US 20130053301A1 (19) United States (12) Patent Application Publication (10) Pub. N0.: US 2013/0053301 A1 Rau et a]. (43) Pub. Date: Feb. 28, 2013

(54) DIPEPTIDE-BASED PRODRUG LINKERS A61P 25/00 (2006.01) FOR ALIPHATIC AMINE-CONTAINING A611) 31/00 (200601) DRUGS A61M 5/31 (2006.01) (75) Inventors: Harald Rau; Dossenheim (DE); Torben ‘461p 3 7/02 (200601) Lessmann; Neustadt an der Weinstrasse A611’ 3/04 (2006.01) (DE) A61P 7/02 (2006.01)

(73)(21) Assignee:Appl. No.: Ascendis13/574,092 Pharma A/S; Hellerup (DK) C07D 413/140 (2006.01)

_ A61P 37/08 (2006.01) (22) PCT Flled: Jan‘ 21’ 2011 (52) us. Cl...... 514/13; 530/308; 540/551; 604/82 (86) PCT No.: PCT/EP2011/050821 (57) ABSTRACT § 371 (0)0), (2); (4) Date: Oct. 15, 2012 The present invention relates to a prodrug or a pharmaceuti _ _ _ _ _ cally acceptable salt thereof; comprising a drug linker conju (30) Forelgn Apphcatlon Prmnty Data gate D-L; Wherein D being a biologically active moiety con Jan. 22, 2010 (EP) ...... 10151465.1 raining an alliphmiC amine group is conjugated to one Or more polymeric carriers via dipeptide-containing linkers L. Such Publication Classi?cation carrier-linked prodrugs achieve drug releases With therapeu (51) Int CL tically useful half-lives. The invention also relates to pharma (‘0 7K 1 7/08 (200601) ceutical compositions comprising said prodrugs and their use A61K 38/05 (2006.01) as medicaments. US 2013/0053301A1 Feb. 28, 2013

DIPEPTIDE-BASED PRODRUG LINKERS dence of the release mechanism of the drug upon biodegra FOR ALIPHATIC AMINE-CONTAINING dation may cause interpatient variability. DRUGS [0007] Alternatively, the drugs may be conjugated to a car [0001] The present application claims priority from PCT rier through permanent covalent bonds. This approach is PatentApplication No. PCT/EP2011/050821 ?led on Jan. 21, applied to various classes of molecules, from so-called small 2011, Which claims priority from European Patent Applica molecules, through natural products up to larger proteins. tion No. EP 10 151 564.1 ?led on Jan. 22, 2010, the disclo [0008] Liraglutide is an example of a peptide drug that sures of Which are incorporated herein by reference in their achieves an extended half-life by permanent covalent modi entirety. ?cation With a palmitoyl moiety. The fatty acid alkyl chain serves to provide albumin binding in vivo and the palmitoy BACKGROUND OF THE INVENTION lated peptide forms an albumin complex that acts as a drug reservoir in the blood stream. 1. Field of the Invention [0009] Albuferon is an example of a protein drug that achieves an extended half-life by permanent covalent modi [0002] The present invention is directed to carrier-linked ?cation With another protein that in itself has a long half-life. prodrugs having temporary amide linkages betWeen substi The corresponding fusion protein of albumin and interferon tuted dipeptide moieties and aliphatic amine groups of bio alpha, Albuferon, exhibits a signi?cantly extended half-life as logically active entities such as peptides, proteins, natural compared to interferon alpha. products or synthetic chemical compounds. Such carrier linked prodrugs are characterized by sloW release of unmodi [0010] Many small molecule medicinal agents, like alka ?ed biologically active entity. loids and anti-tumor agents, shoW loW solubility in aqueous ?uids. One Way to solubiliZe these small molecule com [0003] It is noted that citation or identi?cation of any docu pounds is to conjugate the small molecule compounds to ment in this application is not an admission that such docu hydrophilic (Water-soluble) polymers. A variety of Water ment is available as prior art to the present invention. soluble polymers, such as human serum albumin, dextran, [0004] Typically, carriers employed for extended time-ac lectins, poly(ethylene glycol) (PEG), poly(styrene-co-maleic tion engineering in drug delivery are either used in a non anhydride), poly(N-hydroxypropylmethacrylamide), poly covalent fashion, With the drug physicochemically formu (divinyl ether-co-maleic anhydride), hyaluronic acid have lated into a solvent-carrier mixture, or by permanent covalent been described for this purpose (R. Duncan, Nature Rev. Drug attachment of a carrier reagent to one of the drug’s functional Disc., 2003, 2, 347-360). groups. [0011] Covalent modi?cation of biological molecules With [0005] Non-covalent drug encapsulation into polymeric poly(ethylene glycol) has been extensively studied since the carriers has been applied to depot formulations for long late 1970s. So-called PEGylated proteins have shoWn acting release pro?les. Typically, the drug is mixed With car improved therapeutic e?icacy by increasing solubility, reduc rier material and processed in such fashion, that the drug ing immunogenicity, and increasing circulation half-live in becomes distributed inside the bulk carrier. For instance poly vivo due to reduced renal clearance and proteolysis by mer-drug aggregates may be shaped as microparticles Which enZymes (see, for example, Caliceti P., Veronese F. M., Adv. are administered as an injectable suspension or the polymer Drug Deliv. Rev. 2003, 55, 1261-1277). drug aggregates are formulated as gels Which are adminis tered in a single bolus injection. Known in the art are also [0012] HoWever, many biological molecules such as IFN liposomal formulations, Where the carrier may be a polymeric alfa 2, saquinavir or somatostatin are inactive or shoW or non-polymeric entity capable of solubiliZing the drug. decreased biological activity When a carrier is covalently Drug release occurs When the carrier sWells or physically conjugated to the drug (T. Peleg-Shulman et al., J. Med. deteriorates or chemical degradation alloWs diffusion of the Chem., 2004, 47, 4897-4904). drug to the exterior and subsequently into the biological envi [0013] In order to avoid shortcomings imposed by either ronment. Such chemical degradation processes may be auto the non-covalent polymer mixtures or the permanent covalent hydrolytic or enZyme-catalyZed. An example for a marketed attachment, it may be preferable to employ a prodrug drug based on bolus administration of a drug-polymer gel is approach for chemical conjugation of the drug to the polymer Lupron Depot. An example for a marketed drug based on carrier. In such polymeric prodrugs, the biologically active suspended microparticles is Nutropin Depot. An example for moieties (drugs, therapeutic, biological molecule, etc.) are a marketed drug based on a liposomal formulation is Doxil. typically linked to the polymeric carrier moiety by a tempo [0006] A disadvantage of the non-covalent approach is that rary bond formed betWeen the carrier moiety and a hydroxy, in order to prevent uncontrolled, burst-type release of the amino or carboxy group of the drug molecule. drug, encapsulation of the drug has to be highly e?icient by [0014] Prodrugs are therapeutic agents that are almost inac creating a sterically highly croWded environment. Restrain tive per se but are predictably transformed into active molecu ing the diffusion of an unbound, Water soluble drug molecule lar entities (see B. Testa, J. M: Mayer in Hydrolysis in Drug requires strong van der Waals contacts, frequently mediated and Prodrug Metabolism, Wiley-VCH, 2003, page 4). The through hydrophobic moieties. Many conformationally sen carrier prodrug approach may be applied in such a fashion sitive drugs, such as proteins or peptides, are rendered dys that the drug is released in vivo from the polymer in order to functional during the encapsulation process and/or during regain its biological activity. The reduced biological activity subsequent storage of the encapsulated drug. In addition, of the prodrug as compared to the released drug is of advan such amino-containing drugs readily undergo side reactions tage if a sloW or controlled release of the drug is desired. In With carrier degradation products (see, for example, D. H. Lee this case, a relatively large amount of prodrug may be admin et al., J. Contr. Rel., 2003, 92, 291-299). Furthermore, depen istered Without concomitant side effects and the risk of over US 2013/0053301A1 Feb. 28, 2013

dosing. Release of the drug occurs over time, thereby reduc ration of the prodrug, the amino groups may be more ing the necessity of repeated and frequent administration of chemoselectively addressed and serve as a better handle for the drug. conjugating the carrier and the drug because of their greater [0015] Prodrug activation may occur by enzymatic or non nucleophilicity as compared to hydroxylic or phenolic enzymatic cleavage of the temporary bond betWeen the car groups. This is particularly true for proteins and peptides rier and the drug molecule, or a sequential combination of Which may contain a great variety of different reactive func both, i.e. an enzymatic step followed by a non-enzymatic tionalities, Where non-selective conjugation reactions lead to rearrangement. In an enzyme-free in-vitro environment such undesired product mixtures Which require extensive charac as an aqueous buffer solution, a temporary bond such as an terization or puri?cation and may decrease reaction yield and ester or amide may undergo hydrolysis, but the corresponding therapeutic e?iciency of the product. rate of hydrolysis may be much too sloW and thus outside the [0021] Amide bonds are usually much more stable against therapeutically useful range. In an in vivo environment, hydrolysis than ester bonds, and the rate of clevage of the esterases or amidases are typically present and the esterases amide bond Would be too sloW for therapeutic utility in a and amidases may cause signi?cant catalytic acceleration of carrier-linked prodrug. Therefore it is advantageous to add the kinetics of hydrolysis from tWofold up to several orders of structural chemical components such as neighbouring groups magnitude (see, for example, R. B. GreenWald et al. J. Med. in order to exert control over the cleavability of the prodrug Chem. 1999, 42 (18), 3857-3867). amide bond. Such additional cleavage-controlling chemical [0016] Prodrugs fall in tWo classes, bioprecursors and car structures that are provided neither by the carrier entity nor by rier-linked prodrugs. Bioprecursors do not contain a carrier the drug are termed “linkers”. Prodrug linkers can have a group and are activated by the metabolic creation of a func strong effect on the rate of hydrolysis of a given temporary tional group. In carrier-linked prodrugs the active substance is bond. Variation of the chemical nature of these linkers alloWs linked to a carrier moiety by a temporary linkage. The carrier the engineering of the properties of the linker to a great extent. may be biologically inert (for instance PEG) or may have [0022] Several examples have been published of the pro targeting properties (for instance antibodies). This invention drug activation of amine-containing biologically active moi is concerned With polymeric carrier-linked or macromolecu eties by speci?c enzymes for targeted release. A prerequisite lar prodrugs, Where the carrier itself is a macromolecule such for enzymatic dependence is that the structure of the linker as a carrier protein or polysaccharide or poly(ethylene gly displays a structural motif that is recognized as a substrate by col). a corresponding endogenous enzyme. In these cases, the [0017] Cleavage of a carrier prodrug generates a molecular cleavage of the temporary bond occurs in a one-step process entity (drug) of increased bioactivity and at least one side Which is catalyzed by the enzyme. G. Cavallaro et al. (Bio product, the carrier. After cleavage, the bioactive entity Will conjugate Chem. 2001, 12, 143-151) describe the enzymatic reveal at least one previously conjugated and thereby pro release of an antitumoral agent by the protease plasmin. Cyt tected functional group, and the presence of this group typi arabin is coupled via the tripeptide sequence D-Val-Leu-Lys cally contributes to the drug’s bioactivity. to the polymer alpha, beta-poly(N-hydroxyethyl)-DL-aspar [0018] In order to implement a prodrug strategy, at least one tamide (PHEA). Enzymatic release of cytarabin is effected by selected functional group in the drug molecule is employed the protease plasmin Which concentration is relatively high in for attachment of the carrier polymer. Preferred functional various kinds of tumor mass. groups are hydroxyl or amino groups. Consequently, both the [0023] Enzyme-catalyzed acceleration of prodrug cleavage attachment chemistry and hydrolysis conditions depend on is a desirable feature for organ or cellular targeting applica the type of functional group employed. tions. Targeted release of the bioactive entity is effected, only [0019] Numerous macromolecular prodrugs are described if an enzyme, that selectively cleaves the linkage, is speci? in the literature Where the temporary linkage is a labile ester cally present in the organ or cell-type chosen for treatment. bond. In theses cases, the functional group provided by the [0024] A major draWback of predominantly enzymatic bioactive entity is either a hydroxyl group or a carboxylic acid cleavage is interpatient variability. Enzyme levels may differ (eg Y. Luo, M R Ziebell, G D PrestWich, “A Hyaluronic signi?cantly betWeen individuals resulting in biological AcidiTaxol Antitumor Bioconjugate Targeted to Cancer variation of prodrug activation by the enzymatic cleavage. Cells”, Biomacromolecules 2000, 1, 208-218, J Cheng et al, The enyzme levels may also vary depending on the site of Synthesis of Linear, beta-Cyclodextrin Based Polymers and administration. For instance it is knoWn that in the case of Their Camptothecin Conjugates, Bioconjugate Chem. 2003, subcutaneous injection, certain areas of the body yield more 14, 1007-1017, R. Bhatt et al, Synthesis and in Vivo Antitu predictable therapeutic effects than others. To reduce this mor Activity of Poly(L-glutamic acid) Conjugates of 20(S) unpredictable effect, non-enzymatic cleavage or intramo Camptothecin, J. Med. Chem. 2003, 46, 190-193; R. B. lecular catalysis is of particular interest (see, for example, B. GreenWald,A. Pendri, C. D. Conover, H. Zhao,Y. H. Choe, A. Testa, J. M: Mayer in Hydrolysis in Drug and Prodrug Martinez, K. Shum, S. Guan, J. Med. Chem., 1999, 42, 3657 Metabolism, Wiley-VCH, 2003, page 5). 3667; B. Testa, J. M: Mayer in Hydrolysis in Drug and Pro [0025] Furthermore, it is dif?cult to establish an in vivo-in drug Metabolism, Wiley-VCH, 2003, Chapter 8). vitro correlation of the pharmacokinetic properties for [0020] Especially for therapeutic biomacromolecules but enzyme-dependent carrier-linked prodrugs. In the absence of also for certain small molecule drugs, it may be desirable to a reliable in vivo-in vitro correlation optimization of a release link the carrier to amino groups of the bioactive entity (i.e. pro?le becomes a cumbersome task. N-terminus or lysine amino groups of proteins). This Will be [0026] Other carrier prodrugs employing temporary link the case if masking the drug’s bioactivity requires conjuga ages to amino groups present in the drug molecule are based tion of a certain amino group of the bioactive entity, for on a cascade mechanism. Cascade cleavage is enabled by instance an amino group located in an active center or a region linker compounds that are composed of a structural combi or epitope involved in receptor binding. Also, during prepa nation of a masking group and an activating group. The mask US 2013/0053301A1 Feb. 28, 2013

ing group is attached to the activating group by means of a a stable bond connects the antibody to an activating group, ?rst temporary linkage such as an ester or a carbamate. The carrying an enZymatically cleavable masking group. Upon activating group is attached to an amino-group of the drug enZymatic removal of the ester-linked masking group, a sec molecule through a second temporary linkage, for instance a ond temporary bond cleaves and releases the drug compound. carbamate. The stability or susceptibility to hydrolysis of the [0033] D. Shabat et al. (Chem. Eur. J. 2004, 10, 2626-2634) second temporary linkage (e.g. carbamate) is dependent on describe a polymeric prodrug system based on a mandelic the presence or absence of the masking group. In the presence acid activating group. In this system the masking group is of the masking group, the second temporary linkage is highly linked to the activating group by a carbamate bond. The stable and unlikely to release the drug With therapeutically activating group is conjugated permanently to a polyacryla useful kinetics. In the absence of the masking group, this mide polymer via an amide bond. After enzymatic activation linkage becomes highly labile, causing rapid cleavage and of the masking group by a catalytic antibody, the masking drug release. group is cleaved by cycliZation and the drug is released. The [0027] The cleavage of the ?rst temporary linkage is the activating group is still connected to the polyacrylamide poly rate-limiting step in the cascade mechanism. This ?rst step mer after drug release. may induce a molecular rearrangement of the activating [0034] M.-R. Lee et al. describe (AngeW. Chem. 2004, 116, group such as a 1,6-elimination. The rearrangement renders 1707-1710) a similar prodrug system based on a mandelic the second temporary linkage so much more labile that its acid activating group and an enZymatically cleavable ester cleavage is induced. Ideally, the cleavage rate of the ?rst linked masking group. temporary linkage is identical to the desired release rate for [0035] Nevertheless, in these linkers the 1,6-elimination the drug molecule in a given therapeutic scenario. Further step still generates a highly reactive aromatic intermediate. more, it is desirable that the cleavage of the second temporary Even if the aromatic moiety remains permanently attached to linkage is substantially instantaneous after its lability has the polymeric carrier, side reactions With potentially toxic been induced by cleavage of the ?rst temporary bond. products or immunogenic effects may be caused. [0028] Examples of polymeric prodrugs based on 1,6 [0036] For these reasons, there is a need to provide novel elimination have been described by R. B. GreenWald et al. J. linker technologies for forming polymeric prodrugs of amine Med. Chem., 1999, 42, 3657-3667 & PCT PatentApplication containing active agents using aliphatic prodrug linkers that WO-A-99/30727, F. M. H. DeGroot et al. (WO-A 02/83180 are not enZyme-dependent and do not generate reactive aro and WO-A 04/43493A1), and D. Shabat et al. (WO-A matic intermediates during cleavage. 04/ 1 9993). [0037] A. J. Gannan et al. (A. J. Gannan, S. B. Kalindjan, [0029] Examples of polymeric amino-containing prodrugs FEBS Lett. 1987, 223 (2), 361-365, 1987) use PEG5000 based on trimethyl lock lactoniZation Were described by R. B. maleic anhydride for the reversible modi?cation of amino GreenWald et al. J. Med. Chem. 2000, 43 (3), 457-487; PCT groups in tissue-type plasminogen activator and urokinase. Patent Application No. WO-A-02/089789). In this prodrug Regeneration of functional enZyme from PEG-uPA conjugate system, substituted o-hydroxyphenyl-dimethylpropionic upon incubation at pH 7.4 buffer by cleavage of the maleamic acid is linked to PEG by an ester, carbonate, or carbamate acid linkeage folloWs ?rst order kinetics With a half-life of 6. 1 group as a ?rst temporary linkage and to amino groups of drug h. A disadvantage of the maleamic acid linkage is the lack of molecules by means of an amide bond as second temporary stability of the conjugate at loWer pH values. This limits the linkage. The rate-determining step in drug release is the enZy applicability of the maleamic acid linkage to active agents matic cleavage of the ?rst linkage. This step is folloWed by Which are stable at basic (high) pH values, as puri?cation of fast amide cleavage by lactoniZation, liberating an aromatic the active agent polymer conjugate has to be performed under lactone side product. basic (high pH) conditions to prevent premature prodrug [0030] The disadvantage in the abovementioned prodrug cleavage. systems described by GreenWald, DeGroot and Shabat is the [0038] More recently, R. B. GreenWald et al. (GreenWald et release of highly reactive and potentially toxic aromatic small al. J. Med. Chem. 2004, 47, 726-734 and WO-A 2004/ molecule side products like quinone methides or aromatic 108070) described a PEG cascade prodrug system based on lactones after cleavage of the temporary linkage. The poten N,N-bis-(2-hydroxyethyl)glycine amide (bicine) linker. In tially toxic entities are released in a 1 :1 stoichiometry With the this system tWo PEG carrier molecules are linked via tempo drug and can assume high in vivo concentrations. rary bonds to a bicine molecule coupled to an amino group of [0031] A different group of cascade produgs With aromatic the drug molecule. The ?rst tWo steps in prodrug activation is activating groups based on 1,6-elimination structurally sepa the enZymatic cleavage of the ?rst temporary linkages con rates the masking group and the carrier. This may be achieved necting both PEG carrier molecules With the hydroxy groups by employing a permanent bond betWeen the polymer carrier of the bicine activating group. Different linkages betWeen and the activating group. This stable bond does not participate PEG and bicine are described resulting in different prodrug in the cascade cleavage mechanism. If the carrier is not serv activation kinetics. The second step in prodrug activation is ing as a masking group and the activating group is coupled to the cleavage of the second temporary linkage connecting the the carrier by means of a stable bond, release of potentially bicine activating group to the amino group of the drug mol toxic side products such as the activating group is avoided. ecule. The main disadvantage of this system is the connection The stable attachment of the activating group and the polymer of the polymer to the bicine linker via temporary bonds and also suppresses the release of drug-linker intermediates With the sloW hydrolysis rate of this second temporary bicine unde?ned pharmacology. amide linkage (t1/2>3 h in phosphate buffer) Which results in [0032] AntcZak et al. (Bioorg Med Chem 9 (2001) 2843 the release of a bicine-modi?ed prodrug intermediate that 48) describe a reagent Which forms the basis for a macromo may shoW different pharmacokinetic, immunogenic, toxicity lecular cascade prodrug system for amine-containing drug and pharmacodynamic properties as compared to the parent molecules. In this approach an antibody serves as the carrier, native drug molecule. US 2013/0053301A1 Feb. 28, 2013

[0039] Dipeptides are frequently utilized for prodrug chain residues to achieve extended circulation of the bioactive development for targeting or targeted transport as they are peptide. A signi?cant disadvantage of this approach is that the substrates for enzymes or biotransport systems. Less studied PEG chain has to be linked to the peptide Without compro is the non-enzymatic route for dipeptide prodrug formation, mising its bioactivity, and it is Well knoWn that this is dif?cult namely the ability to undergo intramolecular cycliZation to to achieve for many peptide-based bioactives. Furthermore, form the corresponding diketopiperaZine (DKP) and release as the PEGylated peptide is bioactive, it may be expected that the active drug. the dipeptidic promoiety has an effect on the peptide’s bio [0040] Such dipeptides may be attached to a drug via ester activity and may negatively affect its receptor binding prop bonds as Was described for dipeptide esters of the drug parac er‘ties. As it is Well knoWn, that many peptides may interact etamol (Santos, Gomes et al Bioorganic & Medicinal Chem With more than one receptor and that sequence extensions istry Letters, 2005). In this case, the cycliZation reaction may affect the balance of such multiple receptor binding, consists of a nucleophilic attack of the N-terminal amine of unpredictable in vivo performance and even side effects may the peptide on the ester carbon atom to form a tetrahedral occur. intermediate. This is folloWed by a proton transfer from the [0045] It is noted that in this disclosure and particularly in amine to the leaving group oxyanion With simultaneous for the claims and/ or paragraphs, terms such as “comprises”, mation of a peptide bond to give the cyclic DKP product and “comprised”, “comprising” and the like can have the meaning free drug. The reaction has been described for ester prodrugs attributed to it in US. Patent laW; e.g., they can mean for example for cyclosporin A (Hamel, A R; Hubler, F; Car “includes”, “included”, “including”, and the like; and that rupt, A; Wenger, R M; Mutter, M, J. Pept. Res., vol. 63, num. terms such as “consisting essentially of’ and “consists essen 2 (2004), p. 147-154). This method is applicable to hydroxyl tially of’ have the meaning ascribed to them in US. Patent containing drugs in vitro but has been found to compete With laW, e.g., they alloW for elements not explicitly recited, but enZymatic hydrolysis of the ester bond in vivo, as correspond exclude elements that are found in the prior art or that affect ing dipeptide esters released paracetamol at a much faster rate a basic or novel characteristic of the invention. than in buffer (Gomes et al, Molecules 12 (2007) 2484-2506). [0046] It is further noted that the invention does not intend [0041] The problem of susceptibility of dipeptide-based to encompass Within the scope of the invention any previously prodrugs to peptidases may be addressed by incorporating at disclosed product, process of making the product or method least one non-natural amino acid in the dipeptide motif. Cor of using the product, Which meets the Written description and responding prodrugs of cytarabine (Wipf et al, Bioorg. Med. enablement requirements of the USPTO (35 U.S.C. 112, ?rst Chem. 4 (1996) 1585-1596) and cyclosporineA (Hamel et al, paragraph) or the EPO (Article 83 of the EPC), such that J. Peptide Res. 63 (2004) 147-154) Were synthesiZed and applicant(s) reserve the right to disclaim, and hereby disclose tested. Still, endogenous enZymes capable of cleaving ester a disclaimer of, any previously described product, method of bonds are not limited to peptidases, and the enZyme-depen making the product, or process of using the product. dence of such prodrug cleavage still gives rise to unpredict able in vivo performance. SUMMARY OF THE INVENTION [0042] Enzyme-dependence by design Was engineered into [0047] Therefore, an object of the present invention is to DKP prodrugs as described in US. Pat. No. 7,163,923, Where provide carrier-linked prodrug linkers suitable for drugs con dipeptide ester prodrugs Were formylated at the amino termi taining aliphatic amine groups from Which free drug is nus of the dipeptide, and enZymatic deformylation Was used released With therapeutically useful half-lives. as a trigger to set off diketopiperaZine formation and subse quent cleavage of the ester-dipeptide bond folloWed by drug [0048] This object is achieved by a polymeric prodrug or release. Similarly, vinblastine conjugates bearing an oli pharmaceutically acceptable salt thereof comprising a drug gopeptide Were described (Brady et al, J. Med. Chem. 45 linker conjugate D-L, Wherein (2002) 4706-4715). Here, an octapeptide Was attached by an D is an aliphatic amine containing biologically active moiety; ester linkage to the 4-hydroxyl group of vinblastine and found and to undergo ester bond cleavage by DKP formation after spe L is a non-biologically active linker containing ci?c enZymatic removal of the N-terminal hexapeptide. [0049] i) a moiety Ll represented by formula (I), [0043] Recently the scope of the DKP formation reaction Was extended to amide prodrugs. US. Pat. No. 5,952,294 details prodrug activation using diketopiperaZine formation (I) for dipeptidyl amide prodrugs of cytarabine. In this case, the temporary linkage Was formed betWeen the carbonyl of a dipeptide and the aromatic amino group of cytarabine. In another study, the utility of diketopiperaZine activation Was demonstrated for even more stable aliphatic amide prodrugs (G. A. R. Y. Suaifan et al., Tetrahedron 62 (2006) 11245 11266). Neither of these studies teaches hoW a sloW-release effect can be achieved for such conjugates as there is no carrier or other half-life extending moiety or functionality present in the compounds disclosed. [0044] WO-A 2009/ 99763 describes dipeptide prodrugs of bioactive peptides such as GLP-1 capable of releasing the [0050] Wherein the dashed line indicates the attachment peptide through diketopiperaZine formation of the dipeptidic of L1 to an aliphatic amino group of D by forming an extension. In this case, the bioactive peptide moiety may amide bond; carry an additional PEG chain on one of its amino acid side [0051] X1 is selected from O, S or CHiRla, US 2013/0053301A1 Feb. 28, 2013

[0052] R1 and R1“ are independently selected from H, -continued OH, CH3 [0053] R2, R2“, R4 and R4“ are independently selected from H and C1_4 alkyl, [0054] R3, R3“ are independently selected from H, C1_4 alkyl, and R5 / l [0055] R5 is selected from

NH

[0056] Preferably, one of the pair R3/R3“ is H and the other one is selected from R5 . 6%)ll [0057] Preferably, one of R4/R4“ is H. [0058] Optionally, one or more of the pairs R3/R3“, R4/R4“, R3/R4 may independently form one or more cyclic fragments selected from C3_7 cycloalkyl, 4 to 7 membered heterocyclyl, or 9 to 11 membered heterobi cyclyl. [0059] Optionally, R3, R3“, R4 and R4“ are further sub stituted; Suitable substituents are alkyl (such as C1_6 alkyl), alkenyl (such as C2_6 alkenyl), alkynyl (such as C2_6 alkynyl), aryl (such as phenyl), heteroalkyl, het eroalkenyl, heteroalkynyl, heteroaryl (such as aromatic 4 to 7 membered heterocycle) or halogen moieties. [0060] ii) a moiety L2, Which is a chemical bond or a spacer, and L2 is bound to a carrier group Z, Wherein L1 is substituted With one to four (preferably one) L2 moieties, Z is PEG or a hydrogel, more preferably Z is a hydrogel, even more preferably Z is a PEG-based hydrogel; optionally, L is further substituted. [0061] Suitable substituents are alkyl (such as Cl_6 alkyl), alkenyl (such as C2_6 alkenyl), alkynyl (such as C2_6 alkynyl), aryl (such as phenyl), heteroalkyl, heteroalkenyl, heteroalky nyl, heteroaryl (such as aromatic 4 to 7 membered hetero cycle) or halogen moieties. [0062] The present invention addresses the disadvantages described above. The invention provides for carrier-linked prodrugs characterized by connecting a carrier via a dipeptide linker to a primary or secondary amino group of an aliphatic NH amine-containing drug molecule. The carrier is linked to the dipeptide linker via a permanent linkage and the bond betWeen the dipeptide promoiety and the amine-containing drug molecule is a temporary amide linkage that exhibits extended autohydrolysis at a therapeutically useful rate at pH 7.4 and 37° C., i.e. under physiological conditions. [0063] Due to the presence of a permanent bond betWeen the carrier and the DKP linker, the prodrugs according to the present invention ensure release of unmodi?ed native drug molecules from a stable conjugate comprising carrier and linker moiety. [0064] It Was noW surprisingly found, that aliphatic amide bonds can undergo autohydrolysis at a rate that is useful for NH2 carrier-linked prodrug applications if cycliZation-activation is used as a prodrug principle. In particular detail, it Was surprisingly found that diketopiperaZine formation can be used for carrier-linked amide prodrugs. Speci?cally, the link ers used in these carrier-linked amide prodrugs are designed % such that they consist of a carrier permanently attached to a dipeptide motif in such a fashion that diketopiperaZine-for US 2013/0053301A1 Feb. 28, 2013

mation can still be employed as a self-activation principle. addition, the subterm “aliphatic amine containing” means Suprisingly, in these linker structures, the presence of the that the respective moiety D and analogously the correspond carrier entity still allows for therapeutically useful autohy ing drug D-H contains at least one aliphatic fragment, and drolysis rates, an essential prerequisite for prodrug applica Which at least one aliphatic fragment is substituted With at tions. least one amino group. [0065] In the present application the following terms are [0079] “Non-biologically active linker” means a linker used as described beloW. Which does not shoW pharmacological effects. [0066] “Prodrug”: A prodrug is any compound that under [0080] “Biologically active moiety D” means the part of the goes biotransformation before exhibiting its pharmacological drug linker conjugate, Which results after cleavage in a drug effects. Prodrugs can thus be vieWed as drugs containing D-H of knoWn biological activity. specialiZed non-toxic protective groups used in a transient [0081] Suitable carriers are polymers and can either be manner to alter or to eliminate undesirable properties in the directly conjugated to the linker or via a non-cleavable spacer. parent molecule. The term “prodrug according to the invention” refers to car [0067] “Promoiety” refers to the part of the prodrug Which rier-linked prodrugs of biologically active agents, Wherein the is not the biologically active moiety. Promoiety thus refers to carrier is PEG or a hydrogel, preferably a PEG-based hydro the linker and the carrier, if a carrier is present. gel. The terms “PEG prodrug”, “PEG-linked prodrug”, [0068] “Carrier-linked prodrug” or “carrier prodrug”: A “hydrogel prodrug” and “hydrogel-linked prodrug” refer to carrier-linked prodrug is a prodrug that contains a temporary prodrugs of biologically active agents transiently linked to a linkage of a given active substance With a transient carrier PEG or to a hydrogel, respectively, and are used synony group that produces improved physicochemical or pharma mously. cokinetic properties and that can be easily removed in vivo, [0082] The term “polyethylene glycol based” or “PEG usually by a hydrolytic cleavage. based” as understood herein means that the mass proportion [0069] “Cascade prodrug”: A cascade prodrug is a carrier of PEG chains or in the hydrogel is at least 10% by Weight, prodrug for Which the cleavage of the carrier group becomes preferably at least 25%, based on the total Weight of the effective only after unmasking an activating group. hydrogel. The remainder can be made up of other polymers. [0070] “Polymeric cascade prodrug”: A polymeric cascade [0083] Such other polymers are preferably selected from prodrug is a carrier prodrug that contains a temporary linkage the group consisting of, for example, 2-methacryloyl-oxy of a given active substance With a transient polymeric carrier ethyl phosphoyl cholins, hydrogels, PEG-based hydrogels, group for Which the cleavage of the carrier becomes effective poly(acrylic acids), poly(acrylates), poly(acrylamides), poly only after unmasking an activating group. (alkyloxy) polymers, poly(amides), poly(amidoamines), [0071] “Bioprecursor prodrug”: A bioprecursor prodrug is poly(amino acids), poly(anhydrides), poly(aspartamides), a prodrug that does not imply the linkage to a carrier group, poly(butyric acids), poly(glycolic acids), polybutylene but results from a molecular modi?cation of the active prin terephthalates, poly(caprolactones), poly(carbonates), poly ciple itself. This modi?cation generates a neW compound, (cyanoacrylates), poly(dimethylacrylamides), poly(esters), able to be transformed metabolically or chemically, the poly(ethylenes), poly(ethyleneglycols), poly(ethylene resulting compound being the active principle. oxides), poly(ethyl phosphates), poly(ethyloxaZolines), poly [0072] “Biotransformation”: Biotransformation is the (glycolic acids), poly(hydroxyethyl acrylates), poly(hy chemical conversion of substances by living organisms or droxyethyloxaZolines), poly(hydroxymethacrylates), poly enzyme preparations. (hydroxypropylmethacrylamides), poly(hydroxypropyl [0073] The previous de?nitions are based on IUPAC, as methacrylates), poly(hydroxypropyloxaZolines), poly(imi given under http://WWW.chem.qmul.ac.uk/iupac/medchem/ nocarbonates), poly(lactic acids), poly(lactic-co-glycolic (accessed on 8 Mar. 2004) acids), poly(methacrylamides), poly(methacrylates), poly [0074] “Linker”: Cleavage-controlling chemical structures (methyloxaZolines), poly(organophosphaZenes), poly(ortho or groups present in carrier prodrugs that are not provided by esters), poly(oxaZolines), poly(propylene glycols), poly(si either the carrier entity or by the drug. loxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl [0075] “Sustained release” or “substained release rate” amines), poly(vinylmethylethers), poly(vinylpyrrolidones), means that the administration intervals of the respective pro silicones, celluloses, carbomethyl celluloses, hydroxypropyl drug are expanded. Drugs With a daily dosage may for methylcelluloses, chitins, chitosans, dextrans, dextrins, gela example be turned into a sustained release form With a Week tins, hyaluronic acids and derivatives, mannans, pectins, long or even longer interval betWeen tWo administrations. rhamnogalacturonans, starches, hydroxyalkyl starches, [0076] A strong in vivo/in vitro correlation is observed, if hydroxyethyl starches and other carbohydrate-based poly the release kinetics exhibited by a hydrogel prodrug conju mers, xylans, and copolymers thereof. gate according to the present invention has a half-life in vivo [0084] Suitable carriers can either be directly conjugated to that is not smaller than half the value exhibited by the same the linker or via a non-cleavable spacer. The term “polymer hydrogel prodrug conjugate in aqueous buffer of pH 7.4 at 37° prodrug” refers to carrier-linked prodrugs of a biologically C active agent, Wherein the carrier is a polymer. [0077] “Cis-amide conformation inducer” refers to a moi [0085] The term polymer describes a molecule comprised ety that stabiliZes the preceeding cis-amide bond. Suitable of repeating structural units connected by chemical bonds in cis-amide conformation inducers are, for example, a linear, circular, branched, crosslinked or dendrimeric Way pseudoprolines. or a combination thereof, Which can be of synthetic or bio [0078] “Aliphatic amine containing biologically active logical origin or a combination of both. Typically, a polymer moiety D” means the part, eg the moiety or fragment, of the has a molecular Weight of at least 1 kDa. drug linker conjugate D-L, Which results after cleavage in the [0086] More preferably, Z is a biodegradable polyethylene drug D-H, the active agent, of knoWn biological activity. In glycol based Water-insoluble hydrogel. US 2013/0053301A1 Feb. 28, 2013

[0087] The term “Water-insoluble” refers to a sWellable [0094] “Protective groups” refers to a moiety Which tem three-dimensionally crosslinked molecular network forming porarily protects a functional group of a molecule during the hydrogel. The hydrogel if suspended in a large surplus of synthesis to obtain chemoselectivity in subsequent chemical Water or aqueous buffer of physiological osmolality may take reactions. Protective groups for alcohols are, for example, up a substantial amount of water, eg up to 10-fold on a benZyl and trityl, protective groups for amines are, for Weight per Weight basis, and is therefore sWellable but after example, tert-butyloxycarbonyl, 9-?uorenylmethyloxycar removing excess Water still retains the physical stability of a bonyl and benZyl and for thiols examples of protective groups gel and a shape. Such shape may be of any geometry and it is are 2,4,6-trimethoxybenZyl, phenylthiomethyl, acetamidom understood that such an individual hydrogel object is to be ethyl, p-methoxybenZyloxycarbonyl, tert-butylthio, triph considered as a single molecule consisting of components enylmethyl, 3-nitro-2-pyridylthio, 4-methyltrityl. Wherein each component is connected to each other compo [0095] “Protected functional groups” means a functional nent through chemical bonds. group protected by a protective group. [0088] The term “PEG” or “pegylation residue” is used [0096] “Acylating agent” means a moiety of the structure herein exemplary for suitable Water-soluble polymers char Ri(C:O)i, providing the acyl group in an acylation reac acteriZed by repeating units. Suitable polymers may be tion, optionally connected to a leaving group, such as acid selected from the group consisting of polyalkyloxy polymers, chloride, N-hydroxy succinimide, penta?uorphenol and hyaluronic acid and derivatives thereof, polyvinyl alcohols, para-nitrophenol. polyoxaZolines, polyanhydrides, poly(ortho esters), polycar [0097] “Alkyl” means a straight-chain or branched carbon bonates, polyurethanes, polyacrylic acids, polyacrylamides, chain (unsubstituted alkyl). Optionally, each hydrogen of an polyacry-lates, polymethacrylates, polyorganophosp alkyl carbon may be replaced by a substituent. haZenes, polysiloxanes, polyvinylpyrrolidone, polycy [0098] “Heteroalkyl” refers to analogs of alkyls in Which anoacrylates, and polyesters. Preferred are polyalkyloxy one or more than one methylene group is replaced by a het polymers, especially polyethylene glycol polymers contain eroatom, such as nitrogen, oxygen, sulfur, phosphorus, or ing at least 10% by Weight ethylene oxide units, more pref boron. If the methylene group is replaced by nitrogen, phos erably at least 25% by Weight, even more preferably at least phorous or boron, these heteroatoms may be further substi 50% by Weight tuted. Suitable substituents are alkyl, alkenyl, alkynyl, aryl, [0089] A “hydrogel” may be de?ned as a three-dimen heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl or halo sional, hydrophilic or amphiphilic polymeric netWork gen moieties (such as those described above). The terms capable of taking up large quantities of Water. The networks heteroalkenyl and heteroalkynyl are de?ned accordingly. are composed of homopolymers or copolymers, are insoluble [0099] “Cl_4 alkyl” means an alkyl chain having 1 to 4 due to the presence of covalent chemical or physical (ionic, carbon atoms (unsubstituted C 1_ 4 alkyl), eg if present at the hydrophobic interactions, entanglements) crosslinks. The end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, crosslinks provide the netWork structure and physical integ isobutyl, sec-butyl tert-butyl, or e.g. iCHZi, 4CH2i rity. Hydrogels exhibit a thermodynamic compatibility With CHZi, %H(CH3)i, %H2%H2%H2i, %H Water Which alloWs them to sWell in aqueous media. The (C2H5)i, iC(CH3)2i, When tWo moieties of a molecule chains of the netWork are connected in such a fashion that are linked by the alkyl group. Optionally, each hydrogen of a pores exist and that a substantial fraction of these pores are of C1_4 alkyl carbon may be replaced by a substituent. Accord dimensions betWeen 1 nm and 1000 nm. ingly, “Cl_5O alkyl” means an alkyl chain having 1 to 50 carbon atoms. The term C1_6 is de?ned accordingly. [0090] “Free form” of a drug refers to the drug in its unmodi?ed, pharmacologically active form, such as after [0100] “C2_5O alkenyl” means a branched or unbranched being released from a polymer conjugate. alkenyl chain having 2 to 50 carbon atoms (unsubstituted C2_5O alkenyl), eg if present at the end of a molecule: [0091] The terms “drug , biologically active molecule”, “biologically active moiety”, “biologically active agent”, %H:CH2, %H:CH%H3, iCH2iCH:CH2, “active agent”, and the like mean any substance Which can %H:CH%H2%H3, %H:CH%H:CH2, or e.g. 4CH:CHi, When tWo moieties of a molecule are linked affect any physical or biochemical properties of a biological by the alkenyl group. Optionally, each hydrogen of a C2_5O organism, including but not limited to viruses, bacteria, fungi, alkenyl carbon may be replaced by a substituent as further plants, animals, and humans. In particular, as used herein, speci?ed. Accordingly, the term “alkenyl” relates to a carbon biologically active molecules include any substance intended chain With at least one carbon carbon double bond. Option for diagnosis, cure, mitigation, treatment, or prevention of ally, one or more triple bonds may occur. The term C2_6 disease in humans or other animals, or to otherWise enhance alkenyl is de?ned accordingly. physical or mental Well-being of humans or animals. [0101] “C2_5O alkynyl” means a branched or unbranched [0092] The terms “spacer” or “spacer moieties” refer to any alkynyl chain having 2 to 50 carbon atoms (unsubstituted moiety suitable for connecting tWo moieties, such as Cl_5O C2_5O alkynyl), eg if present at the end of a molecule: alkyl, C2_5O alkenyl or C2_5O alkinyl, Which fragment is %iCH, iCHZiCiCH, CH2%H2%iCH, CHzi optionally interrupted by one or more groups selected from CECiCH3, or e. g. iCECi When tWo moieties of a mol iNHi, iN(Cl_4 alkyl)-, ADi, iSi, iC(O)i, ecule are linked by the alkynyl group. Optionally, each hydro iC(O)NHi, %(O)N(Cl_4 alkyl)-, A)iC(O)i, gen of a C2_5O alkynyl carbon may be replaced by a substituent iS(O)i, iS(O)2i, 4 to 7 membered heterocyclyl, phenyl as further speci?ed. Accordingly, the term “alkynyl” relates to or naphthyl. a carbon chain With at lest one carbon carbon triple bond. [0093] “Functional groups” mean groups of atoms Within Optionally, one or more double bonds may occur. The term molecules that exhibit a speci?c chemical activity. Examples C2_6 alkynyl is de?ned accordingly. are amides, amines, alcohols, carbonyls, carboxylic acids, [0102] “C3_7 cycloalkyl” or “C3_7 cycloalkyl ring” means a thiols. cyclic alkyl chain having 3 to 7 carbon atoms, Which may US 2013/0053301A1 Feb. 28, 2013

have carbon-carbon double bonds being at least partially satu groups can be used according to the invention, for example, as rated (unsubstituted C3_7 cycloalkyl), e.g. cyclopropyl, alkali metal salts, alkaline earth metal salts or as ammonium cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohep salts. More precise examples of such salts include sodium tyl. Optionally, each hydrogen of a cycloalkyl carbon may be salts, potassium salts, calcium salts, magnesium salts or salts replaced by a substituent. The term “C3_7 cycloalkyl” or “C3_7 With ammonia or organic amines such as, for example, ethy cycloalkyl ring” also includes bridged bicycles like norbo lamine, ethanolamine, triethanolamine or amino acids. Pro nane (norbonanyl) or norbonene (norbonenyl). Accordingly, drugs Which contain one or more basic groups, i.e. groups “C3_5 cycloalkyl” means a cycloalkyl having 3 to 5 carbon Which can be protonated, can be present and can be used atoms. according to the invention in the form of their addition salts [0103] “Halogen”means ?uoro, chloro, bromo oriodo. It is With inorganic or organic acids. Examples for suitable acids generally preferred that halogen is ?uoro or chloro. include hydrogen chloride, hydrogen bromide, phosphoric [0104] “4 to 7 membered heterocyclyl” or “4 to 7 mem acid, sulfuric acid, nitric acid, methanesulfonic acid, p-tolu bered heterocycle” means a ring With 4, 5, 6 or 7 ring atoms enesulfonic acid, naphthalenedisulfonic acids, oxalic acid, that may contain up to the maximum number of double bonds acetic acid, tartaric acid, lactic acid, salicylic acid, benZoic (aromatic or non-aromatic ring Which is fully, partially or acid, formic acid, propionic acid, pivalic acid, diethylacetic un-saturated) Wherein at least one ring atom up to 4 ring acid, malonic acid, succinic acid, pimelic acid, fumaric acid, atoms are replaced by a heteroatom selected from the group maleic acid, malic acid, sulfaminic acid, phenylpropionic consisting of sulfur (including iS(O)i, iS(O)2i), oxy acid, gluconic acid, ascorbic acid, isonicotinic acid, citric gen and nitrogen (including :N(O)i) and Wherein the ring acid, adipic acid, and other acids knoWn to the person skilled is linked to the rest of the molecule via a carbon or nitrogen in the art. If the prodrugs simultaneously contain acidic and atom (unsubstituted 4 to 7 membered heterocyclyl). basic groups in the molecule, the invention also includes, in [0105] Examples for a 4 to 7 membered heterocycles are addition to the salt forms mentioned, inner salts or betaines aZetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrro (ZWitterions). The respective salts of the prodrugs of the line, imidaZole, imidaZoline, pyraZole, pyraZoline, oxaZole, present invention can be obtained by customary methods oxaZoline, isoxaZole, isoxaZoline, thiaZole, thiaZoline, Which are knoWn to the person skilled in the art like, for isothiaZole, isothiaZoline, thiadiaZole, thiadiaZoline, tetrahy example by contacting these With an organic or inorganic acid drofuran, tetrahydrothiophene, pyrrolidine, imidaZolidine, or base in a solvent or dispersant, or by anion exchange or pyraZolidine, oxaZolidine, isoxaZolidine, thiaZolidine, cation exchange With other salts. The present invention also isothiaZolidine, thiadiaZolidine, sulfolane, pyran, dihydropy includes all salts of the prodrugs Which, oWing to loW physi ran, tetrahydropyran, imidaZolidine, pyridine, pyridaZine, ological compatibility, are not directly suitable for use in pyraZine, pyrimidine, piperaZine, piperidine, morpholine, tet pharmaceuticals but Which can be used, for example, as inter raZole, triaZole, triaZolidine, tetraZolidine, diaZepane, mediates for chemical reactions or for the preparation of aZepine or homopiperaZine. Optionally, each hydrogen of a 4 pharmaceutically acceptable salts. to 7 membered heterocyclyl may be replaced by a sub stituent. [0109] The term “pharmaceutically acceptable” means [0106] “9 to 11 membered heterobicyclyl” or“9 to 11 mem approved by a regulatory agency, such as the EMEA (Europe) bered heterobicycle” means a heterocyclic system of tWo and/or the FDA (US) and/or any other national regulatory rings With 9 to 11 ring atoms, Where at least one ring atom is agency for use in animals, preferably in humans. shared by both rings and that may contain up to the maximum [0110] “Pharmaceutical composition” or “composition” number of double bonds (aromatic or non-aromatic ring means a composition containing one or more active ingredi Which is fully, partially or un-saturated) Wherein at least one ents, for example a drug or a prodrug, and one or more inert ring atom up to 6 ring atoms are replaced by a heteroatom ingredients, as Well as any product Which results, directly or selected from the group consisting of sulfur (including indirectly, from combination, complexation or aggregation of iS(O)i, iS(O)2i), oxygen and nitrogen (including any tWo or more of the ingredients, or from dissociation of :N(O)i) and Wherein the ring is linked to the rest of the one or more of the ingredients, or from other types of reac molecule via a carbon or nitrogen atom (unsubstituted 9 to l 1 tions or interactions of one or more of the ingredients. membered heterobicyclyl). Accordingly, the pharmaceutical compositions of the present [0107] Examples for a 9 to 11 membered heterobicycle are invention encompass any composition made by admixing a indole, indoline, benZofuran, benZothiophene, benZoxaZole, prodrug of the present invention and a pharmaceutically benZisoxaZole, benZothiaZole, benZisothiaZole, benZimida acceptable excipient. Zole, benZimidaZoline, quinoline, quinaZoline, dihydro [0111] “Stable” and “stability” means that Within the indi quinaZoline, quinoline, dihydroquinoline, tetrahydroquino cated storage time the polymer conjugates remain conjugated line, decahydroquinoline, isoquinoline, and do not hydrolyZe to a substantial extent and exhibit an decahydroisoquinoline, tetrahydroisoquinoline, dihydroiso acceptable impurity pro?le relating to the biologically active quinoline, benZaZepine, purine or pteridine. The term 9 to 11 agent. To be considered stable, the composition contains less membered heterobicycle also includes spiro structures of tWo than 10%, preferably less than 5% of the drug in its free form. rings like l,4-dioxa-8-aZaspiro[4.5]decane or bridged hetero [0112] “Therapeutically effective amount” means an cycles like 8-aZa-bicyclo[3.2. l]octane. Optionally, each amount suf?cient to cure, alleviate or partially arrest the hydrogen of a 9 to 11 membered heterobicyclyl may be clinical manifestations of a given disease and its complica replaced by a substituent. tions. An amount adequate to accomplish this is de?ned as [0108] In case the prodrugs according to the present inven “therapeutically effective amount”. Effective amounts for tion contain one or more acidic or basic groups, the invention each purpose Will depend on the severity of the disease or also comprises their corresponding pharmaceutically or toxi injury as Well as the Weight and general state of the subject. It cologically acceptable salts, in particular their pharmaceuti Will be understood that determining an appropriate dosage cally utiliZable salts. Thus, the prodrugs Which contain acidic may be achieved using routine experimentation, by construct US 2013/0053301Al Feb. 28, 2013

ing a matrix of values and testing different points in the [0123] “Isotonicity modi?ers” refer to compounds Which matrix, Which is all Within the ordinary skills of a trained minimize pain that can result from cell damage due to osmotic physician. Within the scope of this invention, therapeutically pressure differences at the injection depot. effective amount relates to dosages that aim to achieve thera [0124] The term “stabilizers” refers to compounds used to peutic effect for an extended period of time, i.e. for 12 hours, stabilize the polymer prodrug. Stabilisation is achieved by or 24 hours, or three days or longer, for instance one Week or strengthening of the protein-stabilising forces, by destabili tWo Weeks. sation of the denatured state, or by direct binding of excipi [0113] “Excipients” refers to compounds administered ents to the protein. together With the therapeutic agent, for example, buffering [0125] “Anti-adsorption agents” refers to mainly ionic or agents, isotonicity modi?ers, preservatives, stabilizers, anti non-ionic surfactants or other proteins or soluble polymers adsorption agents, oxidation protection agents, or other aux used to coat or adsorb competitively to the inner surface of the iliary agents. HoWever, in some cases, one excipient may have composition’s container. Chosen concentration and type of dual or triple functions. excipient depends on the effect to be avoided but typically a [0114] “Dry composition” means that the prodrug compo monolayer of surfactant is formed at the interface just above sition is provided in a dry form in a container. Suitable meth the CMC value. ods for drying are spray-drying and lyophilization (freeze [0126] “Oxidation protection agents” refers to antioxidants drying). Such dry composition of prodrug has a residual Water such as ascorbic acid, ectoine, glutathione, methionine, content of a maximum of 10%, preferably less than 5% and monothioglycerol, morin, polyethylenimine (PEI), propyl more preferably less than 2% (determined according to Karl gallate, vitamin E, chelating agents such aus citric acid, Fischer). The preferred method of drying is lyophilization. EDTA, hexaphosphate, thioglycolic acid. [0115] “Lyophilized composition” means that the prodrug [0127] “Antimicrobial” refers to a chemical substance that composition Was ?rst frozen and subsequently subjected to kills or inhibits the groWth of microorganisms, such as bac Water reduction by means of reduced pressure. This terminol teria, fungi, yeasts, protozoans and/or destroys viruses. ogy does not exclude additional drying steps Which occur in [0128] “PEG based” as understood herein means that the the manufacturing process prior to ?lling the composition mass proportion of PEG chains in the hydrogel is at least 10% into the ?nal container. by Weight, preferably at least 25%, based on the total Weight of the hydrogel. The remainder can be made up of other [0116] “Lyophilization” (freeze-drying) is a dehydration spacers and/or oligomers orpolymers, such as oligo- or polyl process, characterized by freezing a composition and then ysines. reducing the surrounding pressure and, optionally, adding [0129] The term “hydrolytically degradable” or “biode heat to alloW the frozen Water in the composition to sublime gradable” refers Within the context of the present invention to directly from the solid phase to gas. Typically, the sublimed linkages Which are non-enzymatically hydrolytically degrad Water is collected by desublimation. able under physiological conditions (aqueous buffer at pH [0117] “Reconstitution” means the addition of a liquid to 7.4, 37° C.) With half-lives ranging from one hour to three bring back the original form of a composition. months, include, but are not limited to, aconityls, acetals, [0118] “Reconstitution solution” refers to the liquid used to carboxylic anhydrides, esters, imines, hydrazones, maleamic reconstitute the dry composition of a prodrug prior to admin acid amides, ortho esters, phosphamides, phosphoesters, istration to a patient in need thereof. phosphosilyl esters, silyl esters, sulfonic esters, aromatic car [0119] “Container” means any container in Which the pro bamates, combinations thereof, and the like. Preferred biode drug composition is comprised and can be stored until recon gradable linkages are esters, carbonates, phosphoesters and stitution. sulfonic acid esters and most preferred are esters or carbon [0120] “Buffer” or “buffering agent” refers to chemical ates. It is understood that for in vitro studies accelerated compounds that maintain the pH in a desired range. Physi conditions like, for example, pH 9, 37° C., aqueous buffer, ologically tolerated buffers are, for example, sodium phos may be used for practical purposes. phate, succinate, histidine, bicarbonate, citrate and acetate, sulphate, nitrate, chloride, pyruvate. Antacids such as DETAILED DESCRIPTION OF EMBODIMENTS Mg(OH)2 or ZnCO3 may be also used. Buffering capacity [0130] It is to be understood that the ?gures and descrip may be adjusted to match the conditions most sensitive to pH tions of the present invention have been simpli?ed to illustrate stability. elements that are relevant for a clear understanding of the [0121] A “lyoprotectant” is a molecule Which, When com present invention, While eliminating, for purposes of clarity, bined With a protein of interest, signi?cantly prevents or many other elements Which are conventional in this art. Those reduces chemical and/or physical instability of the protein of ordinary skill in the art Will recognize that other elements upon drying in general and especially during lyophilization are desirable for implementing the present invention. HoW and subsequent storage. Exemplary lyoprotectants include ever, because such elements are Well knoWn in the art, and sugars, such as sucrose or trehalose; amino acids such as because they do not facilitate a better understanding of the monosodium glutamate or histidine; methylamines such as present invention, a discussion of such elements is not pro betaine; lyotropic salts such as magnesium sulfate; polyols vided herein. such as trihydric or higher sugar alcohols, e.g. glycerin, eryth [0131] The present invention Will noW be described in ritol, glycerol, arabitol, xylitol, sorbitol, and mannitol; ethyl detail on the basis of exemplary embodiments. ene glycol; propylene glycol; polyethylene glycol; pluronics; [0132] In the present invention, the hydrolytic lability hydroxyalkyl starches, e.g. hydroxyethyl starch (HES), and required for a temporary linkage may be introduced into the combinations thereof. prodrug amide bond by selecting the structural properties of [0122] “Surfactant” refers to Wetting agents that loWer the the linker for cyclization activation. In cyclization-activated surface tension of a liquid. amide bond cleavage, the cleavage products are a free amine US 2013/0053301Al Feb. 28, 2013

as part of the biologically active moiety and a cycliZed resi nase, agalsidase, alfa-l antitrypsin (AAT), alfa-l proteinase due. The linker structures of the present invention are inhibitor (API), alteplase, amylins (amylin, symlin), anistre designed such that highly stable rings are formed as cleavage plase, ancrod serine protease, antibodies (monoclonal or products and the hydrolysis of the prodrug amide bond facili polyclonal, and fragments or fusions), antithrombin III, antit tates hydrolysis in a time range useful for drug delivery under rypsins, aprotinin, asparaginases, atosiban, biphalin, bivaliru physiological conditions. Preferred cyclic cleavage products din, bone-morphogenic proteins, bovine pancreatic trypsin are diketopiperaZine rings. Prerequisite for such cycliZation inhibitor (BPTI), cadherin fragments, calcitonin (salmon), activation is the presence of an amine-containing nucleophile collagenase, complement Cl esterase inhibitor, conotoxins, in the linker structure and another amide bond Which is not the cytokine receptor fragments, DNase, dynorphine A, endor temporary amide prodrug bond but a permanent amide bond. phins, enfuvirtide, enkephalins, erythropoietins, exendins, Preferably, such linker structures contain a cis-amide confor factor VII, factor VIIa, factor VIII, factor VIIIa, factor IX, mation inducer. Alternatively, the cleavage might occur ?brinolysin, ?broblast groWth factor (FGF), groWth hormone through intramolecular catalysis caused by neighbouring releasing peptide 2 (GHRP2), fusion proteins, follicle-stimu group effects. lating hormones, gramicidin, ghrelin, desacyl-ghrelin, granu [0133] In case of diketopiperaZine-activated prodrug cleav locyte colony stimulating factor (G-CSF), galactosidase, glu age, the amine-containing nucleophile serves to attack the cagon, glucagon-like peptides, glucocerebrosidase, prodrug amide carbonyl group and consequently induces granulocyte macrophage colony stimulating factor (GM transamidation, and the permanent amide bond serves to form CSF), human heat shock proteins (HSP), phospholipase-ac a stabiliZed six-membered ring structure. tivating protein (PLAP), gonadotropin chorionic (hCG), [0134] The formation of the stabiliZed six-membered ring hemoglobins, hepatitis B vaccines, hirudin, human serine structure is facilitated through a cis-amide conformation protease inhibitor, hyaluronidases, idurnonidase, immune inducing pseudoproline. Pseudoprolines are arti?cially cre globulins, in?uenza vaccines, interleukins (l alfa, 1 beta, 2, 3, ated dipeptides, Which contain an oxaZolidine or thiaZolidine 4, 6, 10, ll, l2, 13, 21), IL-1 receptor antagonist (rhIL-lra), ring. In peptide synthesis, pseudoprolines are used to increase insulins, insulin like groWth factors, insulin-like groWth fac solvation and solubility. Due to the preference for a cis-amide tor binding protein (rhIGFBP), interferons (alfa 2a, alfa 2b, bond With the preceding residue of C2-substituted alfa 2c, beta la, beta lb, gamma la, gamma lb), intracellular pseudoprolines, their incorporation results in a kink confor adhesion molecule, keratinocyte groWth factor (KGF), P-se mation of the peptide backbone Which decreases aggregation, lectin glycoprotein ligand (PSGL), transforming groWth fac self-association and p-structure formation. tors, lactase, leptin, leuprolide, levothyroxine, luteiniZing [0135] Preferred linker structures are composed of a dipep hormone, lyme vaccine, natriuretic peptides (ANP, BNP, tide promoiety conjugated through a permanent linkage to a CNP and fragments), neuropeptide Y, pancrelipase, pancre polymer carrier. Corresponding prodrugs are composed of a atic polypeptide, papain, parathyroid hormone, PDGF, pep dipeptide containing a permanent linkage to a polymer carrier sin, peptide YY, platelet activating factor acetylhydrolase and a temporary amide bond to an aliphatic amino-group (PAF-AH), prolactin, protein C, thymalfasin, octreotide, containing drug. secretin, sermorelin, soluble tumor necrosis factor receptor [0136] Preferably, linkers of the present invention have a (TNFR), superoxide dismutase (SOD), somatropins (groWth hydrolysis rate between 1 h and 2 years at pH 7.4 and 37° C. hormone), somatoprim, somatostatin, streptokinase, sucrase, and hydrolysis rates in buffer and plasma are essentially iden terlipressin, tetanus toxin fragment, tilactase, thrombins, thy tical, i.e. the hydrolysis rates exhibit a strong in vivo/ in vitro mosin, thyroid stimulating hormone, thyrotropin, tumor correlation. necrosis factor (TNF), TNF receptor-IgG Fc, tissue plasmi [0137] Preferably, D-H is a small molecule bioactive agent nogen activator (tPA), TSH, urodilatin, urate oxidase, uroki or a biopolymer. nase, vaccines, vascular endothelial groWth factor (VEGF), [0138] Preferably, D-H is a biopolymer selected from the vasoactive intestinal peptide, vasopressin, Ziconotide, lectin group of biopolymers consisting of proteins, polypeptides, and ricin. oligonucleotides, and peptide nucleic acids. [0141] Preferably, D-H is a protein prepared by recombi [0139] “Oligonucleotides” means either DNA, RNA, nant DNA technologies. single-stranded or double-stranded, siRNA, miRNA, aptam [0142] Preferably, D-H is a protein selected from the group ers, and any chemical modi?cations thereof With preferably 2 of proteins consisting of antibodies, antibody fragments, to 1000 nucleotides. Modi?cations include, but are not lim single chain antigen binding proteins, catalytic antibodies ited to, those Which provide other chemical groups that incor and fusion proteins. porate additional charge, polariZability, hydrogen bonding, [0143] More preferably, D-H is a protein selected from the electrostatic interaction, and ?uxionality to the nucleic acid group of proteins consisting of antibody fragments, single ligand bases or to the nucleic acid ligand as a Whole. Such chain antigen binding proteins, catalytic antibodies and modi?cations include, but are not limited to, 2'-position sugar fusion proteins. modi?cations, 5-position pyrimidine modi?cations, 8-posi [0144] Preferably, D-H is a small molecule bioactive agent tion purine modi?cations, modi?cations at exocyclic amines, selected from the group of agents consisting of central ner substitution of 4-thiouridine, substitution of 5-bromo or vous system-active agents, anti-infective, anti-allergic, 5-iodo-uracil; backbone modi?cations, methylations, immunomodulating, anti-obesity, anticoagulants, antidia unusual base-pairing combinations such as the isobases iso betic, anti-neoplastic, antibacterial, anti-fungal, analgesic, cytidine and isoguanidine and the like. Modi?cations can also contraceptive, anti-in?ammatory, steroidal, vasodilating, include 3' and 5' modi?cations such as capping and change of vasoconstricting, and cardiovascular agents With at least one stereochemistry. primary or secondary amino group. [0140] Preferably, D-H is a polypeptide selected from the [0145] Preferably, D-H is a small molecule bioactive agent group of polypeptides consisting ofACTH, adenosine deami selected from the group of agents containing at least one US 2013/0053301A1 Feb. 28, 2013

aliphatic primary amine group: (—)-Dra?aZine, (—)-lndocar tin acetate, Angiotensin II (human), Anisperimus, Antago baZostatin B, (+)-23,24-Dihydrodiscodermolide, (+)-Disco nist-G, Antide,Antide-1, Antide-2, Antide-3, Anti?ammin-l, dermolide, (+)iR-Pramipexole, (R)-(+)-Amlodipine, (R) Anti?ammin-lO, Anti?ammin-2, Anti?ammin-3, Anti?am (+)-TeraZosin, (R)-Ganciclovir cyclic phosphonate, (R) min-4, Anti?ammin-S, Anti?ammin-6, Anti?ammin-7, Anti Sul?nosine, (R)-Zacopride, (S)-(+)-Ketoprofen trometamol, ?ammin-8, Anti?ammin-9, Antileukinate, Antocin ll, Apad (S)-Nor?uoxetine, (S)-Oxiracetam, (S)-Sul?nosine, (S)-Za enoson, Apcitide technetium (99mTc), Aphidicolin copride hydrochloride, [11lln-DTPA-Prol,Tyr4]bombesin, glycinate, Apixaban, Aplonidine hydrochloride, ApoptoZole [90Y]-DOTAGA-substance P, [99Tc]Demobesin 3, [99Tc] 1,ApoptoZole 1, ApoptoZole 2, ApoptoZole 3, Apraclonidine Demobesin 4, [Ala11,D-Leu15]Orexin B, [Arg(Me)9]MS hydrochloride, Apricitabine, Arbekacin, Arbekacin sulfate, 10, [D11G,K26R,Y40YR]-Plectasin, [D11G,M13K,K26R, ArborcandinA, Arborcandin B, Arborcandin C, Arborcandin Y40YR]-Plectasin, [D9N,M13L,Q14R]-Plectasin, [D9S, D, Arborcandin E, Arborcandin F, Arenicin, Arenicin-1, Q14K,V3 6L] -Plectasin, [D-Tyrl ,Arg(Me)9]MS- 10, Arenicin-2, Argatroban monohydrate, Argimesna, Arginine [D-Tyr1,AZaGly7,Arg(Me)9] MS-10, [D-Tyr1]MS-10, butyrate, Argiopine, ArgiotoXin-636, Argipidine, Arotinolol [Gln30]-Pancreatic polypeptide(2-36), [Glut10,Nle17, hydrochloride, Arterolane maleate, Asp(B14)-relaxin, Nle30]-Pancreatic polypeptide(2-36), [Glu10]-Pancreatic Aspoxicillin, Astromicin sulfate, Atenolol, Atosiban, polypeptide(2-36), [L17K,K30R]GLP-2 (1-33), [Leu13] Atreleuton, Atrial natriuretic factor (99-126), AviZafone, Motilin, [N5R,M13KN17R]-Plectasin, [Nle17,Nle30]-Pan Avorelin, AZacitidine, AZacytidine, AZalanstat, AZaromycin creatic polypeptide(2-36), [psi[CH2NH]Tpg4]Vancomycin SC, AZelnidipine, AZetirelin, AZodicarbonamide, AZoXyba aglycon, [Ser12]-Humanin, [Trp19]MS-10, [Tyr24]-Huma cilin, AZtreonam, AZtreonam L-lysine, AZtreonam lysinate, nin, 111ln-Pentetreotide, 13-Deoxyadriamycin hydrochlo AZumamide A, Baclofen, Bactobolin, Balapiravir hydrochlo ride, 13-Deoxydoxorubicin hydrochloride, 17-Amino-17 ride, Balhimycin, Baogongteng A, Barusiban, Batracylin, demethoxygeldanamycin, 17-Aminogeldanamycin, 19-O Batroxostatin, Belactin A, Belactosin A, Belactosin C, Bena Methyl gel danamycin, 1 -Methyl -D-tryptophan, nomicin B, Benexate cyclodextrin, BenZocaine, Besi?oxacin 21-Aminoepothilone B, 2-Aminoaristeromycin, 2-Aminon hydrochloride, Binodenoson, Bivalirudin, BleomycinA2 sul eplanocin A, 3-Chloroprocainamide, 3-DeaZaadenosine, fate, Boceprevir, Body protection compound 15, Bogorol A, 3-MATIDA, 447-480 Human alpha-fetoprotein, 4-Aminopy Boholmycin, Brain natriuretic peptide, Brasilicardin A, ridine, 4-Aminosalicylic acid, 4-Chlorophenylthio-DADMe Bremelanotide, Brivanib alaninate, Brivaracetam, Brodi immucillin-A, 4'-epi-Adriamycin, 4'-epi-Doxorubicin, 5,4‘ moprim, Bromfenac sodium, Bromhexine hydrochloride, Diepiarbekacin, 5-Aminosalicylic acid, 5-AZa-2' Brostallicin hydrochloride, B-Type natriuretic peptide, deoxycytidine, 5-aZacitidine, 5'-Homoneplanocin A, BunaZosin hydrochloride, Buserelin acetate, Butabindide, 6'-Homoneplanocin A, 8(R)-Fluoroidarubicin hydrochlo Butamidine, Buteranol, Cabin 1, Caerulein diethylamine, ride, 99mTc-c(RGDfK*)2HYNlC, 9-Aminocamptothecin, Calcium folinate, Calcium-like peptide 1, Calcium-like pep A-42867 pseudoaglycone, Abacavir succinate, Abacavir sul tide 2, Cambrescidin 800, Cambrescidin 816, Cambrescidin fate, Abanoquil mesilate, Abarelix, Acadesine, Acetyldina 830, Cambrescidin 844, Camostat mesilate, Camostat mesy line, Acetylsalicylic acid lysine salt, Aciclovir, Acri?avine, late, Canfosfamide hydrochloride, Capadenoson, Capeserod Actinomycin D, Acycloguano sine, Acyclovir, Acyclovir elai hydrochloride, Capimorelin, Capravirine, CapraZamycin A, date, Acyclovir oleate, Acyline, AD Peptide, Adamantamine CapraZamycin B, CapraZamycin C, CapraZamycin E, hydrochloride, Adamplatin-IV, Adefovir, Adefovir dipivoxil, CapraZamycin F, Capromorelin, Capsavanil, Cara?ban male Ademetionine tosylate sulfate, Adenallene, Adenophostin A, ate, Carbachol, CarbamaZepine, Carbetocin, Carbovir, Car Adenophostin B, Adenosine, Aerothricin 1, Aerothricin 16, boXyamidotriaZole, Cariporide mesilate, Carisbamate, Car Aerothricin 41 ,Aerothricin 45, Aerothricin 5,Aerothricin 50, nosine Zinc complex (1:1), Carperitide, Carpipramine, Aerothricin 55, Afamelanotide, A?oqualone, Ageliferin diac Carumonam sodium, Caspofungin acetate, Cavtratin, etate, Ageliferin dihydrochloride, Aica-riboside, ALA hexyl CecropinA(1-1 1) D(12-37), Cecropin D, Cefaclor, Cefalexin ester, ALA Me ester, Aladapcin, Alamifovir, Alatro?oxacin monohydrate, Cefcamate pivoxil hydrochloride, Cefcanel mesilate, Albolabrin, Alendronate sodium, Alendronic acid daloxate hydrochloride, Cefcapene pivoxil hydrochloride, sodium salt, Alestramustine, AlfuZosin hydrochloride, Cefdaloxime, Cefdaloxime Pentexil Tosilate, Cefdinir, Aliskiren fumarate, Alloferon- 1, Alogliptin benZoate, alpha Cefditoren pivoxil, Cefepime, Cefetamet pivoxil, Cefetecol, Di?uoromethylornithine hydrochloride, alpha-Human atrial Ce?xime, Ce?uprenam, Cefmatilen hydrochloride hydrate, natriuretic polypeptide, alpha-Methylnorepinephrine, alpha Ce?nenoxime hydrochloride, Cefminox sodium, CefodiZ Methyltryptophan, Altemicidin, Alvespimycin hydrochlo ime, CefodiZime sodium, Cefoselis sulfate, Cefotaxime ride, Amantadine hydrochloride, Ambasilide, AmbaZone, sodium, Cefotetan disodium, Cefotiam cilexetil, Cefotiam Ambroxol nitrate, Amdoxovir, Ameltolide, Amelubant, cilexetil hydrochloride, Cefotiam hexetil, Cefotiam hexetil AmeZinium methylsulfate, Amfenac sodium, Amidox, Ami hydrochloride, Cefotiam hydrochloride, Cefoxitin, CefoZop fostine hydrate, Amikacin, Amiloride hydrochloride, Ami ran, CefoZopran hydrochloride, Cefpirome, Cefpodoxime nocandin, Aminocaproic acid, Aminoglutethimide, Ami proxetil, Cefprenam, CefproZil, CefproZil monohydrate, noguanidine, Aminolevulinic acid hexyl ester, Cefquinome, Cefsulodin sodium, Ceftaroline, CeftaZidime, Aminolevulinic acid hydrochloride, Aminolevulinic acid Cefteram pivoxil, Ceftibuten, CeftiZoxime alapivoxil, Cefto methyl ester, Aminoquinuride, Aminosidine, Amisulpride, biprole, Ceftobiprole medocaril, CeftraZonal bopentil, Amlexanox, Amlodipine, Amlodipine besylate, Amoxanox, CeftraZonal sodium, Ceftriaxone sodium, Cefuroxime, Amoxicillin, Amoxicillin trihydrate, Amoxycillin trihydrate, Cefuroxime axetil, Cefuroxime pivoxetil, Centanamycin, Amphotericin, Amphotericin B, Ampicillin sodium, Cephalexin monohydrate, Ceranapril, Ceronapril, Cerulein, Amprenavir, Ampydin, Amrinone, Amrubicin hydrochloride, Ceruletide diethylamine, Cete?oxacin, Cetrorelix acetate, Amselamine hydrobromide, Amthamine, Anakinra, Anamo Chlorofusin, Chloroorienticin A, Chloroorienticin B, Chlo relin hydrochloride, Anatibant mesilate, Anginex, Angiopep rotetain, Cibrostatin 1, Ciclopiroxolamine, Cidofovir, Cilas US 2013/0053301A1 Feb. 28, 2013

tatin sodium, Cilastatino, Cilengitide, Cimaterol, Cinitapride relin, Exatecan mesilate, Exenatide, Exenatide LAR, hygrogen tartrate, Cinnamycin, Cipamfylline, Circinamide, EXendin-4, EZatiostat hydrochloride, Famciclovir, Famoti Cisapride hydrate, Cispentacin, Citicoline, Citrullimycine A, dine, Famotidine bismuth citrate, Fampridine, Favipiravir, Cladribine, ClaVaninA(K), Clavanin E(3 -23), Clitocine, Clo Feglymycin, Feglymycine, Felbamate, Felbinac lysine salt, farabine, Clopidogrel sulfate, Colivelin, Conantokin-R, Con Fenleuton, Fidarestat, Fidexaban, Filaminast, FilariZone, tulakin G, Cortagine, Coumamidine gammal, Coumamidine Fingolimod hydrochloride, Fish amunine, Flucytosine, Flu gamma2, Cromoglycate lisetil hydrochloride, cyclic-Cido darabine phosphate, FluorobenZyltriamterene, Fluorocy fovir, Cycloplatam, Cycloserine, Cyclotheonamide A, tosine, Fluorominoxidil, Fluoroneplanocin A, Flupirtine Cyclothialidine, Cycloviolin A, Cycloviolin B, Cycloviolin maleate, Fluvirucin B2, Fluvoxamine maleate, Folinic acid, C, Cycloviolin D, Cygalovir, Cypemycin, Cysmethynil, Cys Folinic acid calcium salt, Fortimicin A, Fosamprenavir cal tamidin A, Cystamine, CystaZosin, Cystocin, Cytallene, Cyt cium, Fosamprenavir sodium, Fosaprepitant dimeglumine, arabine, Cytarabine ocfosfate, Cytaramycin, Cytochlor, Fosfomycin trometamol, Fosfomycin tromethamine, Foste Cytomodulin, Dabigatran, Dabigatran etexilate, DACH-Pt abine sodium hydrate, Frada?ban, Freselestat, Frog neuro (II)-bis-ascorbate, Dacopafant, Dactimicin, Dactinomycin, medin U, Frovatriptan, Fudosteine, Furamidine, Gl peptide, Dactylocycline A, Dactylocycline B, DADMe-Immucillin Gabadur, Gabapentin, Gabexate mesilate, Galarubicin hydro G, Dalargin, D-allo-Ileu3 PYY(3-36), Danegaptide hydro chloride, Gallinacin l, Gallinacin lalpha, Gallinacin 2, chloride, Daniquidone, Dapropterin dihydrochloride, Dap Galmic, Galnon, Galparan, Gammaphos, Ganciclovir, Gan sone, Darbufelone mesilate, Darifenacin hydrobromide, ciclovir elaidic acid, Ganciclovir monophosphate, Ganciclo Darinaparsin, Darunavir, Daunomycin, Daunorubicin, Dava Vir sodium, Ganirelix, Ganirelix acetate, Garomefrine hydro saicin, Davunetide, D-Cycloserine, Debrisoquin sulfate, chloride, Gemcitabine, Gemcitabine elaidate, Gemi?oxacin Debrisoquine sulfate, Decahydromoenomycin A, Decapla mesilate, Gibbosin, Gilatide, GiracodaZole, GirodaZole, nin, Decitabine, Declopramide, Deferoxamine, Degarelix Girolline, Glaspimod, Glucagon-like peptide I (7-37), Glu acetate, Deka?n l, Deka?n l0, Dela?oxacin, delta-Aminole cosamine sulfate, Gludopa, Glufanide, Glutathione monoet Vulinic acid hydrochloride, Deltibant, Deltorphin E, Dena hyl ester, Glutathione monoisopropyl ester, Glycine-proline gliptin hydrochloride, Denibulin hydrochloride, Denufosol Melphalan, Glycopin, Glycothiohexide alpha, Golotimod, tetrasodium, Deoxymethylspergualin, Deoxynegamycin, Goralatide, Goserelin, GroWth factor antagoni st-l l 6, GroWth Deoxyspergualin hydrochloride, Deoxyvariolin B, hormone releasing peptide 2, GroWth Inhibitory Peptide, DesacetylvinblastinehydraZide/folate conjugate, Desferriox GuanabenZ acetate, Guanadrel sulfate, Guanethidine mono amine, des-F-sitagliptin, Desglugastrin tromethamine, sulfate, Guanfacine hydrochloride, Gusperimus hydrochlo Deslorelin, Desmopressin acetate, Desulfated hirudin (54 ride, Gusperimus trihydrochloride, Habekacin, Habekacin 65), Desulfated hirugen, Detiviciclovir diacetate, Dexamfe sulfate, Halovir A, Halovir B, Halovir C, Halovir D, Halovir tamine sulfate, Dexamphetamine sulfate, Dexelvucitabine, E, Hayumicin B, Hayumicin Cl, Hayumicin C2, Hayumicin Dexibuprofen lysine, Dexketoprofen D,L-lysine, Dexketo D, Helvecardin A, Helvecardin B, Hepavir B, Heptaminol profen imidaZole salt, Dexketoprofen lysine, Dexketoprofen AMP amidate, Heptaplatin, HeXa-D-Arginine, Hexadecyl trometamol, Dexormaplatin, Dextroamphetamine sulfate, cidofovir, Hexadecyloxypropyl-cidofovir, Hexaminolevuli Dextronatrin, DeZinamide, DeZocitidine, Diadenosine tetra nate, Hexyl aminolevulinate, Hirudin desulfated, Hirulog-l, phosphate, Diaveridine, DichlorobenZoprim, Dicloguamine Histamine dihydrochloride, Histaprodifen, Histrelin, Histre maleate, Didemnin X, DidemninY, Dideoxycytidine, Difura lin acetate, Human adrenomedullin, Human adrenomedullin Zone, Dilevalol, Dilevalol hydrochloride, Dirucotide, Dis (22-52), Human angiotensin II, Human corticotropin-releas agregin, Discoderrnolide, Disermolide, Disitertide, Diso ing hormone, Human lactoferrin (l -l 1), Human proislet pep dium pamidronate, Disopyramide phosphate, di-Val-L-dC, tide, Human Secretin, Hydrostatin A, Hydroxyakalone, Docosyl cidofovir, Dolastatin l4, Dolastatin C, Donitriptan Hydroxycarbamide, Hydroxyurea, Hypeptin, Ibutamoren hydrochloride, Donitriptan mesilate, Doripenem, Dovitinib mesilate, Icatibant acetate, Iclaprim, Icofungipen, Idarubicin Lactate, DoxaZosin mesylate, Doxorubicin hydrochloride, hydrochloride, Ilatreotide, Ilonidap, Imetit, Imidafenacin, Doxycycline hyclate, Doxycycline hydrochloride ethanol ImidaZenil, Imiquimod, Immunosine, Impentamine, Incyc hydrate, D-Penicillamine, Dra?aZine, Droxidopa, DTPA-ad linide, Indanocine, Indantadol hydrochloride, Indium In 111 enosylcobalamin, d-trans-Tetraplatin, Dumorelin, Duramy pentetreotide, Indolicidin-ll, Indolicidin-4, Indolicidin-8, cin, Dyo?n-l, Dyo?n-2, Dyo?n-9, Ebrotidine, Eceno?oxacin Indomethacin trometamol, Indomethacin tromethamine, hydrochloride, Echistatin, Edotreotide yttrium, Efegatran Indoxam, Inogatran, Insulin chain B (9-23) peptide, Intri sulfate hydrate, E?ornithine hydrochloride, Eglumegad ?ban, Iobenguane[l3ll], IodorubidaZone (p), Iotriside, hydrate, Eglumetad hydrate, Eicosyl cidofovir, Elacytara Irsogladine maleate, Isatoribine, Iseganan hydrochloride, bine, Elaidic acid-Cytarabine, Elastatinal B, Elastatinal C, Isepamicin sulfate, IsobatZelline A, IsobatZelline B, Isobat Elpetrigine, Eltrombopag olamine, Elvucitabine, Emoxyl, Zelline C, IsobatZelline D, Isobutyramide, Isodoxorubicin, Emtricitabine, Enalkiren, Endothelin, Endothelin l, Enfu Isopropamide iodide Conotoxin Epofolate, Epostatin, Epsilon aminocaproic acid, Eptaplatin, P VIIA, Kamamicin Bl, Kassinatuerin-l, Katanosin A, Epti?batide, Eremomycin, Eribulin mesilate, Eribulin mesy Katanosin B, Katanosin B, Ketoprofen lysine, Ketorolac late, Erucamide, Esa?oxacin hydrochloride, EslicarbaZepine trometamol, Ketorolac tromethamine, KistamicinA, L-4-OX acetate, Etaquine, Ethanolamine, Ethanolamine oleate, alysine, Labetalol hydrochloride, Labradimil, Ladakamycin Ethiofos (former USAN), Ethyl aminobenZoate, Ethylthio (formerly), Lagatide, Lami?ban, Lamivudine, Lamotrigine, DADMe-immucillin-A, Ethynylcytidine, Etiracetam levo Lanicemine 2(S)-hydroxysuccinate, Lanicemine hydrochlo isomer, Etravirine, Etriciguat, Eurocin, Exalamide, Examo ride, Lanomycin, Lanreotide acetate, Lanthiopeptin, Lara US 2013/0053301Al Feb. 28,2013

Zotide acetate, LaZabemide hydrochloride, L-DOPA 3-O cin A, Octacosamicin B, Octreother, Octreotide acetate, Oct glucoside, L-DOPA 4-O-glucoside, L-Dopa methyl ester reotide LAR, Oglufanide disodium, Olamu?oxacin, Olamu hydrochloride, L-Dopamide, Lecirelin, Leconotide, Lenali ?oxacin mesilate, Olcegepant, Olradipine hydrochloride, domide, Lenampicillin hydrochloride, Leucettamine A, Leu Omaciclovir, Ombrabulin, Ombrabulin hydrochloride, covorin calcium, Leuprolide acetate, Leuprorelin acetate, omega-Conotoxin CVlD, omega-Conotoxin MVllA, Omiga Leurubicin, Leustroducsin A, Leustroducsin B, Leustroduc nan pentahydrochloride, Onnamide A, Opiorphin, Orbo?ban sin C, Leustroducsin H, Levetiracetam, Levodopa, Levodopa acetate, Orienticin A, Orienticin B, Orienticin C, Orienticin 3-O-glucoside, Levodopa 4-O-glucoside, Levodopa methyl D, Oritavancin, Oseltamivir carboxylate, Oseltamivir phos ester hydrochloride, Levofolinate calcium, Levoleucovorin phate, Otamixaban, Otenabant hydrochloride, Ovothiol A, calcium, Levonadi?oxacin arginine salt, L-Histidinol, L-Ho Oxaliplatin, OXalysine-L, OXaZofurin, OXcarbaZepine, Oxi mothiocitrulline, Liblomycin, Linagliptin, Lingual antimi glutatione sodium, Oxiracetam, Oxolide, Oxynor, Oxyphe crobial peptide, Linifanib, Lintopride, Liraglutide, Lirex narsine, Oystrisin, OZareliX, Pachastrissamine, Pachymedusa apride, Lirimilast, Lisdexamfetamine mesilate, Lisinopril, dacnicolor Tryptophyllin-l, Paecilaminol, Pafuramidine L-Lysine-d-amphetamine dimesylate, Lobaplatin, Lobo maleate, Palau’amine, Paldimycin B, Pamidronate sodium, phorin A, Lobradimil, Lobucavir, Lobucavir, Lodenosine, p-Aminoclonidine hydrochloride, Pancopride, Papuamide A, Loloatin B, Lomeguatrib, Lometrexol, Lonafamib, Loracar Papuamide B, Papuamide C, Papuamide D, Parasin 1, Par bef hydrate, Loviride, Loxoribine, L-Simexonyl homocys athyroid hormone (human recombinant), Paromomycin, teine, L-Thiocitrulline, Lymphostin, Lysine acetylsalicylate, Pasireotide, Paulomycin, Paulomycin A, Paulomycin A2, Lysobactin, Mabuterol hydrochloride, Magainin ll, Makalu Paulomycin B, Paulomycin C, Paulomycin D, Paulomycin E, Vamine A, Makaluvamine A, Makaluvamine B, Makalu Paulomycin F, PaZu?oXacin, PaZu?oxacin mesilate, PEG Vamine C, Managlinat dialanetil, Matristatin A2, Maxadilan, Vancomycin, Pelagiomicin C, Peldesine, Pelitrexol, Pemetr Melagatran, Melanotan, Melanotan l, Melanotan ll, eXed disodium, Penciclovir, Penicillamine, Penicillin G Melevodopa hydrochloride, Memantine hydrochloride, procaine, Pentafuside, Pentamidine gluconate, Pentamidine Memno-peptide A, Meprobamate, Meriolin-3, Mersacidin, isethionate, Pentamidine lactate, Peplomycin, Peptide Leu Mesalamine, MesalaZine, Metaraminol, MetaZosin, Meter cine Arginine, Peramivir, PerphenaZine 4-aminobutyrate, elin, Metformin hydrochloride, Methotrexate, Methyl ami Pexiganan acetate, Phakellistatin 5, Phe-Arg-beta-naphthyla noleVulinate, Methyl bestatin, Methyldopa, Methylthio mide, Phenterrnine, Phortress, Phospholine, Pibutidine DADMe-immucillin-A, Metirosine, Metoclopramide hydrochloride, Piceasin, Picumeterol fumarate, Pidorubicin, hydrochloride, Metyrosine, Mexiletine hydrochloride, Pimagedine, Pimeloylanilide o-aminoanilide, Piproxen, Micafungin sodium, Micronomicin sulfate, Midalcipran Piracetam, Pirarubicin, Piscidin l, Piscidin 2, Piscidin 3, hydrochloride, Midaxifylline, Mideplanin, Midoriamin, Pivampicillin, Pixantrone maleate, Plura?avin A, Plura?avin Milacamide tartrate, Milacemide-[2H], Milnacipran hydro B, PlusbacinAl, Plusbacin A2, Plusbacin A3, Plusbacin A4, chloride, Minamestane, Minocycline hydrochloride, Minoxi Plusbacin Bl, Plusbacin B2, Plusbacin B3, Plusbacin B4, dil, Mirabegron, Miriplatin hydrate, Mitomycin, Mitomycin PMEO-5-Me-DAPy, Pneumocandin A0, Pneumocandin B0, C, MiVaZerol, Mivobulin isethionate, MiZoribine, Mocetin Pneumocandin B0 2-phosphate, Pneumocandin D0, Pola ostat dihydrobromide, Moda?nil, Moda?nil sulfone, Moeno preZinc, Polydiscamide A, Polymer bound human leukocyte mycin A chloride bismuth salt, Mofegiline, Mofegiline elastase inhibitor, Poststatin, PPl 1 7-24, Pradefovir mesylate, hydrochloride, Monamidocin, Monodansyl cadaverine, Pradimicin C, Pradimicin E, Pradimicin FA-2, Pralatrexate, Monoethanolamine oleate, Montirelin tetrahydrate, Pralmorelin, Pramipexole hydrochloride, Pramlintide Mosapride citrate, Moxilubant, Moxilubant maleate, acetate, Pranedipine tartrate, PraZosin hydrochloride, Pre MoZenaVir mesilate, m-Phenylene ethynylene, mu-Cono folic A, Pregabalin, Preladenant, PreZatide copper acetate, toxin lllA, Multiple sclerosis Vaccine, muO-Conotoxin Primaquine phosphate, Prinomide tromethamine, Probestin, MrVlB, Muraminomicin A, Muraminomicin B, Muramino Procainamide hydrochloride, Procaine hydrochloride, micin C, Muraminomicin D, Muraminomicin El, Murami Procaine Penicillin, Pro-diaZepam, Propeptin, Propeptin T, nomicin E2, Muraminomicin F, Muraminomicin G, Murami Prostatin, Protegrin lB-367, Prucalopride, Prucalopride nomicin H, Muraminomicin l, Muraminomicin Zl, hydrochloride, Prucalopride succinate, Pseudomycin A', Muraminomicin Z2, Muraminomicin Z3, Muraminomicin Pseudomycin B', Pyloricidin B, Pymadin, PyraZinamide, Z4, Muramyl dipeptide C, Mureidomycin A, Mureidomycin PyraZinoylguanidine, PyridaZomycin, Pyriferone, B, Mureidomycin C, Mureidomycin D, Muroctasin, Myces Pyrimethamine, Pyrodach-2, Quinelorane hydrochloride, tericin E, Myriocin, Nafamostat mesilate, Nafamostat mesy R-(+)-Aminoindane, R9K-Retrocyclin, RagaglitaZar L-argi late, Nafarelin acetate, Naglivan, Nagrestipen, Namitecan, nine salt, Ral?namide, Ramoplanin A'l, Ramoplanin A'2, Naproxen piperaZine (2:1), Napsagatran, Neboglamine, Ramoplanin A'3, Ramorelix, Rat adrenomedullin, Ravido Nebostinel, Nebracetam fumarate, Nelarabine, NeldaZosin, mycin N-Oxide, RaZaXaban hydrochloride, Reblastatin, NelZarabine, Nemi?tide ditri?utate, Nemonoxacin, Neo Receptor mediated permeabiliZer, Recombinant human par acridine, Neomycin B-arginine conjugate, Neomycin athyroid hormone (1-84), Recombinant Jerdostatin, Regad B-hexaarginine conjugate, Neomycin-acridine, Nepafenac, enoson, RelaXin-3/lNSL5 chimeric peptide, Relcovaptan, Nepicastat hydrochloride, Neramexane hydrochloride, Remacemide hydrochloride, Remofovir mesylate, Resiqui Neridronate, Neridronic acid, Nesiritide, Netamiftide tri?uo mod, Restricticin, Retaspimycin hydrochloride, Retigabine roacetate, Netilmicin sulfate, Neuromedin U-25, Neuropep hydrochloride, Rhodopeptin Cl, Rhodopeptin C2, tide S, Neutrophil-activating factor, Niacinamide, Nicotina Rhodopeptin C3, Rhodopeptin C4, Rhodostreptomycin A, mide, Niduline, Nisin, Nitrovin, Nocathiacin l, Nocathiacin Rhodo streptomycin B, Ribamidine hydrochloride, Ribavirin, ll, Nocathiacin Ill, Nocathiacin IV, NO-Gabapentin, Nolatr Ribavirin eicosenate cis, Ribavirin eicosenate trans, Ribavi eXed dihydrochloride, NO-Mesalamine, Noraristeromycin, rin elaidate, Ribavirin oleate, RilmaZafone hydrochloride Nuvanil, O6-BenZylguanine, Ocimumoside A, Octacosami dihydrate, RiluZole, Rimacalib hydrochloride, Rimeporide US 2013/0053301A1 Feb. 28, 2013 14 hydrochloride, Riociguat, Ritipenem acoxil, r-Jerdostatin, Valomaciclovir stearate, Valonomycin A, Valonomycin B, RobalZotan hydrochloride, RobalZotan tartrate hydrate, Valopicitabine, Valpromide, Valrocemide, Vamicamide, Van Rociclovir, Romurtide, Rotigaptide, Roxi?ban acetate, comycin hydrochloride, Vancoresmycin, Vapitadine hydro Ruboxyl, Ru?namide, Rumycin 1, Rumycin 2, S(—)-Norket chloride, Varespladib, Varespladib methyl, Varespladib amine, Sabarubicin hydrochloride, Sabiporide mesilate, Sa? mofetil, Vasonatrin peptide, Velnacrine maleate, Venorphin, namide mesilate, Sa?ngol, Sagamacin, Sampatrilat, Sampir Vesiculin, V1gabatrin, VilaZodone hydrochloride, Vindesine, tine, Saprisartan, Sapropterin dihydrochloride, Saquinavir, Viramidine hydrochloride, Viranamycin-B, Virgisin- 1, Vlrgi Saquinavir mesilate, SardomoZide, SardomoZide hydrochlo sin-2, Vitamin B3, W Peptide, Xemilo?ban, Xenoxin-l, ride, Satoribine, Satraplatin, Saussureamine C, Saxagliptin, XenoXin-2, XenoXin-3, Xylocydine, Yttrium-90 edotreotide, SecobatZelline A, SecobatZelline B, Seglitide, Selanc, Zalcitabine, Zanamivir, Ziconotide, Zileuton, Zofenoprilat Selank, Seletracetam, Semapimod hydrochloride, Sempar arginine, Zoniporide hydrochloride, Zorubicin hydrochlo atide, Senicapoc, Sepimostat mesilate, Seproxetine, ride, Seraspenide, Sermorelin, Sevelamer carbonate, Sevelamer [0146] Preferably, D-H is a small molecule bioactive agent hydrochloride, Shepherdin, Shiga Vaccine, Siamycin I, Sia selected from the group of agents containing at least one mycin ll, Sibra?ban, Sifuvirtide, Silodosin, Silver sulfadiaZ aliphatic secondary amine group: (—)-2-(2-Bromohexade ine, Sipatrigine, Sita?oxacin hydrate, Sitagliptin phosphate canoyl)paclitaxel, (—)-3-O-Acetylspectaline hydrochloride, monohydrate, S-Nitrosoglutathione, So?gatran, Sonedeno (—)-3-O-tert-Boc-spectaline hydrochloride, (—)-Bemoradan, son, Sotirimod, Spar?oxacin, Sperabillin A, Sperabillin B, (—)-Bupivacaine hydrochloride, (—)-Calicheamicinone, (—) Sperabillin C, Sperabillin D, Sphingofungin F, Spi?oxacin Cicloprolol, (—)-Conophylline, (—)-Dra?aZine, (—)-Efaroxan, hydrate, Spinorphin, Spisulosine, Spisulosine 285, (—)-Halofenate, (—)-lndocarbaZostatin B, (—)-Nebivolol, (—) Squalamine lactate, Stearyl-norleucine-VIP, Streptomycin, Norchloro-[18F]?uoro-homoepibatidine, (—)-Salbutamol Stressin1-A, Styloguanidine, Substance P(8-11), Sulcepha hydrochloride, (—)-Salmeterol, (—)-Ternatin, (+)-(S)-Hy losporin, Sul?nosine, Sul?rcin, Sulfostin, SulphaZocine, Sul droxychloroquine, (+)-AZacalanolide A, (+)-Efaroxan, (+) phostin, Sultamicillin tosylate, Sun?ower trypsin inhibitor-1, lndocarbaZostatin, (+)-lsamoltan, (+)-Pemedolac, (+)-R Surfen, Synadenol, Synguanol, Synthetic human secretin, Pramipexole, (+)-Scyphostatin, (+)-SNAP-7180, (+)-Sotalol, Synthetic neutrophil inhibitor peptide, Synthetic porcine (+)-threo-Methylphenidate hydrochloride, (R)-(+)-Amlo secretin, Tabilautide, Tabimorelin, Tacedinaline, Tacrine dipine, (R)-Albuterol hydrochloride, (R)-Bicalutamide, (R) hydrochloride, Tafenoquine succinate, Tage?ar, Talabostat, Clevidipine, (R)-Ganciclovir cyclic phosphonate, (R)-Nigul Talaglumetad hydrochloride, Talampanel, Talipexole dihy dipine hydrochloride, (R)-NSP-307, (R)-Teludipine, (R) drochloride, Tallimustine hydrochloride, Talopterin, Talotr Thionisoxetine, (R)-Tulobuterol, (R)-Zacopride, (R,R) exin, Taltirelin, Tanespimycin, Tanogitran, Targinine, Targi Formoterol tartrate, (S)-Acetorphan, (S)-Clevidipine, (S)i nine hydrochloride, Taribavirin hydrochloride, Technetium N-Desmethyltrimebutine, (S)-Noremopamil, (S) (99mTc) apcitide, Technetium (99mTc) depreotide, Techne RiVoglitaZone, (S)-Sotalol, (S)-Zacopride hydrochloride, tium Tc 99m depreotide, Teicoplanin-A2- 1, Teicoplanin-A2 [1 1 lln-DTPA-Prol,Tyr4]bombesin, [90Y]-DOTAGA-sub 2, Teicoplanin-A2-3, Teicoplanin-A2-3, Teicoplanin-A2-5, stance P, [99Tc]Demobesin 3, [99Tc]Demobesin 4, [Ala11, Telavancin hydrochloride, Telinavir, TemoZolomide, D-Leu15]Orexin B, [Arg(Me)9]MS-10, [D11G,K26R, Temurtide, Tenidap, Tenidap sodium, Tenofovir, Tenofovir Y40YR] -Plectasin, [D11G,M13K,K26R,Y40YR]-Plectasin, DF, Tenofovir disoproxil fumarate, TeraZosin hydrochloride, [D9N,M13L,Q14R]-Plectasin, [D9S,Q14K,V36L]-Plecta Teriparatide, Terlipressin, Tertomotide, Tetracosyl cidofovir, sin, [D-Tyr1,Arg(Me)9]MS-10, [D-Tyr1,AZaGly7,Arg(Me) Tetracycline hydrochloride, Tetra?bricin, Tetrahydrobiop 9]MS-10, [D-Tyr1]MS-10, [Gln30]-Pancreatic polypeptide terin, Texenomycin A, Textilinin-l, TeZacitabine, TGP, Tha (2-36), [Glut0,Nle17,Nle30]-Pancreatic polypeptide (2-36), natin, Theprubicin, ThermoZymocidin, Thioacet, Thiothio, [Glu10]-Pancreatic polypeptide (2-36), [L17K,K30R]GLP-2 ThrlO-Contulakin G, ThraZarine, Thymalfasin, Thymic (1-33), [Leu13]-Motilin, [N5R,M13Y,N17R]-Plectasin, humoral factor gamma-2, Thymoctonan, Thymopentin, Thy [Nle17,Nle30]-Pancreatic polypeptide (2-36), [N-Melle4] mosin alpha 1, Tiamdipine, Tifuvirtide, Tigecycline, Tigilcy cyclosporin, [psi [CH2NH]Tpg4]Vancomycin aglycon, cline, Tilarginine hydrochloride, Timirdine diethane [Ser12]-Humanin, [Trp19]MS-10, [Tyr24]-Humanin, 111ln sulfonate, Timodepressin, Timogen, Tipifarnib, Tiplimotide, Pentetreotide, 12'-Methylthiovinblastine dihydrochloride, TNF-alpha protease enZyme inhibitor, Tobramycin, Tocam 14beta-Hydroxydocetaxel, 14beta-HydroXydocetaxel-1 ,14 ide hydrochloride, Tokaramide A, Tomopenem, Topostatin, acetonide, 14beta-Hydroxytaxotere, 15bbeta-Meth Torcitabine, Tosu?oxacin, Tosu?oxacin tosilate, Tranexamic oxyardeemin, 16-AZa-epothilone B, 16-MethyloXaZolomy acid, Trantinterol hydrochloride, Tranylcypromine sulfate, cin, 1 7-Amino- 17-demethoxygeldanamycin, Trelanserin, Tresperimus tri?utate, Tribavirin, Trichomycin 1 7-Amino geldanamycin, 1 8 -Hydroxycoronaridine, A, Triciribine, Triciribine phosphate, Triciribine-5'-mono 1 8-Methoxycoronaridine, 1 9-0 -Methylgeldanamycin, phosphate, Trientine hydrochloride, TrimaZosin hydrochlo l-Deoxynojirimycin, 2,7-Dibromocryptolepine, 2-Bromo-7 ride, Trimetrexate glucuronate, Trimexautide, Trimidox, Tri nitrocryptolepine, 2'-Palmitoylpaclitaxel, 3-Bromometh platin tetranitrate, Triproamylin acetate, Trova?oxacin, cathinone, 3-Chloroprocainamide, 3-Fluorothalidomide, Trova?oxacin hydrate, Trova?oxacin hydrochloride mesy 3-lndole, 4,5-Dianilinophthalimide, 4,6-diene-Cer, 447-480 late, Trova?oxacin mesilate, Trova?oxacin mesylate, Trox Human alpha-fetoprotein, 4-Chlorophenylthio-DADMe-im acitabine, TrybiZine hydrochloride, Tubastrine ((+)-enanti mucillin-A, 4'-Ethynylstavudine, 4-Hydroxyatomoxetine, omer), Tuftsin, Tumor necrosis factor-alpha protease 5,4'-Diepiarbekacin, S-Fluorodeoxyuridine, 5-lodofrederica inhibitor, Tyroservaltide, Tyroservatide, Tyrphostin 47, Tyr mycin A, 5-Methylurapidil, 5-Phenylthioacyclouridine, 6,7 phostinAG-213, Ubenimex, Ubenimex methyl ester, Ubesta Dichloroisatin 3-oxime, 6alpha-7-Epipaclitaxel, 6-Mercap tin, Ubidine, Uroguanylin, Valaciclovir, Valacyclovir, Val topurine, 7-Bromo-2-chlorocryptolepine, 7-Deoxytaxol, boroPro, Valganciclovir hydrochloride, Valnemulin, 7-Oxostaurosporine, 9,9-Dihydrotaxol, 99mTc-c(RGDfK*) US 2013/0053301A1 Feb. 28, 2013

2HYNIC, 9-Nitropaullone, A-42867 pseudoaglycone, Aba hydrochloride, Apremilast, Aprepitant, Aprikalim, Aprosu cavir succinate, Abacavir sulfate, Abafungin, Abarelix, Abe late sodium, Aptiganel, Aranidipine, Aranorosin, Aranorosi carnil, Abitesartan, Acamprosate calcium, Acarbose, nol A, Aranorosinol B, Aranose, AranoZa, Araprofen, Arba Acebutolol hydrochloride, Aceclofenac, Acemannan, Ace clofen placarbil sodium, Arbekacin, Arbekacin sulfate, neuramic acid sodium salt, Acetamidoxolutamide, Acetami ArborcandinA, Arborcandin B, Arborcandin C, Arborcandin nophen, AcetaZolamide, Acetohexamide, Acetorphan, Ace D, Arborcandin E, Arborcandin F, Arbutamine hydrochlo tylcysteine, Acetyldinaline, Aciclovir, AcitaZanolast, ride, ArchaZolid A, ArchaZolid B, ArchaZolide A, Arcyriacya Acomustine, Acotiamide hydrochloride hydrate, AcreoZast, nin A, Ardeemin, Arenicin, Arenicin-1, Arenicin-2, Arfor Actarit, Actinomycin D, Actinoplanone B, Aculeacin moterol tartrate, Argatroban monohydrate, Argimesna, Agamma, Acycloguanosine, Acyclovir, Acyclovir elaidate, Arginine butyrate, Argiopine, Argiotoxin-636, Argipidine, Acyclovir oleate, Acyline, AD Peptide, Adamantyl globotri Argyrin A, Argyrin B, Arhalofenate, AripipraZole, Ariso statin aosylceramide, Adaphostin, Adaprolol maleate, Adaprolol A, Arofylline, Arotinolol hydrochloride, Arterolane maleate, oxalate, Adatanserin hydrochloride, Adecypenol, Adelm Artilide fumarate, Ascosalipyrrolidinone A, Ascosalipyrroli idrol, Adenopeptin, Aderbasib, Adjudin, Adosopine, AdoZe dinone B, Asobamast, Asp(B14)-relaxin, Asperlicin B, lesin, Adra?nil, Adrogolide hydrochloride, Aerothricin 1, Asperlicin C, Asperlicin D, Asperlicin E, Aspoxicillin, Aerothricin 16, Aerothricin 41 , Aerothricin 45, Aerothricin 5, AstemiZole, Ataciguat, Atalaphillidine, Atalaphillinine, Aerothricin 50, Aerothricin 55, Aeruginosamide, Afamelan Ataquimast, Ataquimast hydrochloride, AtaZanavir sulfate, otide, Afeletecan hydrochloride, AfobaZol, AfobaZole, Age Atenolol, Atevirdine mesylate, AtipameZole, AtiZoram, Ato lasphin 517, Agelasphin 564, Ageliferin diacetate, Ageliferin moxetine hydrochloride, Atorvastatin, Atorvastatin calcium, dihydrochloride, Aglaiastatin C, Agomelatine, Alacepril, Atosiban, Atrial natriuretic factor (99-126), Aureobasidin A, Aladapcin, Aladotril, Alatriopril, Alatro?oxacin mesilate, Auristatin E, Auristatin PE, Avasimibe, Avicin D, Avicin G, AlbendaZole, Albifylline, Albolabrin, Albuterol nitrate, Avitriptan, AviZafone, Avorelin, Avo sentan, Avrainvillamide, Albuterol sulfate, Alchemix, AlfuZosin hydrochloride, Alini Axitinib, Axitirome, AZ-36041, AZaromycin SC, AZasetron, dine, Alisamycin, Aliskiren fumarate, AliZapride, Alkasar AZasetron hydrochloride, AZathioprine, AZatoXin, AZelnid 1 8, Allantoxamic acid, Alloferon- 1, Allopurinol, Alminopro ipine, AZepinostatin, AZetirelin, AZidothymidine, AZidothy fen, Almitrine bismesylate, Almitrine dimesylate, midine phosphonate, AZilsartan, AZilsartan medoxomil, Almorexant, Almotriptan, Alniditan, Aloracetam, Alosetron AZtreonam, AZtreonam L-lysine, AZtreonam lysinate, hydrochloride, Alosetron maleate, Aloxistatin, alpha-C-Ga AZumamide A, AZumamide E, Bactobolin, Bafetinib, Bala lactosylceramide, alpha-Galactosylceramide, alpha-Galacto glitazone, Balamapimod, Balanol, Balaperidone, Balhimy sylceramide-BODIPY, alpha-Human atrial natriuretic cin, Balicatib, Balo?oxacin, Balo?oxacin dihydrate, Bal polypeptide, alpha-Lactosylceramide, alpha-Methylepi salaZide disodium, Bamaquimast, Bambuterol, Bamirastine nephrine, alpha-Methyltryptophan, alpha-Nornicotine, hydrate, Banoxantrone, Baogongteng A, Barixibat, Barnid alpha-Sialosylcholesterol sodium salt, Alprafenone hydro ipine hydrochloride, Barusiban, Basifungin, Batimastat, chloride, Alprenolol hydrochloride, Alprenoxime hydrochlo BatopraZine, Batroxostatin, BatZelline A, BatZelline B, Bat ride, Alsterpaullone, Altemicidin, Altromycin A, Altromycin Zelline C, Beauveriolide I, Beauveriolide Ill, Becampanel, C, Alvespimycin hydrochloride, Alvimopan hydrate, Amac Becatecarin, Bederocin, Bedoradrine sulfate, Befol, etam hydrochloride, Amamistatin A, Amamistatin B, Amba Befunolol hydrochloride, Begacestat, BelactinA, Belactin B, Zone, Ambroxol nitrate, Ameltolide, Amesergide, Ame Belactosin A, Belactosin C, Belaperidone, Belinostat, Belo thocaine hydrochloride, Amfebutamone hydrochloride, tecan hydrochloride, Bemoradan, Benadrostin, Benafentrine Amibegron hydrochloride, Amifostine hydrate, Amiglumide, dimaleate, Benanomicin A, Benanomicin B, BenatopraZole, Amikacin, Amiloride hydrochloride, Amineptine, Ami BenaZepril hydrochloride, Bendro?uaZide, Bendro?umethi nocandin, Aminochinol, Aminoglutethimide, Aminoguani aZide, Benexate cyclodextrin, Benidipine hydrochloride, dine, Aminoquinol, Aminoquinuride, Amisulpride, Amitivir, Benperidol, BenZimidavir, BenZylpenicillin sodium, Ber Amlodipine, Amlodipine besylate, Amobarbital, lafenone hydrochloride, Besonprodil, beta-CCM, beta-Me AmocarZine, Amodiaquine, Amosulalol hydrochloride, thyl-6-chloromelatonin, Betamipron, beta-Sialosylcholes Amoxapine, Amoxicillin, Amoxicillin trihydrate, Amoxycil terol sodium salt, beta-Tethymustine, Betaxolol lin trihydrate, Ampicillin sodium, Ampiroxicam, hydrochloride, Bevantol hydrochloride, Bevantolol hydro Amprenavir, Amrinone, Amsacrine, Amsilarotene, Amsu chloride, BeZa?brate, Bicalutamide, Biemnidin, Bifemelane losin hydrochloride, Amtolmetin guacil, Amylobarbitone, hydrochloride, Bifeprunox mesilate, Bimatoprost, Binode Anabasine hydrochloride, Anagrelide hydrochloride, Anak noson, Binospirone mesylate, Biotinylated idraparinux, inra, Anamorelin hydrochloride, Anandamide, Anatibant Bioxalomycin alpha 1, Bipranol hydrochloride, Bis(7)-cog mesilate, Andolast, Androxolutamide, Anginex, Angiopeptin nitin, Bis(7)-tacrine, Bisantrene hydrochloride, Bisna?de acetate, Angiotensin 11 (human), Anidulafungin, Anisperi mesilate, Bisna?de mesylate, Bisoprolol fumarate, Bitolterol mus, Ansamycin, Antagonist-G, Antide, Antide-1, Antide-2, mesylate, Bivalirudin, BiZelesin, Bleomycin A2 sulfate, Boc Antide-3, Anti?ammin-l, Anti?ammin-lO, Anti?ammin-2, Belactosin A, Boceprevir, Boc-Lysinated betulonic acid, Anti?ammin-3, Anti?ammin-4, Anti?ammin-S, Anti?am Body protection compound 15, Bogorol A, Bohemine, min-6, Anti?ammin-7, Anti?ammin-8, Anti?ammin-9, Anti Boholmycin, Bopindolol, BorteZomib, Bosentan, Bosutinib, leukinate, Antimycin All, Antimycin A12, Antimycin A13, BradyZide, Brain natriuretic peptide, Brasilicardin A, Antimycin A14, AntimycinA15, AntimycinA16, Antocin ll, Brecanavir, Bremelanotide, Brimonidine tartrate, BrinaZ Apadenoson, Apadoline, Apalcillin sodium, Apaxifylline, arone, BrinZolamide, Brivanib, Brivanib alaninate, Brivu Apcitide technetium (99mTc), Apicularen A, Apicularen B, dine, Bromantan, Bromantane, BromaZepam, Bromocriptine Apilimod, Apilimod mesylate, Apiodionene, Aplaviroc mesilate, Bromotopsentin, Bromovinyldeoxyuridine, Bros hydrochloride, Aplidine, Aplindore fumarate, Aplonidine tallicin hydrochloride, Brovavir, B-Type natriuretic peptide, hydrochloride, ApoptoZole 1, ApoptoZole 2, Apraclonidine Bucillamine, Bucladesine sodium, Bu?omedil pyridoxal US 2013/0053301A1 Feb. 28, 2013

phosphate, Bulaquine, Bumetanide, Bupivacaine hydrochlo dine bismuth L-tartrate, Cimetidine nitrate, Cinacalcet hydro ride, Bupropion hydrochloride, Buserelin acetate, Butabin chloride, Cinaldipine, Cinalukast, Cinitapride hygrogen tar dide, Buteranol, Butobarbitone, Butoctamide hemisuccinate, trate, Cinnabaramide A, Cinnamycin, Cinnoxicam, Buto?lolol, Butyl ?ufenamate, ButyZamide, CabaZitaXel, Cipamfylline, Cipemastat, Cipralisant, Cipro?oxacin hydro Cabergoline, Cabin 1, CadralaZine, Cadro?oxacin hydro chloride, Cipro?oxacin silver salt, Ciprokiren, Ciproxifan, chloride, Caerulein diethylamine, Calcium folinate, Cal Circinamide, Cisapride hydrate, Citropeptin, Citrullimycine cium-like peptide 1, Calcium-like peptide 2, Caldaret A, Clamikalant, Clausenamine A, Clavanin A(K), Clavanin hydrate, Caldiamide sodium, Calicheamicin gammal agly E(3-23), ClaZosentan, ClaZosentan sodium, Clevidipine cone, Calindol Dihydrochloride, Calothrixin A, Cambresci butyrate, Clevudine, Clindamycin hydrochloride, Clitocine, din 800, Cambrescidin 816, Cambrescidin 830, Cambresci Clobenpropit, ClonaZepam, Clonidine, Clonidine hydrochlo din 844, Camostat mesilate, Camostat mesylate, Camprofen, ride (hydrochloride), Clopamide, Clopenphendioxan, Clopi Canadensol, Candesartan, Candesartan cilexetil, Cande dogrel sulfate, Cloranolol hydrochloride, CloraZepate dipo sartan hexetil, Candoxatril, Candoxatrilat, Canertinib dihy tassium, Clospipramine hydrochloride, Cloturin, CloZapine, drochloride, Canfosfamide hydrochloride, Cangrelor tetraso CoenZyme PQQ, ColabomycinA, Coleneuramide, Colivelin, dium, Capecitabine, Capimorelin, CapraZamycin A, Coluracetam, Complestatin, Conagenin, Conantokin-R, CapraZamycin B, CapraZamycin C, CapraZamycin E, Coniosetin, Conivaptan hydrochloride, Conophylline, Con CapraZamycin F, Capridine beta, Caprolactin A, Caprolactin tulakin G, Cortagine, Coumamidine gammal, Coumamidine B, Capromorelin, Capsavanil, CapsaZepine, Carabersat, gamma2, Covidarabine, Creatine phosphate, Crilvastatin, Caracasanamide, Caracasandiamide, Cara?ban maleate, Car Crisnatol mesilate, Cronidipine, Cryptophycin 52, Cyclame baZomadurin A, CarbaZomadurin B, CarbaZomycin G, Car nol, Cyclo[His-Pro], Cyclocreatine, Cyclolinopeptide A, baZomycin H, Carbetocin, Carbidopa, Carbovir, Car?lZomib, Cyclolinopeptide B, Cyclomarin A, CyclopenthiaZide, CaripraZine hydrochloride, CarmethiZole, Carmofur, Car Cyclophosphamide, Cycloserine, Cyclosporin, Cyclosporin moterol hydrochloride, Carmoxirole hydrochloride, Carmus A, Cyclosporin J, Cyclosporine, Cyclosporine A, Cyclothe tine, Carnosine Zinc complex (1:1), Carperitide, Carprofen, onamide A, Cyclothialidine, Cycloviolin A, Cycloviolin B, Carquinostatin A, Carsatrin, Carteolol hydrochloride, Cart Cycloviolin C, Cycloviolin D, Cygalovir, Cymserine, Cype eramine A, Carumonam sodium, Carvedilol, Carvotroline mycin, Cystamidin A, Cystemustine, Cystocin, Cytoblastin, hydrochloride, CarZelesin, Caspofungin acetate, Catramilast, Cytochalasin B, Cytomodulin, Cytotrienin A, Cytotrienin l, Cavtratin, Cebaracetam, Cecropin A(1-11) D(12-37), Cytotrienin ll, Cytotrienin Ill, Cytotrienin IV, CytoxaZone, Cecropin D, Cediranib, Cefaclor, Cefalexin monohydrate, Dabelotine mesilate, Dabigatran, Dabigatran etexilate, CefaZolin sodium, CefbuperaZone sodium, Cefcamate piv DabuZalgron hydrochloride, Dacinostat, Dactimicin, Dacti oxil hydrochloride, Cefcanel, Cefcanel daloxate hydrochlo nomycin, Dactylocycline A, DADMe-lmmucillin-G, ride, Cefcapene pivoxil hydrochloride, Cefdaloxime, Cefdal DADMe-lmmucillin-H, Daglutril, Dalargin, Dalbavancin, oxime Pentexil Tosilate, Cefdinir, Cefditoren pivoxil, Dalcetrapib, Dalcotidine, Dalfopristin mesilate, D-allo-lleu3 Cefepime, Cefetamet pivoxil, Cefetecol, Ce?xime, Ce?upre PYY(3 -36), DANA, Danegaptide hydrochloride, Danusertib, nam, Cefmatilen hydrochloride hydrate, Ce?nenoxime Dapivirine, Daporinad, Dapropterin dihydrochloride, Dar hydrochloride, Cefminox sodium, CefodiZime, CefodiZime bufelone, DarglitaZone, Darinaparsin, Darunavir, Dasanta?l, sodium, Cefonicid sodium, CefoperaZone sodium, Cefoselis Dasatinib, Davasaicin, Davunetide, Daxalipram, D-Cyclos sulfate, Cefotaxime sodium, Cefotetan disodium, Cefotiam erine, Debromoshermilamine, Decahydromoenomycin A, cilexetil, Cefotiam cilexetil hydrochloride, Cefotiam hexetil, Decaplanin, Decatromicin A, Decatromicin B, Declopra Cefotiam hexetil hydrochloride, Cefotiam hydrochloride, mide, Deferobiotin, Deferoxamine, Degarelix acetate, Cefoxitin, CefoZopran, CefoZopran hydrochloride, Cefpimi Degrasyn, Dehydrodidemnin B, Dehydrodolastatin-13, Zole sodium, Cefpiramide sodium, Cefpirome, Cefpodoxime Deka?n 1, Deka?n 10, Delaminomycin A, Delaminomycin proxetil, Cefprenam, CefproZil, CefproZil monohydrate, B, Delaminomycin C, Delapril hydrochloride, Delavirdine Cefquinome, Cefsulodin sodium, Ceftaroline, Ceftaroline mesilate, DelfapraZine hydrochloride, Delimotecan sodium, fosamil acetate, CeftaZidime, Cefteram pivoxil, Ceftibuten, Deltibant, Deltorphin E, Delucemine hydrochloride, Dem CeftiZoxime alapivoxil, CeftiZoxime sodium, Ceftobiprole, ethylallosamidin, Demethylasterriquinone B-1, Demetomi Ceftobiprole medocaril, CeftraZonal bopentil, CeftraZonal dine, Demexiptiline hydrochloride, Denibulin hydrochloride, sodium, Ceftriaxone sodium, Cefuroxime, Cefuroxime Denopamine, Denufosol tetrasodium, Deoxycoformycin, axetil, Cefuroxime pivoxetil, Celiprolol hydrochloride, Deoxymethylspergualin, Deoxymulundocandin, Deoxyne Cemadotin hydrochloride, Centanamycin, Cephalexin gamycin, Deoxynojirimycin, Deoxyspergualin hydrochlo monohydrate, CephaZolin sodium, Ceratamine A, Cerata ride, Depsipeptide, Deriglidole, Desacetylvinblastinehy mine B, Cerebrocrast, Cerebroside A, Cerebroside B, Cere draZide, DesacetylvinblastinehydraZide/folate conjugate, broside C, Cerebroside D, Cerulein, Ceruletide diethylamine, Desbutyl ben?umetol, Desbutylhalofantrine hydrochloride, Cethromycin, Cetrorelix acetate, Cevipabulin, Chackol, Cha Desferri-danoxamine, Desferri-nordanoxamine, Desferriox etocin, Chetocin, Chinoin-169, Chloptosin, ChloraZicomy amine, Desferri-salmycin A, Desferri-salmycin B, Desferri cin, ChlordiaZepoxide hydrochloride, Chlorofusin, Chloro salmycin C, Desferri-salmycin D, Desglugastrin orienticin A, Chloroorienticin B, Chloropeptin ll, tromethamine, Desipramine hydrochloride, Desloratadine, Chlorotetain, ChlorothiaZide, Chlorpropamide, Chlor Deslorelin, Desmin-370, Desmopressin acetate, Desulfated propham, Chlortalidone, Chlortenoxicam, Chlorthalidone, hirudin (54-65), Desulfated hirugen, Detomidine hydrochlo Chondramide A, Chondramide B, Chondramide C, Chondra ride, DeVaZepide, Dexecadotril, Dexefaroxan, Dexfen?u mide D, CibenZoline succinate, Ciclosporin, Cifenline succi ramine hydrochloride, Dexketoprofen imidaZole salt, Dexke nate, Cilastatin sodium, Cilastatino, CilaZapril, Cilengitide, toprofen meglumine, DeXlansopraZole, Dexloxiglumide, Cilnidipine, CilostaZol, Ciluprevir, Cimadronate sodium, Dexmedetomidine hydrochloride, Dexmethylphenidate Cimaterol, Cimetidine, Cimetidine bismuth citrate, Cimeti hydrochloride, Dexniguldipine hydrochloride, Dexpemed US 2013/0053301A1 Feb. 28,2013 17 olac, DeXraZoXane hydrochloride, Dexsotalol, Dextronatrin, chloride, Esperamicin A1, Esperatrucin, EtaciZin, Etamsy Dexylosylbenanomycin A, d-Fen?uramine hydrochloride, late, Etaquine, EthaciZin, Ethamsylate, EthimiZol, Ethiofos, D-Fluviabactin, DHA-paclitaxel, Diaplasinin, DiaZepinomi Ethosuximide, EthoXy-idaZoxan, Ethyl lo?aZepate, Eth cin, DiaZoXide, DichlorobenZoprim, Diclofenac potassium, ylthio-DADMe-immucillin-A, Etidocaine hydrochloride, Diclofenac sodium, Diclofenac Zinc salt, Didanosine, Etodolac, Etodolic acid, Etravirine, Eugenodilol, Eurocin, Didemnin X, DidemninY, Dideoxyinosine, Diethyl-lactam, Eurystatin A, Eurystatin B, Examorelin, Exenatide, Diethylnorspermine, DifuraZone, Diheteropeptin, Dihy Exenatide LAR, EXendin-4, EZatiostat hydrochloride, EZlo drexidine, Dihydro-alpha-ergokryptine mesylate, Dihy pitant, Fabesetron, Fabesetron hydrochloride, Fadolmidine droavenanthramide D, Dihydroeponemycin, Dihydroergota hydrochloride, Falnidamol, Famotidine bismuth citrate, mine mesylate, Dilevalol, Dilevalol hydrochloride, Fanapanel, FarglitaZar, Fasidotril, Fasobegron hydrochlo Dimelamol, Dimethynur, Dimiracetam, di-mPEG5-AtaZa ride, Fasoracetam, Fasudil hydrochloride, Feglymycin, Feg navir, Dinapsoline, Dinoxyline, Dioxolane T, Dioxolane lymycine, Felodipine, Fenoldopam mesilate, Fenoterol thymine nucleoside, Diperamycin, Dipivefrine hydrochlo hydrobromide, Fenoximone, Fepradinol, Ferrochloroquine, ride, Dipranol hydrochloride, Diquafosol tetrasodium, Ferroquine, Ferulinolol, Fidarestat, Fiduxosin hydrochloride, Dirithromycin, Dirlotapide, Dirucotide, Disagregin, Disala FilariZone, Fimasartan, Fimbrigal P, Fina?oxacin hydrochlo Zine, Discodermide, Discodermide acetate, Discorhabdin D, ride, Finasteride, FipameZole hydrochloride, Fish amunine, Discorhabdin P, Discorhabdin S, Discorhabdin T, Discorhab Flecamide acetate, Flibanserin, Flindokalner, Flomoxef din U, Disitertide, Dithiosteine, d-Methamphetamine hydro sodium, Flopristin, Flopristine, Florbetaben, Flovagatran chloride, Dobutamine hydrochloride, Dobutamine phos sodium, Floxuridine, Flucytosine, Flufenoxine, FlumeZap phate, Docarpamine, Docetaxel, Docetaxol, Dofetilide, ine, Fluodipine, Fluorocytosine, Fluorofur, Fluoroindolocar Dolasetron, Dolasetron mesilate, Dolastatin 10, Dolastatin baZole A, FluoroindolocarbaZole B, FluoroindolocarbaZole 13, Dolastatin 14, Dolastatin 15, Dolastatin C, Dolastatin D, C, Fluorouracil, Fluoxetine hydrochloride, Fluparoxan, Flu Domitroban calcium hydrate, Domperidone, Donitriptan pirtine maleate, Fluspirilene, Flutamide, Fluvirucin B2, Foe hydrochloride, Donitriptan mesilate, Dopexamine, Dopex tidine 1, Foetidine 2, Folinic acid, Folinic acid calcium salt, amine hydrochloride, Doramapimod, Doripenem, Dor FomepiZole, Fondaparin sodium, Fondaparinux sodium, mitroban, Dorrigocin A, Dorrigocin B, DorZolamide hydro Fonsartan potassium, Forasartan, Foretinib, Formobactin, chloride, Dovitinib Lactate, Doxi?uridine, DoXoTam 12, Formoterol fumarate, Forodesine hydrochloride, Fosalvu d-Pseudoephedrine hydrochloride, Dra?aZine, Dronedarone dine tidoxil, Fo samprenavir calcium, Fo samprenavir sodium, hydrochloride, Droperidol, Droxinavir, d-threo-Meth Fosaprepitant, Fosaprepitant dimeglumine, Fosopamine, ylphenidate hydrochloride, DTPA-adenosylcobalamin, Fosphenyloin sodium, Fostamatinib, Fostamatinib disodium, Duloxetine hydrochloride, Dumorelin, Duocarmycin A, Fotemustine, FoZiVudine tidoxil, Frada?ban, Franidipine Duocarmycin B1, Duocarmycin B2, Duocarmycin C1, Duo hydrochloride, Freselestat, Frog neuromedin U, Frovatriptan, carmycin C2, Duocarmycin SA, Duramycin, Dutasteride, Frusemide, Ftorafur, Furaldipine, Furavir, Fumidipine, Furo Dynemicin A, Dynemicin C, Dyo?n-1, Dyo?n-2, Dyo?n-9, semide, G1 peptide, Gabadur, Gabapentin enacarbil, Gabex EbalZotan, Ebanicline, Ebrotidine, Ecadotril, Echistatin, ate mesilate, Gaboxadol, Gadobenate dimeglumine, Gadobe Ecomustine, Ecteinascidin 1560, Ecteinascidin 722, Ectein nic acid dimeglumine salt, Gadocoletic acid trisodium salt, ascidin 729, Ecteinascidin 736, Ecteinascidin 743, Ecteinas Gadodenterate, Gadodiamide, Gadodiamide injection, Gado cidin 745, Ecteinascidin 770, Ecteinascidin 875, Edaglita linium DTPA, Gadolinium DTPA-BMA, Gadomelitol, Zone, Edonentan hydrate, Edotecarin, Edotreotide yttrium, Gadopentetate dimeglumine, Gadoterate meglumine, Edoxaban tosilate, Efaproxiral sodium, Efaroxan, EfaVirenZ, Gadoversetamide, Galactomycin I, Galactomycin II, Efegatran sulfate hydrate, Efepristin, E?ucimibe, E?umast, Galdansetron, Gallinacin 1, Gallinacin 1alpha, Gallinacin 2, Efonidipine hydrochloride ethanol, Eformoterol fumarate, Galmic, Galnon, Galocitabine, Galparan, Gammaphos, Gan Elacridar, Elagolix sodium, Elaro?ban, Elastatinal B, Elasta ciclovir, Ganciclovir elaidic acid, Ganciclovir monophos tinal C, ElbaniZine, Eldacimibe, Elesclomol, Eletriptan, phate, Ganefromycin alpha, Ganefromycin beta, Ganglio side Elgodipine hydrochloride, Elina?de mesilate, Elinogrel GMI, Ganirelix, Ganirelix acetate, Ganstigmine hydrochlo potassium, Elliptinium acetate, Elliptoside A, Elliptoside E, ride, Ganto?ban, Garenoxacin mesilate, Garomefrine hydro Elnadipine, ElopipraZole, Eltrombopag olamine, Embusar chloride, GastraZole, GastrophenZine, Gati?oxacin, Gavesti tan, Emicerfont, Emivirine, Emonapride, Emricasan, Enala nel sodium, Gedocamil, Ge?tinib, Ge?tinib hydrochloride, pril maleate, Enalapril nitrate, Enalaprilat, Enalkiren, EnaZa Gemopatrilat, Gibbosin, GidaZepam, Gilatide, Gilvusmycin, drem, Endothelin, Endothelin 1, Enfuvirtide, Eniluracil, GiracodaZole, Giripladib, GirodaZole, Girolline, Givinostat, Enkastin (D), Enkastin AD, Enkastin AE, Enkastin ID, Glaspimod, Glibenclamide, GliclaZide, Glidobactin PF-l, Enkastin IE, EnkastinVD, EnkastinVE, Enocitabine, Enoxa Glimepiride, GlipiZide, Gliquidone, Glucagon-like peptide I cin, Enoximone, Entecavir, Enteric neural peptide, Enti (7-37), Glucarolactam potassium, Glucolanomycin, Glu nostat, EnZastaurin hydrochloride, EpereZolid, EpereZolid dopa, Glufanide, Glufosfamide, Glutapyrone, Glutathione N-oxide, Epervudine, Epibatidine, Epidepride-(125I), monoethyl ester, Glutathione monoisopropyl ester, Glute Epiderstatin, Epipachysamine E, Epithalon, EpocarbaZolin thimide, Glyburide, Glycine-proline-Melphalan, Glycopin, A, EpocarbaZolin B, Epofolate, Epolactaene, Eponemycin, Glycopril, Glycothiohexide alpha, Gold talapor?n sodium, Epostatin, Epoxomicin, Epristeride, Eprobemide, Epro Golotimod, GomisinA glycinosuccinate sodium salt, Gora tirome, Eptastigmine tartrate, Epti?batide, ErbuloZole, latide, Goserelin, Gosogliptin hydrochloride, Granisetron Erdosteine, Eremomycin, Ergotamine tartrate, Eribaxaban, hydrochloride, Grepa?oxacin hydrochloride, GroWth factor Eritoran tetrasodium, Erlosamide, Erlotinib hydrochloride, antagonist-116, GroWth hormone releasing peptide 2, Ersentilide, Ersentilide hydrochloride, Ertapenem sodium, GroWth Inhibitory Peptide, GuanabenZ acetate, Guanadrel Erythromycin salnacedin, Erythromycin stinoprate, Esculeo sulfate, Guanethidine monosulfate, Guanfacine hydrochlo genin A, Esculeoside A, Eserine salicylate, Esmolol hydro ride, Gusperimus hydrochloride, Gusperimus trihydrochlo US 2013/0053301A1 Feb. 28, 2013

ride, Gypsetin, Habekacin, Habekacin sulfate, Halimide, nopraZole, Lemutepor?n, Lemuteporphin, Lenalidomide, Halofuginone hydrobromide, Halovir A, Halovir B, Halovir Lenampicillin hydrochloride, Lenapenem hydrochloride, C, Halovir D, Halovir E, Harkoseride, HelVecardinA, HelVe Lenapenem hydrochloride hydrate, Lercanidipine hydro cardin B, Heptaminol AMP amidate, Heptylstigmine tartrate, chloride, Lerisetron, Lestaurtinib, Leteprinim potassium, Herquline B, Hesperadin, HeXa-D-Arginine, Himastatin, LetraZuril, Leualacin, Leucovorin calcium, Leuprolide Hirudin desulfated, Hirulog- 1, Hispidosperrnidin, Histamine acetate, Leuprorelin acetate, Leurubicin, Levalbuterol hydro dihydrochloride, Histaprodifen, Histrelin, Histrelin acetate, chloride, Levobetaxolol hydrochloride, Levobunolol hydro Homoepibatidine, Homoindanomycin, Hormaomycin, chloride, Levobupivacaine hydrochloride, Levofolinate cal Human adrenomedullin, Human adrenomedullin (22-52), cium, Levoleucovorin calcium, Levonadi?oxacin arginine Human angiotensin H, Human corticotropin-releasing hor salt, Levonebivolol, Levosalbutamol hydrochloride, Levosi mone, Human lactoferrin (1-11), Human proislet peptide, mendan, Levosulpiride, L-Fluviabactin, L-Fluvibactin, Human Secretin, Hyaluronan, Hyaluronate sodium, Hydrala L-Fluvibactine, L-Histidinol, L-Homothiocitrulline, Liaro Zine hydrochloride, HydrochlorothiaZide, Hydro?umethiaZ Zole, LiaroZole hydrochloride, Liblomycin, Licostinel, Lida ide, Hydrostatin A, Hydroxyakalone, Hydroxycarbamide, midine hydrochloride, Lidanserin, Lidocaine hydrochloride, Hydroxychloroquine sulfate, Hydroxymycotrienin A, LifariZine, LifariZine hydrochloride, Lignocaine, LimaZocic, Hydroxymycotrienin B, Hydroxyurea, Hymenistatin 1, LinapraZan, Linarotene, LinaZolast, Linetastine, LineZolid, Hypeptin, lbipinabant, lbodutant, lbopamine, lbrolipim, LineZolid oxide, Lingual antimicrobial peptide, Linifanib, lbutamoren mesilate, lbutilide fumarate, lcatibant acetate, Linopristin, Linopristine, Linotroban, Lintitript, Lintopride, lcopeZil maleate, ldaZoXan hydrochloride, ldrabiotaparinux Lipohexin, LipoXaZolidinone A, LipoXaZolidinone B, sodium, ldrapril, lfetroban, lfosfamide, lganidipine hydro LipoXaZolidinone C, Liraglutide, Lirexapride, Lirimilast, chloride, lguratimod, llapraZole, llatreotide, llepatril, llom Lisdexamfetamine mesilate, Lisinopril, Lisuride maleate, astat, lmatinib mesylate, lmetit, lmexon, lmidacrine, lmi Lisuride TTS, Litoxetine, Lixivaptan, L-Lysine-d-amphet dapril, lmidapril hydrochloride, lmidaZoacridinone, amine dimesylate, l-Nebivolol, Lobatamide C, Lobatamide lmidaZole 24b, lmipemide, lmipenem, lmirestat, lmiso F, LobeglitaZone sulfate, LobenZarit sodium, Lobophorin A, pasem manganese, lmmepip, lmmepyr, lmmethridine, Lobophorin B, Lobradimil, Lobucavir, Lodamin, Lodena?l, lmmucillin-H, lmmunosine, lmoproxifan, lmpentamine, Lofexidine hydrochloride, Loloatin B, Lome?oxacin hydro lmplitapide, lmprogan, lncadronate, lncadronic acid sodium chloride, Lomeguatrib, Lometrexol, Lopinavir, Loprinone salt, lndacaterol, lndanomycin, lndantadol hydrochloride, hydrochloride, Loracarbef hydrate, LoraZepam, Lorcaserin, lndapamide, lndeloxazine hydrochloride, lndibulin, lndi Lorglumide, Lornoxicam, Losartan, Lotra?ban, Loviride, navir sulfate, lndisetron hydrochloride, lndisulam, Indium In Loxiglumide, Loxistatin, Loxoribine, L-Simexonyl 111 pentetreotide, lndole-3-propionic acid, lndolicidin-11, homocysteine, L-Thiocitrulline, L-threitol ceramide, lndolicidin-4, lndolicidin-8, lndolmycin, lndomethacin L-threo-C6-pyridinium-ceramide-bromide, LubaZodone phenethylamide, lndomethacin-Simvastatin, lndoramin hydrochloride, Lu?ronil, Lumiracoxib, Lurosetron, LuZin hydrochloride, lnogatran, lnosine pranobex, lnosiplex, lnsu dole, Lycopersicin, Lymphostin, Lysinated-betulonic acid, lin chain B (9-23) peptide, lntaxel (from Himalayan YeW), Lysobactin, Lysuride maleate, Mabuterol hydrochloride, lntegramycin, lntoplicine, lntri?ban, lobenguane[131l], Macitentan, Magainin ll, Makaluvamine C, Makaluvamine lobitridol, lodixanol, lodoproxyfan, lodorubidaZone (p), D, Makaluvamine E, Makaluvamine F, Makaluvone, Mana lofetamine hydrochloride 1-123, lofratol, lohexyl, lolopride glinat dialanetil, Manidipine hydrochloride, Manifaxine (1231), lomeprol, lopamidol, lopentol, lopromide, lotriside, hydrochloride, Manitimus, Mannopeptimycin alpha, Man lotrol, lotrolan, loversol, loxilan, loxipride, lpaZilide fuma nopeptimycin beta, Mannopeptimycin delta, Mannopeptimy rate, lptakalim hydrochloride, lrbesartan, lrciniastatin A, cin epsilon, Mannopeptimycin gamma, Manumycin A, lrciniastatin B, lroxanadine, lrtemaZole, lsaglidole, lsaglita Manumycin B, Manumycin C, Manumycin E, Manumycin F, Zone, lsalsteine, lsatoribine, lsaVuconaZonium chloride Manumycin G, ManZamine A, ManZamine B, ManZamine C, hydrochloride, lseganan hydrochloride, lsepamicin sulfate, ManZamine D, ManZamine E, ManZamine F, Maprotiline lsocarboXaZid, lsofagomine tartrate, lsoniaZid, lsoquine, lso hydrochloride, Maraviroc, Maribavir, Marimastat, Maropi segoline A, lsoVanihuperZine A, lspronicline, lsradipine, tant, Masilukast, Masitinib mesylate, Masnidipine hydro ltasetron, ltopride, ltopride hydrochloride, ltriglumide, chloride, MASTPROM, Matlystatin A, Matlystatin B, lturelix, lxabepilone, Janthinomycin A, Janthinomycin B, Matlystatin D, Matlystatin E, Matlystatin F, Matristatin A1, Janthinomycin C, Jaspamide, Jasplakinolide, K9-Retrocy Matristatin A2, Matristatin B1, Matristatin D1, Matristatin clin-1, Kahalalide F, Kaitocephalin, Kanglemycin A, kappa E1, Matristatin F1, Maxadilan, MaZokalim, Mebrofenin, Conotoxin P VllA, Kassinatuerin-l , Katanosin A, Katano sin Mecamylamine hydrochloride, Meclinertant, Meclofe B, Ketamine hydrochloride, Ketanserin, Kifunensine, Kine namate sodium, Medetomidine, Mefenamic acid, Me?oquine tin, Kistamicin A, Kopsinine, Korupensamine A, Korupen hydrochloride, Megovalicin A, Megovalicin B, Megovalicin samine B, Korupensamine C, Kosinostatin, Kurasoin B, C, Megovalicin D, Megovalicin G, Megovalicin H, Melagat Kynostatin-227, Kynostatin-272, Labedipinedilol A, Labe ran, Melanotan, Melanotan l, Melanotan ll, Meldonium, dipinedilol B, Labetalol hydrochloride, Labradimil, Lacid Melogliptin, Meloxicam, Meluadrine, Meluadrine tartrate, ipine, Lacosamide, Lactosylphenyl trolox, Ladasten, Lados Memno-peptide A, Memoquin, Mephenyloin, Mephobar tigil tartrate, La?unimus, Lafutidine, Lagatide, Lamectacin, bital, Mepindolol sulfate, Mepindolol transdermal patch, Lami?ban, Landiolol, Lanepitant, Lanreotide acetate, Lanso Mepirodipine hydrochloride, Mepivacaine hydrochloride, praZole, Lanthiopeptin, Lapatinib ditosylate, LaraZotide Mercaptopurine, Merimepodib, Meriolin-3, Meropenem, acetate, Laromustine, Larotaxel dihydrate, Lasinavir, Lata Mersacidin, Mesopram, Metaglidasen, Me-Talnetant, Meta moxef sodium, Latrunculin S, Lavanduquinocin, LaZabe nicotine, Metaproterenol sulfate, Meterelin, Metergoline, mide hydrochloride, Lecimibide, Lecirelin, Leconotide, Metesind glucuronate, Metformin hydrochloride, Metham LedaZerol, Le?unomide, Lefrada?ban, Leinamycin, Lemi phetamine hydrochloride, Methanobactin, Methicillin US 2013/0053301A1 Feb. 28, 2013

sodium, Methimepip, Methoctramine, Methoin, Methotrex ride, Nilotinib hydrochloride monohydrate, Nilutamide, Nil ate, Methoxatin, MethyclothiaZide, Methyl bestatin, Methyl Vadipine, Nimesulide, Nimodipine, Nipradilol, Nipradolol, histaprodifen, Methylhomoindanomycin, Methylphenidate Nisin, Nisoldipine, NitaZoxanide, Nitracrine dihydrochloride hydrochloride, Methylphenobarbital, Methylphenobarbi hydrate, NitraZepam, Nitrendipine, Nitrofenac, Nitroparac tone, Methylthio-DADMe-immucillin-A, Methypranolol, etamol, Nitroso-nifedipine, Nitrosopine, Nitrovin, Nivad Methysergide maleate, Meticillin sodium, Metipranolol, ipine, NiZatidine, Noberastine, Noberastine citrate, Metoclopramide hydrochloride, MetolaZone, Metoprolol Nocathiacin I, Nocathiacin ll, Nocathiacin Ill, Nocathiacin fumarate, Metoprolol succinate, Metoprolol tartrate, MeZa IV, NO-cipro?oxacin, N-Octyl-beta-Valienamine, NO-ibu copride, Mibefradil, Mibefradil hydrochloride, Micafungin profen, Nolatrexed dihydrochloride, Nolomirole hydrochlo sodium, Michellamine B, Microcin 25, Microcin J25, Micro ride, NO-Nifedipine, Nooglutil, Nooglutyl, NO-Paraceta colin A, Microcolin B, Micronomicin sulfate, Midafotel, mol, NorastemiZole, NordaZepam, Nor?oxacin, Nomicotine, Midaxifylline, Mideplanin, Midesteine, Midostaurin, Mila Norsegoline, Nortopixantrone hydrochloride, Nortopsentin cemide-[2H], Milataxel, Milbemycin alpha-9, Milfasartan, A, Nortopsentin B, Nortopsentin C, Nortopsentin D, Nortrip Milrinone, Milrinone lactate, MimopeZil, Minalrestat, tyline hydrochloride, Nostocyclopeptide M1, N-Retinoyl-D Minaprine hydrochloride, Minopafant, Mipragoside, Mira glucosamine, N-tert butyl isoquine, Nubiotic 2, Nutlin-3, begron, Mirisetron, Mirodena?l hydrochloride, Mitiromycin, Nutlin-3A, Nutlin-3-enantiomer A, Nuvanil, O6-BenZylgua Mitomycin, Mitomycin C, Mitoxantrone hydrochloride, nine, Obatoclax mesylate, Oberadilol, Oberadilol monoethyl MitoZantrone hydrochloride, MiVaZerol, Mivobulin isethion maleate, Octacosamicin A, Octacosamicin B, Octreother, ate, Mivotilate, Mixanpril, MiZolastine, MobaZol, Mocetin Octreotide acetate, Octreotide LAR, Odanacatib, O-Demeth ostat dihydrobromide, Moclobemide, Modecamide, Modi ylmurrayafoline A, Oglufanide disodium, Olanexidine pafant, Moenomycin A chloride bismuth salt, Moexipril hydrochloride, OlanZapine, OlanZapine pamoate, Olaparib, hydrochloride, Moexiprilat, Monamidocin, Monodansyl Olcegepant, Olmesartan, Olmesartan medoxomil, Olprinone cadaverine, Mono-L-aspartyl chlorin e6, Monophosphoryl hydrochloride, Olradipine hydrochloride, Omaciclovir, lipid A, Montirelin tetrahydrate, MoraciZine hydrochloride, Omapatrilat, Ombrabulin, Ombrabulin hydrochloride, Moranolin, MoriciZine hydrochloride, Morni?umate, omega-Conotoxin CVID, omega-Conotoxin MVIIA, Ome Mosapramine hydrochloride, Mosapride citrate, Motesanib praZole, Omiganan pentahydrochloride, Onnamide A, Onta diphosphate, Motretinide, Moxalactam disodium, Moxifetin Zolast, Opaviraline, OPC-17083, Opiorphin, Orbi?oxacin, hydrogen maleate, Moxi?oxacin hydrochloride, Moxonidine Orbo?ban acetate, Orciprenaline sulphate, Orienticin A, Ori hydrochloride hydrate, Mozavaptan hydrochloride, enticin B, Orienticin C, Orienticin D, Oritavancin, Orlipastat, mu-Conotoxin lllA, Multiple sclerosis Vaccine, muO-Cono Orlistat, Ortataxel, Oseltamivir carboxylate, Oseltamivir toxin MrVlB, Muraminomicin A, Muraminomicin B, phosphate, OsemoZotan hydrochloride, Osutidine, Otamixa Muraminomicin C, Muraminomicin D, Muraminomicin E1, ban, Otastat potassium, Otenabant hydrochloride, Oteracil Muraminomicin E2, Muraminomicin F, Muraminomicin G, potassium, Ovalicin A, Ovothiol B, Oxam?atin, Oxatomide, Muraminomicin H, Muraminomicin I, Muraminomicin Z1, OXaZepam, Oxeclosporin, Oxiglutatione sodium, Oximidine Muraminomicin Z2, Muraminomicin Z3, Muraminomicin Ill, Oxonic acid, Oxprenolol hydrochloride, OXymetaZoline Z4, Muramyl dipeptide C, Mureidomycin A, Mureidomycin hydrochloride, Oxymethacyl, OXymorphaZole dihydrochlo B, Mureidomycin C, Mureidomycin D, Mureidomycin E, ride, Oxynor, Oxypertine, Oystrisin, OZareliX, OZenoxacin, Mureidomycin F, Mureidomycins, Muroctasin, Mycalamide Pachymedusa dacnicolor Tryptophyllin-l, Pachysamine E, A, Mycalamide B, Myxovirescin A1, Myxovirescin B, Paclitaxel, Paclitaxel ceribate, Pactimibe, Padelipor?n potas N1 ,N8 -Bisnorcymserine, N1 -Phenethylnorcymserine, sium, Pafenolol, Palau’amine, Paldimycin B, Palinavir, Pal N4-Hexadecyl-dC-AZT, Naamidine A, N-Acetylcolchinol, indore fumarate, Palmidrol, Palmitoylethanolamide, Palosu N-Acetylcysteine, N-Acetylesperamycin A1, N-Acetyles ran sulfate, Pamapimod, p-Aminoclonidine hydrochloride, peramycin Alb, N-Acetylesperamycin A2, N-Acetyl-L-cys Pancopride, Pancratistatin disodium phosphate, Pancratista teine, Nadolol, Nafadotride, Nafamostat mesilate, Nafamo tin-3,4-cyclic phosphate sodium salt, Panobinostat, Pan stat mesylate, Nafarelin acetate, Naglivan, Nagrestipen, tethine, PantopraZole, Papuamide A, Papuamide B, Papua Nagstatin, Naltrindole, NaluZotan hydrochloride, Naminidil, mide C, Papuamide D, Paracetamol, Paraherquamide E, Naproxen piperaZine (2:1), Napsagatran, Napsamycin A, Paraherquamide F, Paraherquamide G, Parasin I, Parathyroid Napsamycin B, Napsamycin C, Napsamycin D, Naratriptan hormone (human recombinant), Parcetasal, Pardoprunox hydrochloride, Nardeterol, Nateglinide, Navelbine, Navuri hydrochloride, Parodilol hemifumarate, Parogrelil hydro dine, Naxifylline, NaZasetron, NaZasetron hydrochloride, chloride, Paroxetine, Paroxetine ascorbate, Paroxetine cam N-demethylated sildena?l, N-Desmethylmilameline, Nebiv silate, Paroxetine hydrochloride, Paroxetine mesilate, Pasi olol, Neboglamine, Nebostinel, Necrostatin-l, Ne?racetam, reotide, PaZelliptine trihydrochloride, PaZelliptine Neihumicin, Nel?navir mesilate, Nemi?tide ditri?utate, trihydrochloride monohydrate, PaZopanib hydrochloride, Nemonapride, Neo-acridine, Neomycin B-arginine conju PEG40000-Paclitaxel, PEGSOOO-Paclitaxel, PEG-Vancomy gate, Neomycin B-hexaarginine conjugate, Neomycin-acri cin, Peldesine, Pelitinib, Pelitrexol, Pemetrexed disodium, dine, Nepadutant, NepapraZole, Nepicastat hydrochloride, Pemirolast, Pemirolast potassium, Pemoline, Penbutolol sul Neratinib, Ner?lin I, Nesbuvir, Nesiritide, Netamiftide trif fate, Penciclovir, Penicillin G procaine, Penicillin G sodium, luoroacetate, Netilmicin sulfate, Netivudine, NetoglitaZone, Pentafuside, Pentobarbital sodium, Pentobarbitone sodium, Neu5Ac2en, Neuromedin U-25, Neuropeptide S, Neutrophil Pentostatin, Peplomycin, Pepticinnamin E, Peptide Leucine activating factor, Nevirapine, Ngercheumicin A, Arginine, Peramivir, Perfosfamide, Pergolide mesylate, Per Ngercheumicin B, Ngercheumicin C, Ngercheumicin D, indopril, PerZinfotel, Pexiganan acetate, PG-camptothecin, Ngercheumicin E, Nibentan, Nicardipine hydrochloride, Phakellistatin 5, Phakellistatin 7, Phakellistatin 8, Phakel Nicavir, Nicorandil, Nicotredole, Niduline, Nifedipine, listatin 9, Phe-Arg-beta-naphthylamide, Phendioxan, Phenel Nifekalant hydrochloride, NifurZide, Niguldipine hydrochlo famycin F, PhenelZine sulfate, Phenobarbital, Phenobarbi