodrug is 189 expected to cause negligible or insignificant gastrointestinal damage as the plasma concentration of the drug never reaches to the toxic levels. Similar release profile was observed with I-C1-NOPQ5A but for a shorter period of time. Unexpectedly, we have also observed as recorded in Table 4, nearly equal drug AUC values for aspirin and I-Cl -NOPD5B (i.e., 923.63 ± 182.08 for aspirin vs 951.98 ± 11.58 for I-C1-NOPD5B) which indicates that the prodrug is as bioavailable as its parent drug, but prodrug does not cause gastric damage. Surprisingly, neither the prodrug nor the salicylate was found in the plasma of the animals fed with I-C1-NOPD6 (data not included in the graph) at any point of time tested, the reasons for which are not known. Figure 1. Plasma salicylate profile of aspirin and its NO-releasing prodrugs. The data values are expressed as Mean ± S.E.M, n=3-4 animals. The data values at time points 6 and 10 hours is an average from two animals only. Table 4. Comparison of pharmacokinetic parameters of aspirin and its nitro derivatives Parameters* Aspirin I-C1-NOPD4 I-Cl-NOPD5A I-Cl-NOPD5B Cmax (|ag/mL) 98.67 ±12.64 53.24 ± 6.39 50.14 ± 10.12 66.08 ±3.31 Tmax (h) 0.50 ±O.OO 4.66 ± 0.57 3.0O ±0.57 4.OO ±O.81 190 AUCo-24h(µg/mi) 905.84 ± 173.14 749.36 ±69.38 557.80 ± 97.65 922.89 ± 12.50 AUCO-a(h.µg/ml) 923.63 ± 182.08 772.17 ±75.68 565.30 ± 96.78 951.98 ±11.58 TI/2 (h) 3.56 ±0.42 3.98 ±0.25 3.35 ±0.32 4.14 ±0.24 The data values are mean ± SEM, n = 3-4 Ulcerogenic activity: Gastrointestinal ulceration is a serious side effect associated with NSAIDs. The clinical uses of potent NSAIDs are greatly limited by its gastrointestinal toxicity. We tested ulcerogenic potential of the test compounds, I-C1-NOPD6, I-C1-NOPD4, I-Cl-NOPD5A, and I-C1-NOPD5B in rats. Overnight fasted rats were given orally 100 mg/kg equivalent doses of aspirin and prodrugs (in the case of 1-C1-NOPD5A and I-Cl-NOPD5B, 200 mg/kg equivalent doses were administered). The animals were sacrificed at 3 hours after drug administration. Stomachs of treated rats were separated, perfused with 10 ml of 2 % formalin, and then cut open over the greater curvature. The severity of the mucosal damage was then assessed on the basis of size (area) of the observed ulcers under surgical microscope with a square grid as per the established procedure (Takeuchi et al., J. Pharmacol. Exp. Ther. 1998, 286 (1), 115-121). Interestingly, none of the animals treated with the test compounds showed any signs of deve10pment of ulcers. However, severe haemorrhagic lesions (Mean ± S.E.M.: 2.7 ± O.9 mm ) were seen in aspirin treated rats. Anti-inflammatory activity: Anti-inflammatory activity of test compounds was measured in carrageenan-induced rat paw edema model (Takeuchi et al., J. Pharmacol. Exp. Ther. 1998, 286 (1), 115-121). The activity of aspirin and test compounds (75 mg/kg equivalent dose of aspirin) is shown in Table 5. Aspirin at 75 mg/kg, p.o. exhibited anti-inflammatory activity from 1 hr through 6 hr with peak maximal activity at 4 hr. I-C1-NOPD4 showed significant activity during the first two hours after drug administration but its activity was not as good as that of aspirin from 2 hr through 6 hr. Surprisingly, I-C1-NOPD5A showed negligible anti-inflammatory activity at any time point tested (data not incorporated). We have not yet evaluated I-Cl-NOPD5Bin this efficacy test. 191 Table 5 Compound Rat paw edema (% inhibition) Mean ± SEM, n = 6 1 hour 2 hour 4 hour 6 hour Aspirin 30.706 ± 7.2 52.5 ±3.4 6O.7 ± 6.9 42.8 ± 6.9 I-C1-NOPD4 42.4 ± 13.3 44.9 ± 12.9 24.3 ± 7.7 8.6 ±5.1 The results indicate the fol10wing: 1. Sustained release of the active drug over a period of 10-11 hours, which is good for twice daily dosage regimen, and 2. Exceptional gastrointestinal safety even at high equivalent doses of prodrugs compared to aspirin, which caused severe ulcers at equivalent doses. 192 We claim: 1. A compound of formula (I) or pharmaceutically acceptable salts thereof: wherein, a is O-2; B independently represents a bond, (CH2)b, (CH2CH2O)c, S-S, S-SO, S-SO2 or S-S=NH; bis 1-6; c is 1-100O; A and A1 independently represent a bond, (CH2)d, 1,2-phenylene, 1,3-phenylene or 1,4- phenylene; d is 1-8; D1 represents a therapeutic agent comprising one or more of the functional groups selected from the group consisting of -OH, -SH, -NHR1, -CO2H, -CONHR1, - OC(=O)NHR1, -SO2NHR1, -OSO2NHR1, -N(R)C(=O) NHR1 and -N(R1)SO2NHRI; D independently represents D , a peptide, protein, monoc10nal antibody, vitamin, R~, R , R4, NO, NO2, NONOate or any other nitric oxide-releasing group or molecule, a group or molecule comprising one or more of water-solubilizing functional groups, a polymer or an amino acid; E independently represents CH2 or a bond; L and L independently represent a bond, O, S, NR , L, or a linkage selected from the group consisting of: 193 L is R12 or a group with bonding in any direction, independently selected from the group consisting of: X independently represents a bond, C, O, S, or NR1; Y independently represents a bond, C=O, OS, S=O, SO2, P(=O)XR], or (CH2)d; wherein d is as defined; Z independently represents a bond, or (CH2)J; wherein, j is 1-4; R1 independently represents a bond, H, (C1-C8)alkyl, substituted(C1-C8)alkyl, (C5- C14)aryl, aralkyl or Mc+; R2 independently represents H, NH2, or NHAc; R3 independently represents H, CO2R5 or CH2CO2R5; R4 independently represents H, OH, O-(C1-C8)alkyl, OMe+, or a group selected from the group consisting of: 194 M independently represents Na, K or a pharmaceutically acceptable metal ion; e- 1-3; R5 independently represents at each occurrence H, Me+, (C1-C8)alkyl, (C3-C8)cyc10alkyl, substituted (C5-C14)aryl, hetero(C2-CH)aryl, C(=O)(CH2)fCHR9CO2R5, CH2C(=O)OR5, P(=O)(OR5)2, X2 independently represents O, S, SO, SO2, orNR5; R6 independently represents H, Na+, K+ any other pharmaceutically acceptable metal ion, (C1-C8)alkyl, or (C3-C8)cyc10alkyl; R7 independently represents at each occurrence same or different R5; R8 independently represents CH2, O, NR4, S, S=O or O=S=O; R9 independently represents H, (C1-C8)alkyl or an amino acid; f is O-6; g is O-1; h is 1-2OOO; i is 1-4; 195 R10and R11 independently represent H, (C1-C8)alkyl, (C3-C8)cyc10alkyl, or a group selected from the group consisting of: with a proviso that when R is selected from the above group, R represents H or (C1- C8)alkyls and when R11 is selected from the above group, R10 represents H or (C1- C8)alkyl; R12 independently represents a group selected from the group consisting of: 196 197 3. The compound according to claim 2, wherein D is a group or molecule comprising one or more water solubilizing functional groups selected from the group consisting of hydroxyl, amino, acylamino, carboxyl, sulphate, sulfonate, phosphate, phosphonate, N-acylsulfonamide, N-acylsulfamate, N-acylcarbamate, N-acylcarbamate metallic salts, and amino acids to form water-soluble prodrugs. 4. The compound according to claim 2, wherein D is selected from the group of amino acids consisting of Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamine, Glutamic acid, Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, and Valine. 5. The compound according to claim 2 wherein D2 is a polymer. 6. The compound according to claim 5, wherein the polymer is selected from the group consisting of dextran, modified dextran, arabinogalactan, polyamino acids, and polyethylene glycol. 7. The compound according to claim 6, wherein the polymer is a polyaminoacid selected from group consisting of poly(l-glutamic acid), poly(d-glutamic acid), po!y(dI-glutamic acid), poIy(l-aspartic acid), poly(d-aspartic acid), poly(dl- aspartic acid), copolymers of the polyaminoacids and polyethylene glycol, polycaprolactone, polyglycolic acid, polylactic acid, polyacrylic acid, poly(2-hydroxyethyl 1-glutamine), dextran aldehyde, carboxymethyl dextran, arabinogalactane aldehyde, carboxymethyl arabinogalactane, and hyaluronic acid. 8. The compound according to Claim 5, wherein the polymer has a molecular weight of about 5000 to about 100,000 Daltons. 9. The compound according to Claim 5, wherein the polymer has a molecular weight of about 10,000 to about 50,000 Daltons. 10. The compound according to claim 2 wherein D2 is a dipeptide. 11. The compound according to claim 2, wherein D2 is a vitamin selected from the group consisting of vitamin A, vitamin C, thiamine, folic acid, biotin, inositol, nicotinic acid, nicotinamide, riboflavin, pyridoxine, pyridoxal 5-phosphate, ergosterol, vitamin D2, vitamin D3, vitamin D4, vitamin E, menadoxime, menadiol, and vitamin K5. 198 12. The compound according to claim 2, L is O; A and A are independently (CH2)d, 1,2-phenylene, 1,3-phenylene, or 134-phenylene; d is 1-4; B is S-S, S-S=O, S-SO2 or S-S=NH; D is NO, NO2 or a NONOate selected from the group consisting of: T 1 13. The compound according to claim 2, wherein L is O; A and A are CH2; E is CH2; B is a bond or (CtWbJ b is 1-6; a is O; D2 is NO2 and L1 is a group selected from wherein, XisO, SorNR1;and Y and Z are as defined. 14. The compound according to claim 2, selected from the group consisting of: 199 15. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 2, or a pharmaceutical salt thereof and one or more pharmaceutically acceptable carriers, vehicles or diluents. 16. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 14, or a pharmaceutical salt thereof and one or more pharmaceutically acceptable carriers, vehicles or diluents. 17. The compound as in claim 2, wherein D1 and D2 represent known and investigational amino-, hydroxyl-, carboxyl-, and keto- containing drugs compiled in drug databases comprising the Merck Index, IDdb, Prous Science's Integrity®, Prous Science Drugs of the Future™, and The Ensemble®. 18. The composition of claim 15 comprising therapeutically effective amount of pairs of drugs selected from: Paclitaxel and Doxorubicin; Paclitaxel and Mitomycin C; Paclitaxel and 9-aminocamptothecin; 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), 3-Aminopyridine-4-methyl-2-carboxaldehyde thiosemicarbazone (3-AMP) and Paclitaxel, Doxorubicin, Mitomycin C; CC-1065 and Paclitaxel, Doxorubicin, Mitomycin C; Trans-Resveratrol [(E)-3,4',5-trihydroxystilbene) 210 and Paclitaxel, Doxorubicin, Mitomycin C; Retinoic acid and Butyric acid; Paclitaxel and Captopril; Doxorubicin and Biotin; 5-Fluorouracil and Cytarabine; Edatrexate and Paclitaxel; Cepha10sporanic acid and Paclitaxel; Cepha10sporin and Paclitaxel; Paclitaxel and Gemcitabine; Levodopa and Carbidopa; Amoxicillin and Clavulanic acid; Ampicillin and Clavulanic acid; Amoxicillin and Pencillinic acid sulfone; Ampicillin and Pencillinic acid sulfone; Olivanic acid and 3-substituted Z-2-acylaminopropionic acid; Lifibrol and 10vastatin/Pravastatin/Fluvastatin/Atorvastatin/Simvastatin; Ezetimibe and 10vastatin/ Pravastatin/ Fluvastatin/Atorvastatin/Simvastatin; Am10dipine and 10vastatin/Pravastatin/Fluvastatin/Atorvastatin/Simvastatin; Metformin and Nateglinide/Glipizide/Glibenclamide (Glyburide); Metformin and 10vastatin/Pravastatin/Fluvastatin/Atorvastatin/Simvastatin; Pseudoephedrine and Fexofenadine/Cetirizine/Des10ratadine/Epinastine; Salbutamol and Ipratropium bromide; Mometasone and Formoterol/Salmeterol; Fluticasone and Formoterol/Salmeterol; Budesonide and Formoterol/Salmeterol; Dec10fenac and Misoprostol; Dec10fenac and Omeprazole/Lansoprazol/Rabeprazole/Leminoprazole/Pantoprazole; Naproxen and Prophenazone; Acetaminophen and ch10rzoxazone/metaxa10ne/mephenoxa10ne; Zidovudine and Lamivudine; Triple prodrug of Zidovudine; Lamivudine and Abacavir (Ziagen); 10pinavir and Ritonavir; Lamivudine and Adefovir/dipivoxil; Amprenavir and Zidovudine; Nelfinavir and Zidovudine/Lamivudine; Stavudine and Zidovudine/Lamivudine; Dideoxyinosine and Zidovudine/Lamivudine; Emtricitabine and Pencic10vir/Famcic10vir; Acyc10vir and deoxycholate/chenodeoxycholate and ursodeoxycholate; Triple and Zidovudine; and Lamivudine and Efavirenz; 19. A therapeutically effective amount of the pharmaceutical composition as in claim 15, comprising a two or more drugs, a drug and its own prodrug, a drug and a different prodrug, two different prodrugs, a drug and a mutual prodrug, mutual prodrug and its own drugs or a mutual prodrug and one of its constituent drugs. 20. The compound according to claim 2, wherein D1 and D2 are therapeutic agents selected from the group consisting of: Sedatives, Hypnotics, Antidepressants, Antipsychotics and Antimanics, Analgesics, Antipyretics, Antimigraine agents, Anticonvulsants, Drugs used in parkinsonism and movement disorders, Drug for dementia, Antiemtics, drugs for Vertigo, CNS Stimulants activators; Antiinfective eye 211 preparations; Antiinflammatory; antiallergic preparations, antiglucoma drugs; preparations to cure eye diseases; aural, nasal and oropharyngeal preparation, Antiarrhythemic drugs, Antihypertensives, alfa/beta-b10ckers, channel b10ckers, ACE inhibitors, Angiotensin II receptor antagonists, diuretics, Antianginals, nitrates, calcium channel b10ckers, Drugs for cardiac failure and shock, Vasodilators, Coagulants, Anticoagulants, Thrombolytics, antiplatelet drugs, Respiratory stimulants, Antitissives, Expectorants, Mucolytics, Decongestants, Antihistamine agents, antiasthmatics; Antiulcer, Antisecretory drugs, H2 receptor antagonists, Proton Pump Iinhibitors, Prostaglandin ana10gues, Antacids, Antispasmodics, drugs modifying intestinal motility, Antidiarrhoeals, antimotility drugs, antimicrobial drugs, drugs acting on gall bladder, Urinary antiinfectives, Diuretics, Urinary analgesics, Antispasmodics, Antiinfective drugs acting on urethra and vagina, drugs acting on uterus, Drugs for prostatic hypertrophy, alfa b10ckers, antiandrogens, Drugs for erectile dysfunction, Spermicidals, nonhormonal contraceptives, Emollients, keratolytics, topical antiinfectives, topical antifungals, topical parasiticidals, topical steroids, topical drugs for acne vulgaris, drugs for psoriasis, pigmentation disorders, and Antiseborrhoeics, Non Steroidal Anti Inflammatory Drugs (NSAIDs), COX-2 inhibitors, Antiarthritic agents, Immunosuppressants, Topical analgesics, Muscle relaxants, Neuromuscular Drugs, Penicillin antibiotics, Cepha10sporin antibiotics, Quino10ne, Fluoroquino10ne antibiotics, Macrolide antibiotics, Ch10ramphenicol, Tetracyline antibiotics, Sulfonamides, Antianaerobics, Metronidazole, Antitubercular drugs, Antileprosy drugs, Antifungals, Antiprotozoals, Anthelminthics, Antiinfestive Drugs, Antimalarials, Antivirals, Anabolics, androgenic steroids, Corticosteroids, Oestrogens, Progestogens and Hormonal contraceptives, Fertility Agents, Trophic hormones and related drugs, Thyroid and antithyroid drugs, Antidiabetics and hyperglycaemics, Vitamins, Amino acids, Anti-obesity drugs, Hypolipidaemic drugs, fibric acid derivatives, statins, HMG CoA reductase inhibitors, nicotinic acid group, drugs used for Gout, drugs affecting bone metabolism, bisphosphonates, Anticancer drugs, alkylating agents, cytotoxic antibiotics, antimetabolites, cytarbine, Fludarbine, 5-Fluorouracil, Mercaptopurine, Thioguanine, Vinca alka10ids, Etoposide, Taxanes, Topoisomerase 1 inhibitors, Cytotoxic immunosuppressants, Immunostmulants, Cytoprotectives, Amifostine, Oestrogens, 212 Progestogens, hormon antagonists, antineoplastic drugs, Antiallurgics, non-sedative antihistamins, Cetirizine, Des10ratadine, Terfenadine, Fexofenadine, sedative histamines, histamine receptor b10ckers, 10cal anaesthetics, intravenous anaesthetics, inhalation anaesthetics, and muscle relaxants. 21. The compound according to claim 2, wherein D1 and D2 are from same or different therapeutic class and exhibit either the same or different mechanisms of action or work on same or different bio10gical targets or work on same or different disease conditions. 22. The novel intermediates obtained in the preparation of compounds of claim 1, wherein the intermediates are selected from: 213 23. The novel intermediates as claimed in of claim 22 wherein the said intermediates are emp10yed in the preparation of compounds of formula I as claimed in claim 1. 24. The process for the preparation of the compound as in claim 1, or a pharmaceutically acceptable salts thereof, wherein the process is selected from: Process 1: A) Monoprotection of Bis-(2-hydroxyethyl)disulphide (SL-1) with an appropriate hydroxyl protecting group to give the corresponding monoprotected intermediate LI-lx, B) Converting LI-lx, obtained in step A to an activated formyl intermediate Ll-lxy by treating with phosgene or its equivalent, and 215 C) Reacting Ll-lxy obtained in the step B with an appropriate amino- or hydroxyl containing drug (D1) to give the corresponding compound of formula I; Process 2: A) Converting carboxyl containing drug (D1) into its activated acyl halide or imidazolide or isocyanate by known methods, and B) Reacting the intermediate obtained in the step A with the linker intermediate LI-lx to obtain the compound of formula I; Process 3: Mixing a selectively protected and activated drug with a solution of 2-((2- hydroxyethyl)dithio)ethyl nitrate (LI-2b) in a suitable solvent in presence of a suitable coupling agent to obtain the compound of formula I and pharmaceutically acceptable salt thereof, wherein D2 is NO2; Process 4: Converting 2-((2-hydroxyethyl)dithio)ethyl nitrate (LI-2b) into its formyl halide or imidazolide (LI-4x) by using a phosgene or its equivalent reagent and mixing/reacting the resulting reactive intermediate with a suitable amino- or hydroxy- containing drug in suitable solvent in presence of a suitable base to obtain the compound of formula I and pharmaceutically acceptable salt thereof, wherein D2 is NO2; Process 5: Mixing/reacting a an appropriately protected and activated drug with a solution of 2-((2-aminoethyl)dithio)ethyl nitrate (LI-5) in a suitable solvent in presence of a suitable coupling agent and/or base to obtain the compound of formula I and pharmaceutically acceptable salt thereof, wherein D2 is NO2; and Process 6: A ) Monoprotection of Bis-(2-hydroxyethyl)disulphide (SL-1) with an appropriate hydroxyl protecting group to give the corresponding monoprotected intermediate LI-lx, B) Reacting formyl linker intermediate Ll-lxy with amino or hydroxyl containing drug (D1) to obtain the prodrug of formula I with free hydroxyl group on the linker, C) Converting the intermediate obtained in the step B into activated formyl halide or imidazolide derivative, and D) Reacting the intermediate obtained in the step C with the drug D2 to obtain the mutual prodrug of formula I. Dated this 21st day of March 2OO7. DR. SANCHITA GANGULI of S.MAJUMDAR&CO. Applicants' Agent 216 Abstract PRODRUGS CONTAINING NOVEL BIO-CLEAVABLE LINKERS The invention provides the compounds of formula (I) or pharmaceutically acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one more of pharmaceutically acceptable carriers, vehicles or diluents. The invention further provides methods of preparation and methods of use of prodrugs including NO-releasing prodrugs, double prodrugs and mutual prodrugs comprising the compounds of formula I. 217

Documents:

439-mumnp-2007-abstract(26-3-2007).pdf

439-mumnp-2007-abstract.doc

439-mumnp-2007-abstract.pdf

439-MUMNP-2007-ANNEXURE TO FORM 3(16-8-2011).pdf

439-mumnp-2007-annexure to form 3(18-6-2007).pdf

439-MUMNP-2007-ANNEXURE TO FORM 3(20-6-2011).pdf

439-mumnp-2007-annexure to form 3(6-8-2007).pdf

439-MUMNP-2007-ASSIGNMENT DEED(12-3-2010).pdf

439-MUMNP-2007-ASSIGNMENT(4-10-2012).pdf

439-MUMNP-2007-CLAIMS(AMENDED)-(25-5-2012).pdf

439-mumnp-2007-claims(complete)-(26-3-2007).pdf

439-MUMNP-2007-CLAIMS(MARKED COPY)-(25-5-2012).pdf

439-mumnp-2007-claims.doc

439-mumnp-2007-claims.pdf

439-MUMNP-2007-CORRESPONDENCE (18-08-2008).pdf

439-MUMNP-2007-CORRESPONDENCE(12-3-2010).pdf

439-mumnp-2007-correspondence(12-8-2008).pdf

439-MUMNP-2007-CORRESPONDENCE(16-8-2011).pdf

439-MUMNP-2007-CORRESPONDENCE(17-7-2009).pdf

439-MUMNP-2007-CORRESPONDENCE(24-2-2009).pdf

439-MUMNP-2007-CORRESPONDENCE(24-9-2012).pdf

439-MUMNP-2007-CORRESPONDENCE(29-5-2012).pdf

439-MUMNP-2007-CORRESPONDENCE(30-11-2009).pdf

439-MUMNP-2007-CORRESPONDENCE(4-10-2012).pdf

439-mumnp-2007-correspondence-others.pdf

439-mumnp-2007-correspondence-received.pdf

439-mumnp-2007-deed of assignment(12-3-2010).pdf

439-mumnp-2007-description (complete).pdf

439-mumnp-2007-description(complete)-(26-3-2007).pdf

439-mumnp-2007-form 1(21-5-2007).pdf

439-mumnp-2007-form 1(7-5-2007).pdf

439-MUMNP-2007-FORM 13(4-10-2012).pdf

439-MUMNP-2007-FORM 18 (18-08-2008).pdf

439-mumnp-2007-form 2(complete)-(26-3-2007).pdf

439-mumnp-2007-form 2(title page)-(complete)-(26-3-2007).pdf

439-mumnp-2007-form 3(26-3-2007).pdf

439-mumnp-2007-form 5(26-3-2007).pdf

439-mumnp-2007-form 6(12-3-2010).pdf

439-MUMNP-2007-FORM 6(4-10-2012).pdf

439-mumnp-2007-form-1.pdf

439-mumnp-2007-form-2.pdf

439-mumnp-2007-form-26.pdf

439-mumnp-2007-form-pct-ib-304.pdf

439-mumnp-2007-form-pct-ib-306.pdf

439-MUMNP-2007-GENERAL POWER OF ATTORNEY(12-3-2010).pdf

439-mumnp-2007-general power of attorney(26-3-2007).pdf

439-MUMNP-2007-HIGH COURT BOMBAY(4-10-2012).pdf

439-MUMNP-2007-OTHER DOCUMENT(12-3-2010).pdf

439-MUMNP-2007-PETITION UNDER RULE-137(24-9-2012).pdf

439-mumnp-2007-power of attorney(12-3-2010).pdf

439-MUMNP-2007-REPLY TO EXAMINATION REPORT(20-6-2011).pdf

439-MUMNP-2007-REPLY TO EXAMINATION REPORT(25-5-2012).pdf

439-MUMNP-2007-US & EP PATENT DOCUMENT(20-6-2011).pdf

439-mumnp-2007-wo international publication report(26-3-2007).pdf

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