Title of Invention

A COMPOUND COMPRISING A TRANSPORTOPHORE

Abstract

ABSTRACT 1815/CHENP/2004 A COMPOUND COMPRISING A TRANSPORTOPHORE The present invention relates to a compound which is a non-antibiotic therapeutic agent comprising a transportophore wherein T is i transportophore, L is a bond or a linker having a molecular weight of up to 240 dalton, C is a non-antibiotic therapeutic agent, selected from non-steroidal anti-inflammatory, anti-viral, anti-fungal, immune suppressant, cytostatic, anti-parasitic, lipid lowering, a sterol synthesis modifying, or metabolarcgulatory therapeutic agents, and mis 1,2, 3, 4. 5, 6,7, or 8, in which the transportophore has an immune selectivity ratio of at least 2, the transportophore is covalently bonded to the non-antibiotic therapeutic agent via the bond or the linker, and the compound has an immune selectivity ratio of at least 2, wherein said compound corresponds to the formula

Full Text

The present invention relates to compound wInch is is a non-antibiotic srapeutic agent comprising a transportophore. BACKGROUND Successful therapy with a pharmaceutical agent requires that the agent satisfy imerous requirements imposed by the physiology of the host and of Ine disease or ndition. The requirements include: (i) adequate ability to interact with the target ceptor(s); (u) appropriate physical properties for presence at the location of the ceptors in concentrations that permit the interactions noted above; (iii) appropriate tysical properties to allow the agent to enter the body and distribute to the location 'the receptors by any means; (iv) sufficient stability in fluids of the body; (v) the isence of toxic effects in compartments where the therapeutic agent is most incentrated, or in any other compartment where the therapeutic agent is located; and i) the absence of sequestration into non-physiological compartments and so on. In general, these compounding requirements limit the nature of pharmaceutical impounds that have utility in vivo and thus reduce the probability of discovering lequately active molecules from de novo starting points, In response to these instraints, significant effort has been applied to the question of predicting ideal tysical properties for pharmaceutical molecules. Authors such as Lipinski (Lipinski al., 2001) have described rules of therapeutic agent design wInch, amongst other irameters, predicts that ideal therapeutic agents will have few functions such as 'droxy groups, a molecular weight below 500 Da, mild basicity, and moderate lopInhcity (logP 500) such as e compounds disclosed here. Recently, improvements in the technology of synthetic chemistry and molecular biology have allowed the testing of large numbers of molecules and the discovery of many ligands with adequate affinity to their targets to have some potential in vivo. Many such molecules prove inadequate on in vivo testing largely due to the manifold, stringent, and often conflicting (i,e. stability without toxicity) requirements outlined above. In addition to the difficulties facing many new molecules, many existing molecules in clinical use also exInbit inadequate properties of uptake, distribution, stability and toxicity (Lipinski et al. 2001). These observations demonstrate, that in general, deficiencies in uptake, distribution, and stability result in inadequate therapy from existing molecules and inadequate and uneconomical probabilities of success in the discovery of new molecules. Such problems often fell witInn the scope of therapeutic agent delivery - a discipline wInch combines many aspects of formulation with techniques for introducing the agent into the host body. Delivery methods are frequently designed to permit passage through a single barrier (i.e. the skin) (WO 01A3957) ortfae intestine (WO 01/20331) after wInch the agent must again conform with the general requirements above in order to act at the in vivo target. Certain delivery strategies involve a physical preparation such as liposomes (Debs et a). 1990; Jaafari, Poldvari, 2002) or anti-body conjugates (Everts et ah, 2002) wInch further direct the molecules witInn the host body. Others rely on the addition of cationic lipids to formulations, the use of transport proteins as a route of uptake (WO 01/20331). The use of transport processes deliberately in therapeutic agent design is perhaps best illustrated by the nucleoside therapeutic agents, wInch to varying degrees, are taken up as metabolites and whose transport to mitochondria is a major cause of toxicity (WO 9S/29437) For example, see European Patent No. 0009944B1, European Patent No. 0044090A3, and Japanese Patent No. 05163293. Such methods may enhance perfbrmance in therapy or reduce toxicity but they increase cost and require direct introduction into the blood stream wInch is impractical in chronic use. More preferable would be small molecules that possess the appropriate structures and properties to mediate efficient uptake and stability. Such small molecules would ideally be able to carry a range of therapeutic agents of varying properties such that they could be commercialized in more than one indication. However, there is a requirement that they be inactive arid stable enough to ensure that the cargo molecule is carried in the periphery (Harada et al. 2000). Ths present invention represents a significant advance ID that it provides for 2 means of improving the bioavailability and efficacy of a variety of molecules in vtvo using a series of rational and facile assays to select desirable compounds based on known pharmacophores or pharmaceutical lead structures that have not been optimized for in vivo action. SUMMARY The invention relates to a compound useful for enhancing efficacy of a therapeutic agent, a method for identifying such a compound, and a method of treating diseases including mflammation, graft rejection, infection, cancer, allergies, metabolic cardiovascular, puraionary,dermatoIogical, rneumatological and hepatic; diseases. The invention further comprises compositions and formulations selected using the method and applications for same. The invention provides for a method for identifying compounds that act a$ carriers or "transportophores" (i.e., a transport mediating molecule) that when combined, either directly or via a linker, to a wide variety of therapeutic agents, improres one ormore of the following characteristics of (he agent; ease of formulation, gastric stability, bioavailability, stability, disposition, elimination, half life, efficacy, safety, duration of action and selectivity. In one aspect, tIns invention features a compound of the following formula (or referred to as T-L-C hereinafter): wherein T is a transportophore, L is a bond ox a linker having a molecular weight up to 240 dalton^ C is anon-antibiotic therapeutic agent, andm is 1,2,3,4, 5, 6,7, c,T 8, in wInch the txansportophore has an immune selectivity ratio of at least 2, the transportophcjre is covalently bonded to the non-antibiotic therapeutic agent via the bond or the linker, and the compound has an immune selectivity ratio of at least X Note that whfcn there are more than one L or C moieties (i.e., m is greater than 1), the L moieties or the C moieties, independently, can be the same or different. The same rule applies to other similar situations. The transportophore can be a metabolite, a natural product, a metabolite mimic, a metabolite derivative {e.g., a sugar, amino, or peptide derivative), a fatty ' . acid, a bile acid, a vitamin, a nucf eobase, an alcohol, or an organic acid or base, a portion of wInch resembles and is recognized as a substrate for transport protein(s). It can be an ampInpInlic molecule having a pKa value of 6.5 to 9.5, or a cyclic or heterocyclic molecule (e.g-, lactone, lactam, ether, cyclic acetal or hemi-acetal). The cyclic or heterocyclic molecule can have an attached sugar. The cyclic or heterocyclic molecule can be a macrolactone or macroether, including a macrolactone or macroether having an attached sugar. The cyclic or heterocyclic molecule can also be a macrolide or ketolide having an amino sugar, including a macrolide having mono-, di-, or tri-basic groups (e.g.» an amine). In some embodiments, the macrolide has no intrinsic antibacterial activity (inactive at 50 uM or Ingher concentrations when tested against Bacillus invitro see protocol) and a pKa value of less than 9.0 (e.g., 8.5,8.0, 15, 7.0, or any number in between). In some embodiments, the compound has the following formula (in wInch a bond, drawn without any attached groups, means a methyl group. The same rale applies to other similar situtations): ll J ft * t wherein alkyl, alkenyl, alkynyl, cycloalkyl. heterocyeloalkyl, aryl, beteroaryl groups are optionally substituted by one to five substituents selected independently from halogen, (C,-Gi)allcyl, (C-C^alkcoyl, (Ci-GOalkynyl, (Ca-OOcycloalkyl, (Cr Cojheterocycloalkyl, (Ce-CttOaryl, (CrC&)heteroaryl, (Cj-C^atkoxy,hydroxy, nitro, cyano, azido, mercapto, RVN-, R30C(=O)-, R20C(-O)O-, R^OCt-O)-, R^NHCfK))-, RMC(O)NH-,R20R21NC(-0)-, and R20OC(=O)O-, -Y-therapeutic agent or -therapeutic agent, (C3-Cl0)cycloancy)(C!-Cs)alkyl (C2~C9)heterocycloaJkyl(Ci -C6)allcyl (C6-C]o)aryl(Ci-C6)alkyl or (C2-C9)heteroaryl(Ci-C6)alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryL and heteroaryl groups are optionally substituted by one to three halo, (CrC^alkoxy, hydroxy, oitro, cyano, R8, -C(=0)-OR8, -C(0)N(H)R8, CCVCjo)aiyL (C3-C)heteroaryl, N*RVR7 wherein * is no or a positive charge, ortberapeutic agent Preferred molecules can be compounds that are recognized by a transport enzyme in the membrane of the cell of the tissue that is to target TIns can be a molecule that fulfills the structural requirements in order to be recognized by an oligo-peptide transporter. Compounds recognized by transport enzymes can be identified by performing a transport assay 'with the compound in question in cells expressing the transport protein in question, and comparing the level of compound accumulation with those from parallel uptake assays performed using cells wInch do not express the target transport protein. In these examples K. (including R) and R2) may represent a chemical residue that will modify the recognition by the transporting enzyme or at least not inInbit it. R may be comprised of the therapeutic agent that is to be delivered or the pharmaceutical entity is for example an amino acid itself as in example A. Necessary for transport through an oligopeptide transporter seems to be a basic group spaced 4 or 5 bonds from an hydrogen bond accepting group like preferably carboxylate (example A-C) or less preferred amide (example D). Example A: Ri and R2 are hydrogen or lower alkyl, branched or linear from C] to C5, or benzyl or p-hydroxy benzyl, or hydroxy or mercapto methyl, or any group responsible for the desired pharmacological effect Example B: R can be the moiety responsible for the pharmacological effect, or the pharmacologically relevant group linked on the carbon chain by a chemical linker like an amide (amide- R = NH(00)-R' (R' ■= pharmacologically relevant group)). Example C: R can be the moiety responsible for the pharmacological effect, or the pharmacologically relevant group linked on the carbon chain by a chemical linker like an amide (amide- R = NH(C=0)-R' (R' = pharmacologically relevant group)). Example D: K2 can be hydrogen or lower alkyl, branched or linear from CI to C5, orben2yl or p-hydroxy benzyl, or hydroxy or mercapto methyl, wInle Rl consists of the pharmacologically relevant therapeutic agent Preferably the therapeutic agent would contain a carboxylic acid that by linking to the amino function of an amino acid hydra2ide would obtain the general structure of example D. Thcrapeutic agents and Transportophores can be directly connected or via a linking element. TIns element typically is abufUnctional molecule of low molecular mass, wInch can react subsequently with the therapeutic agent and the transportophore. Ideally the therapeutic agent can be released from tIns linker under physiological conditions. TIns may be acIneved oxidativery (i.e. by action of a cytochrome C), reductively (i.e. by action of NADH), hydrolytically (i.e. by action of a protease), or initiated by radicals (i.e. by the action of superoxide radicals). The mechanisms of therapeutic agent release are not limited to the above examples. Linkers have the following formula: F'-M-F2 Where can be: F1, F2" independently a functional group, suitable to react with a counterpart in the therapeutic agent Or in the transportophoTe. F1 and F2 are, but are not limited to X' wherein X1 is a halogen atom or a sulfonate ester or another suitable leaving group; C(0)X2 wherein X* is Cl. Br or I, CHO; C(=0)OR1 wherein R" is (Ci-C^aHcyl or aryl, optionally substituted by 1-5 halogen atoms; C(«0)OC(«0)ORb wherein Rh is (Q-C^alkyl or (Ci-Q)alfcenyl; OH; NHRC wherein Rc is H, (C,-C*)a]]cyl; NCX3 wherein X3 is S or O; C(=0)CR=CHR', wherein R and R' are independently -H, -CHj, -Cl, -Br, -F, -0(C,-C4)alkyl, -C(-0)0(Ci-C4)alkyl, -NOj, -S(=0)k(0),(Ct-C4)alkyl wherein k is 0, 1 or 2 and 1 is 0 or 1, SiR'R2R3 whereinR^R2 andR3 independently are (Ci-C4)allcyl; SX4 wherein X4 is -H, -Cl, -S^Ci-GOaBeyl, Sk(C6-Cici)aryl wherein k is 1 or 2. F1 and F2 can be connected to form a cyclic anhydride or di- or trisulfide. M is a spacing element wInch is, but is not limited to (Ci-Cg)alkyl, (Ci-C8)alkenyl, (C,-CB)aflcynyI, (C3-Cio)cycloaflcyl, CC6-Cio)aryl, (C2-C9)heteroalkyl, (C2-^9)heteroaryl. Aikyl-, allcenyl, aBcynyl, cycloallcyl, aryl or heteroaryl spacing elements are optionally substituted by (Ci-C6)alkyl, 1-4 halogens, (CrC4)aIkoxy, (Cr C^aHcoxycarbonyl, hydroxy, amino, (CrQ)alkylamino, ((VC-Odialkylamina, (C3-Cia)cycloa]kyl, (CI-C6)aHcylcaibonyloxy, (Ci-C^aUcylcarbonylairadlo, (Cr C])aIkylamidocarboiiyl, (CrC^dialkylarnidocarbonyl, nitro, cyauo, (Cr C^alkylimirio, mercapto and (Ci-Cj)alkylinercaptQ functions. The non-antibiotic therapeutic agent can be an anti-inflammatory agent, an anti-infectious agent (including anti-virals), an anti-cancer agent, an allergy-suppressive agent, an immune-suppressant agent, an agent for treating a hematopoietic disorder, a lipid lowering agent, an agent for treating, a lysosomal storage disorder, a sterol synthesis modifying agent, agents active on protozoa, or an agent for treating a metabolic disease. As used herein, an "immune selectivity ratio" is the ratio of the concentration of a compound in immune cells (e.g., neutropInls, monocytes, and lymphocytes) to the concentration of the compound in erythrocytic cells after the compound has been incubated in z mixture of blood cells including erythrocytes. A protocol of determining the immune selectivity ratio is described in Example 1. A "therapeutic agent," as used herein, is a molecule with pharmacological activity (eg., a therapeutic agent, medicine, medicament, or active agent), a disease modification agent, or any other molecule that can be covalently attached to a transportophore via a bond or a linker wInch may have a desirable mode of action in immune or target cells. A therapeutic agent may be released from a compound described above in response to the enzyme activity or the physicochemical environment of the targeted cells. Thus, the therapeutic agent is selectively accumulated in a cell due to specific characteristics of the cell membranes, specific expression of membrane proteins, specific conditions witInn the cell, notably to expression of specific proteins such as granule proteins, binding sites m the cytoplasm, or other membrane bound or soluble proteins, and iE thus trapped in the cell and therefore exInbits an enhanced or desired activity therein. An "amphopInlic molecule,** as used herein! is a molecule having a hydroplane (polar) and hydrophobic (non-polar) functional groups (e.g_, atoms) or a combination of groups (or atoms). The pKa of tIns molecule is in the range of 6J5 to 9.5. The term "cyclic" refers to a hydrocarbon cyclic ring including fully saturated, partially saturated, and unsaturated mono-, bi-, and tri-cyclic rings having 4 to 34 ring atoms, preferably, 7 to 10, or 10 to 15 ring atoms. The term "heterocyclic** refers to a hydrocarbon cyclic ring including fully saturated, partially saturated* and unsaturated mono-, bi, and tri-cyclic rings having 4 to 34 ring atoms, preferably, 7 to 10, or 10 to 15 ring atoms having one or more heteroatoms, such as S, O, or N in each ring. The term "sugar" refers to a mono-, di-3 OT tri-saccharide including deoxy-, tIno-, and amino-saccharides. Examples of sugar include, but are not limited to, furanose and pyranose. The terms "halogen" and "halo" refer to radicals of fl«orme,.chlorine, bromine or iodine. The term "macrolactone" refers to a large lactone ring (i.e., cyclic ester) having at least 10 (e.g., 10 to 25) ring atoms, ' The term "macrocyclic ether" refers to an ether having at least 10 (e.g, 10 to 25) ring atoms. The term "macrolide" refers to a chemical compound characterized by a large lactone ring (having at least 10, e.g., 10 to 25 ring atoms) containing one or more keto and hydroxy! groups, or to any of a large group of antibacterial antibiotics containing a large lactone ring linked glycosidically to one or more sugars; they are produced by certaiii .species of Streptoimcft and inInbit protein synthesis by binding to the 50S subunits of 70S ribosomes. Examples include erythromycin, azithromycin, and clarithromycin. The term "ketolide" refers to a chemical compound characterized by a large lactone ring (having at least 10 ring atoms) containing one or more keto groups. The term "alkyl" (or "aBcem/I" or "alkynyl") refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-Cm indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkcnyl groups and alkynyl groups have one or more double or triple carbon-carbon bonds, respectively, in the chain. The term "aryl" refers to a hydrocarbon ring system (mono-cyclic or M-cyclic) having the indicated number of carbon atoms and at least one aromatic ring-Examples of aryl moieties include, but are not limited to, phenyl, naphthyJ, and pyrenyl. The term "heteroaryl" refers to a ring system (mono-cyclic or bi-cyclic) having the indicated number of ring atoms including carbon atoms and at least one aromatic ring. The ring system includes at least one hcteroatom such as O, N, or S (e.g., between 1 and 4 heteroatoms, inclusive, per ring) as part of the ring system. Examples of heteroaryl moieties include, but are not limited to, pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, tInophenyl ortInenyl, quinolinyi, indolyl, and thjazolyl. The term "alkoxy" refers to an -O-alkyl radical. The term "cycloaDcyr refers to a nonaromatic hydrocarbon ring system (mono-cyclic or bi-cyclic), containing the indicated number of carbon atoms. The term "heterocycJoaDcyl" refers to a nonaronifltic ring system (mono-cyclic or bi-cyclic), containing the indicated number of ring atoms including carbon atoms and at least one heteroatom such as 0, N, or S (e.g.s between 1 and 4 heteroatoms, inclusive, per ring) as part of the ring system. "Alkyliden" is a bivalent alkyl group. "Aiyliden" is a bivalent aryi group. "Erythrocytic cell" is a mature red blood cell that normally does not have a nucleus: it is a very small, circular disk with both faces' concave, and contains hemoglobin, wInch carries oxygen to the body tissues. The compounds described above include the compounds themselves, as well as their salts, if applicable. Such salts, for example, can be formed between a positively charged substituent (e.g.7 amino) on a compound and an anion. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a negatively charged subBtituerd (e.g., carboxylate) on a compound can fbnn a salt with a cation. Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetmmeuylammonirim ion. Bi addition, some of the compounds of tIns invention have one ormore double bonds, or one or more asymmetric centers. Such compounds can occur as racematcs, racemic mixtures, single enantiomers, individual diastereomers, diastereomerie mixtures, and cis- or trans- or E- or Z- double isomeric forms. Further, the aforementioned compounds also include their JV-oxides. The term vW-oxides" refers to one or more nitrogen atoms, when present in a compound, are in W-oxide fonn, i.e, N-> 0. Combinations of substituents and variables envisioned by tIns invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds wInch possess stability sufficient to allow manufacture and wInch maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., treating a disease). In another aspect, tIns invention features a method for treating an inflammatory disorder. The method includes administering to a subject in need thereof an effective amount of a compound described above, wherein the compound contains a non-antibiotic therapeutic agent that is an anti-inflammatory agent Optionally, the method includes co-usage with other anti-inflammatory agents or therapeutic agents. The method is able to improve therapy by concentrating a compound preferentially in immune cells including neutropInls, monocytes, eosinopInls, macrophage, alveolar macrophage, B and T-lymphocytes, NK cells, giant cells, Kupfer cells, glial cells, and similar target cells using a variety of means of concentrative compound uptake common to such cells. As such, the invention is advantageous in that selective Concentration of compounds conforming to the definition of 'therapeutic agent" above, can improve therapy and mat, for the purposes of illustration only, concentration of agents in immune cells can confer improved characteristics on compounds with suitable modes of action for the treatment of inflammatory diseases. In another aspect, the invention features a means of improving the action of a compound in vivo by reducing its exposure to the action of detoxification enzymes. Such reduced exposure is a result of the structure of the conjugate molecule causing it to be differently retained in the cells and organs of the organism and thus reducing or limiting the amount of material in a given metabolic compartment. m another aspect, the invention provides for means to improve me action of a compound through improved retention in the cells and tissues of the organism such that it is Jess efficiently eliminated by the normal processes of circulation and filtration. Such avoidance of elimination is, at least in part, a consequence of efficient uptake into cells resulting in reduced concentrations of the drug being available ftom plasma. In another aspect, the invention provides for a means of improving the action of a drag by assisting its uptake from the intestine through the overall effects on membrane permeability of the Compound that are associated with the invention. Uptake from oral administration is a means of providing sustained exposure to thff compound from the parts of the intestine to wInch it is permeable. Oral availability is not a property of all compounds. TIns invention also features a method of treating a disease (e.g., an infections disease including viral, fungal, or parasitic diseases, cancer, allergy, metabolic, cardiovascular, pulmonary, dermatological, rheumatological or immune disease). The method comprises administering to a subject m need thereof an effective amount of a compound described above, wherein the compound contains a non-antibiotic therapeutic agent (e.g,, an anti-infectious agent, an anti-cancer agent, an agent for treating a hematopoietic disorder, an agent for treating a lysosomal storage disorder, an allergy-suppressive agent, a lipid lowering agent, a sterol synthesis modifying agent, agents active on protozoa or an immune-suppressant agent). Optionally, the method includes co-usage with other therapeutic agents. As described above, the method provides for means to improve therapy by concentrating a compound preferentially in any of the myeloid, hepatic, respiratory, epithelial, endothelial, after target and immune cells. Therefore, the invention is advantageous in that selective concentration of compounds confortBmg to the definition of 'therapeutic agent" above, via the methods described, can. improve therapy and that, for the purposes of illustration only, concentration of agents in immune cells can confer improved characteristics on compounds with suitable modes of action for the treatment of diseases of infectious, allergic, autoimmune, transplant, traumatic or neoplastic origin or association. The present invention also features a pharmaceutical composition including at least one compound of tIns invention and a pharmaceutjcally acceptable carrier. Optionally, the pharmaceutical composition includes one or more other therapeutic agents. TIns invention farther features a method for making any of the compounds described above. The method includes taking any intermediate compound delineated herein, reacting it with any one orrnore reagents to form a compound of mis invention including any processes specifically delineated herein. In another aspect, tIns invention features a method of identifying a compound useful for enhancing efficacy of a therapeutic agent. The metfiod includes incubating a compound in blood cells; separating immune cells from erythrocytic cells (e.g., by density gradient cratrifiigation, antibody mediated capture, lectin based capture, absorption to plastic, setting, simple centrifugation, peptide capture, activation mediated capture, or flow cytometry); and determining the ratio of the concentration of the compound in the immune cells to the concentration of the compound in the eryihwcytic cells (e.g., by mass spectrometry, NMR, PET, fluorescence detection, infrared fluorescence, colorimetry, normal detection methods associated with gas chromatography, Founier transform spectrometry method, or radioactive detection); wherein the compound comprises a transportophore and a therapeutic agent, in wInch the transportophore is covalently bonded to the therapeutic agent via a bond or a linker. The therapeutic agent can be, for example, an anti-inflammatory agent, an anti-infectious agent, an anti-cancer a^ent, an allexgy-suppressive agent, an immune-suppressant agent, an agent for treating a hematopoietic disorder, a lipid lowering agent, an agent for treating a lysosomal storage disorder, a sterol synthesis modifying agent, agents active on protozoa, or an agent for treating a metabolic disease. In still further another aspect, tIns invention features a method for delivering a therapeutic agent with a selective concentration. The method includes identifying a compound using the just-described method, and delivering the compound to a cell (c.g., a cell of respiratory tissue, a cell of neoplastic tissue, or a cell mediating allergic responses). Also witInn the scope of tIns invention are a composition having one ormore of the compounds of tins invention (optionally including one or more other therapeutic agents) for use in treating various diseases described above, and (he use of such a composition for the manufacture of a medicament for the just-described use. The invention provides several advantages. For example, a compound of tIns invention acIneves one or more of the following improvements relative to a therapeutic agent itself: (i) improved uptake across the intestinal, jejunal, duodenal, colonic, or other mucosa; (ii) reduced first pass effect by mucosal oxygenases-, (iii) reduced or altered detoxification by degradative enzymes of the body; (iv) reduced efflux; (v) selective accumulation of me merapeutic agent in one or more immune, fibroblast, hepatic, renal, glial, or other target cells; (vi) potential for hydrolytic or other forms of separation on a timeBcale compatible with therapy and the other desired disposition events; (vi) enhanced pharmacological effect in the target cells through greater concentration, sustained release, reduced substrate competition effect or olher mechanisms; (vii) reduced or modified dose; (viii) modified route of administration; (ix) reduced or altered side effects; (x)" alternative uses; and (xi) alternative formulab'ons- Other advantages, objects, and features of the invention will be apparent from the description and drawings, and from the claims. DESCRIPTION OF DRAWINGS FIG 1 depicts comparison of selective uptake of diverse structure types into wInte blood cells from a complex blood mix. These data show that an amino acid (4), a macrolide (5), a sugar (1), a piperazine (2), and a macrolide (3). These data show that diverse properties can be exploited for concentrative uptake and that macrolides can mediate even distribution of their cargo in the cytoplasm. FIG. 2 depicts comparison of sugar and prperazine driven uptake of a fluorophore, FIG. 3 is bright-field overlay and fluorescent image of polymorphonuclear cells that have taken up a fluorescent macrolide (compound 3). The images suggest even distribution with some concentration near the nucleus. FIG. 4 is an example of results from a proliferation assay showing increased efficacy of a T-L-C conjugate following concentrative uptake into lymphocytes. FIG. 5 depicts a model to demonstrate the advantage of uptake into target cells. FIG. 6 is an example ofa response ofHeLa cells to a mycophenolic acid conjugate. FIG. 7 is an example of guanosine amelioration following treatment of fresh PBMNCs with either mycophenolic acid or a T-L-C conjugate thereof. FIG. S shows changes in normalized paw tInckness (left) and the corresponding arthritic scores (right) of mice treated with different conjugates. Saline • and unconjugated compounds are included as controls. FIG. 9 shows survival of skin transplant following treatment with an example T-L-C conjugate. FIG. 10 shows dose tapering used in skin transplant model to study a T-L-C conjugate. DETAILED DESCRIPTION The invention describes a method for identifying compounds that act .to improve the uptake of therapeutic agents into cells such as those that constitute the immune system in mammals. The invention further comprises compounds identified using the method and compounds that could be made based on the teacInng provided. The invention provides for the rational improvement of therapeutic agents intended for action in inflammatory disease, infection, cancer, allergy, transplantation, cardiovascular., pulmonary, dermatological, rheumatological and metabolic disease. The invention also provides for methods to engender unoptimized molecules or those with activity only in vitro with improved properties in vivo through simple conjugation with molecules that meet the criteria outlined herein. The method provides for the selection, in vitro, of combinations of a transportophore and a therapeutic agent that exInbits adequate concentrative uptakft and also scission with a half life adequate for agent accumulation and agent action. To identify such a combination, one can contact a sample of native mammalian blood cells (e.g., Innnan blood cell), wInch contain atleast erythrocytes, neutropInls, monocytes, and lymphocytes, with one or more transportophores and determining the relative concetitration of those transportophores in the immune cells (at least neutropInls, monocytes and lymphocytes) relative to the concentration of them in the erythrocytes. Then, one can select a transportophore with significantly enhanced concentration in the immune cells and. use the transportophore to covalently link to one or more therapeutic agents, via a bond or a linker, to obtain a compound of tIns invention. Such a compound, containing the transportophore and the therapeutic agent, is also concentrated in immune cells after it is incubated with blood cells. Finally, one can select a linker that provides appropriate cleavage rates between the transportophore and the therapeutic agent in the target cells. More Specifically, a method described in Example 1 acIneves an estimate of immune cell selective uptake in a complex and competitive biological fluid such that the observed uptake is relevant to the in vivo situation wInle simultaneously measuring cell specific uptake. Data from other Examples suggest that the molecules th&t exInbit preferential uptake in tIns system are also Inghly available via the oi^l route wInle also being stable in the liver. A number of variations are possible in the application of the method. The basic method includes contacting the immune cell-erythrocyte preparation with a compound or known compounds and specifically detecting those molecules and their metabolites. A farther variation is the use of the method in screening complex mixtures of compounds with separation and detection of the resultant cytoplasmic extracts Using Mass selective detection combined with a chromatograpInc separation technique. In a further variation, the compounds designated as transportophores are used in the synthesis of libraries such that the final reaction combines library elements with a transportophore using a labile bond allowing the preferential uptake of a compound and its likely scission in an intracellular compartment. Such libraries have the advantage that in cell based assays, there is a reasonable likelihood of adequate therapeutic agent being present at the site of action. The compound described in the "Summary" section can be prepared by methods known in the art, as well as by the synthetic routes disclosed herein. For example, one can react a transportophore having a reactive moiety with a therapeutic agent haviDg another reactive moiety. One of the two reactive moieties is a leaving group (e.g., -CI, OR) and the other is a derivatizable group (e.g., -OH, or-NH-)-Then, the transportophore is covalently bonded to the therapeutic agent via a reaction between the two reactive moieties, In the case when a linker is present, each of the two reactive moieties, independently, is a leaving group or a derivatizable group, and each reacts with its reactive counterpart in the linker to form a covalant bond. Detailed routes including various intermediates are illustrated in the examples herein. The chemicals used in the afore-mentioned methods may include, for exsmplei solvents, reagents, catalysts, protecting group and deprotecting group reagents and the lite. The methods described above may also additionally comprise steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimalery allow synthesis of the compound of the formulae described herein. As can be appreciated by the skilled artisan, the synthetic routes herein are not intended to comprise a comprehensive list of all means by wInch the compounds described and claimed in tIns application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (19S9); T.W. Greene and P.G.M Wuts, Proteaive Groups in Organic Synthesis, 2d. Ed.. John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed\, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. A therapeutic agent includes any with modes of action that include anti¬inflammatory, anti-viral, anti-fungal, immune suppressant, cytostatic, anti-parasitic, lipid lowering, a sterol synthesis modifying, or metabolaregulatory action. The following is a non-exclusive list of potentially useful therapeutic agents. Anti-frlflflnnnatory therapeutic agents Non-steroidal anti-inflammatory therapeutic agents Diclofenac, Diflunisal, Etodolac, Fenoprofen, Floctafenine, Flurbiprofen, Ibuprofcn, Indomethacin, Ketoprofen, Meclofenamate, Mefcnamic, Meloxicam, Nabumetone, Naproxen, Oxaproztn, Phenylbutazone, Piroxicam, Sulindac, Tcnoxicam, Tiaprofenic, Tohnenn, Acetaminophen, Aspirin, Salicylamide, acetylsalicyu'c acid, salicylsalicylic acid. Celecoxib, rofecoxib, JTE-522, Corticosteroids Betamethasone, Budesonide, Cortisone, Dcxamethasone, Hydrocortisone, Methylprednisolone, Prednisolone, Prednisone, Triamcinolone, Fluticasone Anti-viral systemic: (i) nucleoside/nucleotide reverse transcriptase inInbitors (NRTIs) including but not limited to zidovudine (AZT), didanosine (ddl), zalcitabtiie (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine [(-)FTC], tenofovir (PMPA) disoproxil fumarate and phosphoTamidate and cyclosaligenyl pronucleotides of d4T ot similar chemistries. (ii) npn-nuclooside reverse transcriptase inInbitors (NNRTIs) including but not limited to, nevirapine, delavirdine, efavirenz, emivirine (MKC-442) or recent derivatives including capravirine and the novel qumoxaline, qninazolinone, phenylethyWiiaLolyltInoiiTea (PETT) and emiviiine (MKC-442) analogues. (iii) protease inInbitors (Pis) including but not limited to, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and Iopinavir or those based on alternative non-peptidic scaffolds such as cyclic urea (DMP 450), 4-hydroxy-2-pyrone (tipranavir) (iv) vjral entry, through blockade of the viral coreceptors including but not limited to, CXCR4 and CCR5 [bicyclams (i.c. AMD310Q), polyphcmusms CT22), TAK-779, MIP-1 alpha LD78 beta isofonn]; (v) vims-cell fusion, through binding to the viral glycoprotein including hut not limited to, gp41 [T-20 (pentafuside) (DP-17S), T-1249 (DP-107), siamycins, betulinic acid derivatives], and potentially zintevir, L^cIncoric acid, CGP64222; (vi) viral assembly and disassembly, through NCp7 zinc finger-targeted agents including but not limited to, [2,2 -ditInobisbenzamides (DIBAs), azadicaibonamide (ADA) and NCp7 peptide mimics]; (vii) proviral DNA integration, through iutegrase inInbitors such as I^cIncoric acid and dflceto acids (i.e. L-731.98S); (viii) viral mRNA transcription, through inInbitors of the transcription (transactivation) process (fluoroquinolone K.-12, Streptomyccs product EM2487, temacrazine, CGP64222). (ix) adefovir dipivoxil, emtricitabine and entecavir, aciclovir, valaciclovir, penciclovir, famciclovir, idoxuridine, trifluridine, brivudin, ganciclovir, foscarnct, cidofovir, fornivirsen, raaribavir, amantadine and rimantadine, the neuraminidase inInbitors, zanamivir and oseltamivir, ribavirin, levovirin Antifengal. systemic— candiddin, ecInnocandin caspofungin,, Azole antifungal therapeutic agents Imidazoles: Clotrimazole, ketoconazole, miconazole, Butocona2.oIe, econazole, oxiconazole, Sulconazoie, Triazoles: fluconazole, itraconazole, Terconazole, Tioconazole ( Fluorinated pyrimidines, fIncytosme/5-fmctfocytDsniE, 5-fluoroittacil, Penicillium-derivatives, griseoiurvij] (oral), Anylamine and moipboline antifungal therapeutic agents, squaiene epoxidase inInbitors naftifine, terbinaiine, amorolfine, Other, Dapsone, Haloprogin, Cytostatics and immune suppressants Alkylating agents,, Nitrogen Mustard Derivatives, Chlorambucil* Cyolophosphaniide, Ifosfamide, Mechlorethaxoine, Melphalan, Uracil Mustard, Nitrosoureas, Carmustine, Lomustine,, Streptozocin, Aaridrae, TInotepa, Melhanesolfonate Ester, Busulfsn, chrome myelogenous leukemia Nonclasic Agents, Dacarbazine, Procarbazirje, Platinum Complexes, Carboplatin, Cisplatin, Antitumor antibiotics, Dactinomycin, Daunorubicm,, Doxorubicin,, Idarubicin,, Mitomycin,, Mitoxantrone, Antimetabolites, Fluorouracil, Floxuridine, Capecitabine, Cytidine Analogs, Cytarabine, Gemcitabine, Purines, Cladribine, Fludarabine, Mercaptopurine, Methotrexatei Pentostatin, TInoguanine Plant Alkaloids,, (DNA repair enzyme inInbitors) Semisynthetic Podophylline Derivitives, Etoposide, Teniposide Taxoid Plant Alkaloids, DocetaxeL, PatHtaxel, Synthetic camptothecin Plant Alkaloid Derivitives, Irinotecan, Topotecan, Vinca Alkaloids, Vinblastine, Vincristine, Vinorelbine, Other agents,, All-trans-retinoic acid, Imarinab mesylate, 2-deaxyeofqimycra, all-trans retinoic, thalidomide calicbeamycin, protein kinase inInbitors Therapeutic agents active on allergy Anti-Instamims Asteraizole, Azatadine, Brompheniramine, Cetirizine, Chlorpheniramine, Clemastine, Cyproheptadine, Dexchloipheniramine, Dirnenhydrmate, Kphenhydramine, Doxylaroine, Hydroxyzine, Loratadine, Phenindamine, Terfenadine, Tripelerraarnine. Lipid lowering and sterol ;rnQdifving agents, Atorvastatin, Pravastatin, Simvastatin, Lovastatin, Cerivastatin, Roxuvastatin. Fluvastatio, Gemfibrozil Also witInn the scope of tIns invention is a pharmaceutical composition ths* contains an effective amount of at least one of the compound of mis present invention and a pharmaceutically acceptable carrier. PbannaceuticaHy acceptable salts of the compounds of tIns invention include those derived from pharmaceutically acceptable inorganic and organic acids and tases, 'Examples vf suitable acid sans include acetate, ajftpale, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphoTSulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, . ethanesulfonate, formate, ftiniarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromidc, hydroiodide, 2* hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, mesylate, 2-naphtbalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, miocyanate, tosylate and undecanoate. Other acids, such as oxalic, wInle not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alfcyI)fl salts. TIns invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersfble products may be obtained by such quaternization. Further, tIns invention covers a method of administering an effective amount of one or more compounds of tIns invention to a subject {a human, a mammal, ox an animal, e.g., dog, cat, horse, cow, or cIncken) in need oftreatment for a disease or disease symptom (e.g., an inflammatory disease, an infectious disease, cancer, allergy, or an immune disease, or symptoms thereof). The term "treating" or "treated" refers to administering a compound of tIns invention to a subject with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect a disease, the symptoms of the disease or the predisposition toward the disease. "An effective amount" refers to an amount of a compound wInch confers a therapeutic effect on the treated subject The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). An effective amount of the compound described above may range from about 0.1 mg/Kg to about 20 rag/Kg. Effective doses will also vary, as recognized by mose skilled in the art, depending on route of administration, exeipient usage, and the possibility of co-usage with other agents for treating a disease, including an inflammatory disease, a cardiovascular disease, an infectious disease, cancer, allergy, and an immune disease. The methods delineated herein can also include the step of identifying that the subject is in need oftreatment of for a disorders and or condition in athe subject The identification can be in die judgment of a subject or a health professional and can be subjective (e.g., opinion) or objective (e.g^ measurable by a test or a diagnostic method). The following is a non-exclusive list of diseases and disease symptoms, wInch maybe treated or prevented by administration of the compounds and compositions thereof herein and by the methods hereto. Inflammation and related disorders Inflammation secondary to trauma or injury Post traumatic regeneration injury including but not limited to Ischemia, reperftision injury, scarring, CNS trauma, spinal section, edema, repetitive strain injuries including tendonitis, carpal tunnel syndrome, Cardiovascular diseases specifically atherosclerosis, inflamed or unstable plaque associated conditions, restenosis, infarction, thromboses, post-operative coagulative disorders, acute stroke, Autoimmune diseases Alopecia Areata, Ankylosing Spondylitis, Antiphospholipid Syndrome, Autoimmune Addison's Disease, aplastic anemia, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis, Behcet's Disease, biliary cirrhosis, Bullous PempIngoid, Canavan Disease, Cardiomyopathy, Celiac Sprue-Dermatitis, Chronic Fatigue Immune Dysfunction Syndrome (CFDDS), Chronic Inflammatory Demyelinating Polyneuropathy, Churg-Strauss Syndrome, Cicatricial PempIngoid, CREST Syndrome, Cold Agglutinin Disease, Crohn's Disease, dermatomyositis, Diffuse Cerebral Sclerosis of ScInlder, Discoid Lupus, Essential Mixed Cryoglobulinemia, Fibromyalgia- FibromyosIns, Fuch's heterochromic iridocyclitis, Graves' Disease, Guillain-Barre, HasInmoto's Thyroiditis, IdiopatInc Pulmonary Fibrosis, IdiopatInc Thrombocytopenia Purpura (ITP), IgA Nephropathy, Insulin dependent Diabetes, Intermediate uveitis, Juvenile Arthritis, Lichen Planus, Lupus, Meniere's Disease, Mixed Connective Tissue Disease, Multiple Sclerosis, Myasthenia Gravis, nephrotic syndrome. PempIngus Vulgaris, Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes, Polymyalgia Rheumatica, Polymyositis and Dermatomyositis, Primary Agammag- lobulinemia, Primary Biliary Cirrhosis, Psoriasis, Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Scleroderma, Sjogren's Syndrome, Stiff-Man Syndrome, Takayasu Arteritis, Temporal Arteritis/Giant Cell Arteritis, Ulcerative Colitis, Vasculitis, Vitiligo, VKH (Vogt-Koyanagi-Harada) disease, Wegener's Granulomatosis, Anti-Phospholipid Antibody Syndrome (Lupus Anticoagulant), Churg-Strauss (Allergic Granulomatosis), Dermatomyositis/Polymyositis, Goodpasture's Syndrome, Interstitial Granulomatous Dermatitis with Arthritis, Lupus Erythematosus (SLE, DLE, SCLE), Mixed Connective Tissue Disease, Relapsing Polychondritis, HLA-B27 asssociated conditions including Ankylosing spondylitis, Psoriasis, Ulcerative colitis, Crohn's disease, IBD, Reiter's syndrome, Uveal diseases: Uveitis, Pediatric Uveitis, HLA-B27 Associated Uveitis, Intermediate Uveitis, Posterior Uveitis, Iritis, Dermatological disease Psoriasis, atopic dermatitis, acne Rheumatoiogical disease Osteoarthritis and various forms of autoimmune arthritis. Neurodegenerative disease Inflammatory degenerative diseases Including variants and major forms of: Alzheimer's, Huntington's Parkinson's and Creutzfeldt Jakob disease Infection Respiratory diseases of diverse origin including: Pharyngitis ("sore throat"), Tonsilitis, Sinusitis & Otitis Media, Influenza, Laryngo-Tracheo BroncIntis (Croup), Acute BroncInolitis, Pneumonia, Bronchopneumonia, BroncInolitis, BroncIntis, Acute pharyngitis with fever, Pharyngoconjunctival fever, Acute follicular conjunctivitis, Pneumonia (and pneumonitis in cInldren), COPD, asthma, Gastrointestinal diseases Gastroenteritis of diverse origin Viral diseases Target viuses include but are not limited to'. Paramyxo-, Picorna-, rInno-, coxsackie-, Influenza-, Herpes-, adeno-, parainfluenza-, respiratory syncytial-, echo-, corona-, Epstein-Barr-, Cytomegalo-, Varicella zoster, Hepatitis variants including hepatitis C Virus (HCV), Hepatitis A Virus (HAV), Hepatitis B Virus (HBV), Hepatitis D Virus (HDV), Hepatitis E Virus (HEV), Hepatitis F Virus (HFV), Hepatitis G Virus (HGV), Human immunodeficiency-Parasitic diseases HelmintInases and similar diseases Larva Migrans, Toxocara canis. Hookworm Infections (Ancylostomiasis) Nccator spp. Ancylostoma duodenale and Necator americanus, Filariasis, Wuchereria bancrofbl & Brugia malayi, Loiasis, Ascariasis, Ascaris lurnbricaides -, Dracimculiasis, ScInstosomiasis, ScInstosoma mausoui, male & female [P Darben] -(AU), Onchocerciasis (River Blindness), WInpworm Infections, Ascaris lumbricoides and Trichuris rrichrura, TricInnosis, TricInnella, Cestode Infections, Dipbyllobothriasis, DiphyHobcthriurn spp., EcInnococcosis, EcInnococcisis (Hydatid Disease), EcInnococcus mulhTocularis, Taeniasis, (Tapeworm Infection), Cysticeieosis Leishmaniasis (Kala AZHT), Leisbmaaaia donovani, Eaterobius vermicularis, Anal Pinworms, Dientamoebiasis, Dientamocba rragilis, Anisalriasis, Anisalris simplex, Giardiasis, Giaidia lamblia, Giardia minis Protozoan infection Acanthamoeba sp. Flagellates, Amebiasis, Naegleria, Acanthamoeba and BalamulIns, Entamoeba, Trichomonas Infections, Blastocyetis homiuis mfections (not on MeSH), Malaria, Hasmodram falciparum, Toxoplasmosis, Cryptosporidiosis. Cyelosporiasis, Cyclospora cayetanensis, Babesiosis, Trypanosomiasis, Trypanosomiasis, Trypanosoma brucei, Chagas Disease Neoplastic disease leukemia, lymphoma, myeloma hepatomas, other major organ carcinomas and sarcomas glioma, neuroblastoma. Astrocytic and glial tumors, Invasive or non-invasive (Anaplastic (malignant) astrocytoma, Glioblastoma multiforme variants: giant cell glioblastoma, gtiosarcoma, Pilocytic astrocytoma, Subependymal giant cell astrocytoma, PleomorpInc xanthoastrocytoma) Olieodendroglial tumors Ependymal cell tumors, Mixed gliomas, Neuroepithelial tumors of uncertain origin. Tumors of the choroid plexus, Neuronal and mixed neuronal-glial tumors, Pineal Parenchyma Tumors, Tumors with neuroblastic or glioblastic elements (embryonal tumors), Neuroblastoma, ganglioneuroblastoma, Tumors of the Sellar Region, Hematopoietic tumors, Primary malignant lymphomas, Plasmacytoma, Granulocytic sarcoma, Germ Cell Tumors, Tumors of the Meninges Allersv RInnitis, broncIntis, asthma and conditions relating to excessively active or stimulated eosinopInls, Transplant medicine Renal, hepatic, corneal, stem cell, pulmonary, cardiac, vascular, and myeloid transplants Metabolic disease. Various disorders clustered in the liver cirrhosis, dyslrpidemia, diabetes, obesity and hypercholesterolemia groupings. Benefits of the invention: The conjugates described here represent improvements on their parent therapeutic agents in two main respects. First, these conjugates provide a facile means of improving the activity of a therapeutic agent through their ability to make the therapeutic agent more easily available either from the gut, or from the blood stream. TIns is especially important for those therapeutic agents mat have good activity in vitro but are unable to exert that activity in vivo. Where the non-mamfestarion of activity is related to inefficient uptake and distribution, simple conjugations according to the schemes described here are an efficient means to generate improved activity. The invention also has specific benefits. By targeting cells, and acIneving Ingher concentration in those cells than in plasma or general tissue, the therapeutic agent may exert a more specific action resulting in fewer systemic side effects. Where efficacy is limited by the ability to place sufficient therapeutic agent at the site of action, such concentration effects, are significant in acIneving improved in vitro effect. TIns may be understood more clearly by examination of non-limiting but representative examples from different therapeutic areas. In Examples 10-16, improved anti-inflammatory therapeutic agents are described in wInch the active moleculs are concentrated into immune cells in vitro through conjugation with a macrolide. These conjugates display superior immune suppressive and anti-inflammatory action in vivo when compared with the effect of a mixture of the two component molecules in the same system. The mechanism for tIns action is unknown hut the effect in protection appears to be qualitatively similar for the mixture and the conjugate suggesting that the conjugate is largely a delivery mechanism for the therapeutic agent. One potential non-exclusive explanation is that immune cells produce Ingh levels of aracIndonate, the substrate of cyclooxygenase enzymes, resulting in competition between tIns substance and NSAII) therapeutic agents for sites on cyclo-oxygenase enyzymes (substrate competition is known in the art as a common means of reducing the efficiency of an inInbitor). Enhanced concentration of the therapeutic agent has the potential to overcome tIns feedback inInbition resulting in a greater inInbition of flux through the enzyme. The conjugate also has other potential benefits including the prevention of metabolism through steric effects, increased residence time and traffic to sites of raflamniation when it is taken up Into target cells wInch are tropic for the inflamed tissues. Some action of the conjugate itself cannot be ruled out when it is present at Ingh concentrations in a cell. In example 24, an anti-viral therapeutic agent conjugate is cited that also acIneves Ingher levels in immune cells wInch may act as a reservoir of integrated viral material. If therapeutic agent is selectively conjugated such mat it is concentrated in these cells, it has two potential benefits including, the ability to suppress viral replication at lower systemic doses, and the ability to prevent resistance through the maintenance of persistently Ingher concentrations of therapeutic agent such that mutations with minor effect cannot accumulate.- Similar themes but contrasting mechanisms apply to the field of graft rejection where one focus of therapy is the prevention of T-cell responses to the donor organ. Various mechanisms are known but all would benefit if a greater proportion of chemical effect were focused on the T-cells themselves such that the systemic dose were reduced. Example 21. cites conjugates ofmycophenolic acid that are Inghly concentrated m immune cells. These conjugates are also Inghly bioavailable in the rat and cleave slowly to release jnycophenolie acid. Despite slow cleavage, the compounds have very similar anti-proliferative activity in vitro when compared with unconjugated mycophenolic acid suggesting that concentration can compensate for slow hydrolysis such that the conjugate becomes an intracellular reserve for the slow release of mycophenolate. Similar advantages can be cited for cancer where those neoplasms are of a type that takes up the conjugates to the same extent seen in immune cells. Cancers of myeloid origin are a good example of a target neoplasm. In such cancers, concentration of the therapeutic agent has potential to compensate for common resistance mechanisms such as gene amplification and the over expression of efflux systems. In certain cancers, the tumour is associated with an intense local inflammation. The inflammatory infiltrate may serve as a means of further concentration of the conjugate drugs in the environs of the tumour. In cardiovascular diseases such as atherosclerosis, it is commonly known that there is a strong inflammatory component to the events wInch result in the tInckening and fragmentation of the plaque. TIns inflammation may be effectively reduced by the application of a range of agents including conjugates of compounds that are anti¬inflammatory in effect. Data to support these observations may be found in various examples and is summarized here by reference in a non-limiting manner. To practice the method of treating a disease, the compounds of tIns invention can be administered to a patient, for example, in order to treat a disease described above. The compound can, for example, be administered in a phannaceutically acceptable carrier such as physiological saline, in combination with other therapeutic agents, and/or together with appropriate excipients. The compound described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoaeally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, by inhalation, by intracranial injection or infusion techniques, with a dosage ranging from about 0.1 to about 2Q mg/kgofbody weight, preferably dosages between lOmg and lOOOmg/dose, every 4 to 120 hours, or according to the requirements of the particular therapeutic agent. The methods herein contemplate administration of an effective amount of compound or compound composition to acIneve the desired or stated effect. Lower or Ingher doses Stan those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, therapeutic agent combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician. Pharmaceutical compositions of tIns invention comprise a compound of tIns invention or a pharmaceutically acceptable salt thereof; and any pharmaceutically acceptable carrier, adjuvant or veIncle. Such compositions may optionally comprise additional therapeutic agents. The compositions delineated herein include the compounds of the fonnulae delineated herein, as well as additional therapeutic agents if present, in amounts effective for acIneving a modulation of a disease. The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of tIns invention, and wInch does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. Pharmaceutically acceptable carriers, adjuvants and veIncles that may be used in the pharmaceutical compositions of tIns invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecitInn, self-emulsifying therapeutic agent delivery systems (SEDDS) such as D-alpha-tocopheroI polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylceiInlose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as a-, p-, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextriris, including 2- and 3-hydroxypropyl-p-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein. Oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents wInch are commonly used in the formulation of phamiaceuti catty acceptable dosage forms such as emulsions and or suspensions. The pharmaceutical compositions of tIns invention may be orally administered in any orally acceptable dosage form including, but not iimited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers wInch are commonly used include lactose and com starch-Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried com starch-When aqueous suspensions and/or emulsions are administered orally, the active ingredient maybe suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. The phannaceutical compositions of tIns invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of tIns invention with a suitable non-irritating excipient wInch is solid at room temperature but liquid at the recta) temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols. Topical administration of the pharmaceutical compositions of tIns invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of tIns invention include, but are not limited to, mineral oil, liquid petroleum, wInte petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The phannaceutical compositions of tIns invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation, TopicaJly-transdermal patches are also included in tIns invention. The pharmaceutical compositions of tIns invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/ox other solnbilizing or dispersing agents known in the art A suitable in vitro assay can be used to preliminarily evaluate a compound of tIns invention in treating a disease. In wo screening can also be performed by following procedures well known in the art See the specific examples below. All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications. The invention will be further described in the following example. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting tIns invention in any manner. EXAMPLES example number Subject 1. Method for determining immune cell partition 2. Transportophore: Compound 39 3. Transportophore: Compound 40 4. Transportophore: Compound 41 5. Transportophore: Compound 42 6. Transportophore: Compound 44 7. Transportophore: Compound 45 8. Transportophore: Compound 46 9- Transportophore: Compound 47 10. Transportophore: Compound 48 11- Transportophore: Compound 49 12. Transportophore: Compound 50 13. NSATD Conjugate- Diclofenac Conjugates; Compound 52, 53, 54, & 55 14. NSAID Conjugate: Compound 56 15. NSAID Conjugate: Compound 57 16- NSAID Conjugate: Compound 58 17. NSAID Conjugate: Compound 59 IS. NSAID Conjugate: Compound 60 19. NSAID Conjugate: Compound 61 20. Conjugates of cytotoxic agents: Compound 62 21. Conjugates of cytotoxic agents: Compound 64 " 22. Neotrofin conjugate; Compound 65 23. Gemfibrozil conjugate: Compound 66 24. Mycopbenolic Acid conjugates: Compounds 67,68, 69,71, 73,74,75,78, 79, 30, & 81 25. Steroid Conjugates: Compounds S2, 83,84, 85, & 86 26. Statin Conjugates: Compounds 87 & 88 27. Antifungal Conjugate: Compound 89 28. Antiviral Nucleoside Conjugates: Compounds 90,92,94, 97, & 101 29. NSAID Conjugate: Compound 106 30. Coumarin Conjugates: Compounds 108,109 31. Imatinab Conjugate: Compound 110 32. Proliferation Assay 33. Cell-Eased IMPDH Assay with Guanosine Rescue 34. Efficacy Testing of Drugs using Collagen-mduced Arthritis in Mice 35. Efficacy Testing of Immunosuppressive Drugs Using a Mouse Skin Transplant Model 36. Testing of Antibiotic Activity of Drugs Example 1; Determination of the Immune Selectivity Ratio Coefficient fPISRI Uptake of compounds Freshly drawn heparinised blood or buffy coat preparations are used for the determination of immune cell partition ratios. Buffy coat preparations are preferred. These may be obtained from donor blood by simple centrifugation of whole blood (4795 % for 10 minutes). Following centrifugation, plasma is collected from the surface, after wInch immune cells are expressed from the donor bags along with the erythrocytes lying immediately below the leukocyte layer. TIns ensures Ingh yields and a sufficient population of erythrocytes for partition. 5 ml of the resulting cell suspension are dispensed into T25 culture flasks. Substrates are added to a final concentration between 1 and 10 uM and fhe suspensions incubated at 37°C, in a 5% CO2 atmosphere. For analysis of uptake kinetics, samples are withdrawn at 0,2,5,10, 30, 60,90, ISO, or 240 min after substrate addition. For screening purposes, samples arc taken at 0 and 120 minutes. Buffers and solutions PBS 73 mM NaQ, 2.7 mM KC1,1.5 mM KH3JPO4. 8 mM NaaHPO^ pH 7.4 DPBS 137 mM Naa 3 mM KC1, S mM Na2HP04, 1 mM KH3PO4,1 mM CaCfc, 0.5 mM MgCb. 5 mM Glucose, pH 7.4 Separation of blood cell fractions - density gradient centrifugation Cell fractions were prepared using density gradient centrifugation. Mononuclear cells and polymorphonuclear cells are separated from erythrocytes essentially by layering the cell suspension on a viscous medium typically composed of a solution containing Ficoll or similar (commercial suppliers include; Lymphoprep, Axis SIneld, 1031966; Lymphoflot HLA, B24010; or PMN Separation Medium Robbins Scientific 106S-00-0). The layered suspension is then centrifuged at 600 g» 20 min, after wInch the cell fractions and the plasma (incubation medium) fraction are removed by gentle aspiration, washed twice in PBS buffer, followed by estimation of the cell number and pellet volume. Analysis Uptake of fluorescent compounds is monitored using fluorescence microscopy. Excitation and emission wavelengths depend of the fluorescence label in use. A typical label is a methoxy coumarin for wInch the appropriate wavelengths are 360 and 450 nm respectively. Fluorescent analogs of the compounds under study permit the estimation of appropriate uptake intervals as well as the likely intracellular distribution of the compounds. Fluorescent analogs also allow the estimation of losses in wasInng or other cell manipulations. Cell preparations are lyscd in water and the debris sedimented at 16100 g, 10 min. The supernatant is recovered and sub-sampled for protein and DNA content Protein in the supernatant is precipitated by bringing the solution to 100 % v/v ethanol and centrifugmg again at 16100 g, 10 min. Compound uptake is normalized according to cytoplasmic volume of calk in order to obtain the average concentration in the cells. Cell volume is estimated by correlation of DNA, protein or haem content of Jysed cell aliquots to cell number and packed volume prior to lysis. Cell lysates are analysed using a HP 1100 HPLC System (Agilent Technologies, Waldbronn, Germany) with a Kromasil 3.5u CI8, 50 x 2.0 mm column nd guard cartridge system (both, Phenomenex, Aschaffenburg, Germany) nm at 0DC. A gradient elution was performed using water, 0.05% foiroic acid (A) and cetonjtrile 0.05% formic acid (B) (0 min. 5% B, 2.5 min 5% B, 2.8 min 40% B, 10.5 lin 85% B, 12.0 min 95% B, 16.5 min 95% B) at a flow rate of 300 uVmin. Re-quilibration of column was at 5% B, at a flow rate of 750 ul/min for 2.4 min. The DPLC-eluate from retention rime 0.0 min to 2.5 min was directed directly to waste. >etection was via a UV cell at 214 nm followed by a 1/6 split to an An APT-qTOF 1 Micromass, Manchester, UK) mass spectrometer, (calibrated daily using a mixture of laL Rbl and CsT). The mass spectrometer is routinely operated in the positive lectrospray ionization mode using the following settings: Capillary voltage 4000 V; uone voltage 30 V; EF Lens offiet 0.38 V; source block temperature S0°C; desolvation gas temperature 140°C; desolvation gas 240 Vh; LM/ HM Resolution 0.0; Collision energy 4.0 V; Ion energy 5.0 V. Masses are monitored according to the known or expected M/Z ratios. Ion currents across the expected range of masses (including metabolites) are recorded and the chrom&tograms for specific masses used to estimate the peak area for a given molecular ion (area proportional to concentration over a given range). Normalisation to DNA and/or protein and/or baem content of cells (all three measured with standard methods (Bisbenzimide staining (Sigma), BCA protein assay kit (Pierce) and haem absorbance at 535 ran, respectively)) to cell number (hemocytometercount) and cell volume is employed to calculate average compound concentration in the cell fraction (expressed in uM). Formation of metabolites or hydrolysis products was also monitored for each T-L-C conjugate and the rate of hydrolysis estimated from both the total uptake and the loss of metabolites to the medium. The final ratio is computed by comparing the concentration of a component in the immune cell compartment 'with that in both the erythrocytes and the plasma. The PISK, is then the concentration in immune cells/concentration in erythrocytes using the same concentration units. Thus a PISR of 2 indicates a two-fold concentration relative to erythrocytes. Selection and definition of carrier compounds Immune cell selectivity assays provide data in the form of micrographs of fluorescent analogs and quantitative estimates of compound concentration. Micrographs are useful in detennining the intracellular disposition of compounds (FIG 1). It is apparent from the illustratians that compound distribution is generally uniform with some examples appearing granular or nuclear. The analysis of fluorescent libraries by tIns method provides an efficient means of selecting T molecules that are capable of mediating the transport of diverse substances into a cell. Examples of molecules assayed in tIns way are summarized in Table 2 along with their uptake data and selectivity. These data show ifcat similar molecules with similar properties can exInbit quite different uptake into immune cells, hence the difficulty m employing general specifications known in the art (Lrpinski et al., 2001) Further, it is clear from the images obtained during the course of uptake (FIG 1, FIG 2, or FIG 3) that for some structures, the process is a slow one relative to pure lipopInlic diffuaion. TIns is indicative of processes in uptake that depend on factors other than diffusion alone. Certain investigators have proposed that compounds of the macrolide type are subject to active, protein mediated concentrative mechanisms although these remain unknown (Labro, 1998)^ The data presented here for compounds 4 and 5 suggest that uptake is rapid but that it varies with each structure wInch floes not exclude a concentrative mechanism involving protein action. Compounds exInbiting Ingh uptake are outlined in Table 2 along with similar structures mat do not. It is clear from an inspection of the structures that there exist a variety of chemical and physical properties compatible with selective entry into wInte blood cells. These data are consistent with there being a multiplicity of mechanisms for cell entry and accumulation including passive entry and active uptake. These data further suggest mat compounds with properties supposedly compatible with facile uptake into actively metabolizing cells such as immune cells do not exInbit such properties. Simple addition of basic functions is not always effective, even in in vitro screening. In contract, addition of sugars, amino acids, or peptides can enhance entry of fluorescent compounds. Based on both the micrographs above and analysis of immune cells following uptake, it is clear that macrolide structures are very effective at mediating the entry of fluorescent molecules into cells and that other basic compounds did not exInbit tIns property. In sum, it is clear that an empirical method is the only reliable means of selecting and guiding synthetic chemistry toward compounds that are well distributed and concentrated in immune cells. Transportopbores EXAMPLE 2: COMPOUND 39 15.B g (21.1 rnmol) Azithromycin (9a-aza-9a-metbyl-9-deGxo-9a-homoerythromycin A, Confound 43) was dissolved m an iceeold 6 N hydrogen chloride solution (100 ml). The reaction mixture was stirred at 0°C for 4 horns. The solution turned from yellow to green. The solution was poured on ice (200 g) and 28 ml sodium hydroxide solution (50%) were added. The solution was extracted with ethylacetate (300 ml). The organic layer was discarded. After addition of 30 ml aodium hydroxide solution (50%) to the water layer a colorless precipitate formed. The suspension was extracted with dichloromethane (300 ml). The organic layer was separated, dried over Na2S04 and concentrated under reduced pressure. After drying in Ingh vacuum 12.8 g (100%) of a colorless foam were obtained wInch were used without further purification. The product was dissolved in dry dichloromethane (150 ml) and 3.3 ml (32.7 mmo!) acetic acid anhydride were added. The solution was stirred at room temperature overnight, then diluted with dichloromethane (200 ml) and washed with saturated sodium bicarbonate solution (150 ml). The organic layer was separated, dried over NasSOi and concentrated under reduced pressure. 12.3 g (92%) of compound 39 were obtained as a colorless foam, wInch was dried in Ingh vacuum and used without further purification. EXAMPLE 3: COMPOUND 40 A solution of 610 mg (4.5 mmol) N-chlorosucciniinide in dry dichlDramethane (50 ml) was cInlled lo -30DC and 0.59 ml (8 mmol) dimetbylsulfide were added. A colorless precipitate formed immediately and the suspension was kept between * 30°C and -10°C for 30 min. Then the reaction mixture was cooled to -40"C and 1.9 g (3.0 nunol) of compound 43 were added m one portion. After 20 min the precipitate was completely dissolved and 0.77 ml (4.5 mmol) of ethyl diisopropylainine were added to the colorless solution. The reaction mixture was allowed to reach ambient temperature slowly. Sfering was continued at room temperature for another hour. The reaction mixture was diluted with CHjCfe (50 ml) and washed with saturated sodium bicarbonate solution (100 ml). The organic layer was separated, dried over NajSOj and concentrated under reduced pressure. A colorless oil was obtained wInch was redissoJved in methanol (75 ml) and stirred at 50"C overnight The solvent was removed under reduced pressure and the residue subjected to column chromatography on silica gel with chloroform/methanol/7N ammonia in methanol (20:1:1) as eInent to yield 1.0 g (59%) of compound 40 as a colorless oil. FX AMPLE 4: COMPOUND 41 To a solution of 35 ml of diethylamine in 50 ml of etJimol was added 1-5 ml of 1,4-butandioldiglycidyl ether. The solution was allowed to stand for 48 h at ambient temperature. All volatiles were evaporated then and the residue used without further purification. EXAMPLE 5: COMPOUND 42 A solution of 15 g (20 nunol) of Compound 43 in 5 0 m) of acetic anhydride is treated with 2 g of potassium carbonate and heated to reflux for 3 h. After cooling the mixture is poured onto ice and neutralized with potassium carbonate. The mixture is extracted with ethyl acetate, -washed with water and brine and concentrated after drying (NajSOj). The residue is redissolved in. methanol and heated to 50_°C overnight. After removal of the methanol in vacuum the residue id redissolved in chloroform- Triethylamine (10 ml) is added and the solution cooled to 0°C. Under stirring methansulfonic acid chloride (46 ml, 60 mmol) is added witInn 15 tnin and the mixture is allowed to warm to ambient temperature. After 3 h the mixture is washed with aqueous potassium carbonate solution and brine, dried (NajS04) and concentrated in vacuum. The residue is chromatographed on silica gel, elution with ethyl acetate to yield 3.5 g (22%) of slightly yellowish roam that is used without further purification. EXAMPLE .6: COMPOUND 44 To a solution of Compound 42 (850 mg, Immol) in DMF (7mL), prepared as described before, N-methyl amiivo-2-ethanol (0.12 ml, 2 mmol) is added. After stirring for 24 h at 70°C the mixture is concentrated In vacuum and the residue is dissolved in ethyl acetate, washed with water and brine, dried (NajSO^) and the solvent evaporated in vacuum to yield 544 mg (80%) of yellowish foam that can be used without further purification- EXAMPLE 7: COMPOUND 45 A solution of 1.1 g (1.5 mmol) of Compound 96 (See Example 24) in 5 ml of diehloromethane was combined with 415 mg (2,25 mmol) of iodo acetic acid afld 450 . mg (2.25 irunol) of DCC. After 2 h at ambient temperature the mixture was filtered and used without purification or concentration. EXAMPLE 8; COMPOUND 46 A solution of 2.0 g (2.5 mmol) of Compound 44 in 50 ml of 6 M HC1 is kept for 15 min at ambient temperature and then extracted with 10 ml of ethyl acetate. The organic phase is discarded and the aqueous phase neutralised with potassium carbonate and extracted with ethyl acetate. The combined organic phases are dried (NajSO-O and concentrated in vacuum to yield 1.47 g (91%) of a sKghtly yellowish solid that is used without further purification- EXAMPLE 9: COMPOUND 47 To a solution of 3.75 g (5.0 mmol) of Compound 43 in 5 ml of DMF is added 2.5 ml of epichlorohydrin and the mixture is heated to 60-65 "C for 2 d. After cooling most of the volatiles are removed in vacuum and the residue poured onto water and extracted with ethyl acetate. The combined organic phases are washed with brine, dried (Na2SC4) and concentrated in vacuum. The residue is chromatograpbed on silica gel, elution with ethyl acetate to yield 1.4 g (40%) of a colorless waxy solid. EXAMPLE 10: COMPOUND 48 A solution of 1.5 g(2.1 mmol) ofCcnnpound47and2ralofinorphoIinein 15 ml of isopropanol is heated to reflux for 12 h- The mixture is cooled, poured onto water and extracted with ethyl acetate. The organic phase is washed with water, then with brine, dried (Na2SO EXAMPLE II: COMPOUND 49 A solution of 1.63 g (12.0 mmol) N-chlorosuccanimide in dry dichloromethane (50 ml) was chilled to -40°C and 13 nil (18 mmol) dimettiylsulfide were added. A colorless precipitate formed immediately and the suspension was kept at - 20°C for 30 min. The reaction mixture was cooled to -40°C and 1.9 g (3.0 mmol) of compound 43 prepared as described above were added in one portion. After 15 min 2.0 ml (12.0 mmol) of ethyl diisopropylamine were added. The precipitate dissolved and the solution was allowed to reach ambient temperature slowly. Stirring was continued at room temperature for 1 hour. The reaction mixture was diluted with CHzCfe (50 ml) and washed with saturated sodium bicarbonate solution (100 ml). The organic layer was separated, dried overNa^SO* and concentrated under reduced pressure. A colorless oil was obtained which was redjssolved in methanol (75 nil) and stirred at 50°C overnight The solvent was removed under reduced pressure and the residue subjected to column chromatography on silica gel with chloroforrn/methanol/7N annnoniainmethariol(30;l:l)aaeluent to yield l.Ig(62%) of compound 49 as a colorless foam. EXAMPLE 12: COMPOUND 50 To a stirred solution of 589 mg (1 mruol) of Compound 40 in methanol (20 ml) "was added 1.26 mi (10 mmol) of hydrogen peroxide (30%). After stirring for 3 days at room temperature ibe reaction mixture was chilled to -78°C and a solution of 126 g(lOnnnol) sodium sulfite in 10 ml of water was added. The suspension was allowed to warm up to room temperature and then all volatile compounds removed under reduced pressure. The residue was resuspended in methanol and filtered. The filtrate was concentrated under reduced pressure to fiimish the crude product Column chromatography on silica gel with chlorofonn/methanol/7N ammonia in methanol (15:4:1) as the eluent yielded 327 mg (54%) of compound 51 as a colorless oil. To a stirred solution of 870 mg (1.4 mmol) of Compound 51 in dry N,Nr-dnnotylacetamide (20 ml) was added 370 mg (3.3 mmol) potassium tert-butoxide. The colorless solution turned slowly orange and was chilled to -15*0.0.25 ml (2.2 mmol) ethyl bromoacetate were added and the reaction mixture allowed to warm up to room temperature. 2.0 ml of triethylamine were added and stirring continued ibr another hour. The reaction mixture was diluted wifli ethanol (20 ml) and acetic acid (2.0 ml) and 0.3 g of PdVC (10%) were added. The reaction mixture was shaken under an atmosphere of hydrogen overnight. After filtration, all volatile compounds were removed under reduced pressure. The crude product was subjected to column chromatography on silica gel with chloroform/methanol/7N ammonia in methanol (15:1:1) as the elueat to yield 340 mg (35%) of compound 50 as a colorless oil. Acids EXAMPLE 13:_ DICLOFENAC CONJUGATES COMPOUI-TO 52 A solution of Diclofenac (0.67& 2.25 mmol) in methylene chloride (10ml), is treated with N,N'-caAonyldtinadaz»le (0-38g; 2-25 mmol). After stirring for 30 min at HT, Compound 43 (Q37g; 0,75 mmof) is added. Reaction is stiirod for 3 h at RT. The reaction solution was concentrated in vacuum and die residue purified by column chromatography on silica gel, station with chlcn*>fbnn/isopropanol/metiianolic ammonia 60:1:1 to yield Compound 52 (0.15g; yield: 20%) as a white foam. COMPOUND 53 A suspension of 590 mg (2.0 mmoT) of diclofenac in 6 ml of dichJommethace is treated with 324 mg (2.0 mmol) of carbonyl dzinudazole at 0°C After 5 min at this temperature 294 mg (0.5 mmol) of Compound 40 is added and the mixture 3tept at ambient temperature for 48 h. The mixture is then concentrated and the residue chromatographed on silica gel, elution with cWoroform/isopTOpanoi/methanolic ammonia 40:1:1 to yield 330 mg(76%) of a colorless solid. To a turbid solution of 740 mg (2.5 mmol) diclofenac in dry dichloromethane (20 ml) was added a solution of IN hydrogen chloride in ether (2.5 ml) and 440 mg (2.7 mmol) of 14 '-eaibonyldiiiaidazoJe. The solution was stirred for 60 min at room temperature. Then 5S7 mg (1 mmol) of Compound 49 were added and stirring continued overnight The mixture was diluted with CHaCfe (30 ml) and washed with saturated sodium bicarbonate solution (50 ml). The organic layer was separated, dried over Na^SCU and concentrated under reduced pressure to furnish a reddish oil. Column chromatography on silica gel with chlorofbnn/methanol/7N ammonia in methanol (30:1:1) as eluent yielded 450 mg (52%) of compound 54 as a colorless oil. To a turbid solution of 740 mg (2.5 mmol) diclofenac in dry dichloiomethane (20 ml) was added a solution of IN hydrogen chloride in ether (2.5 ml) and 440 mg (2.7 mmol) of lj'-carbonyldiimidazole. The solution was stirred for 60 rain at Toom temperature. Then 340 mg (0.5 mmol) of compound 50 prepared as described above were added and stirring continued overnight. The mixture was diluted with CH3CI2 (30 ml) and washed with saturated sodium bicarbonate solution (50 ml) . The organic layer was separated, dried over NajSQ* and concentrated under reduced pressure to furnish a reddish oil. Column chromatography on silica gel with cbJorofom^methanoVW ammonia in methanol (10:1:1) as ement yielded 214 mg (45%) of compound 55 as a colorless oil. A solution of Meclofcnamic acid (0.36g; 1.2 mmol) in methylene chloride (15 ml), is treated with K^N'-caibonyldiimidazole (0.20gj 1 .2 mmol). After stirring for 30 min at RT, Compound 44 cruoToform/isopropanoVmethanoHc ammonia 60:1 A. The appropriate fractions are collected and concentrated to yield 0.17g (25%) of Compound 56 as a white foam. EXAMPLE 15: COMPOUHP 57 A solution of Mefenamic acid (0.2? g; 1.2 rmnol) in methylene chloride (5m]), is treated with N,K'-carbonyldiiniidazols (0.20 g; 1.2 mmol). After stirring for 30 min at ambient temperature, Compound 44 (0.4? g; 0.75 mmol) is added. Reaction is starred for 3 h at ambient temperature. The reaction solution is concentrated in vacuum and the residue purified by column chromatography, emtion with c&loj^fonn/isc^ropanoiymethanofc collected and concentrated to produce Compound 57 (0.16g; yield: 25%) as a white foam. EXAMPLE 16: COMPOUND 58 A solution of Indomethacin (0.80g; 2.25 mmol) in methylene chloride (10ml), is treated with N^T'-caibooyldiimidazoIe (0.38g, 225 mmol). After stirring for 30 min at RT, Compound 40 (0.44g; 0.75 mmol) is added. Reaction is stirred for 3 h at E.T. The reaction solution was concentrated in vacuum and the residue purified by column chromatography on silica gel, elution with isopropanol to yield 0.20 g (25%) of Compound 58 a white foam. EXAMPLE 17: COMPOUNDER Asolution of 360 mg (2.0 mmol) of acetyl salicylic acid is treated with 1.5 ml (16 mmol) oxalylic chloride in 10 ml of chloroform. A drop DfDMF is added and the mixture is allowed to stand at ambient temperature for 1 h. All volatfles are removed in vacuum and the residue dissolved in 20 ml of dichlorometbaiie. After cooling to 0°C 376 mg (0.65 mmol) of Compound 104 (See Example 24) is added followed by 1 ml of pyridine. The mixture is allowed to warm to ambient temperature and after 2 h concentrated in vacuum. The residue is chromatograpned on silica gel, ehition with chlaroforni/isopropaool/methaDolic ammonia 60:1:1 to yield 205 mg (35%) of Compound 59 as a white solid. EXAMPLE 18: COMPOUND 60 A solution of Ibuprofen (0.47g; 225 mmol) in methylene chloride (10ml), i5 treated with N,N'-carbonyldumidazoIe (0.38^ 225 mmol). After stirring for 30 min. at RT, Compound 43 (0.56g; 0.75 mmol) is added. Reaction is stirred for 3 h at RT. The reaction, solution was concentrated in vacuum and the residue purified by cohimn chromatography pn silica gel, ehition with isopropanol to yield 0.17g (25%) of white foam, Compound 60. A solution of flurbiprofen (0.27g; 1.2 nnnol) in methylene chloride (5ml), is treated with N^'-carbonyldiimidazole (0.20g; 1.2 mmol). After stirring for 30 min. at ambient temperature, Compound 46(0.47g; 0.75 nanol) ie added. Reaction is stirred for 3 h at ambient temperature. The reaction solution was concentrated in vacuum and the residue purified by column chromatography on silica gel, and elution with chloroform/isopropanol/methanoh'c ammonia 60:1:1 to yield 0.l6g (25%) of product Compound 61, a white foam. 4 600 mg of melphalan (63) is suspended in 25 ml of water containing 500 mg of sodium carbonate. lOmlofdioxaneisaddedandl mlof acetic anhydride. After stirring at ambient temperature for 1 h citric acid is added and the mixture extracted with ethyl acetate. After washing with water and brine the organic phase is dried (sodium sulfate) and concentrated in vacuum. Removal of all volatiles yields the crude N-acetylmelphalan that is carried on to the next step without further purification. A solution of N-acetyknelphalaD (035g; l.Omnaol) dissolved m methylene chloride (5ral), is treated withN^'-carbonyldiiniidazole (O.I7g; 1.0 mmol). After ptirrmg for 30 mm. at RT, Compound 43 (029g; 050 mmol) is added. After 3 h the reaction solution is concentrated in vacuum and the residue purified by column chromatography on silica gel, elution with cblorofonn/isopxopanol/methanolic ammonia 60:1:1. The appropriate fractions are collected and concentrated to produce 0.12 g (25%) of Compound 62 as a white foam. To a solution of chlorambucil (303 mg;l mmol) in methylene chloride (5 ml), is added N^'-carbouyldiimidazoIe (130 mg; 1 mmol). After 30 min stirring at ambient temperature, Compound 43 (750 mg; 1 mmol) is added. After stirring al the same temperature for 3 h the mixture is washed with ice water and ice cold Na2COj solution. The organic layer is dried (Na2S04), concentrated in vacuum and chromatographed on silica gel, elution with isopropanol to afford 207 mg (20%) of a white foam, Compound 64, MS (M+2Jf: 517). A suspension of neotrofin (0.73 g; 225 rninol) in methylene chloride (15 ml), is treated with N^N'-carbonyldiimidazole (038g; 225 mmol). After stirring for 2 h at ambient temperature Compound 43 (0.57g; 0.75 mmol) is added. Reaction is stirred for 48 b at ambient temperature. The reaction solution is concentrated in vacuum and the residue purified by column chromatography on silica gel, elutiem with chloTOform/i5opropanoi/me1hanoKc ammonia 60:1:1. The appropriate fractions are collected and concentrated to produce Compound 65 (0.20g; yield: 25%) as a white foam. A solution of Gemfibrozil (0.56g; 2.25 mmol) in methylene chloride (10mO> is treated with N,N'-carbonyIdimiidazole (0-38g; 2.25 mmol). After staring for 30 mm. at ambient temperature, Compound 40 (0.44g; 0.75 mmol) is added. Reaction is stirred for 48 h at ambient temperature. The reaction, solution was concentrated in vacuum and the residue purified by column chromatography on silica gel, elution with chlcrofonn/isopiopanol/methanolic ammonia 60:1:1. The appropriate fractions are collected and concentrated to producs Compound 66 (0.15g; yield: 25%) as a white foam. py AMPLE 24: M YCOPHENQT - ATE DERIVATIVES Compound 67 To a mixture of 375 mg of Compound 43,400 mg of triphenyl phosphine and 960 jngpfmycoffoenoSc add is added 4-m)c£7HF under nitrogen. UnsppropyJ azodicarboxylate (0.3 ml) is added drop wise at 0°C wittiin 4 h while the reaction mixture is rapidly stirred. Cooling is continued for another 4 h and the mixture then allowed to warm to ambient temperature within 5 h. The mixture is then dissolved in a mixture consisting of 50 ml of toluene and 20 ml of ethyl acetate and extracted with ice-cold 0.5 M hydrogen chloride (3 x 150 ml). The aqueous phase is washed several times with small amounts of toluene and then with potassium carbonate till no foaming occurs any more upon addition. The mixture is extracted with dichloromethane and the organic phase is washed with brine, dried and concentrated in vacuum to yield white solid foam that can be used without further purification, or further purified on a silica gel column, elutmg with isopropanol. Compound 68 To a solution of 170 mg of Compound 41,400 mgof triphenylphosphine and 500 mg of mycophenolic acid in 3 ml ofTHF -were added under nitrogen 0.3 ml of diisopropy] azodicarboxylaie within 4 h at 0°. The mixture was allowed to stir at 0°C for 3 b and was then allowed to warm to ambient temperature slowly. The reaction mixture was diluted with 70 ml of toluene and 30 ml of ethyl acetate and extracted repeatedly with ice-cold 0.5 M hydrogen chloride. The combined aqueous phases were extracted several times with a small quantity of toluene- The organic phases were discarded. The aqueous phase was treated with potassium carbonate till gas evolution had stopped and was then extracted with dichloromethane. Drying (sodium sulfate) and concentration in vacuum yielded an oily residue that was purified by filtration through a short pad of siHca gel (elution with ethyl acetate-triemylamiiie) to afford 185 mg (39%). Compound 69 A solution of 750 mg (1.0 tranol) of Compound 43 in 10 ral of dicblorornetbane is "treated vith 100 mg (1.0 mraol) of succinic anhydride. After stirring at ambient temperature for 12 h the mixture is concentrated in vacuum to yield Compound 70, a colorless solid that is used with out further purification. To a solution of mycophenolic acid ethyl ester (175mg, 0.5mmol) in chloroform (1 ral) is added efryldnsoprnpylamine (85ull/mL solution in chloroform) is added drop-wise. The mixture is stirred at 0-4DC for 0.5 h and 12 h at room temperature. The mixture is concentrated in vacuum and the residue chromatographed on silica gel, ehraon with cbJorofonn/2-propanol/amraonia 30:1:1, affording 147 mg (25%) of a colorless solid. To mycophenolic acid (0.50g; l-Smmol) and eaibonyldiimidazole (0.25& \ .5mmol), dissolved in methylene chloride (2mL) is added after 1 minute stirring at 0-4°C a solution of Compound ?2(0-27g, 0.5iranol) in 1 ml of dichloromemane. After stirring for 30min at 0-4°C the mixture is stood for 12 h at room temperature. The mixture is concentrated in vacuum and the residue chromatographed on silica gel, elntion with cbloroform/2-propanol/ammonia 30:1:1, affording 98 mg (23%) of a colorless solid. Mycophenolic acid (0.50 g*, 1.5 mmol) is suspended in 3 ml of didhlorometbane and treated with caibonyidiiniidaiole (0.25g; 1.5iomol). After 10 rain asolutionofCon^oimd44(OJSg;0.5ininoI)indichlororaethaQci£ added. After 30min at 0 "C the mixture is stirred for 12 h at room temperature. The mixture is concentrated in vacuum and the residue chromatographed on silica gel, elution with. chlorofonti/2-propaool/animoma 30:1:1, affording 126 mg (22%) of a colorless foam. A solution of Compound 73 in 6 M HO (20 ml) is kept at ambient temperature for IS min and then extracted 5 ml of ethyl acetate. The organic phase is discarded and the aqueous phase neutralized with potassium carbonate and extracted with methylene chloride. The organic phase is dried (Na2S04) and concentrated in vacuum to yield 400 mg (84%) of a colorless foam. A solution of 1.1 g(1.5 mmol) of Compound 43 in 5 ml of dictaloromethane was combined with 415 mg (2.25 mmol) of iodoacetic acid and 450 mg (2.25 mmol) of DCC. After 2 hat ambient temperatwe me mixture was filtered and the resulting Compound 76 was used without purification or concentration. A solution 720 mg of (0.8 mmol) of Compound 76 in 3 ml of dichloramethaoej prepared as described above, is diluted with 20 ml of DMF and 0.1 ml (1.2 mmol) of N-mstbyl amino ethanol is added- The mixture is kept at ambient temperature for 24 h. The mixture is poured onto a solution of potassium carbonate in water and extracted with dichloromethane. The organic phase is washed with brine, dried (Na2S04 and concentrated in vacuum. The residue is chromatographed on silica gel, elutiOT vvim chlorofi^io/isopropanol/methanoljc ammonia S0:1;I to yield 210 mg (31%) of Compound 77, a colorless solid. A suspension of mycophenolic acid (0.50g; I-Smmol) in 8 ml of dichloromethane was treated with carbonyldihnidazole (0.25g; 1 ,5mmolat 0°C- After 10 min a solution of Compound 77 (0.40 g, 0.5 mmol) in 2 ml of dichloromethane was added. After stirring for 30min. at 0-4°C the mixture is stirred for 24 h at room temperature- The mixture is concentrated in vacuum and the residue chromatographed on silica ge], elution with chloroform/2-propanol/aiiiinoiiia 30:1:1, affording 175mg (32%) of Compound 75. A solution of Compound 75 (550 mg, 0.5mmol) prepared as described before in 20 ml of 6 M HC1 is kept at ambient temperature for 10 min and then extracted with diethylether. The organic phase is discarded and the aqueous phase neutralized with potassium carbonate and extracted with dichloromethane. The organic phase is washed with brine, dried (Na2S04) and concentrated in vacuum to yield 420mg (S9%) as a slightly yellowish foam. A suspension of mycophenolic acid (0.30g; GJfcnmoi) in S ml of dichloromethajie is treated wife carbonyldiimidazole (0.15 g; 0.9 tmnol) at 0°C. After lOmin a solution of Compound 40 (0.20 & 0.3 mmol) in 2 ml of dichloromethane was added. After stirring for 30min, at 0-4°C the mixture is stirred for 24 h at room temperature. The mixture is concentrated in vacuum and the residue chromatographed on silica gel, elution with cWoroforrn/2-propanoI/ainmoiiia 30:1 ;1, affording lOOmg (35%) of a colorless foam. Amixture of 120 mg of Compound 48,320 nig of mycophenolic acid and 300 mg of triphenyl phosphine is dissolved in 2 ml of THF under nitrogen. At 0°C 0.1 ml (0.5 mmol) djisopropyl azodicarboxylate is added in several portions within 4 h. After tbis time the mixture is allowed to warm to ambient temperature overnight The reaction mixture is concentrated in vacuum and chromatograpbed on silica gel, elution with isopropanol. To a solution of 188 mg of Compound 41,400 mg of triphenylphosphine and 500 mg of mycDphonolic acid in 3 ml ofTHF were added under nitrogen 03 ml of diisopropyl azodicarboxylate within 4 h at O^C. The mixture was allowed to stir at 0°C for 3 h and was then allowed to warm to ambient temperature slowly. The reaction mixture was diluted with 70 ml of toluene and 30 ml of ethyl acetate and extracted repeatedly wim ice-cold 0.5 M hydrogen chloride. The combined aqueous phases were extracted several times with a small quantity of toluene. The organic phases were discarded. The aqueous phase was treated with potassium carbonate until gas evolution had stopped and was then extracted with dichloromethane. Drying (N^SCu) and concentration in vacuum yielded an oily residue that was purified by filtration through a short pad of silica gel (elution with ethyl acetate-triethyl amin) to yield 255 mg (52%) of a yellowish oil. Prednisolone (180 mg, 0.5 mmol) is suspended in 3 ml of chloroform and 55 mg (0.55 mmol) of succinic anhydride is added- After 24 h at ambient temperature the mixture is cooled to 0°C and 325 mg of Compound 46 (0.5 mmol) is added followed by chlor-AW^-trimemylpiupeoanrine (0.2 ml, 1.5 mmol) in several portions. The resulting solution is subjected to column chromatography on silica gel, elation with isopropanol to yield a "white solid- Dexamethasone (196 mg, 0.5 mmol) is suspended in 3 ml of chloroform and 55 mg (0.55 mmol) of succinic anhydride is added. After 24 h at ambient temperature 375 mg of Compound 43 (0.5 mmol) is added followed by cMoit»-AW^2-trimethylpropwiamine (0.2 ml, 1.5 mmol) in several portions. The resulting solution is after 1 b subjected to column chromatography on silica gel, elution with isopropanol to yield 198 mg (32%) of a white solid. A solution of 295 rog (0-5 mmol) of Compound 40 in 4 ml of dichloromethane is treated with 55 mg (0.55 mmol) of succinic anhydride and the mixture stirred at ambient temperature overnight. To the reaction mixture ciiethylstttbestrol (174 mg, 0.5 mmol) and 0.15 ml of diisopropylethylamine is added followed by 0.133 ml of ^ow-N,NJ2~tnmsthylprop(3i3smne (1.0 mmol) in several portions. After 1 h the reaction mixture is concentrated in vacuum and the residue chromatographed on silica gel, clution with ethyl acetate, changing to isopropanol, to yield 74 mg (16%) of a colorless solid. A solution of 217 mg (0.5 mmol) of triamcinolone acetonide, 5$ mg (0.55 mmol) of succinic anhydride in 3 ml of dichlorornthane and 1 ml of pyridine is reacted 2 d at ambient temperature. After this period all volatiles are removed and the residue taken up in THF- To this mixture 100 mg (0,62 mmol) of carbonyldihnidazole is added under nitrogen, followed by 300 mg (0.51 mmol) ofCompound40.The mixture was heated to 50°C for %6 h_ After cooling the mixture was concentrated in vacuum and the residue cbromatographed on silica gel, elution with ethyl acetate, changing to isopropanol to yield 34 mg (6%) of a colorless solid. Prednisolone (ISO mg, 0.5 mmol) is suspended in 3 ml of chloroform and 55 nig (0.5 5 mmol) of succinic anhydride is added. After 24 h at ambient temperature the mixture is cooled to 0°C and 295 mg of Compound 40 (0.5 mmol) is added followed by chIor-#,N',2-trmetoylpropenamine (0.2 ml, 1.5 mmol) in several portions. The resulting solution is subjected to column chromatography on silica gel, elution with isopropanol to yield 165 mg (32%) of a white solid A solution of 560 mg(l mmol) of atorvastaiin in lOmlofdichloromethaneis treated with 2 ml of a 1 M solution of HC1 in diethyl ether at ambient temperature for 12 h. The reaction mixture is washed with water and brine, dried (NaiSCUj and concentrated in vacuum. The residue is dissolved in S ml of chloroform and treated with 120 mg (1.2 mmol) of succinic anhydride and 123 mg (1.0 mmol) of DMAP under nitrogen. After 24 h at ambient temperature 194 mg (1.2 mmol) of cainonyldiimidazole is added, followed after 10 min by 700 mg (1.2 nunol) of Compound 40. The mixture is heated to 50°C for 36 h and then cooled, concentrated in vacuum and chromatographed on silica gel, elution with chlorofbrm/2-propaooVammonia 30:1:1 to yield 125mg(10%) of a colorless solid. A solution of 25 rug (0.06 mmol) of lovastatin in 1 ml of dichloromethane was treated with 10 rag (0.1 mmol) of sw:cmic anhydride Trader nitrogen. The mixture was kept at ambient temperature for 4ff h and then 12 mg of carbonyldiiinidazole is added followed after10 mm by 70 mg (0.11 mmol) of Compound 46. After stirring for 4$ h at ambient temperature the mixture is concentrated in vacuum and the residue chromatographed on silica gel, elution with chlorofomi/2-propanol/arnmonia 30:1:1 to yield 13 mg (19%) a white solid. To a stirred solution of Fluconazole (0.67 g, 2.2 raraol) in anhydrous CR2Oz (20 ml) was added triethylarnine (0.31 ml, 2.2 mmol) and succinic anhydride (0.22 g, 2.2 mmol). After stirring for 2 hours at ambient temperature N,Nr-carbonyldiimidazole (0.37 g, 2.3 mmol) was added and stirred for another 2 hours. Subsequently Compound 43 (1.12 g, 1.5 mmol) was added and stirring continued overnight. Then the reaction mixture was diluted with CHzClz (20 ml) und a saturated aqueous solution of sodium bicarbonate (30 ml). After separation, the organic layer was dried over NajSC^, filtered and then concentrated under reduced pressure to furnish the crude product Silica gel chromatography with THF-Hexane-NEtj (10:10.0.1) yielded Compound 89 as a white solid (0.20 g, 12%). To a mixture of 800 mg glutaric acid (6 mmol, 6 eq.) and 500 mg CDI (3 mmol, 3 cq.) dissolved in 10 ml dry acetonitrile and stiired for 30 minutes at room temperature under argon, is added a solution of 750 mg Compound 43 (1 mmol) in the presence of a catalytic amount of DMAP dissolved in 5 ml acetonitrile. The reaction is refluxed overnight. The solvent is removed in vacuo. The crude mixture is then purified by chromatography with chlomfona/insftaDol/animoaia (94.5:10:0.5). The collected fractions yielded a white solid (340 mg, 45%). The expected Compound 91 is characterized by TLC (Rf- 0.4 in cWcrofoim/methaDal/ammoria (90:9:1)) and by MS([M+H]+ = S63). 43 mg Compound 9] (0.05 mmol) and 15 mg Abacavir (0.05 mmol) are reacted in the presence of 12 mg DCC (0,06 mmol, 1.2 eq.). The mixture is dissolved in 1 ml of dry THF and stirred overnight at room temperature. The cloudy solution is filtered off and the solvent is removed in vacuo. The crude product is purified by chromatography. The collected fractions are concentrated to yield a white solid (20 mg, 40%). The expected Compound 90 is characterized by TLC (Rr= 0.6 in chloroform/methanol/ammonia (90:9:1)) and by MS (M+2H, 566). This protocol can be applied to other alcohols, some of which are listed in Table 3 200 mg of Compound 43 (0.27 mmol) are treated with 30 mg succinic anhydride (0.3 mmol, 1.1 eq.)in 1 ml pyridine in the presence of a catalytic amount of DMAP. The reaction is stirred for 5 h at 4G°C. After the completion of the reaction the product is separated by precipitation using hexane. The solution is decanted, and the recovered precipitate is washed several tiroes with nexane to remove pyridine. The isolated compound is dried by high vacuum and yielded to a white solid (180 mg, 90%). The expected Compound 93 is characterised by MS ([M+HJ+ = 850). 42 mg of Compound 93 (0.05 mmol) and 13 mg AZT (0.05 mmol) are coupled by using 11 mgDCC (0.055 mmol) in 0.5 ml of dry THF. The mixture is stirred overnight at room temperature. The c}oudy solution is men filtered off to remove the urea. The isolated crude product, obtained after removal of solvent, is purified by chromatography. The collected fractions yield after cvaporatioTi to a white solid (30 mg, 50%). The expected compound Compound 92 is characterized by TLC (Rf-* 0.3 in cMorofbnu/methanol/ammonia (90:9:1)) and by MS (M+2H, 549.7). This protocol can be applied to other alcohols, some of which are listed in Table 3. To a cloudy solution of 52 mg A2T (0.2 mmol), 43 mg 5-bromovaleric acid (0.24 mmol, 1.2 eq.), 106 mg BOP (0,24 mmol, 1.2 eq.), »nd a catalytic amount of DMAP in 1 ml dry THF are added 100 til trietfaylamme (72 mg,700 jonol, 3 eq.). The clear solution is then stirred for 4 h at room temperature. After completion of reaction the crude mixture is purified by preparative TLC. Removal from the plate yields a yellowish oily solid (60 mg, 70%). The expected compound 95 is characterised by TLC (Rf« 0.7, chloroform/metiianol/ammonia90:9;l)- A solution of 6.0 g (8.0 mmol) of Compound 43 in 20 ml of THF is treated with 1.97 g (8.8 mmol) of N-iodosuccinic imide in several portions at 0°C. The mixture is kept at 10X for J 2h and then poured into a solution of potassium carbonate in water and extracted with dichloromethane. The organic phase is dried (Na2S04), concentrated in vacuum and the residue chromatographed on silica gel, eluticm Tvith cyclohexane/ ethyl acetate/ isopropanoV trietnylamin 9:1:0.2:0.2 to yield 1.5 g (34%) of Compound 96, a colorless solid. To a cloudy solution of 8 mg Compound 95 (0.02 mmol) and 26 mg Compound 96 (0,035 mmol, 2 eq.) jn acetonitrile (0.5 ml) is added am excess of potassiuni carbonate. The reaction mixture is then set to 50aC for 48 h. The crude mixture is purified by chromatography to yield a yellowish solid (4.5 mg, 20%). The expected Compound 94 is characterized by TLC (Rf - 0-5 in chlorofoim/mBlhanoVanunonia (90:9:1)) and by MS ([M+H]+ -11.13). This protocol can be applied to other alcohols, some of which are listed in Table 3- 665 mg benzybdene-pratected Ribavirin (2 mrnof), 1.34 g glutaric acid (10 mmol, 5 eq.)> 1 g CI>I (6-2 mmol), and a catalytic amount of I>MAP are suspended and heated in 20 ml of Chloroform for 3 h. The solvent is removed and the residue suspended in 1 M HClt saturated with sodium chloride. The mixture is extracted twice with ethyl acetate, the organic layers are dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography to yield 760 mg (85%) of Compound 98, characterized by TLC (Rf * 0.16 in THF/Hexane/Acetic acid 7:7:0.5) andMS([M+H]+ = 447). To a solution of 267 mg Z-fl-alanine (1.2 mmol, 12 eq.) and 190 mg CDI (1.2 mmol, 1.2 eq.) in 2 ml of dry THF, which had been stirred for 30 minutes at room temperature under argon, 749 mg Compound 43 are added (1 mmol). The mixture is then stijred overnight at 40"C. The clear and colorless solution is purified by flash chromatography. The collected fractions are concentrated to yield to a yellow solid (460 mg, 50%). The expected compound is characterized by TLC (Rj ■ 0.2 in chJoroform/methanol/ammonia (90:9:1)) and by MS (£M+H]+ » 954.7). 450 mg of this compound (0.45 mmol) are dissolved in 5 ml of ethanol, to which an excess of Pd/C is added under argon. The flask with hydrogen. The mixture is shaken gently overnight at room temperature. The Pd/C is removed passing the solution through a celite plug. The removal of solvent yielded a slighty black solid (2S0 mg, 76%), a mixture of Compound 99 and Compound 43. The expected Compound 99 is characterized by TLC (Rf -= 0.2 in chloTofonu/rnethanol/atnmoma (94.5:5:0.5)) and by MS([M+H]+=-S90.5). To a cloudy solution of 23 mg Compound 98 (0.05 mmol), and 41 mg free Compound 99. (0.05 mmol), 25 mg BOP (0,055 mmol, 1-1 eq.) and a catalytic amount ofDMAPin 0.5 tnlofdryTHF are added 15 ul of triethylamifle (11 mg,0-ll mmol, 2 eq.). The clear solution is stirred overnight at room temperature. The mixture is purified by chromatography and yields 5 mg (10%) of a light yellowish solid. The expected Compound 100 is characterized by TLC (Rf - 0.25 in chlOToform/methanDl/ammonia (90:9:1)) and by MS ([M+H]+ -1249). 5 mg of Compound 100 arc dissolved in 5 ml 2-propano) and a tip of a spatula of Pd/C is added. The mixture is hydrogenated overnight The catalyst is extracted with ethyl acetate and the extract purified by preparative TLC to yield 2.3 mg of the desired Compound 97, characterized by TLC (Rf = 0.45., chlororform/2-propairal/methanol/amnioma 25:3:1:1) and MS ((M+H]+= 1151). 900 mg of Compound 43 (1.2 mrool) are treated with 10ml 12 N HC1 m an iced-water bath overnight The completed reaction is worked up by an extraction with chloroform. The aqueous phase is further neutralized at 0°C by addition of potassium hydroxide pellets to have a pH at 9-10. The orange basic aqueous phase is then extracted several times with chloroform. The combined organic layer is washed with brine and then dried over sodium sulphate. The erode product after evaporation of the solvent is purified by flash column chromatography to yield to a light yellowish solid (400 rag, 90%). The expected Compound 302 is characterized by TIC (Rf = 0.35 in cMoroform/methanol/ammoiiia (90:9:1)) and by MS ([M+HJf ~ 434). 300 mg of the Compound 102 (0.7 mmol),, 190 mg iodoacetic acid (1 mmol, 1.5 eq.) and 210 mg DCC (1 mmol, 1-5 eq.) are dissolved in 5 ml of dry chloroform at 0°C under argon atmosphere under protection from light The mixture is stirred overnight at room temperature. The yellowish cloudy solution is filtered off and the filtrate is concentrated under vacuum- ChTomatography yields a fraction mat contains mainly the monoacetylated product, Compound 103, (yield: 175 mg, 50%) is 1 characterized by TLC (Rra,0.35 in chlomfbrrn/memanoVammorjia (90:9:1)) and by MS([M+H]+*602). To a solution of 150 mg of Compound 103 (0.25 mmol) ID 2 ml of dry acetooitrile are added 50 ul of diethanclamine (0.5 mmol, 2 eq.). The mixture is stirred at room temperature for 1 h. After removal of the solvent the erode mixture is purified by flash chromatography. The collected fractions are concentrated under vacuum and yield a yellowish solid (60 mg, 40%). The expected compound 104 is characterized by TLC (Rr = 0.15 in chlorofonn/mefianol/ammonia (90:9:1)) and MS flM+HJ+-57$). To a mixture of 800 mg glutaric acid (6 mmol, 6 eq.) and 500 mg CDI (3 mmol, 3 eq.) dissolved in 10 ml of dry acetonitrile, which is stirred for 30 minutes at room temperature under argon, are added 266 mg AZT (1 mmol) and a catalytic amount of DMAP. The cloudy reaction mixture is stirred overnight at 70°C. Chromatography yields a colorless sticky solid (120 mg, 35%). The expected compound 105 was characterized by TLC (Rr = 0.25 in cMorofornVmetbimol/ainmonia (90:9:1)) and MS ({M+H]+ = 381). To a cloudy solution of 55 mg of Compound 105 (0.15 mmol, 3 eq.), and 29 mg of Compound 104(0.05 mmol, 1 eq.), 38 mg BOP (0.1 S mmol, 3.3 eq.) and a catalytic amount of DMAP in 0.5 ml of dry THF are added 30 u) of triemylarnine (0.25 mmol, 4 eq.). The clear solution is then stirred overnight at room temperature. The mixture is purified by chromatography. The collected fractions yielded to a light yellowish solid (5 mg, 10%). The expected double acylated Compound 101 is characterized by TLC (Rf = 0.25 in cWorofOTm'methanol/ammoma (90:9:1)) and by MS([M+H}+=1306). This protocol can be applied to other alcohols, some of which are listed in Table 3. Abbreviations: DMAP = 4-(N3^-63memylamino)pyridiDe BOP = (Benzobia2ol-l-yloxy)'tris-(dimemy]amnjo>pbi)^onium-hexailuorophospbate CDI» Carbonyldiimidazole Z- ** BeDzyloxycarboayl- 286 mg of Celecoxib (750uniol), 300 mg of succinic anhydride (3 tranol, 4 eq,), and 50 mg of DMAP are dissolved in 8 ml of dry acetonmile. 420 ul (300ug, 3 mmol, 3 eq-) of trieihylamine are added, and the reaction mixture is stirred overnight 3 ml 1M aqueous sodium hydroxide and 5 ml ofTHF are added to remove excess succinic anhydride, the mixture is stirred for 2h. 180 ul of acetic acid (3.1 mmol) are added and the mixture is evaporated to dryness- The resulting oil is suspended in ethyl acetate. Diluted aqueous ammonia is added, and the aqueous phase is separated and evaporated until the gas evolution ceases. Concentrated HC1 is added to obtain a yellow precipitate. The residue is dissolved in ethanol, evaporated to dryness and dried at 30°C/0.01mbar for 2 h. The yield of the resulting Compound 107 is 350 mg (93 %), and can be used for the following step without farther purification. 240 mg of Compound 107 (SOOumol) are stirred together with 110 mg of CD1 (650umol, 1.3 eq.) in 8 ml of dry dichloromethane for 2 b~ 300 mg (400umol, 0.8 eq.) of Compound 43 are added and the mixture is stirred for an other 2 h. The mixture is subjected to chromatography after evaporation to yield 80 mg (16%) of the desired product, Compound 106 (MS: [M+H]+ *= 1213). To a stirred solution of 1.12 g erythromycin A osime (1.5 mmoT} in 50 ml THF was added 1-5 ml 1 N potassium hydroxide solution (1.5 mrnol) and 0-44 g 4-bromomethyl-657-dimetboxycoQmarin (1-5 mmol). The reaction mixture was stirred al room temperature for 6 h and then filtered and treated with 44 fil of acetic acid. The solvent was removed undo- reduced pressure and the residue purified on silica gel, erutingiwii) CHCls/MeOH/N&OH (6:1:0.1) to afford 0.4 g (28%) of Compound 108 a colorless foam. (MS: [M+H}+ - 96S). To a stirred suspension of 0-46 g (6J7Hjimethoxy-2-oxo-2H-chrDmen-4-yi methylsulfanyl)acetic acid (1.5 mmol) in 20 ml of dry CHzCl2 are added 250 nig HN'-carbonyldiimidazcle (1.55 mmol). The reaction mixture is stared for 2 h, the© a solution of 1.0 g Compound 43 (1.3 mmol)mlOMofdryCH;>Clzis added and stimng continued for 48 n. A saturated aqueous solution of sodium bicarbonate (30 ml) is added. The organic layer is dried over Na2SO*, filtered and then concentrated under reduced pressure to furnish the crude product Chromatography affords the Compound 109 as a white foam (0.7 g, 52%). (MS: [M+H]+~ 1042). Imatinab may be selectively altered without compromising the interaction with the kinase and thus its biological activity (Schindler et aL, Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Science 289,193S-1942,2000). 2.2g of 4-(4iperazine--l-carboxylic acid 9H-fluoren-9-ylmethyI ester and 1.15 g 4-Methyl-N3-(4-pyridin-3-yl-pyrimidin"2--yl>-benzene-1,3-diamine (US 5,521,154) are reacted in 50 ml of dimethytfonnamide in the presence of 600 rag dimethylaniline for 24 h. The mixture is poured into 250 ml of ice-cold water. After filtration, the crude product is dried in vacuo and treated witii a mixture of methanol and triethylamine (10:1). After evaporation of the solvent, Has residue is subjected to chromatography to yield Compound 111. 40 mg of Compound U1 are dissolved in 2 ml dry ethanol at 60"C and reacted with 31 mg of Compound 111 for 10h. The mixture is cooled to -21X and filtered. The product, Compound 110, was obtained after recrystallisation. (MS: [M+2EQ34' -628). Biological Methods EXAMPLE 32: PROLIFERATION ASSAY Assay to determine the w vitro rate of, for example, lymphocyte proliferation. Lymphocytes are purified out of ant coagulated (CPDA, citrate or heparin) mammalian blood using the Lymphoprep™ system (supplier). Purified cells are counted using a hemocytometer following Trypan Blue staining, arid a cell concentration of 1 x 106 cells/ml established in RPMi 1640 medium with 10% FCS and antibiotics as required (all from Biochrome). Following the addition of a cell proliferation stimulant, for example phytohemagglutanin (Sigma) at, for example an end concentration of 5 ug/ml fhe cells are incubated with different concentrations of the to be investigated compound in 100 fd end volume in a 96-well microtiter plate in an incubator (37°C, 5% CQ2, 95% humidity) for 72h- Cell proliferation is quantified following BrdU incorporation for 16 h by ELISA and subsequent colorimetric development (Cell Proliferation ELISA BrdU (colorimetric) kit from Roche Diagnostics). The ICso (uM) values arc then calculated, and used to compare compound efficacy. To determine the influence of the T-L-C modification on in vitro cellular drug uptake and pharmacology, the above assay is additionally modified and an additional "wash" step included. In addition to running the assay for 72h with the compounds to be tested, the assay is also run for just 2h, then compound is washed away in three serial washing steps using 200 fU of medium at each step, and the cells subsequently incubated For a further 70h. The determined IC50 (uM) values following 2h and ?2h incubation are compared and a ratio calculated (2b: 72b). The lower the number, the better thft uptake and drug release from the T-L-C in the cells (see results in Table 4 for examples), and improvement overmycophenolic acid. EXAMPLE 33: CELL-BASED IMDPH ASSAY WITH GUANOSIKE RESCUE Cytotoxicity assay HeLa cells (DSMZ, ACC 57) and lurkat cells'(DSMZ, ACC 232) in exponential growth phase are exposed for 3 days to test compounds. The number of surviving cells is then determined by theAlamar Blue assay (Serotec inc.). This assay incorporates a fluorometric growth indicator based on detection of metabolic activity. Specifically, the system incorporates an oxidation-reduction indicator that fluoresces in response to chemical reduction of the growth medium resulting from cell growth. As cells grow in culture, innate metabolic activity results in a chemical reduction of the immediate surrounding environment Continued growth maintains a reduced environment while inhibition of growth maintains an oxidized environment Reduction from growth causes the Redox indicator to change from an oxidized to a reduced form. Fluorescence is monitored at 560 nm (Exc.) and 590 nm Em. General procedure: HeLa cells (1 xl 03) or JURKAT cells (1 xlO3) are plated in 100 ul MEM medium (with Earle's salt; Biochrom KG) containing 10% FBS, 2 mM L-glutaminE, and non-essential animo acids in 96-well plates and incubated at 37°C and 5% C02 atmosphere. After 24 hours, the test compounds are added over a concentration range and the cells incubated for a further 48 hours. Alamar Blue reagent (20 ul) is added to each well, and the cultures incubated for a further 4 to 6 hours. The fluorescence is then measured as described above and the LD^o is determined based on ajngmoidal dose response regression. In order to determine the toxicity of T-L-C conjugates of mycophenolic acid not due to the inhibition of IMPDH, excess-guanosine is added into the culture medium to a final concentration of 50 uM. Any toxicity still detected can then be ascribed either to other biological effects of the of T-L-C conjugate of mycophenolic acid, or is due to the very high intracellular concentration of mycophenolic acid, following concentrative uptake into the cell. Cytotoxicity assay with fresh PBMMCs The cytotoxicity of T-L-C conjugates of mycophenolic acid can be demonstrated directly on freshly isolated mammalian PBMNCs. The cells are prepared as described in Example 29, and the level of cytotoxicity determined by the Alamar Blue assay, as described above. As described for both HeLa and JURKAT cells, guanosine can also be used here to ameliorate the effect of mycophenolic acid on the activity of IMPDH. Results: L The toxicity of mycophenolic acid conjugates may be assessed most conveniently in a cell based system, preferably with a rapidly growing cell line such as HeLa or JURKAT. hi normal culture conditions, mycophenolic acid has an IC50 of less than 2 uM, and its effect can be completely removed in the presence of 50 nM guanosine. For many of the T-L-C conjugates of mycophenolic atid, alleviation with guanosine is possible, but this is not always complete, which could for example be due to either to other biological effects of the of T-L-C conjugate of mycophenolic acid, or is due to the very high intracellular concentration of mycophenolic acid, following concentrative uptake into the cell. prepared as described in Example 29, and the level of cytotoxicity determined by the Alamar Blue assay, as described above. As described for both HeLa and JURKAT cells, guanosine can also be used here to ameliorate the effect of mycophenolic acid on the activity of IMPDH. Results; The toxicity of mycophenolic acid conjugates may be assessed most conveniently in a cell based system, preferably with a rapidly growing cell line such as HeLa or JURKAT. In nonnal culture conditions, mycophenolic acid has an ICso of less than 2 uM, and its effect can be completely removed in the presence of 50 uM guanosine. Formany of theT-L-C conjugates of mycophenolic acid, alleviation with guanosine is possible, but this is not always complete, which could for example be due to either to other biological effects of the of T-L-C conjugate of mycophenolic acid, or is due to the very high intracellular concentration of mycophenolic acid, following concentrative uptake into the cell. EXAMPLE 36: Testing of antibiotic activity of drugs Assay summary The TC50 or MIC procedure for antibiotic sensitivity testing involves an antibiotic dilution assay, which can be performed in microtitre plates. A series of twofold dilutions of each antibiotic are made in the wells, and then all wells are inoculated with a standard amount of the same test organism. After incubation, growth in the presence of the various antibiotics is observed by measuring turbidity. Antibiotic sensitivity is expressed as the concentration of the antibiotic that inhibits 50% of the growlii (TCs>). Alternatively it could be expressed as the highest dilution of antibiotic that completly inhibits growth (MIC). Bacteria: B. pumilus and E -coli fJDHSa) Bacteria] cultures are initiated from the plates for 2 to 3 weeks. After this time period bacteria are streaked out on new plates from the backups strored at -80"C. Due to the lack of resistance of the bacteria, new cultures are not to be initiated from an old plate or any liquid cultures derived from old plates. Growth medium (GM)(per liter): 10 g Bacto-tryptone, 5 g Bacto-yeast extract, 6 g HEPES (25 mM), 5.4 g NaCl, pH 7.3 Compound stocks lOor 100 mM in DMSO stored at-2Q°C. Procedure 1. Grow B.pumilus from an LB agar plate in a flask (max. 10% volume) up to about 50 ml in growth medium (GM) 2. Dilute overnight suspension 1:10 in GM 3. Determine OD«» of diluted bacterial suspension 4. Dilute bacterial suspension in GM to an OD000 of 0.03 - 0,04. (6 ml / plate) 5. Add 200ul GM to the outer wells (Row A, Row H, Column 1, Column 12) 6. Add 100 ul GM to each well starting from C2, row 3. 7. Controls: Wells B2 - B4 growth control. Wells B6 - B8 blank. Row C growth inhibition control. 7.1. To wells B2 - B4 add; 96ul GM, 4ul DMSO, and 1 OOp.1 bacterial suspension adjusted to an ODBQO of 0.03 - 0.04. 7.2. To wells B6 - B8 add: 196 ul GMjand 4 Ml DMSO 7.3. Dilute a 10 mM COMPOUND 43 '(positive control) stock to 800 pM (120 Hi /plate) in GM. Add 100 ul of S00 jiM COMPOUND 43 solution to well C2. 8. Samples ; i 8.1. Dilute the 10 or 100 mM stock solutions to S00 fiM (250 jil / piate) in GM. S 2. Add 100 u] of 800 uM sample in duplicates to wells D2 / E2 resp. F2 / G2. S.3. 2-fbId serial dilution of all samples and Azithromycin S.3.1. Rows C-G, Columns 2: Mix and transfer 100 pi from each row to Column 3f and continue until column. 11. The remaining 100 pi out of column 11 are disposed. | 9- Add 100 fil of bacterial suspension (OD^O-OS - 0.04) to each well from C2 -Gil. 10. Incubate plates on shaker, 750 rpm, 37 DC]iuntil the growth controls have reached anOD6ooof0.6-0.8 (approximately 6 - 8 h), 11. Determine ODeoo on plate reader. OTHER EMBODIMENTS Al] of the features disclosed in this specification maybe combined in any combination. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features. It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. CITATIONS ■ Alberola A., Antolin L.F., Gonzalez A.M., Laguna M.A-, and Pulido F J.; J. Heterocyclic Chern; 23; 1035; (1986). • Alberola A., Antolin L.F., Gonzalez AM., Pulido F.J.; Base-induced Ring Cleavage of 4-FunctionaIized 3-Unsubstituted Isoxazoles. 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Patents: • US392695S 09(1912 Burton et al. 260/239 • US552U84 04/1994 Zimmermann 514/252 • US5721277 04/1995 Tang 514/646 • US6271383 07/1999 Gravestock 546/209 • US6136796 10/00 Kozak 514/75 • US2001/00537S2A) 12/2000 Blumenkopfet al. 514/258 WE CLAIM : 1. A compound of the following formula: wherein T is a tnuuportophore, L is i bond or a linker having a molecular weight of up to 240 dalton, C is a non-antibiotic therapeutic agent, (elected from non-steroidal anti-inflammatory, anti-viral, anti-fungal, immune suppressant, cytostatic, anti-parasitic. Lipid lowering, a sterol synthesis modifying, metabolaregulatory therapeutic agents, an allergy suppressive agent, an agent for treating a hematopoietic disorder and an agent for treating a lysosomal storage disorder, and mis 1,2, 3, 4, 5, 6, 7, or 8, in which the transportophore has an immune selectivity ratio of at least 2, the transportophore is covalently bonded to the non-antibiotic therapeutic agent via the bond or the linker, and the compound has an immune selectivity ratio of at least 2, wherein said compound corresponds to the formula wherein alky)-, alkeny], alkynyl, cycloaikyl, aryJ or heteroaiy] spaC1ng elements are optionally substituted by (C1-C6)alkyl, 1-4 halogens, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, hydroxy, amino, (Q-C*)alkylamino, (CrC4>Jia)ky!amtno, (C3-C1oJcycloallcyl, (C1-C6alkylcarbonyloxy, (CrC^aJkylcarbonylamido^C,-C4)aIicyIaraidocarbooyI, (C1-C4)diaUcylamidocartx)nyI, nitro, cyano, (d-C«)alkylunino, mercapto or (C1-C^alkylmercapto.

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