US 20140243254A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0243254 A1 Hersel et al. (43) Pub. Date: Aug. 28, 2014

(54) POLYMERC HYPER BRANCHED Publication Classification CARRIER-LINKED PRODRUGS (51) Int. Cl. (75) Inventors: Ulrich Hersel, Heidelberg (DE); A647/48 (2006.01) Guillaume Maitro, Mannheim (DE); (52) U.S. Cl. Herald Rau, Dossenheim (DE); Tobias CPC. A61 K47/48338 (2013.01); A61K 47/48215 Voigt, Heidelberg (DE) (2013.01) USPC ...... 514/1.3; 544/282; 530/331 (73) Assignee: Ascendis Pharma A/S, Hellerup (DK) (21) Appl. No.: 14/237,833 (57) ABSTRACT (22) PCT Fled: Aug. 10, 2012 The present invention relates to water-soluble carrier-linked prodrugs of formula (I), wherein POL is a polymeric moiety, (86) PCT NO.: PCT/EP2012/065736 each Hyp is independently a hyperbranched moiety, each S371 (c)(1), moiety SP is independently a spacer moiety, each L is inde (2), (4) Date: May 13, 2014 pendently a reversible prodrug linker moiety, m is 0 or 1, each n is independently an integer from 2 to 200 and each X is (30) Foreign Application Priority Data independently 0 or 1. It further relates to pharmaceutical compositions comprising said water-soluble carrier-linked Aug. 12, 2011 (EP) ...... 111774O6.3 prodrugs and methods of treatment. US 2014/0243254 A1 Aug. 28, 2014

POLYMERC HYPER BRANCHED from twofold up to several orders of magnitude. Therefore, CARRIER-LINKED PRODRUGS the cleavage is predominantly controlled by the enzymatic reaction. 0001. The present application claims priority from PCT 0010. A major drawback of predominantly enzymatic Patent Application No. PCT/EP2012/065736 filed on Aug. cleavage is interpatient variability. Enzyme levels may differ 10, 2012, which claims priority from European Patent Appli significantly between individuals resulting in biological cation No. EP 11177406.3 filed on Aug. 12, 2011, the disclo variation of prodrug activation by the enzymatic cleavage. sures of which are incorporated herein by reference in their The enzyme levels may also vary depending on the site of entirety. administration. For instance it is known that in the case of Subcutaneous injection, certain areas of the body yield more FIELD OF THE INVENTION predictable therapeutic effects than others. To reduce this unpredictable effect, non-enzymatic cleavage or intramo 0002. It is noted that citation or identification of any docu lecular catalysis is of particular interest. ment in this application is not an admission that such docu 0011. Therefore, enzyme-independent autocatalytic ment is available as prior art to the present invention. cleavage of carrier and drug is preferred. In most cases this is 0003 Drugs frequently exhibit short plasma half-life due achieved by an appropriately designed linker moiety between to renal and receptor-mediated clearance, aggregation, pro the carrier and the drug, which is directly attached to the teolytic degradation, poor bioavailability and physical prop functional group of a drug via a covalent bond. erties which preclude efficient formulations. This is highly 0012. A number of such enzyme-independent prodrugs undesirable as it leads to the need for frequent and repeated suitable for different classes of biologically active moieties administration of the drug, resulting in increased costs and are known in the art. Examples can be found in the interna inconvenience for the patient. tional patent applications WO-A 2005/099768, WO-A 2006/ 0004 One mechanism for enhancing the availability of 13565869, WO-A 2009/095479, and WO-A 2011/012722. drugs is by conjugating it with derivatizing compounds, 0013 Typically, carrier-linked prodrugs have a stoichiom which include, for example, poly(ethylene glycol) (PEG) and etry of one drug molecule conjugated to one carrier moiety. poly(propylene glycol). Some of these benefits recognized However, for many medical applications such stoichiometry include lowered immunogenicity and antigenicity, increased is disadvantageous as large Volumes of Such conjugates duration of action, and altered pharmacokinetic properties would have to be applied to a patient to ensure a high enough (Veronese, F. M.. “Enzymes for Human Therapy: Surface drug dose, causing undue pain and possibly requiring Structure Modifications.” Chimica Oggi, 7:53-56, 1989). increased amounts of time for the administration process and 0005 To enhance physicochemical or pharmacokinetic thus increasing the costs of the treatment. In Such situations, properties of a drug in vivo, drugs can be bound to carriers in carrier-linked prodrugs in which more than one drug moiety a non-covalent way, using physicochemical formulations of is conjugated to a carrier molecule might be better Suited as drug-solvent-carrier mixtures. However, the non-covalent they provide a higher drug loading and thus require Smaller approach requires a highly efficient drug encapsulation to Volumes of the pharmaceutical composition to be adminis prevent uncontrolled, burst-type release of the drug. Restrain tered to a patient. ing the diffusion of an unbound, water Soluble drug molecule (0014 U.S. Pat. No. 7,744,861 B2 discloses multi-arm pro requires strong van der Waals contacts, frequently mediated drugs in which at least three arms extend from a branching through hydrophobic moieties. Many conformationally sen core and each of these arms carries one drug moiety. Simi sitive drugs, such as proteins or peptides, are rendered dys larly, WO-A 2010/019233 discloses multi-arm prodrugs of functional during the encapsulation process and/or during which each arm of a carrier moiety is conjugated to one drug Subsequent storage of the encapsulated drug. In addition, moiety. Despite the multi-arm backbone structure. Such car Such amino-containing drugs readily undergo side reactions rier-linked prodrugs still have a relatively low drug load. with carrier degradation products. Furthermore, dependence 00.15 More carrier-linked prodrugs with two polymer of the release mechanism of the drug upon biodegradation based arms are disclosed in WO-A 2008/034119, wherein may cause interpatient variability. each arm is attached to a drug moiety, diagnostic agent or 0006 Alternatively, the drugs may be conjugated to a car targeting moiety. rier via a transient linker molecule, resulting in carrier-linked 0016 Prodrugs of the anti-malaria drug artelinic acid are prodrugs. This approach is applied to various classes of mol disclosed in U.S. Pat. No. 6,461,603 B2. The polymeric pro ecules, from So-called Small molecules, through natural prod drugs are also based on a backbone moiety from which arms ucts up to larger peptides and proteins. extend which each carry one drug moiety at their terminus. 0007 Prodrug activation may occur by enzymatic or non 0017. Another approach to high-loading carrier-linked enzymatic cleavage of the bond between the carrier and the prodrugs involves the use of dendrimers. Dendrimers are drug molecule, or a sequential combination of both, i.e. an repeatedly branched, roughly spherical, large molecules. enzymatic step followed by a non-enzymatic rearrangement. Dendrimers have been used to non-covalently embed drug moieties and for covalent attachment of drug moieties to the 0008 Enzymatically induced prodrug activation is char termini of the dendrimer. acterized in that the cleavage in enzyme-free in vitro environ (0018 Taite & West (J. Biomater. Sci. Polymer Edn, 2006, ment such as an aqueous buffer Solution, of e.g., an ester or 17, 1159–1172) describe lysine-based dendrimer moieties in amide may occur, but the corresponding rate of hydrolysis which free amines have been converted to diazeniumdiolate may be much too slow and not therapeutically useful. NO-donors through the reaction with NO gas. The dendrim 0009. In an in-vivo environment, esterases oramidases are ers released NO over a period of 60 days. However, this typically present and the esterases and amidases may cause approach does not allow for the adjustment of release speed as significant catalytic acceleration of the kinetics of hydrolysis no reversible prodrug linkers have been used to attach the NO US 2014/0243254 A1 Aug. 28, 2014

to the termini of the dendrimer and this approach is also not high drug loading due to the presence of the hyperbranched transferable to other drug moieties. moieties. In addition, the polymeric moiety allows for 00.19 US 2010/0160299 A1 discloses dendrimers to increased water-solubility. which therapeutic agents for the reduction and/or elimination of pain are connected in a reversible manner. Similarly, DETAILED DESCRIPTION OF EMBODIMENTS WO-A 2010/075423 discloses modular dendrimer platforms 0035. It is to be understood that the figures and descrip suitable for the delivery of therapeutic agents, for example. tions of the present invention have been simplified to illustrate 0020. However, dendrimers typically exhibit a low degree elements that are relevant for a clear understanding of the of water-solubility. When poorly water-soluble drug moieties present invention, while eliminating, for purposes of clarity, are coupled to the functional groups of Such dendrimers the many other elements which are conventional in this art. Those resulting conjugates are even less water-soluble. Therefore, of ordinary skill in the art will recognize that other elements although dendrimers provide a high drug loading, their appli are desirable for implementing the present invention. How cability for prodrug approaches is limited. ever, because Such elements are well known in the art, and 0021. It is noted that in this disclosure and particularly in because they do not facilitate a better understanding of the the claims and/or paragraphs, terms such as "comprises'. present invention, a discussion of Such elements is not pro “comprised', 'comprising and the like can have the meaning vided herein. attributed to it in U.S. patent law; e.g., they can mean “includes”, “included”, “including, and the like; and that 0036. The present invention will now be described in terms such as "consisting essentially of and "consists essen detail on the basis of exemplary embodiments. tially of have the meaning ascribed to them in U.S. patent 0037. Within the present invention the terms are used hav law, e.g., they allow for elements not explicitly recited, but ing the meaning as follows. exclude elements that are found in the prior art or that affect 0038. The terms “drug”, “biologically active molecule'. a basic or novel characteristic of the invention. “biologically active moiety”, “biologically active agent'. 0022. It is further noted that the invention does not intend “active agent”, “active substance' and the like mean any to encompass within the scope of the invention any previously Substance which can affect any physical or biochemical prop disclosed product, process of making the product or method erties of a biological organism, including but not limited to ofusing the product, which meets the written description and viruses, bacteria, fungi, plants, animals, and humans. In par enablement requirements of the USPTO (35 U.S.C. 112, first ticular, as used herein, the terms include any Substance paragraph) or the EPO (Article 83 of the EPC), such that intended for diagnosis, cure, mitigation, treatment, or preven applicant(s) reserve the right to disclaim, and hereby disclose tion of disease in organisms, in particular humans or other a disclaimer of any previously described product, method of animals, or to otherwise enhance physical or mental well making the product, or process of using the product. being of organisms, in particular humans or animals. 0039 “Biologically active moiety D' means the part of a biologically active moiety-reversible prodrug linker conju SUMMARY OF THE INVENTION gate or the part of a biologically active moiety-reversible 0023 Therefore, there is a need to provide novel water prodrug linker-carrier conjugate, which results after cleavage soluble carrier-linked prodrugs that at least partially over in a drug D-H of known biological activity. come the above-mentioned shortcomings. This object is 0040 “Amine-containing biologically active moiety' or achieved with water-soluble carrier-linked prodrugs of for "hydroxyl-containing biologically active moiety' means the mula (I): part (moiety or fragment) of a biologically active moiety reversible prodrug linker conjugate or the part of a biologi cally active moiety-reversible prodrug linker-carrier conju 0024 wherein gate (active agent) of (known) biological activity, and which 0025 Hyp-POL-Hyp form a carrier moiety, and part of the drug comprises at least one amine or hydroxyl wherein group, respectively. 0026 POL is a polymeric moiety having a molecular 0041. In addition, the subterm “aromatic amine-contain weight ranging from 0.2 kDa to 160 kDa, ing' means that the respective biologically active moiety D 0027 each Hyp is independently a hyperbranched and analogously the corresponding drug D-H contains at least moiety, one aromatic fragment which is Substituted with at least one 0028 each SP is independently a spacer moiety, amino group. The Subterm “aliphatic amine-containing 0029 each L is independently a reversible prodrug means that the respective biologically active moiety D and linker moiety, analogously the corresponding drug D-H contains at least one aliphatic fragment which is substituted with at least one 0030 each D is independently a biologically active amino group. Without further specification the term “amine moiety, containing is used generically and refers to aliphatic and 0031 m is 0 or 1, aromatic amine-containing moieties. 0032 each n is independently an integer from 2 to 0042. The subterm “aromatic hydroxyl-containing 200, in particular from 2 to 64, more preferably from means that the respective moiety D and analogously the cor 2 to 32 and even more preferably from 2 to 16, each x responding drug D-H contains at least one aromatic fragment, is independently 0 or 1: which is substituted with at least one hydroxyl group. The 0033 or a pharmaceutically acceptable salt thereof. Subterm “aliphatic hydroxyl-containing means that the 0034. It was now surprisingly found that such water hydroxyl group of the respective moiety D and analogously soluble carrier-linked prodrugs can be used as Sustained the corresponding drug D-His connected to an aliphatic frag release dosage forms of biologically active moieties with a ment. Without further specification the term “hydroxyl-con US 2014/0243254 A1 Aug. 28, 2014 taining is used generically and refers to aliphatic and aro tins, 6-opioid receptor ligands, cholecystokinin A receptor matic hydroxyl-containing moieties. ligands, ligands specific for angiotensin AT1 or AT2 recep 0043 “Free form of a drug refers to the drug in its tors, peroxisome proliferator-activated receptor w ligands, unmodified, pharmacologically active form, such as after B-lactam antibiotics such as penicillin, Small organic mol being released from a carrier-linked prodrug. ecules including antimicrobial drugs, and other molecules 0044 Targeting moieties are moieties that when present in that bind specifically to a receptor preferentially expressed on a molecule. Such as for example a prodrug, allow preferential the Surface of tumor cells or on an infectious organism, anti localization of such larger molecule in specific target areas of microbial and other drugs designed to fit into the binding the organism to which it has been administered. Such specific pocket of a particular receptor based on the crystal structure target areas might be organs, certain cell types or Subcellular of the receptor or other cell Surface protein, ligands of tumor compartments. “Preferential localization' means that at least antigens or other molecules preferentially expressed on the 10%, preferably at least 20% and more preferably at least Surface of tumor cells, or fragments of any of these molecules. 30% of the biologically active moieties administered to a Examples of tumor-specific antigens that can function as patient reach said specific target areas. targeting moieties include extracellular epitopes of a member 0045 Targeting moieties may be divided into 3 classes of the ephrin family of proteins, such as EphA2. EphA2 according to size: expression is restricted to cell-cell junctions in normal cells, 0046 small molecular targeting moieties, for example but EpbA2 is distributed over the entire cell surface in meta C-glucuronide, cobalamin, vitamins such as folic acid static tumor cells. Thus, EphA2 on metastatic cells would be (folate) and analogs and derivatives, carbohydrates, bis accessible for binding to, for example, a Fab fragment of an phosphonates, N-acetylgalactosamine, antibody conjugated to an immunogen, whereas the protein 0047 peptides, for example bombesin, somatostatin, would not be accessible for binding to the Fab fragment on LHRH, EGF, VEGF, hCG, fragments of luteinizing hor normal cells, resulting in a targeting moiety specific for meta mone (LH), octreotide, vapreotide, lanreotide, RC-3940 static cancer cells. series, decapeptyl, lupron, Zoladex, cetrorelix, peptides 0050. Further examples for such targeting moieties are: or peptidomimetics containing the NGR or RGD motifs FSH-33, allatostatin 1, hepatocarcinoma targeting peptide, or derived from these motifs such as CNGRC (linear), peptide GFE, anti-EGFR antibodies and/or antibody frag GNGRG (cyclic), ACDC RGD CFCG (cyclic), ments, in particular cetuximab, CendR, iRGD peptide (RGD CDCRGDCFC, CNGRC (cyclic), CRGDCGG, CendR hybrid peptide), small molecules, antibodies and/or CNGRC, or other peptides such as ATWLPPR, throm antibody fragments binding to cancer-specific epitopes like bospondin (TSP)-1 mimetics, (RGD peptidomimetic), e.g. CEA, gastrin-releasing peptide receptors, Somatostatin CTTHWGFTLC, CGNKRTRGC, neuropeptide sub receptors, galanin receptors, follicle-stimulating hormone stance P. SSP, the Sar9, Met(O2)11 analog of substance receptors, p32 protein, fibroblast growth factor receptors, P. cholecystokinin (CCK), corticotropin-releasing hor HepG2, epidermal growth factor receptors, integrin CVB6. mone/factor (CRH/CRF), dermorphin, FGF-2 or basic neuropilin-1 receptor and VEGF receptors. fibroblast growth factor, galanin, melanopsin, neuro 0051. The phrases “in bound form”, “connected to’, and tensin, “moiety” refer to sub-structures which are part of a molecule. 0048 and protein or macro- molecular targeting moi The phrases “in bound form or “connected to are used to eties, for example IL-2, GM-CSF, TNF-a, transferrin, simplify reference to moieties or functional groups by nam immunoglobulins, acetylated-LDL, lactoferrin (Lif) ing or listing reagents, starting materials or hypothetical start (also called lactotransferrin) and lactoferricin (Lcin), ing materials well known in the art, and whereby “in bound gambogic acid (GA), antibody fragments and affinity form' and “connected to means that for example one or more scaffold proteins. hydrogen radicals (—H) or one or more activating or protect 0049. In principle, any ligand of a cell surface receptor ing groups present in the reagents or starting materials are not may be advantageously used as a targeting moiety. For present in the moiety when part of a molecule. instance, ATWLPPR peptide is a potent antagonist of VEGF: 0.052 To enhance physicochemical or pharmacokinetic thrombospondin-1 (TSP-1) induces apoptosis in endothelial properties of a drug in Vivo, Such drug can be conjugated with cells, RGD-motif mimics block integrin receptors, NGR a carrier, as in the present invention. If the drug is transiently containing peptides inhibit aminopeptidase N, and cyclic bound to a carrier and/or a linker, as in the present invention, peptides containing the sequence of HWGF selectively Such systems are commonly assigned as "carrier-linked pro inhibit MMP-2 and MMP-9. LyP-1 peptide specifically binds drugs'. According to the definitions provided by IUPAC (as to tumor lymphatic vessels. Illustrative other ligands include given under http://www.chem.qmul.ac.uk/iupac/medchem/ peptide ligands identified from library screens, tumor cell ah.html, accessed on Mar. 7, 2011), a carrier-linked prodrug specific peptides, tumor cell-specific aptamers, tumor cell is a prodrug that contains a temporary linkage of a given specific carbohydrates, tumor cell-specific monoclonal or active Substance with a transient carrier group that produces polyclonal antibodies, Fab or Sclv (i.e., a single chain vari improved physicochemical or pharmacokinetic properties able region) fragments of antibodies such as, for example, a and that can be easily removed in vivo, usually by a hydrolytic Fab fragment of an antibody directed to EphA2 or other cleavage. proteins specifically expressed or uniquely accessible on 0053. The term “promoiety” refers to the part of the pro metastatic cancer cells, Small organic molecules derived from drug which is not the drug, thus meaning linker and carrier combinatorial libraries, growth factors, such as EGF, FGF, and/or any optional spacer moieties. insulin, and insulin-like growth factors, and homologous 0054 The terms “reversible prodrug linkers' or “transient polypeptides. Somatostatin and its analogs, transferrin, lipo prodrug linkers' refer to linkers that are non-enzymatically protein complexes, bile salts, selecting, steroid hormones, hydrolytically degradable, i.e. cleavable, under physiological Arg-Gly-Asp containing peptides, retinoids, various Galec conditions (aqueous buffer at pH 7.4, 37°C.) with half-lives US 2014/0243254 A1 Aug. 28, 2014

ranging from, for example, one hour to three months. On the 0065. The term “PEG based polymer” or “PEG-based other hand, stable linkers have stable linkages, which are polymer as understood herein means that the mass propor typically non-cleavable permanent bonds, meaning that they tion of the polymeric moiety POL is at least 10% by weight, have a half-life of at least six months under physiological preferably at least 25%, more preferably at least 50% by conditions (aqueous buffer at pH 7.4, 37° C.). weight, even more preferably at least 80% by weigth poly 0055. A “traceless prodrug linker” refers to a linker from (ethylene glycol) (PEG), which is optionally capped, based which a drug is released in its free form, meaning that upon on the total weight of the polymeric moiety POL. The remain release from the promoiety the drug does not contain any der can be made up of other polymers. In one embodiment, traces of the promoiety. “PEG based polymer or “PEG-based polymer also encom 0056 “Non-biologically active linker” means a linker passes POL moieties consisting of poly(ethylene glycol) which does not show the pharmacological effects of the drug (PEG), which is optionally capped. The term “poly(oxazo (D-H) derived from the biologically active moiety. line)-based polymer is defined accordingly. 0057 The term “polymer describes a molecule compris 0066. A "peptide' is a single linear polymer chain of up to ing, in particular consisting of repeating structural units con about 100 amino acids, preferably up to about 50 amino acids, nected by chemical bonds in a linear, circular, branched, more preferably up to about 25 amino acids bonded together crosslinked or dendrimeric way or a combination thereof, by peptide bonds between the carboxyl and amino groups of which can be of synthetic or biological origin or a combina adjacent amino acid residues. Preferably, a peptide is a single tion of both. It is understood, that e.g. capping moieties may linear polymer chain of at least about 4 amino acids, more be present in a polymer. preferably of at least about 6 amino acids. A “protein' or 0058. The term “polymeric' refers to a moiety comprising "polypeptide' is a single linear polymer chain of more than one or more polymer. about 100 amino acids bonded together by peptide bonds 0059. The term “hyperbranched moiety” refers to a moiety between the carboxyl and amino groups of adjacent amino comprising at least one branching point. Such branching acid residues. Proteins or polypeptides may comprise modi point comprises, for example, an at least 3-fold Substituted fications, for example by C-terminal amidation. carbocycle, an at least 3-fold substituted heterocycle, a ter 0067. The term "peptide fragment as used herein refers to tiary carbon atom, a quaternary carbon atom or a tertiary a polypeptide moiety or peptide moiety comprising at least 3 nitrogen atom. amino acids and comprising at least one alanine, and/or one 0060 A carbocycle and heterocycle may be substituted by serine and/or one proline. Coalkyl, optionally interrupted or terminated by heteroa 0068. The term “polymer cassette' relates to peptides of toms or functional groups selected from the group consisting defined, individual amino acid stretches. Polymer cassettes of-O-, -S. , N(R), C(O), C(O)N(R), and N(R)C(O), may be used to form a polypeptide moiety POL. Thus, a wherein R is hydrogen or a Coalkyl chain, which is option polypeptide moiety POL comprises, preferably consists of ally interrupted or terminated by one or more of the above one or more, in particular of 1,2,3,4,5,6,7,8,9, 10, 11, 12, mentioned atoms or groups which further have a hydrogen as 13, 14, 15, 16, 17, 18, 19 or 20 polymer cassette(s), which terminal atom. may be of the same or of different sequence. 0061 The term “functional group' refers to specific 0069. As used herein, the term “random coil” relates to groups of atoms within molecules that can undergo charac any conformation of a polymeric molecule, including pro teristic chemical reactions. Examples of functional groups teins, in which the individual monomeric elements that form are hydroxyl, carbonyl, aldehyde, carboxyl, ester, ketal, said polymeric structure are essentially randomly oriented hemiketal, acetal, hemiacetal, primary/secondary/tertiary towards the adjacent monomeric elements while still being amine, cyanate, disulfide, Sulfhydryl, Sulfonyl, and phosphate chemically bound to said adjacent monomeric elements. In groups. particular, a polypeptide or protein having random coil con 0062) If a functional group is coupled to another func formation Substantially lacks a defined secondary and tertiary tional group, the resulting chemical structure is referred to as structure. The nature of polypeptide random coils and their “linkage'. For example, the reaction of an amine functional methods of experimental identification are known to the per group with a carboxyl functional group results in an amide son skilled in the art. In particular, the lack of secondary and linkage. Further examples for linkages are ester, ether, ketal, tertiary structure of a protein may be determined by circular acetal, secondary/tertiary amine, carboxamide, Sulfide and dichroism (CD) measurements. CD spectroscopy represents disulfide linkages. a light absorption spectroscopy method in which the differ 0063 A “therapeutically effective amount of carrier ence in absorbance of right- and left-circularly polarized light linked prodrug as used herein means an amount Sufficient to by a Substance is measured. The secondary structure of a cure, alleviate or partially arrest the clinical manifestations of protein can be determined by CD spectroscopy using far a given disease and its complications. An amount adequate to ultraviolet spectra with a wavelength between approximately accomplish this is defined as “therapeutically effective 190 and 250 nm. At these wavelengths the different secondary amount. Effective amounts for each purpose will depend on structures commonly found in conformations each give rise to the severity of the disease or injury as well as the weight and a characteristic shape and magnitude of the CD spectrum. general state of the subject. It will be understood that deter Accordingly, by using CD spectrometry the skilled artisan is mining an appropriate dosage may be achieved using routine readily capable of determining whether an amino acid poly experimentation, by constructing a matrix of values and test mer adopts random coil conformation at physiological con ing different points in the matrix, which is all within the ditions. ordinary skills of a trained physician. 0070. When determining whether a peptide or protein 0064 “Free form of a drug refers to the drug in its adopts random coil conformation under experimental condi unmodified, pharmacologically active form, such as after tions using the methods as described herein, the biophysical being released from a carrier-linked prodrug. parameters such as temperature, pH, osmolarity and protein US 2014/0243254 A1 Aug. 28, 2014

content may be different to the physiological conditions nor animal, vegetable or synthetic origin, including but not lim mally found in vivo. Temperatures between 1° C. and 42°C. ited to peanut oil, soybean oil, mineral oil, Sesame oil and the or preferably 4°C. to 25°C. may be considered useful to test like. Water is a preferred excipient when the pharmaceutical and/or verify the biophysical properties and biological activ composition is administered orally. Saline and aqueous dex ity of a peptide or protein under physiological conditions in trose are preferred excipients when the pharmaceutical com vitro. position is administered intravenously. Saline Solutions and 0071. Several buffers, in particular in experimental set aqueous dextrose and glycerol Solutions are preferably tings (for example in the determination of protein structures, employed as liquid excipients for injectable solutions. Suit in particular in circular dichroism (CD) measurements and able pharmaceutical excipients include starch, glucose, lac other methods that allow the person skilled in the art to tose, Sucrose, mannitol, trehalose, gelatin, malt, rice, flour, determine the structural properties of a protein/polypeptide or chalk, silica gel, Sodium Stearate, glycerol monostearate, talc, peptide stretch) or in buffers, solvents and/or excipients for Sodium chloride, dried skim milk, glycerol, propylene, gly pharmaceutical compositions, are considered to represent col, water, ethanol and the like. The composition, if desired, “physiological Solutions' or “physiological conditions in can also contain minor amounts of wetting or emulsifying vitro. Examples of such buffers are, e.g. phosphate-buffered agents, pH buffering agents, like, for example, acetate. Suc saline (PBS: 115 mM NaCl, 4 mM. KHPO, 16 mM cinate, tris, carbonate, phosphate, HEPES (4-(2-hydroxy NaHPO pH 7.4), Tris buffers, acetate buffers, citrate buffers ethyl)-1-piperazineethanesulfonic acid), MES (2-(N-mor or similar buffers such as those used in the appended pholino)ethanesulfonic acid), or can contain detergents, like examples. Generally, the pH of a buffer representing physi Tween, poloxamers, poloxamines, CHAPS, Igepal, or amino ological conditions should lie in a range from 6.5 to 8.5. acids like, for example, glycine, lysine, or histidine. These preferably in a range from 7.0 to 8.0, most preferably in a compositions can take the form of Solutions, Suspensions, range from 7.2 to 7.7 and the osmolarity should lie in a range emulsions, tablets, pills, capsules, powders, Sustained-release from 10 to 1000 mmol/kg HO, more preferably in a range formulations and the like. The composition can beformulated from 50 to 500 mmol/kg HO and most preferably in a range as a Suppository, with traditional binders and excipients such from 200 to 350 mmol/kg HO. Optionally, the protein con as triglycerides. Oral formulation can include standard tent of a buffer representing physiological conditions may lie excipients such as pharmaceutical grades of mannitol, lac in a range from 0 to 100 g/l, neglecting the protein with tose, starch, magnesium Stearate, Sodium saccharine, cellu biological activity itself, whereby typical stabilizing proteins lose, magnesium carbonate, etc. Examples of Suitable phar may be used, for example human or bovine serum albumin. maceutical excipients are described in “Remington's 0072 Other established biophysical methods for deter Pharmaceutical Sciences” by E. W. Martin. Such composi mining random coil conformation include nuclear magnetic tions will contain a therapeutically and/or diagnostically resonance (NMR) spectroscopy, absorption spectrometry, effective amount of the water-soluble carrier-linked prodrug, infrared and Raman spectroscopy, measurement of the hydro preferably in purified form, together with a suitable amount of dynamic Volume via size exclusion chromatography, analyti excipient so as to provide the form for proper administration cal ultracentrifugation and dynamic? static light scattering as to the patient. The formulation should suit the mode of admin well as measurements of the frictional coefficient or intrinsic istration. Viscosity. 0076. The term “pharmaceutically acceptable” means 0073. The terms “spacer”, “spacer group”, “spacer mol approved by a regulatory agency Such as the EMEA (Europe) ecule', and 'spacer moiety are used interchangeably and and/or the FDA (US) and/or any other national regulatory refer to any moiety Suitable for connecting two moieties, such agency for use in animals, preferably in humans. as Clso alkyl, C2-soalkenyl or C2-soalkinyl, which moiety is 0077. “Dry composition” means that the pharmaceutical optionally interrupted by one or more groups selected from composition comprising water-soluble carrier-linked pro —NH , —N(C. alkyl)-, —O— —S , —C(O)—, drug according to the present invention is provided in a dry —C(O)NH , —C(O)N(C. alkyl)-, —O—C(O)—, form in a container. Suitable methods for drying are spray —S(O)— —S(O). , 4- to 7-membered heterocyclyl, phe drying and lyophilization (freeze-drying). Such dry compo nyl and naphthyl. sition of water-soluble carrier-linked prodrug has a residual 0074 "Pharmaceutical composition” or “composition' water content of a maximum of 10%, preferably less than 5% means a composition containing one or more drugs or pro and more preferably less than 2% (determined according to drugs, and optionally one or more pharmaceutically accept Karl Fischer). The preferred method of drying is lyophiliza able excipients, as well as any product which results, directly tion. "Lyophilized composition” means that the pharmaceu orindirectly, from combination, complexation or aggregation tical composition comprising water-soluble carrier-linked of any two or more of the excipients, or from dissociation of prodrug was first frozen and Subsequently Subjected to water one or more of the pharmaceutically acceptable excipients, or reduction by means of reduced pressure. This terminology from other types of reactions or interactions of one or more of does not exclude additional drying steps which may occur in the pharmaceutically acceptable excipients. Accordingly, the the manufacturing process prior to filling the composition pharmaceutical compositions of the present invention into the final container. encompass any composition obtainable by admixing a water 0078 “Lyophilization' (freeze-drying) is a dehydration soluble carrier-linked prodrug of the present invention and process, characterized by freezing a composition and then optionally one or morepharmaceutically acceptable excipi reducing the Surrounding pressure and, optionally, adding ent. heat to allow the frozen water in the composition to sublime 0075. The term “excipient” refers to a diluent, adjuvant, or directly from the solid phase to gas. Typically, the sublimed vehicle with which a water-soluble carrier-linked prodrug is water is collected by desublimation. administered. Such pharmaceutical excipient can be sterile 0079 “Lyophilized composition” means that the pharma liquids, such as water and oils, including those of petroleum, ceutical composition comprising water-soluble protein car US 2014/0243254 A1 Aug. 28, 2014

rier-linked prodrug was first frozen and Subsequently Sub - C=CH, -CH C=CH, CH, CH, C=CH, CH jected to water reduction by means of reduced pressure. This C=C CH, or e.g. —C=C when two moieties of a mol terminology does not exclude additional drying steps which ecule are linked by the alkynyl group. Optionally, one or more may occur in the manufacturing process prior to filling the hydrogen atom(s) of a Clso alkynyl carbon may be replaced composition into the final container. by a substituent as further specified. Accordingly, the term 0080 “Alkyl means a straight-chain (linear, unbranched) “alkynyl relates to a carbon chain with at least one carbon or branched carbon chain (unsubstituted alkyl). Optionally, triple bond. Optionally, one or more double bonds may occur. one or more hydrogen atom(s) of an alkyl carbon may be I0088 “C., cycloalkyl or “C., cycloalkyl ring” means a replaced by a Substituent as indicated herein. In general, a cyclic alkyl chain having 3 to 7 carbon atoms, which may preferred alkyl is Calkyl. "Calkyl means an alkyl chain have carbon-carbon double bonds being at least partially satu having 1 to 4 carbon atoms (unsubstituted C alkyl), e.g. if rated (unsubstituted C-7 cycloalkyl), e.g. cyclopropyl. present at the end of a molecule: methyl, ethyl, n-propyl. cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohep isopropyl. n-butyl, isobutyl, sec-butyl tert-butyl, or e.g. tyl. Optionally, one or more hydrogenatom(s) of a cycloalkyl —CH2—, —CH2—CH2—, —CH(CH)— —CH2—CH2— carbon may be replaced by a Substituent as indicated herein. CH2—, —CH(CHs)— —C(CH) , when two moieties The term "C., cycloalkyl or “C., cycloalkyl ring also of a molecule are linked by the alkyl group (also referred to as includes bridged bicycles like norbonane (norbonanyl) or C. alkylene). Optionally, one or more hydrogen atom(s) of norbonene (norbonenyl). Accordingly, "Cs cycloalkyl a C alkyl carbon may be replaced by a substituent as indi means a cycloalkyl having 3 to 5 carbon atoms. Accordingly, cated herein. Accordingly, "Clso alkyl means an alkyl chain “Clio cycloalkyl means a cycloalkyl having 3 to 10 carbon having 1 to 50 carbon atoms. atOmS. I0081) “Calkyl” means an alkyl chain having 1-6 carbon I0089) “Halogen' means fluoro, chloro, bromo or iodo. It is atoms, e.g. if present at the end of a molecule: C. alkyl, generally preferred that halogen is fluoro or chloro. methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, Sec-bu (0090. “4 to 7 membered heterocyclyl or “4 to 7 mem tyl, tert-butyl, n-pentyl, n-hexyl, or e.g. —CH2—, —CH2— bered heterocycle” means a ring with 4, 5, 6 or 7 ring atoms CH2—, —CH(CH)—, C(CH2) , CH-CH that may contain up to the maximum number of double bonds CH2—, —CH(CHs)— —C(CH) , when two moieties (aromatic or non-aromatic ring which is fully, partially or of a molecule are linked by the alkyl group (also referred to as un-saturated) wherein at least one ring atom up to 4 ring C. alkylene). One or more hydrogenatom(s) of a C- alkyl atoms are replaced by a heteroatom selected from the group carbon may be replaced by a substituent as indicated herein. consisting of Sulfur (including —S(O)— —S(O) ), oxy The terms C as alkyl or Cs alkylene are defined accord gen and nitrogen (including=N(O)—) and wherein the ring ingly. is linked to the rest of the molecule via a carbon or nitrogen 0082 “Calkenyl' means an alkenyl chain having 2 to 6 atom (unsubstituted 4 to 7 membered heterocyclyl). For the carbon atoms, e.g. if present at the end of a molecule: sake of completeness it is indicated that in Some embodiments -CH=CH, -CH=CH-CH, CH-CH=CH, of the present invention, 4 to 7 membered heterocyclyl has to -CH=CH-CH CH-CH=CH-CH=CH, or e.g. fulfill additional requirements. Examples for a 4 to 7 mem —CH=CH , when two moieties of a molecule are linked bered heterocycles are azetidine, oxetane, thietane, furan, by the alkenyl group. One or more hydrogenatom(s) of a C thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyra alkenyl carbon may be replaced by a Substituent as indicated Zole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, herein. thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, I0083. The term Calkenyl is defined accordingly. thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrroli 0084 “C. alkynyl' means an alkynyl chain having 2 to 6 dine, imidazolidine, pyrazolidine, oxazolidine, isoxazoli carbon atoms, e.g. if present at the end of a molecule: dine, thiazolidine, isothiazolidine, thiadiazolidine, Sulfolane, -C=CH, -CH C=CH, CH-CH C=CH, CH pyran, dihydropyran, tetrahydropyran, imidazolidine, pyri C=C CH, or e.g. —C=C when two moieties of a mol dine, pyridazine, pyrazine, pyrimidine, piperazine, piperi ecule are linked by the alkynyl group. One or more hydrogen dine, morpholine, tetrazole, triazole, triazolidine, tetrazoli atom(s) of a C- alkynyl carbon may be replaced by a Sub dine, diazepane, azepine or homopiperazine. Optionally, one stituent as indicated herein. The term C alkynyl is defined or more hydrogen atom(s) of a 4 to 7 membered heterocyclyl accordingly. may be replaced by a Substituent. 0085 “Clso alkenyl' means a branched or unbranched (0091 “8 to 11 membered heterobicyclyl” or “8 to 11 mem alkenyl chain having 2 to 50 carbon atoms (unsubstituted bered heterobicycle” means a heterocyclic system of two Clso alkenyl), e.g. if present at the end of a molecule: rings with 8 to 11 ring atoms, where at least one ring atom is -CH=CH, -CH=CH-CH, CH-CH=CH, shared by both rings and that may contain up to the maximum -CH=CH-CH CH-CH=CH-CH=CH, or e.g. number of double bonds (aromatic or non-aromatic ring —CH=CH , when two moieties of a molecule are linked which is fully, partially or un-saturated) wherein at least one by the alkenyl group. Optionally, one or more hydrogenatom ring atom up to 6 ring atoms are replaced by a heteroatom (s) of a C-soalkenyl carbon may be replaced by a Substituent selected from the group consisting of Sulfur (including as further specified. —S(O)— —S(O) ), oxygen and nitrogen (including I0086 Accordingly, the term “alkenyl relates to a carbon —N(O)—) and wherein the ring is linked to the rest of the chain with at least one carbon carbon double bond. Option molecule via a carbon or nitrogenatom (unsubstituted 8 to 11 ally, one or more triple bonds may occur. The term "Cs membered heterobicyclyl). Examples for a 8 to 11 membered alkenyl' is defined accordingly. heterobicycle are indole, indoline, benzofuran, ben 0087. “Clso alkynyl means a branched or unbranched Zothiophene, benzoxazole, benzisoxazole, benzothiazole, alkynyl chain having 2 to 50 carbon atoms (unsubstituted benzisothiazole, benzimidazole, benzimidazoline, quinoline, Clso alkynyl), e.g. if present at the end of a molecule: quinazoline, dihydroquinazoline, quinoline, dihydroquino US 2014/0243254 A1 Aug. 28, 2014 line, tetrahydroquinoline, decahydroquinoline, isoquinoline, (R'R'''), or C, alkyl, wherein C, alkyl is decahydroisoquinoline, tetrahydroisoquinoline, dihydroiso optionally substituted with one or more halogen, quinoline, benzazepine, purine or pteridine. The term 8 to 11 which are the same or different, membered heterobicycle also includes spiro structures of two 01.00 Rbl s Rb 1 1a, Rb12, Rb12a, Rb12b a indepen rings like 1,4-dioxa-8-azaspiro4.5 decane orbridged hetero dently selected from the group consisting of H; or C. cycles like 8-aza-bicyclo[3.2.1]octane. The term "9 to 11 alkyl, wherein Calkyl is optionally substituted with membered heterobicyclyl or “9 to 11 membered heterobi one or more halogen, which are the same or different. cycle' is defined accordingly. 0101 The term “interrupted' means that between two car 0092. The term “aliphatic' means fully saturated. bons a group is inserted or that at the end of the carbon chain 0093. The term “interrupted” means that between two car between the carbon and hydrogen. bon atoms of for example, a linker or a spacer or at the 0102. In general the term “comprise' or “comprising also respective end of the carbon chain between the respective encompasses "consist of or “consisting of. carbonatom and the hydrogenatom a group (such a —O— or 0103) In the following section the invention is described in —NH ) is inserted. further detail. 0094. In general the term “substituted” preferably refers to 0104. The present invention refers to a water-soluble car substituents, which are the same or different and which are rier-linked prodrug of formula (I): independently selected from the group consisting of halogen, ((D-L-(SP } }.Hyp–)-POL-Hyp--(-(SP)-L-D), (I), CN, COOR, OR, C(O)R’, C(O)N(RR), S(O)N (Rh9Rh9a), S(O)N(RR9), S(O)R’, S(O)R’, N(R)S 01.05 wherein (O)N(RaR), SR, N(R'R''), NO, OC(O)R’, 01.06 Hyp-POL-Hyp form a carrier moiety, and N(R9)C(O)R9, N(R)S(O).R., N(R9)S(O)R’9, wherein N(R)C(O)OR, N(R)C(O)N(RR), OC(O)N 0107 POL is a polymeric moiety having a molecular (R'R''), T. Clso alkyl, Clso alkenyl, and Clso alkynyl, weight ranging from 0.2 kDa to 160 kDa, I0095 wherein T. Clso alkyl, Clso alkenyl, and Clso 0108) each Hyp is independently a hyperbranched alkynyl are optionally substituted with one or more R', moiety, which are the same or different, and wherein Clso alkyl: 0109 each SP is independently a spacer moiety, C2-so alkenyl; and C2-so alkynyl are optionally inter 0110 each L is independently a reversible prodrug rupted by one or more groups selected from the group linker moiety, 0111 each D is independently a biologically active moiety, 0112 m is 0 or 1, 0113 each n is independently an integer from 2 to 200, in particular from 2 to 64, more preferably from 2 to 32 and even more preferably from 2 to 16, (R11) : and OC(O)N(R'R'' 1); 0114 each x is independently 0 or 1; 0096. R. R. Rare independently selected from 0115 or a pharmaceutically acceptable salt thereof. the group consisting of H. T. and C-so alkyl: C-so 0116. The moieties Hyp of the water-soluble carrier alkenyl; and Clso alkynyl, linked prodrug of formula (I) may be the same or different. I0097 wherein T”, C, so alkyl, Clso alkenyl, and Preferably all moieties Hyp of formula (I) are the same. Clso alkynyl are optionally Substituted with one or 0117. The moieties SP of the water-soluble carrier-linked more R', which are the same or different, and prodrug of formula (I) may be the same or different. Prefer wherein Clso alkyl, C2-soalkenyl; and C2-so alkynyl ably all moieties SP of formula (I) are the same. are optionally interrupted by one or more groups 0118. The moieties L of the water-soluble carrier-linked selected from the group consisting of T, C(O)O , prodrug of formula (I) may be the same or different. Prefer ably all moieties L of formula (I) are the same. 0119 The moieties D of the water-soluble carrier-linked prodrug of formula (I) may be the same or different. Prefer ably all moieties D of formula (I) are the same. I0120 Each n of the water-soluble carrier-linked prodrug of formula (I) may be the same or different. Preferably all n of formula (I) are the same. I0121 Each x of the water-soluble carrier-linked prodrug nyl, naphthyl, indenyl, indanyl, tetralinyl, Co of formula (I) may be the same or different. Preferably all x of cycloalkyl, 4- to 7-membered heterocyclyl, and 9- to formula (I) are the same. 11-membered heterobicyclyl, wherein T is option 0.122 Preferably, all n, X and all moieties Hyp, SP. L., D of ally substituted with one or more R', which are the the water-soluble carrier-linked prodrug of formula (I) are the same or different, SaC. 0099 R is halogen, CN, oxo (=O), COOR, I0123. It is understood that n is equal to or less than the OR 12, C(O)R2, C(O)N(R2R12), S(O)N number of functional groups of Hyp of formula (I). (Rb12Rb12a), S(O)N(Rb12Rb2a), S(O).R., S(O) 0.124. In one embodiment m is 0. Rb12, N(R12)SO)N(R2R12), SR 12, 0.125. In another embodiment, m is 1. N(R 2Rb 12)NO, OC(O)R’ 12, N(R 2)C(O)R’ 2a, 0.126 The moiety POL has a molecular weight from 0.2 N(R12)SO). R12, N(R12)SCo)R12, N(R12)C kDa to 160 kDa, preferably from 2 kDa to 80 kDa, and more (O)OR 12a, N(R 2)C(O)N(R 2aRb 12b). OC(O)N preferably from 5 kDa to 40 kDa. US 2014/0243254 A1 Aug. 28, 2014

0127. In a preferred embodiment, POL comprises, prefer preferably a permanent linkage comprising, preferably con ably consists of a polymer selected from the group of poly sisting of a linkage group selected from amine, amide, car mers consisting of polypeptides, 2-methacryloyl-oxyethyl bamate, thioether, or ether groups, and most preferably each phosphoyl cholins, water-soluble hydrogels, water-soluble permanent linkage between POL and Hyp of formula (I) is an PEG-based hydrogels, water-soluble hyaluronic acid-based amide linkage. hydrogels, poly(acrylic acids), poly(acrylates), poly(acryla mides), poly(alkyloxy) polymers, poly(amides), poly(ami 0143. In another preferred embodiment, POL comprises, doamines), poly(amino acids), poly(anhydrides), poly(aspar preferably is a polypeptide or protein, in particular a non tamides), poly(butyric acids), poly(glycolic acids), immunogenic polypeptide, even more preferably a polypep polybutylene terephthalates, poly(caprolactones), poly(car tide as described below. bonates), poly(cyanoacrylates), poly(dimethylacrylamides), 0144. In one preferred embodiment, the moiety POL of poly(esters), poly(ethylenes), poly(ethyleneglycols), poly formula (I) is a polypeptide which comprises at least about (ethylene oxides), poly(ethyl phosphates), poly(ethyloxazo lines), poly(glycolic acids), poly(hydroxyethyl acrylates), 100 amino acid residues, in particular which consists of at poly(hydroxyethyloxazolines), poly(hydroxymethacry least about 100 amino acid residues. In a preferred embodi lates), poly(hydroxypropylmethacrylamides), poly(hydrox ment, amino acids selected from alanine, serine and/or pro ypropyl methacrylates), poly(hydroxypropyloxazolines), line residues are present, in particular alanine, serine and poly(iminocarbonates), poly(lactic acids), poly(lactic-co proline residues are mainly present, and which polypeptide glycolic acids), poly(methacrylamides), poly(methacry moiety preferably has a random coil conformation at physi lates), poly(methyloxazolines), poly(organophosphaZenes), ological conditions. It is understood that such a polypeptide poly(ortho esters), poly(oxazolines), poly(propylene gly cols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), moiety POL may transiently or temporarily not form a ran poly(vinyl amines), poly(Vinylmethylethers), poly(vinylpyr dom coil, for example when present in a lyophilisate or dried rolidones), silicones, celluloses, carbomethyl celluloses, composition. hydroxypropyl methylcelluloses, chitins, chitosans, dex 0145 A moiety POL of formula (I) may have a random trans, dextrins, gelatins, hyaluronic acids and derivatives, coil conformation with an amino acid sequence consisting of functionalized hyaluronic acids, mannans, pectins, rham maximally about 1500 amino acid residues, preferably of nogalacturonans, starches, hydroxyalkyl starches, hydroxy ethyl starches and other carbohydrate-based polymers, maximally about 900 amino acid residues, more preferably of Xylans, and copolymers thereof. maximally about 800 amino acid residues, even more prefer 0128. The polymeric moiety POL may comprise a linear ably of maximally about 700 amino acid residues, particu or branched polymer. Preferably, POL comprises, in particu larly preferably of maximally about 600 amino acid residues. lar consists of a linear polymer. Thus, the amino acid sequence forming random coil confor 0129. In one preferred embodiment, POL comprises, in mation may consist of maximally about 500 amino acid resi particular consists of a PEG-based polymer or a poly(oxazo dues or of maximally about 450 amino acid residues. Accord line)-based polymer, more preferably a linear PEG-based ingly, the amino acid sequence forming random coil polymer. conformation may consist of about 100 to about 1500 amino 0130. If m in formula (I) is 0, it is preferred that POL comprises, preferably consists of a structure of the formula acid residues. 0146 In particular embodiments said amino acid sequence forming random coil conformation consists of 0131 wherein about 100 to 1000 amino acid residues as characterized I0132 n is 1, 2, 3, or 4, preferably n is 1, 2, or 3, and more herein, i.e. comprising alanine, serine and proline as main or preferably 2 or 3: unique residues as defined below. 0.133 p is an integer from 5 to 2000, preferably p is an 0.147. In a preferred embodiment, a polypeptide moiety integer from 10 to 1000, more preferably p is an integer from 100 to 1000; POL consists mainly of the amino acid residues alanine, 0.134 X2 is a functional group covalently linked to Hyp: serine and proline, whereby proline residues represent pref and erably about 4% to about 40% of the polypeptide moiety 0.135 X1 is selected from H, CH, and C.H. POL. The alanine and serine residues comprise the remaining 0136. If m in formula (I) is 1, it is preferred that POL at least 60% to 96% of the polypeptide moiety POL. However, comprises, preferably consists of a structure of the formula as will be detailed herein below said polypeptide moiety POL may also comprise further amino acids differing from ala —X3-(CH2)—(OCH2CH2) O-(CH2)2 X2-, nine, serine, and proline, i.e. as minor constituents. 0.137 wherein 0.148. The term “minor constituent as used herein means 0.138 n1 and n2 are independently 1, 2, 3, or 4, prefer that maximally 10% (i.e. maximally 10 of 100 amino acids) ably n1 and n2 are independently 1, 2, or 3, more pref erably 2 or 3: may be different from alanine, serine and proline, preferably 0.139 p is an integer from 5 to 2000, preferably p is an maximally 8% (i.e. maximally 8 of 100 amino acids) may be integer from 10 to 1000, more preferably p is an integer different than alanine, serine and proline, more preferably from 100 to 1000; and maximally 6% (i.e. maximally 6 of 100 amino acids) may be 0140 X2 and X3 are independently a functional group different from alanine, serine and proline, even more prefer covalently linked to Hyp. ably maximally 5% (i.e. maximally 5 of 100 amino acids) 0141. In a preferred embodiment m in formula (I) is 0. may be different from alanine, serine and proline, particularly 0142 Preferably, a linkage between a moiety POL and a preferably maximally 4% (i.e. maximally 4 of 100 amino moiety Hyp of formula (I) is a permanent linkage, more acids) may be different from alanine, serine and proline, more US 2014/0243254 A1 Aug. 28, 2014

particularly preferably maximally 3% (i.e. maximally 3 of (O155 x is an integer from 0 to 6, 100 amino acids) may be different from alanine, serine and 0156 each y is independently an integer from 1 to 6, proline, even more particularly preferably maximally 2% (i.e. 0157 each Z is independently an integer from 1 to 6. maximally 2 of 100 amino acids) may be different from alanine, serine and proline and most preferably maximally 0158 n is any integer so that a polypeptide moiety POL 1% (i.e. maximally 1 of 100 of the amino acids) may be consists of at least about 100 amino acid residues, and in different from alanine, serine and proline. Said amino acids particular of at least about 100 to about 3000 amino acid different from alanine, serine and proline may be selected residues, preferably to about 2000 and more preferably from the group consisting of different from alanine, serine to about 1000 amino acid residues. and proline may be selected from the group of natural or 10159. The integersy and z in the n monomers Ala, Ser proteinogenic amino-acids consisting of Arg, ASn, Asp, Cys, may be the same or different. Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Thr, Trp, Tyr, Val, 0160. In another preferred embodiment, a moiety POL of Selenocystein, selenomethionin, and hydroxyproline. Minor formula (I) comprises no more than 5 identical consecutive constituents may also be selected from non-naturally occur amino acid residues, more preferably no more than 4 identical ring amino acids. consecutive amino acid residues and most preferably no more 0149. The term “at least about 100/150/200/250/300/300/ than 3 identical consecutive amino acid residues. 350 (etc) amino acid residues is not limited to the concise 0.161. As already indicated herein above, a moiety POL of number of amino acid residues but also comprises amino acid formula (I) comprises in one embodiment proline residues, stretches that comprise an additional 10% to 20% or comprise wherein said proline residues constitute more than about 4%, 10% to 20% less residues. For example “at least about 100 preferably more than about 5%, even more preferably more amino acid residues' may also encompass 80 to 100 and than about 6%, particularly preferably more than about 8%, about 100 to 120 amino acid residues without deferring from more particularly preferably more than about 10%, even more the gist of the present invention. particularly preferably more than about 15% and most pref 0150. In one embodiment, the moiety POL of formula (I) erably more than about 20% of the amino acids of the moiety comprises a plurality of polymer cassettes wherein said poly POL of formula (I). mercassettes consist of one, two or three, preferably three of 0162. In another preferred embodiment, a moiety POL of the amino acids selected from Ala, Ser, and Pro and wherein formula (I) comprises more than about 4% but less than about no more than 6 consecutive amino acid residues are identical 50%, preferably more than about 10% but less than about and wherein said proline residues constitute more than 4% 50% and most preferably more than about 20% but less than and less than 40% of the amino acids of said moiety POL. about 50% alanine residues of the amino acids constituting 0151. A moiety POL of formula (I) may comprise a plu the moiety POL of formula (I). rality, in particular 2, 3, 4, 5 or more of identical polymer cassettes or a plurality of non-identical polymer casettes. 0163. In a further preferred embodiment, a moiety POL of Preferred examples of polymer cassettes consisting of Ala, formula (I) comprises more than about 4% and less than about Ser and Pro residues are provided herein below; see SEQID 50%, preferably more than about 10% but less than about NO:9, SEQID NO:10, SEQID NO:11, SEQID NO:12, SEQ 50% and most preferably more than about 20% but less than ID NO:13 and SEQID NO:14 or peptide fragments or mul about 50% serine residues of the amino acids constituting the timers of these sequences. A polymer cassette may consist of moiety POL of formula (I). at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 0164 Preferably, a moiety POL of formula (I) comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more amino acid about 35% proline residues, about 50% alanine residues and residues, wherein each polymer cassette comprises (an) Ala, about 15% serine residues of the amino acids constituting the Ser, and Pro residue(s). moiety POL of formula (I). Alternatively, a moiety POL of 0152. In one embodiment, the polymer cassette according formula (I) may comprise about 35% proline residues, about to the present invention does not comprise more than 100 15% alanine residues and about 50% serine residues of the amino acid residues. Preferably, a polymercassette as defined amino acids constituting the moiety POL of formula (I). herein comprises more than about 4%, preferably more than (0165 Preferably, a moiety POL of formula (I) comprises about 5%, even more preferably more than about 6%, par one or more of the following alanine-serine polymer cas ticularly preferably more than about 8%, more particularly Settes: preferably more than about 10%, even more particularly pref erably more than about 15% and most preferably more than SEQ ID NO: 1 about 20% proline residues. Such polymer cassette as defined AAAASSASSASSSSSAAASA herein preferably comprises less than about 40% or less than about 35% proline residues. SEQ ID NO: 2 0153. In one preferred embodiment the moiety POL of AASAAASSAAASAAAASASS formula (I) comprises, in particular consists of formula (a): SEQ ID NO: 3 ASASASASASASSAASA ASA Ser, Ala Ser), (a), SEQ ID NO: 4 0154 which formula further comprises proline residues SAASSSASSSSAASSASAAA as defined herein and wherein US 2014/0243254 A1 Aug. 28, 2014 10

- Continued 0170 Therefore, preferred polymer cassettes for a moiety POL of formula (I) are selected from the following SEO ID NO : 5 SSSSAASA ASAAAAASSSAS Sequences:

SEQ ID NO: 6 SSASSSAASSSASSSSASAA (SEO ID NO: 9) ASPAAPAPASPAAPAPSAPA, SEO ID NO : 7 SASASASASASA ASSASSAS, (SEQ ID NO: 10) AAPASPAPAAPSAPAPAAPS, and (SEQ ID NO: 11) SEQ ID NO: 8 APSSPSPSAPSSPSPASPSS, ASSAAASAAAASSAASASSS. (SEQ ID NO: 12) 0166 The multimers of these alanine-serine polymer cas SSPSAPSPSSPASPSPSSPA settes may form random coil conformation in case the result (SEQ ID NO: 13) ing amino acid sequence further comprises proline residues AASPAAPSAPPAAASPAAPSAPPA, and as defined herein above. (SEQ ID NO: 14) 0167. In a preferred embodiment, a moiety POL of for ASAAAPAAASAAASAPSAAA; mula (I) comprises one or more of the following polymer CaSSettes: 0171 or circular permuted versions or (a) multimer(s) of these sequences as a whole or parts of these Sequences. SEO ID NO : 9 0172 Again, also (a) peptide fragment(s) or (a) multimer ASPAAPAPASPAAPAPSAPA (s) or circularly permuted versions of these sequences and the SEO ID NO: 10 sequences provided herein above may be employed in context AAPASPAPAAPSAPAPAAPS of the present invention as polymer cassettes for a moiety SEO ID No: 11 POL of formula (I). APSSPSPSAPSSPSPASPSS, 0173 Accordingly, the exemplified polymer cassettes and may also provide for individual peptide fragments which may be newly combined to form further polymer cassettes. SEO ID NO: 15 0.174. In accordance with the above, a moiety POL of SAPSSPSPSAPSSPSPASPS. formula (I) may comprise a multimer of sequences consisting (0168 SEQID NO:15 corresponds to the herein provided of either one of the amino acid sequences with SEQID NO:9, SEQID No:11 in a circularly permuted form, wherein the last 10, 11, 12, 13 or 14 as disclosed herein above or may com serine was removed and another serine was appended as prise a multimer of sequences consisting of more than one of starting amino acid. As a consequence, multimers of this amino acid sequences SEQID NO:9, 10, 11, 12, 13 and 14. modified sequence possess essentially the same internal Furthermore, it is envisaged that also peptide fragments or repeating unit as multimers of the non-modified sequence, circularly permuted versions of these exemplified sequences except for the very first and the very last residue. Accordingly, may be used to build up further polymer cassettes of a moiety SEQID NO:15 may be considered as an example of a further POL of formula (I). polymer cassette for a polypeptide moiety POL. It is clear for 0.175. In another embodiment, a moiety POL of formula the person skilled in the art that also other polymer cassettes (I) may comprise a multimer of sequences consisting of a and (shorter) peptide fragments or circularly permuted ver (circular) permutation of the amino acid sequence selected sions of the herein provided amino acid polymers may be from the group consisting of SEQID NOs: 9, 10, 11, 12, 13, used as polymer cassettes for a moiety POL of formula (I). 14, 15 or (a) multimers(s) of these (circular) permutated 0169. Yet, even further and illustrative amino acid poly Sequences. mers forming random coil conformation may comprise 0176). In yet another embodiment, a moiety POL of for amino acid sequences that may be selected from the group mula (I) may comprise a multimer consisting of a peptide consisting of the following sequences: fragment/part of the amino acid sequence selected from the group consisting of SEQID NO: 9, 10, 12, 13, 14, 15 or (a) multimers(s) of these exemplified polymer cassettes. SEO ID NO: 12 SSPSAPSPSSPASPSPSSPA 0177 Peptide fragments of these sequences to be employed for the generation of a polypeptide moiety POL SEO ID NO: 13 may consist of at least 3, preferably of at least 4, more pref AASPAAPSAPPAAASPAAPSAPPA, erably of at least 5, even more preferably of at least 6, still and more preferably of at least 8, particularly preferably of at least SEO ID NO: 14 10, more particularly preferably of at least 12, even more ASAAAPAAASAAASAPSAAA. particularly preferably of at least 14, still more particularly preferably of at least 16, and most preferably of at least 18 US 2014/0243254 A1 Aug. 28, 2014

consecutive amino acids of the amino acid sequence selected gated to at least 2 moieties L (either directly or indirectly) and from the group consisting of said SEQID NOs: 9, 10, 11, 12, has at most 31 branchings and is at most conjugated to 32 13 and 14. moieties L (either directly or indirectly). 0.178 For example, individual peptide fragments of the 0186. In a preferred embodiment, a moiety Hyp of the inventive polymer cassettes may be combined to further indi water-soluble carrier-linked prodrug of formula (I) com vidual polymer cassettes as long as the above-identified rules prises, preferably consists of a moiety selected from for the overall distribution and amount of alanine, serine and proline are respected. Again, these polymer cassettes may 0187 a polyalcohol in bound form comprising at least 2 also comprise further amino acid residues, however only as hydroxyl groups (preferably further comprising a func minimal or minor constituents, i.e. maximally 10%, prefer tional group, which is preferably an additional amine ably maximally 2% of the individual polymer cassette. POL group or a carboxylic acid group, more preferably an moieties of formula (I) comprising polymer cassettes consist, additional carboxylic acid group), in one embodiment of the present invention, of at least about 0188 preferably selected from glycerol, pentaerythri 100 amino acid residues. Individual polymer cassettes may be tol, dipentaerythritol, tripentaerythritol, hexaglycerine, combined in order to form longer random coil forming amino Sucrose, Sorbitol, fructose, mannitol, glucose, cellulose, acid polymers, whereby a maximal length of a moiety POL is amyloses, starches, hydroxyalkyl starches, polyvinylal about 1500 amino acids. cohols, dextranes, and hyualuronans, (0179. In one preferred embodiment, the moiety POL of formula (I) is covalently linked to at least one moiety Hyp, in 0189 or a polyamine in bound form comprising at least particular by a permanent linkage, more preferably by a per 2 amine groups (preferably further comprising a func manent amide linkage. tional group, which is preferably an additional hydroxyl 0180 According to formula (I), a moiety Hyp of formula group or a carboxylic acid group, more preferably a (I) is connected to n moieties L., either directly (if x of formula carboxylic acid group), preferably selected from orni (I) is 0) or indirectly through SP (if x of formula (I) is 1). It is thine, diornithine, triornithine, tetraornithine, pentaorni understood that each linkage between a moiety Hyp and a thine, hexaornithine, heptaornithine, octaornithine, non moiety L of formula (I) may independently be director indi aornithine, decaornithine, undecaornithine, rect through a moiety SP. Preferably, all linkages between a dodecaornithine, tridecaornithine, tetradecaornithine, moiety Hyp and a moiety L of formula (I) are either director pentadecaornithine, hexadecaornithine, heptadecaorni thine, octadecaornithine, nonadecaornithine, diami indirect through a moiety SP. nobutyric acid, di(diaminobutyric acid), tri(diaminobu 0181. In a preferred embodiment, a moiety Hyp of formula tyric acid), tetra(diaminobutyric acid), penta (I) is connected to a moiety SP (if x of formula (I) is 1) or to (diaminobutyric acid), hexadiaminobutyric acid), hepta a moiety L (if X of formula (I) is 0) through a linkage group (diaminobutyric acid), octa(diaminobutyric acid), nona selected from amide, carbamate, ester, ether, amine or thio (diaminobutyric acid), decadiaminobutyric acid), ether; preferably, a moiety Hyp of formula (I) is connected to undecacdiaminobutyric acid), dodecadiaminobutyric a moiety SP (if x of formula (I) is 1) or to a moiety L (if x of acid), tridecadiaminobutyric acid), tetradecac diami formula (I) is 0) through a linkage group selected from amide, nobutyric acid), pentadecadiaminobutyric acid), hexa thioether or ether, even more preferably through an amide decadiaminobutyric acid), heptadecacdiaminobutyric group. acid), octadecacdiaminobutyric acid), nonadecac diami 0182 Optionally, a functional group of Hyp which is not nobutyric acid), lysine, dilysine, trilysine, tetralysine, connected to a moiety SP or a moiety L of formula (I) may be pentalysine, hexylysine, heptalysine, octalysine, nonal capped with a suitable capping reagent or may optionally be ysine, decalysine, undecalysine, dodecalysine, tridecal connected to at least one targeting moiety, in particular ysine, tetradecalysine, pentadecalysine, hexadecal through permanent linkages. Preferably, all functional groups ysine, heptadecalysine, octadecalysine, nonadecalysine, of a moiety Hyp of formula (I) are connected to a moiety L or oligolysines, triornithine, tetraornithine, pentaornithine, SP. Targeting moieties, if present, may be conjugated to Hyp hexaornithine, heptaornithine, octaornithine, nonaorni either directly or indirectly through spacer moieties. thine, decaornithine, undecaornithine, dodecaornithine, 0183 Examples of suitable capping moieties are linear, tridecaornithine, tetradecaornithine, pentadecaorni branched or cyclic Cls alkyl groups. thine, hexadecaornithine, heptadecaornithine, octadeca 0184. In one embodiment, each moiety Hyp of formula (I) ornithine, nonadecaornithine, tridiaminobutyric acid, is directly or indirectly connected to at least two moieties L. tetradiaminobutyric acid, pentadiaminobutyric acid, Such as to at least three moieties L., to at least four moieties L hexadiaminobutyric acid, heptadiaminobutyric acid, or to at least five moieties L. octadiaminobutyric acid, nonadiaminobutyric acid, 0185. In a further preferred embodiment, each branched decadiaminobutyric acid, undecadiaminobutyric acid, moiety Hyp has at least 1 branching and is conjugated to at dodecadiaminobutyric acid, tridecadiaminobutyric least 2 moieties L (either directly or indirectly) and has at acid, tetradecadiaminobutyric acid, pentadecadiami most 63 branchings and is at most conjugated to 64 moieties nobutyric acid, hexadecadiaminobutyric acid, hepta L (either directly or indirectly). More preferably each decadiaminobutyric acid, octadecadiaminobutyric acid, branched moiety Hyp has at least 1 branching and is conju nonadecadiaminobutyric acid, US 2014/0243254 A1 Aug. 28, 2014 12

0.190 or a polycarboxylate inbound form comprising at tetradiaminobutyric acid, pentadiaminobutyric acid, hexadi least 2 carboxylate groups, (preferably further compris aminobutyric acid, heptadiaminobutyric acid, octadiami ing a functional group, which is preferably an additional nobutyric acid, nonadiaminobutyric acid, decadiaminobu amine group or a hydroxyl group, more preferably an tyric acid, undecadiaminobutyric acid, additional amine group), dodecadiaminobutyric acid, tridecadiaminobutyric acid, tet 0191 preferably selected from di(glutamic acid), tri radecadiaminobutyric acid, pentadecadiaminobutyric acid, (glutamic acid), tetra (glutamic acid), penta(glutamic hexadecadiaminobutyric acid, heptadecadiaminobutyric acid), hexa(glutamic acid), hepta(glutamic acid), octa acid, octadecadiaminobutyric acid, nonadecadiaminobutyric (glutamic acid), nona (glutamic acid), decac glutamic acid, di(glutamic acid), tri(glutamic acid), tetra(glutamic acid), undecaglutamic acid), dodecacglutamic acid), acid), penta(glutamic acid), hexacglutamic acid), hepta tridecacglutamic acid), tetradecaglutamic acid), penta (glutamic acid), octa(glutamic acid), nona (glutamic acid), decac glutamic acid), hexadecaglutamic acid), hepta decac glutamic acid), undecaglutamic acid), dodeca decac glutamic acid), octadecacglutamic acid), nonadeca (glutamic acid), tridecacglutamic acid), tetradecacglutamic (glutamic acid), di(aspartic acid), tri(aspartic acid), tetra acid), pentadecaglutamic acid), hexadecac glutamic acid), (aspartic acid), penta(aspartic acid), hexacaspartic acid), heptadecac glutamic acid), octadecacglutamic acid), nona hepta(aspartic acid), octa(aspartic acid), nona (aspartic decac glutamic acid), di(aspartic acid), tri(aspartic acid), tetra acid), decacaspartic acid), undecacaspartic acid), dodeca (aspartic acid), penta(aspartic acid), hexacaspartic acid), hep (aspartic acid), tridecacaspartic acid), tetradecacaspartic ta(aspartic acid), octa(aspartic acid), nona (aspartic acid), acid), pentadecacaspartic acid), hexadecacaspartic acid), decacaspartic acid), undecacaspartic acid), dodecacaspartic heptadecacaspartic acid), octadecacaspartic acid), nona acid), tridecacaspartic acid), tetradecacaspartic acid), penta decacaspartic acid), polyethyleneimines, and polyviny decacaspartic acid), hexadecacaspartic acid), heptadeca?as lamines. partic acid), octadecacaspartic acid), nonadecacaspartic acid), 0.192 In a preferred embodiment, a moiety Hyp is selected polyethyleneimines, and low-molecular weight PEI. from the group comprising, in particular consisting of, in 0193 More preferably, a moiety Hyp is selected from the bound form, dilysine, trilysine, tetralysine, pentalysine, group comprising, more preferably consisting of in bound hexylysine, heptalysine, octalysine, nonalysine, decalysine, form, trilysine, tetralysine, pentalysine, hexylysine, heptal undecalysine, dodecalysine, tridecalysine, tetradecalysine, ysine, octalysine, nonalysine, decalysine, undecalysine, pentadecalysine, hexadecalysine, heptadecalysine, octade dodecalysine, tridecalysine, tetradecalysine, pentadecal calysine, nonadecalysine, triornithine, tetraornithine, pen ysine, hexadecalysine, and heptadecalysine, even more pref taornithine, hexaornithine, heptaornithine, octaornithine, erably a moiety Hyp of formula (I) comprises, preferably nonaornithine, decaornithine, undecaornithine, dodecaorni consists of, in bound form, trilysine, heptalysine or pentade thine, tridecaornithine, tetradecaornithine, pentadecaorni calysine. thine, hexadecaornithine, heptadecaornithine, octadecaorni 0194 More preferably, a moiety Hyp of formula (I) is thine, nonadecaornithine, tridiaminobutyric acid, selected from any one of the following structures:

(ii) US 2014/0243254 A1 Aug. 28, 2014 13

-continued (iii)

(iv) US 2014/0243254 A1 Aug. 28, 2014 14

(0195 wherein moieties and/or capping groups, preferably via permanent 0.196 the dashed lines marked with an asterisk indicate linkages. It is preferred that a moiety Hyp has at least 7 attachment to POL, branchings and is conjugated to at least 8 moieties SP, L, 0.197 the unmarked dashed lines indicate attachment to targeting moieties and/or capping groups, preferably via per a sub-structure —(SP)-L-D of formula (I), manent linkages, and a moiety Hyp has at most 31 branchings 0198 q is an integer from 0 to 15, in particular from 3 to and is at most conjugated to 32 moieties SP. L. targeting 7. More preferably, q is 6. moieties and/or capping groups, preferably via permanent (0199 Preferably, a moiety Hyp of formula (I) is a heptal linkages. ysinyl group, in particular of formula (II) above. Preferably, 0201 Preferably, a moiety Hyp is a hyperbranched oli all moieties Hyp of formula have the same structure. gopeptide. Preferably, such oligopeptide comprises lysine in 0200 Preferably, a moiety Hyp of formula (I) has a bound form. molecular weight from 0.1 kDa to 4 kDa, more preferably 0202 Preferably, a moiety Hyp has a molecular weight from 0.4kDa to 2 kDa. Preferably, a moiety Hyp has at least from 0.1 kDa to 4 kDa, more preferably from 0.4 kDa to 4 3 branchings and is conjugated to at least 4 moieties SP, L, kDa, in particular from 0.4 kDa to 2 kDa. targeting moieties and/or capping groups, preferably via per (0203 Preferably, m is 0 and the sub-structure POL-Hyp manent linkages, and a moiety Hyp has at most 63 branchings of formula (I) is selected from one of the following sub and is at most conjugated to 64 moieties SP, L, targeting structures (v), (vi), (vii) and (viii):

(vi) US 2014/0243254 A1 Aug. 28, 2014 15

-continued O N

NH

(vii) US 2014/0243254 A1 Aug. 28, 2014 16

-continued (viii)

HN

O O -N-no-h- NI, O

0204 wherein 0215 T is selected from the group consisting of phenyl: 0205 dashed lines indicate attachment to sub-struc naphthyl; indenyl; indanyl, tetralinyl; Co cycloalkyl, tures —(SP)-L-D of formula (I), 4- to 7-membered heterocyclyl; or 9- to 11-membered (0206 p is an integer from 5 to 2000, preferably from 10 heterobicyclyl, wherein T is optionally substituted with to 1000, more preferably from 10 to 500, and even more one or more R, which are the same or different; preferably from 100 to 1000, 0207 q is an integer of from 0 to 15, in particular from 0216 R is halogen; CN; oxo (=O); COOR: OR; 3 to 7, more preferably q is 6. C(O)R: C(O)N(R'R''); S(O)N(R'R''); S(O)N 0208. A moiety SP of formula (I) is a spacer moiety con (RR), S(O).R.: S(O)R; N(R)S(O)N(R'R''); necting a moiety Hyp to a moiety L of formula (I). SR; N(RR):NO: OC(O)R: N(R)C(O)R’; N(R) 0209 Preferably, SP of formula (I) is selected from S(O).R.'; N(R)S(O)R’; N(R)C(O)OR; N(R)C COOR: OR: C(O)R'; C(O)N(R'R''); S(O)N(R'R''); (O)N(R'R''); OC(O)N(R'R''); or C alkyl, wherein S(O)N(R'R''); S(O).R'; S(O)R'; N(R')S(O)N(R'R''); C. alkyl is optionally substituted with one or more SR'; N(R'R''); OC(O)R'; N(R')C(O)R'': N(R')S(O).R; halogen, which are the same or different; N(R')S(O)R'': N(R')C(O)OR'': N(R')C(O)N(R'R''); 0217 R. R. R. R. Rare independently selected OC(O)N(R'R''); T: C, so alkyl: Clso alkenyl; and Clso from the group consisting of H; and C alkyl, wherein alkynyl, C. alkyl is optionally substituted with one or more 0210 wherein T. Clso alkyl, Clso alkenyl, and C-so alkynyl are optionally substituted with one or more R, halogen, which are the same or different. which are the same or different, 0218. A moiety L of formula (I) may be chosen depending 0211 and wherein Clso alkyl, C-so alkenyl; and C-so on the one or more functional groups present in the corre alkynyl are optionally interrupted by one or more groups sponding drug of a biologically active moiety D of formula Selected from the group consisting of-T-, —C(O)O—; (I). Suitable moieties L are known to the person skilled in the -O-; C(O) ; –C(O)N(R)-; –S(O)N(R)–: art and examples are given in the following sections. —S(O)N(R)-; –S(O) ; S(O)–: N(R)S(O) 0219. In a preferred embodiment, a moiety L of formula N(R)-; S : N(R) ; OC(O)R: N(R)C (I) is a traceless prodrug linker. Preferably, all moieties L of (O) ; N(R)S(O) : N(R)S(O) ; N(R)C formula (I) are traceless prodrug linkers. (QQ N(R)C(O)N(R) ; and OC(O)N (RR): 0220 A preferred reversible prodrug linker moiety for 0212 R', R', R'' are independently selected from the amine-comprising drugs is described in WO-A 2005/099768. group consisting of H. T. and Clso alkyl, C2-soalkenyl; and Therefore, the following sub-structures selected from the C2-so alkynyl, general formulae (II) and (III) are preferred embodiments for 0213 wherein T. Clso alkyl, Clso alkenyl, and Clso —(SP)-L-D for the water-soluble carrier-linked prodrug of alkynyl are optionally substituted with one or more R, the present invention according to formula (I): which are the same or different, 0214 and wherein Clso alkyl, C-so alkenyl; and C-so alkynyl are optionally interrupted by one or more groups (II) Selected from the group consisting of T. —C(O)C)—; -O-; C(O) ; –C(O)N(R)-; –S(O)N(R)–: R4 —S(O)N(R)-; –S(O) ; – S(O)–: N(R)S(O) Y (SP), , Ys N(R)-; S : N(R)-; OC(O)R: N(R)C (O) ; N(R)S(O) : N(R)S(O) ; N(R)C X-Y-(O)--Y-I-D. (O)O ; N(R)C(O)N(R) ; and OC(O)N Nu-W-Y 'A R3 (RR): US 2014/0243254 A1 Aug. 28, 2014

-continued 0238 Another suitable reversible prodrug linker moiety (III) for amine-comprising drugs is described in WO-A 2006/ 136586. Accordingly, the following sub-structures selected from the general formulas (IV), (V) and (VI) are preferred R4) (SP), embodiments for —(SP)-L-D for the water-soluble carrier Y R2 Ys linked prodrug of the present invention according to formula X-Y-(O)--Y-I-D. (I): Nu-W-Y R3 (IV) R7 R5 0221 wherein the dashed line indicates attachment to a moiety Hyp of formula (I), which moiety Hyp of for R2-O mula (I) is connected to m Sub-structures of formula (s) |R8 R6N. R4 O (II) and/or (III), and N-I-D 0222 SP, X, Y, YYYYs, R2, R3, R4, Nu, W. m. R12 R1O (SP) and D of formulas (II) and (III) have the following mean 1ng: R3-O -- 0223 D is an amine-comprising biologically active R11 R9 moiety D of formula (I) which is attached to the rest of the sub-structure shown in formula (II) or (III) by form ing a O (C=O) N. ; O-(C=S) N. ; | (V) S—(C=O) N—; or —S (C=S) N— linkage, 0224 SP is the spacer moiety SP of formula (I), 0225 x is 0 or 1, R7 (SP), 0226 Y and Y are each independently O, S or NR6, R2-O 0227 Y, is O or S, R4 O R8 R6 0228 Y is O, NR6, or—C(R7)(R8)-, N D, 0229. Y is O or S, 0230 each of R2 and R3 is a moiety selected from the R12 R1O R5 group consisting of hydrogen, Substituted or unsubsti R3-O tuted linear, branched or cyclical alkyl or heteroalkyl groups, aryls, Substituted aryls, Substituted or unsubsti R11 R9 tuted heteroaryls, cyano groups, nitro groups, halogens, carboxy groups, carboxyalkyl groups, alkylcarbonyl (VI) groups and carboxamidoalkyl groups, 0231 R4 is selected from the group consisting of hydro gen, Substituted or unsubstituted linear, branched or cyclical alkyls or heteroalkyls, aryls, Substituted aryls, (SP), R5 substituted or unsubstituted heteroaryl, substituted or unsubstituted linear, branched or cyclical alkoxys. Sub stituted or unsubstituted linear, branched or cyclical het eroalkyloxys, aryloxys or heteroaryloxys, cyano groups and halogens, 0232 R6 is selected from hydrogen, substituted or unsubstituted linear, branched or cyclical alkyls or het eroalkyls, aryls, Substituted aryls and Substituted or B unsubstituted heteroaryls, 0233 R7 and R8 are each independently selected from the group consisting of hydrogen, Substituted or unsub 0239 wherein the dashed line indicates attachment to a stituted linear, branched or cyclical alkyls or het moiety Hyp of formula (I), which moiety Hyp of for eroalkyls, aryls, Substituted aryls, Substituted or unsub mula (I) is connected to m Sub-structures of formula (s) stituted heteroaryls, carboxyalkyl groups, alkylcarbonyl (IV), (V) and/or (VI), and groups, carboxamidoalkyl groups, cyano groups, and 0240 wherein SP, X, R2, R3, R4, R5, R6, R7, R8, R9, halogens, R10, R11, R12 and D of formulas (IV), (V) and (VI) 0234 W is selected from substituted or unsubstituted have the following meaning: linear, branched or cyclical alkyls, aryls, Substituted 0241. D is an amine-comprising biologically active aryls, substituted or unsubstituted linear, branched or moiety D of formula (I), cyclical heteroalkyls, substituted or unsubstituted het eroaryls, 0242 SP is the spacer moiety SP of formula (I), 0235 Nu is a nucleophile, 0243 x is 0 or 1, 0236 m is zero or a positive integer, and 0244 Y1 is O, S, NR6, succinimide, maleimide, an 0237 Aris a multi-substituted aromatic hydrocarbon or unsaturated carbon-carbon bond, or any heteroatom multi-substituted aromatic heterocycle. containing a free electron pair or Y1 is absent, US 2014/0243254 A1 Aug. 28, 2014

0245 R2 and R3 are selected independently from 0263. In the sub-structure —(SP)-L-D of formula (VII) hydrogen, acyl groups, and protecting groups for the moiety L is of formula (VIIa): hydroxyl groups; 0246 R4 to R12 are selected independently from hydrogen, Substituted or non-substituted linear, (VIIa)

branched or cyclical alkyl or heteroalkyl, aryls, substi R1 R1a tuted aryls, substituted or non-substituted heteroaryls, cyano, nitro, halogen, carboxy, and carboxamide. -N-S-S 0247 Another suitable reversible prodrug linker moiety R2 R2a . for primary amine- or secondary amine-comprising drugs is described in WO-A2009/095479. Accordingly, the following sub-structure of the general formula (VII) is a preferred 0264 wherein embodiment for —(SP)-L-D for the water-soluble carrier 0265 the dashed line indicates attachment to D of for linked prodrug of the present invention according to formula mula (VII), and (I): 0266 X, XI, X, R', R, R2, R2, R, and R of for mula (VIIa) are defined as in formula (VII). 0267 Optionally, Linformula (VII) is further substituted, (VII) provided that the hydrogen marked with the asterisk in for mula (VII) is not replaced by a substituent. Preferably, the one R3a Q RI R la or more further optional substituents are independently D selected from the group consisting of halogen, CN, COOR, ---SP- R31 N SX X NN1 X Nx s OR, C(O)R’, C(O)N(RR), S(O)N(RR), S(O)N (RR), S(O),R, S(O)R, N(R)S(O)N(R'R''), SR, R2 R2a . O N(RR), NO, OC(O)R’, N(R)C(O)R, N(R)S(O).R., N(R)S(O)R, N(R)C(O)OR, N(R)C(O)N(RR), 0248 wherein the dashed line indicates attachment to a OC(O)N(RR").T.C. so alkyl, C-soalkenyl, and Clso alky moiety Hyp of formula (I), which moiety Hyp of for nyl, 0268 wherein T. Clso alkyl, C-so alkenyl, and C-so mula (I) is connected to m Sub-structures of formula alkynyl are optionally substituted with one or more R', (VII); which are the same or different, and wherein Clso alkyl, (0249 the moiety 4 (SP), is attached to any one of R', Clso alkenyl; and Clso alkynyl are optionally inter R'', R, R2, R, R, X, and X; and rupted by one or more groups selected from the group 0250 wherein SP, x, D, X, XI, X, R', R, R2, R2, R, consisting of T. —C(O)O——O——C(O)— —C(O) and R' of formula (VII) have the following meaning: N(R') :-S(O)N(R') :-S(O)N(R') :- S(O) 0251 D is a primary amine- or secondary amine-com ; – S(O)–: N(R')S(O)N(R') ; – S : prising biologically active moiety D; N(R') ; OC(O)R'': N(R')C(O) ; (0252 SP is the spacer moiety SP of formula (I); N(R')S(O) : N(R')S(O) ; N(R')C(O) O. : N(R')C(O)N(R') ; and OC(O)N 0253 x is 0 or 1: (R' IRI la); 0254 X is C(R'R''); N(R). O: C(RR) C(RR): (0269. R. R. R” are independently selected from the C(RR) C(RR): C(RR) N(R); N(R) C group consisting of H. T. and Clso alkyl, C-so alkenyl; and (RR): C(RR). O: or O C(R'R''); C2-so alkynyl, 0255 X is C; or S(O); 0270 wherein T. Clso alkyl, C-so alkenyl, and C-so (0256 X is C(R', R7); or C(R7, R7), C(R,R): alkynyl are optionally substituted with one or more R', 0257 R", R1a, R°, R2, R, R3a, R, R4, R, R5, R°, R7, which are the same or different, and wherein Clso alkyl, R. R. Rare independently selected from the group Clso alkenyl; and Clso alkynyl are optionally inter consisting of H; and C alkyl; rupted by one or more groups selected from the group 0258 optionally, one or more of the pairs R/R', R'/ consisting of T. —C(O)O— —O—, —C(O)— —C(O) R, R/R, R/R, R7/R form a chemical bond; N(R') , S(O)N(R') , S(O)N(R') , S(O) (0259 optionally, one or more of the pairs R/R'', R/R2, R/R, R/R, R7/R7, R/R are joined together with the atom to which they are attached to form N(R')C(O)N(R') , and OC(O)N(R'R''), a C-7 cycloalkyl or 4- to 7-membered heterocyclyl; 0271 T is selected from the group consisting of phenyl, 0260 optionally, one or more of the pairs R/R. R/R. naphthyl, indenyl, indanyl, tetralinyl, Co cycloalkyl, R"/R, R/R, R/R, R/Rare joined together with the 4- to 7-membered heterocyclyl, and 9- to 11-membered atoms to which they are attached to form a ring A: heterobicyclyl, wherein T is optionally substituted with 10261) optionally, R/R" are joined together with the one or more R', which are the same or different, nitrogen atom to which they are attached to form a 4- to 0272 R is halogen, CN, oxo (=O), COOR, OR, 7-membered heterocycle; C(O)R2, C(O)N(R'R'2), S(O)N(R2R12), S(O)N 0262 A is selected from the group consisting of phenyl, (R'R'?), S(O).R', S(O)R', N(R')S(O)N naphthyl, indenyl, indanyl, tetralinyl, Co cycloalkyl, (R2R12), SR2, N(R2R12), NO, OC(O)R', N(R') 4- to 7-membered heterocyclyl, and 9- to 11-membered C(O)R 12, N(R'2)S(O).R2, N(R'2)S(O)R2, N(R'2) heterobicyclyl. C(O)OR3, N(R')C(O)N(R'R'2), OC(O)N US 2014/0243254 A1 Aug. 28, 2014 19

(R'R''), or C, alkyl, wherein Calkyl is optionally -continued substituted with one or more halogen, which are the same or different, (0273 R'', R'', R, R2, R'' are independently selected from the group consisting of H; or C. alkyl, wherein C alkyl is optionally substituted with one or more halogen, which are the same or different. 0274 The term “interrupted' means that between two car

bons a group is inserted or at the end of the carbon chain R3a between the carbon and hydrogen. 0275 Preferred moieties L according to formula (VII) are selected from the group consisting of: US 2014/0243254 A1 Aug. 28, 2014 20

-continued -continued

0276 wherein 0277 dashed lines indicate attachment to D of formula (VII), 1. (0278 R is Hor Calkyl, 0279 Y is NH, O or S, 0280 and R', R, R2, R2, R, R, R, X, X, X? have the meaning as indicated in formula (VII). US 2014/0243254 A1 Aug. 28, 2014 21

0281 Even more preferred moieties L according to for- -continued mula (VII) are selected from the group consisting of US 2014/0243254 A1 Aug. 28, 2014 22

-continued -continued US 2014/0243254 A1 Aug. 28, 2014 23

-continued -continued US 2014/0243254 A1 Aug. 28, 2014 24

-continued -continued US 2014/0243254 A1 Aug. 28, 2014 25

-continued -continued SR

SR

SR

O NH O H:Y. 1N1 F

O

SR

O NH O H:YN 1N1 p

O A. SR

O NH O H:N US 2014/0243254 A1 Aug. 28, 2014 26

-continued 0295). In the sub-structure —(SP)-L-D of formula (VIII) the moiety L is of formula (VIIIa): (VIIIa)

RI

X

O

0296 wherein 0297 the dashed line indicates attachment to D of for mula (VIII) and 0298 X, R' and R' of formula (VIIIa) are defined as in formula (VIII). 0299 More preferably, L of the sub-structure of formula (VIII) comprises one of the fragments of formulas (VIIIb) or (VIIIc), wherein the dashed line marked with an asterisk indicates attachment to D by forming an amide bond with the aromatic amino group of D and the unmarked dashed line indicates attachment to the rest of L of formula (VIII) and wherein the structures of formulas (VIIIb) and (VIIIc) are optionally further substituted:

F w (VIIIb) f w A. w F w Y& O w : A. w 0282 wherein O

F w (VIIIc) 0283 dashed lines indicate attachment to D of formula A. w A. w (VII), and F w 0284 R is H or C alkyl. Y{ N w : 0285. In yet another preferred embodiment the sub-struc A. H w ture —(SP)-L-D of formula (I) for the water-soluble carrier O linked prodrug of the present invention is of formula (VIII): (0300 More preferably, L of the sub-structure of formula (VIII) comprises one of the fragments of formulas (VIIIba), (VIII) (VIIIca), or (VIIIcb), wherein the dashed line marked with an RI R1a asterisk indicates attachment to D of formula (VIII) by form D, ing an amide bond with the aromatic amino group of D and ---SP- X the unmarked dashed line indicates attachment to the rest of L O of formula (VIII): (VIIIba) 0286 wherein the dashed line indicates attachment to a moiety Hyp of formula (I), which moiety Hyp of for N x mula (I) is connected to m Sub-structures of formula (VIII), w O O (0287 the moiety 4 (SP), is attached to any one of R', (VIIIca) R', and X; and 0288 wherein SP, X, D.X. R', and R' of formula (VIII) , N x have the following meaning: 0289 D is a primary amine- or secondary amine-com w O O prising biologically active moiety D, (VIIIcb) 0290 SP is the spacer moiety SP of formula (I); O & 0291 x is 0 or 1: 0292 X is H or Clso alkyl, optionally interrupted by as N y : one or more groups selected from —NH-, —C(Ca alkyl)-, —O— —C(O)—or —C(O)NH , w O 0293 R' and R'' are independently selected from the group consisting of H and C-C alkyl, 0301 Another preferred reversible prodrug linker moiety 0294 Optionally, the sub-structure of formula (VIII) is L for aromatic amine-comprising drugs is described in WO further substituted. 2011/012721. Therefore, the following sub-structure of the US 2014/0243254 A1 Aug. 28, 2014 27 general formula (IX) is a preferred embodiment for —(SP)- 0321 wherein L-D for the water-soluble carrier-linked prodrug of the 0322 the dashed line indicates attachment to D of for present invention according to formula (I): mula (IX), and 0323 X', X, R, and R* of formula (IXa) are used as defined in formula (IX). (IX) 0324 More preferably, the moiety L according to formula O (IX) is selected from the following formulas: ---SP- R2NN l x21 X D, O O k- O 2 ? 0302 wherein the dashed line indicates attachment to a *s-s-s-s moiety Hyp of formula (I), which moiety Hyp of for mula (I) is connected to m Sub-structures of formula O O (IX), 0303 D is connected to the rest of the sub-structure of forumala (IX) through an aromatic amine group of D by forming an amide bond, (0304) the moiety 4 (SP), is attached to any one of R, R’, X', and X; and 0305 wherein D, SP, X, X', X, R, and R' in formula (IX) have the following meaning: 0306 D is an aromatic amine-comprising biologically active moiety D, (0307 SP is the spacer moiety SP of formula (I), 0308 x is 0 or 1, 0325 wherein the dashed line indicates attachment to D 0309 X is C(R'R'') or a cyclic fragment selected from of formula (IX), and C-7 cycloalkyl, 4- to 7-membered heterocyclyl phenyl, 0326) R' and Rare used as defined in formula (IX). naphthyl, indenyl, indanyl, tetralinyl, and 9- to 11-mem 0327 Preferably, in formula (IX) R', R. R. R. R. bered heterobicyclyl, and Rare independently selected from the group consisting 0310 X is a chemical bond or selected from C(RR), of H, and C alkyl. N(R), O, C(RR) C(RR), C(RR) N(R), 0328. Another preferred reversible prodrug linker moiety N(R) C(R'R''), C(RR) O, and O C(RR), L for aromatic amine-comprising drugs is described in WO 0311 wherein in case X" is a cyclic fragment, X is a 2011/012722. Therefore, the following sub-structure of the chemical bond, C(RR), N(R) or O, general formula (X) is a preferred embodiment for —(SP)- 0312) optionally, in case X" is a cyclic fragment and X L-D for the water-soluble carrier-linked prodrug of the is C(RR), the order of the X fragment and the X present invention according to formula (I): fragment within the sub-structure —(SP)-L-D shown in formula (IX) may be changed, (X) 0313 R', RandR are independently selected from the O group consisting of H, C, alkyl and N(RR), 0314) R', R. R. R. R* and Rare independently ---SP- R2NN l x21 X D, Selected from the group consisting of H, and C alkyl, s 0315 optionally, one of the pairs R/R, R/R, R*/ H O R" are joined to form a 4- to 7-membered at least par tially saturated heterocycle, 0329 wherein the dashed line indicates attachment to a 0316 R is C(O)R, moiety Hyp of formula (I), which moiety Hyp of for 0317 R is C alkyl, and mula (I) is connected to m Sub-structures of formula (X), 0318 optionally, one of the pairs R''/R', R/R or 0330 D is connected through an aromatic amine group R'R' form a chemical bond. of D to the rest of the sub-structure of formula (X) by 0319 Optionally, the sub-structure —(SP)-L-D of for forming an amide bond, mula (IX) is further substituted. 0331 the moiety : (SP), is attached to any one of R, 0320 In the sub-structure —(SP)-L-D of formula (IX) X', and X; and the moiety L is of formula (IXa): 0332 wherein D, SP, X, X', X, R, and R in formula (X) have the following meaning: 0333 D is an aromatic amine-comprising biologically (IXa) active moiety D, 0334 SP is the spacer moiety SP of formula (I), 0335 x is 0 or 1, 0336 X" is C(R'R'') or a cyclic fragment selected from C-7 cycloalkyl, 4 to 7 membered heterocyclyl phenyl, naphthyl, indenyl, indanyl, tetralinyl, and 9 to 11 mem bered heterobicyclyl, US 2014/0243254 A1 Aug. 28, 2014 28

0337 wherein in case X" is a cyclic fragment, said -continued cyclic fragment is incorporated into —(SP)-L-D of for (iv) mula (X) via two adjacent ring atoms and the ring atom O O of X", which is adjacent to the carbonatom of the amide 2 ? bond, is also a carbon atom, is-- M s 0338 X is a chemical bond or selected from C(RR), H* N(R), O, C(RR) C(RR), C(RR) N(R), (v) N(R) C(R'R''), C(RR) O, and O C(RR), O O 0339 wherein in case X" is a cyclic fragment, X is a R2 f chemical bond, C(RR), N(R) or O, NN y (0340 optionally, in case X" is a cyclic fragment and X M ? s is C(RR), the order of the X fragment and the X H* fragment within the sub-structure —(SP)-L-D shown in (vi) formula (X) may be changed and the cyclic fragment is incorporated into the sub-structure —(SP)-L-D of for mula (X) via two adjacent ring atoms, (0341) R', RandR are independently selected from the group consisting of H. C. alkyl and N(RR), 0342 R', R. R. R* and R are independently (vii) Selected from the group consisting of H, and C alkyl, 0343 R is C(O)R, (0344) R' is Calkyl, (0345 optionally, one of the pairs R''/R, R/R or R"/R" form a chemical bond, provided that the hydro gen marked with the asterisk in formula (X) is not replaced by the moiety 4 (SP)—of formula (X). 0346. In the sub-structure —(SP)-L-D of formula (X) the (viii) moiety L is of formula (Xa): (Xa)

(ix) 0347 wherein 0348 the dashed line indicates attachment to D of for mula (X), and (0349 X', X, and R of formula (Xa) are used as defined in formula (X). 0350 Optionally, the moiety L of formula (X) is further substituted. 0351 More preferably, the moiety L according to formula

(X) is selected from the group consisting of formulas (i) through (XXix): (i)

(ii)

(xi)

(iii)

US 2014/0243254 A1 Aug. 28, 2014 30

-continued 0365 More preferably, L of formula (X) is selected from: (xxvi) R2 V N (i) (4 O (xxvii) R2 O Y. ? (ii)

41O R1x R1a )' s (xxviii) R2 R3 O

Y. ? O (iii)

(1x)O RI R1a (XXix) O O H F n F (iv) R2 N lus M ? H* RI R1a 0352 wherein the dashed line indicates attachment to D, and 0353 R', R', R. R., and R are used as defined in (v) formula (X). 0354) The amino substituent of the aromatic fragment of D forms together with the carbonyl-fragment (—C(O)—) on the right hand side of L (as depicted informula (X)) an amide bond between Land D. By consequence, D and L of formula (X) are connected (chemically bound) by an amide fragment (vi) of the general structure Y' C(O) N(R) Y.Y' indicates the remaining parts of the sub-structure of formula (X) and Y indicates the aromatic fragment of D. R is a Substituent. Such as C. alkyl or preferably hydrogen. 0355. As indicated above, X" of formula (X) may also be (vii) a cyclic fragment such as C-7 cycloalkyl, phenyl or indanyl. In case X" is such a cyclic fragment, the respective cyclic fragment is incorporated into L of formula (X) via two adja cent ring atoms (of said cyclic fragment). For example, if X is phenyl, the phenyl fragment of L is bound to X of L via a first (phenyl) ring atom being in C-position (adjacent) to a second (phenyl) ring atom, which itself is bound to the carbon atom of the carbonyl-fragment on the right hand side of L according to formula (X), i.e. the carbonyl fragment which (viii) together with the aromatic amino group of D forms an amide bond. 0356. Preferably, L of formula (X) is defined as follows: 0357 X is C(R'R''), cyclohexyl, phenyl, pyridinyl, norbonenyl, furanyl, pyrrolyl or thienyl, 10358 wherein in case X" is a cyclic fragment, said cyclic fragment is incorporated into L of formula (X) via two adjacent ring atoms; (ix) 0359 X is a chemical bond or selected from C(RR), N(R), O, C(RR) O or C(RR) C(R'R''); 0360 R', RandR are independently selected from H, Calkyl and N(RR): 0361) R', R, R and Rare independently selected from Hand C alkyl; 0362 R is C, alkyl: 0363 R is C(O)R; 0364 R is C alkyl:

US 2014/0243254 A1 Aug. 28, 2014 32

-continued

(xxiii) (XI)

H*, ---SP--Z'-O-D, R2 0371 wherein the dashed line indicates attachment to a moiety Hyp of formula (I), which moiety Hyp of for mula (I) is connected to m Sub-structures of formula (XI), (xxiv) 0372 D is connected through a hydroxyl group of D to R2 O the rest of the sub-structure of formula (XI), and Y. ? 0373) wherein D, SP, x and Z' in formula (XI) have the following meaning: (ryx 0374 D is a hydroxyl-comprising biologically active O E F moiety D comprising O.

(XXv) 0375 SP is the spacer moiety SP of formula (I), 0376 x is 0 or 1, 0377 Z is the moiety -L- of formula (I) and is X C (O), X O C(O), X S(O), X C(S), X O S (O), X S(O)N(R'), X CH(OR), X C(OR") (OR), XO C(O)N(R'), X P(=O)(OH)O, X P (xxvi) (—O)(OR)O, X P(=O)(SH)O, X P(=O)(SR) O, X P(=O)(OR), X P(—S)(OH)O, X P (—S)(OR)O, X P(—S)(OH)N(R'), X P(—S) (OR')N(R), X P(=O)(OH)N(R') or X P(=O) (OR)N(R), (xxvii) 0378 R', Rare independently selected from the group R2 O consisting of Calkyl; or R' and Rjointly form a C alkylene bridging group, Y. ' 0379 X is (X) (X), 0380 m1, m2 are independently 0 or 1, 41 RIx Ria ) s 0381 X is T', (xxviii) (0382 X" is a branched or unbranched Co alkylene R2 R3 O group which is unsubstituted or substituted with one or Y. ? more R, which is/are the same or different, O 0383 Rishalogen, CN, C(O)R,C(O)OR, OR, C(O) R, C(O)N(RR), S(O)N(RR), S(O)N(RR), (1x)O R. Rila S(O).R., S(O)R, N(R)S(O)N(R'R''), SR, (XXix) N(RR), NO, OC(O)R, N(R)C(O)R, N(R) O O SOR, N(R)S(O)R“, N(R)C(O)N(RR), N(R) H t C(O)OR, OC(O)N(RR), or T, R2n N lu F ? (0384) R', R", Rare independently selected from the A ? group consisting of H. T. C. alkyl, C2a alkenyl, and H* RI R1a A. C2-alkynyl, wherein C alkyl, C2-alkenyl, and C2 alkynyl are optionally substituted with one or more R. which is/are the same of different, 0366 wherein the dashed line indicates attachment to 0385) Rishalogen, CN, C(O)R,C(O)OR, OR, C(O) D, R°, C(O)N(RR), S(O)N(RR), S(O)N(RR), 0367 Riis C(O)R, and S(O).R, S(O)R, N(R)S(O)N(RR), SR, N(RR), NO, OC(O)R, N(R)C(O)R, N(R) 0368 R', R', R, R and R are independently from SOR, N(R)S(O)R, N(R)C(O)N(RoR), N(R) each other C. alkyl. C(O)OR, or OC(O)N(RR), 0369 L of formula (X) is substituted with one moiety 0386 R. R. Rare independently selected from the 4 (SP), and preferably said substitution occurs at R, i.e. group consisting of H. C. alkyl, C2-alkenyl, and C2 preferably R is substituted with one moiety —(SP; ) . alkynyl, wherein Ce alkyl, Calkenyl, and C- alky nyl are optionally Substituted with one or more halogen, 0370. Yet another preferred reversible prodrug linker moi which is/are the same of different, ety L for hydroxyl-comprising drugs is described in WO (0387 Tis phenyl, naphthyl, azulenyl, indenyl, indanyl, 2011/012721. Therefore, the following sub-structure of the C., cycloalkyl, 3- to 7-membered heterocyclyl, or 8- to general formula (XI) is a preferred embodiment for —(SP)- 11-membered heterobicyclyl, wherein T", is optionally L-D for the water-soluble carrier-linked prodrug of the substituted with one or more R7, which is/are the same or present invention according to formula (I): different, US 2014/0243254 A1 Aug. 28, 2014 33

0388 R7 is halogen, CN, COOR, OR, C(O)R, C(O) 0403 SP is the spacer moiety SP of formula (I), N(RR), S(O)N(RR), S(O)N(RR), S(O).R., 0404 x is 0 or 1, S(O)R, N(R)S(O)N(RR), SR, N(RR), NO, 04.05) R' is selected from the group consisting of Ca OC(O)R, N(R)C(O)R’, N(R)S(O).R., N(R)S(O) alkyl, heteroalkyl, C., cycloalkyl, and R, N(R)C(O)OR, N(R)C(O)N(RR), OC(O)N (RR) oxo (=O), where the ring is at least partially Saturated, Co alkyl, C- alkenyl, or C2-alkynyl, R3 R2 wherein Ce alkyl, C- alkenyl, and C alkynyl are optionally substituted with one or more R, which is/are the same or different, R3a R2a 0389. R. R. Rare independently selected from the group consisting of H. C. alkyl, C2-alkenyl, and C2 alkynyl, wherein C alkyl, Calkenyl, and C- alky 04.06 each R, each R', R, R are independently nyl are optionally substituted with one or more R', selected from hydrogen, substituted or non-substituted which is/are the same of different, linear, branched or cyclic C alkyl or heteroalkyl, 0390 R. R'' are independently selected from the 04.07 m is 2, 3 or 4. group consisting of halogen, CN, C(O)R'', C(O)CR'', 0408. In the sub-structure —(SP)-L-D of formula (XII) OR'', C(O)R'', C(O)N(R'R''.) S(O)N(R'R'')S the moiety L is of formula (XIIa): (O)N(R'R''), S(O).R'', S(O)R'', N(R'')S(O)N (R' la Rl 1)SR N(R IRI la), NOOC(O)R' l, N(R' C (O)R' 1a, N(R' ')SOR' la, N(R' ')S(O)R' 1a, N(R' C (XIIa) (O)N(R'R''), N(R')C(O)OR'', and OC(O)N O (R' IRI (), 10391) R', R''", R'' are independently selected from Ril N.) : — the group consisting of H. C. alkyl, Calkenyl, and C2-alkynyl, wherein C- alkyl, C2-alkenyl, and C2 R3 2a iii. alkynyl are optionally substituted with one or more halo gen, which is/are the same of different, and 0392 wherein (SP), of formula (XI) is covalently 04.09 wherein attached to X'. 0410 the dashed line indicates attachment to D of for mula (XII), and 0393 Preferably, Z is X C(O), X C(O)C, or X' S 0411) R', each R, each R', R, R and m of formula (O). More preferably, Z is X” C(O) or X C(O)O. Even (XIIa) are used as defined in formula (XII). more preferably, Z is X C(O). 0412 Optionally, L of formula (XII) is further substituted. 0394 Preferably, X is unsubstituted. 0413. In yet another preferred embodiment the sub-struc 0395 Preferably, m1 is 0 and m2 is 1. ture —(SP)-L-D of formula (I) for the water-soluble carrier 0396 Preferably, X is C(R'R)CH, wherein R and R. linked prodrug of the present invention is given in formula are independently selected from the group consisting of H and Calkyl, provided that at least one of R, R is other than (XIII): H, or (CH), wherein n is 3, 4, 5, 6, 7 or 8.

0397 Preferably, the moiety (SP), of formula (XI) is covalently attached to X" via an amide group. (XIII) 0398. In yet another preferred embodiment the sub-struc ture —(SP)-L-D of formula (I) for the water-soluble carrier linked prodrug of the present invention is of formula (XII): (XII) O R3 R’ D, ---SP- N R R2a iii. 0414 wherein the dashed line indicates attachment to a 0399 wherein the dashed line indicates attachment to a moiety Hyp of formula (I), which moiety Hyp of for moiety Hyp of formula (I), which moiety Hyp of for mula (I) is connected to m Sub-structures of formula mula (I) is connected to m Sub-structures of formula (XIII), (XII), 0415 D is connected through an aliphatic amine group 04.00 D is connected through an aromatic hydroxyl of D to the rest of the sub-structure of formula (XIII) by group of D to the rest of the sub-structure of formula forming an amide group, (XII) by forming a carbamate group, the moiety (SP) 0416) the moiety (SP), is attached to any one of R', is attached to any one of R',R,R,R, and R'; and R, R2, R,R,R,R, and X; and 04.01 wherein D, SP, x, R. R. R. R. R. and m in 0417 wherein D, SP, X, X, R', R. R. R. R. Rand formula (XII) have the following meaning R" in formula (XIII) have the following meaning: 0402 D is an aromatic hydroxyl-comprising biologi 0418 D is an aromatic amine-comprising biologically cally active moiety D, active moiety D, US 2014/0243254 A1 Aug. 28, 2014 34

0419 SP is the spacer moiety SP of formula (I), 0430. In the sub-structure —(SP)-L-D of formula (XIII) 0420 x is 0 or 1, the moiety L is of formula (XIIIa): 0421 X is selected from O, S or CH-R'', 0422) R' and R" are independently selected from H. OH, CH, (XIIIa) 0423. R. R. R. and R“ are independently selected from Hand C alkyl, 0424) R, R are independently selected from H. C. alkyl, and R. 0425 R is selected from

OH

OH 0431 wherein 0432 the dashed line indicates attachment to D of for mula (XIII), and 0433 X, R, R2, R2, R, R, R and R“ of formula (XIIIa) are used as defined in formula (XIII). to K -( 0434 Optionally, L of formula (XIII) is further substi tuted. Suitable Substituents are alkyl (such as C. alkyl). alkenyl (such as Calkenyl), alkynyl (such as C-alkynyl). aryl (such as phenyl), heteroalkyl, heteroalkenyl, heteroalky nyl, heteroaryl (Such as aromatic 4- to 7-membered hetero cycle) or halogen moieties. 0435. In yet another preferred embodiment the sub-struc ture —(SP)-L-D of formula (I) for the water-soluble carrier linked prodrug of the present invention is of formula (XIV):

(XIV) O R R3 R3a C D N r R4 Spa - O 2 R Ra R4a

0436 wherein the dashed line indicates attachment to a moiety Hyp of formula (I), which moiety Hyp of for mula (I) is connected to m Sub-structures of formula (XIV), 0437 D is connected through an aromatic amine group of D to the rest of the sub-structure of formula (XIV) by forming an amide group, 0438 the moiety (SP), is attached to any one of R', R'', R,R,R,R, and R'; and 0439 wherein D, SPX,R,R,R,R,R,R,R and R" in formula (XIV) have the following meaning: 0426 Preferably, one of the pair R/R of formula (XIII) 0440 D is an aromatic amine-comprising biologically is Hand the other one is selected from R. active moiety D, 0427 Preferably, one of R/R' of formula (XIII) is H. 0441 SP is the spacer moiety SP of formula (I), 0428 Optionally, one or more of the pairs R/R, R/R“, 0442 x is 0 or 1: R/R of formula (XIII) may independently form one or more 0443 R', R. R. R. R, R and R are indepen cyclic fragment(s) selected from C-7 cycloalkyl, 4- to dently selected from H and C alkyl. 7-membered heterocyclyl, and 9- to 11-membered heterobi 0444 Optionally, any two of R', R', R. R. R. R. and cyclyl. R“ of formula (XIV) may independently form one or more 0429 Optionally, R. R. RandR' of formula (XIII) are cyclic fragment(s) selected from C-7 cycloalkyl, 4- to further substituted. Suitable substituents are alkyl (such as 7-membered heterocyclyl phenyl, naphthyl, indenyl, inda C. alkyl), alkenyl (Such as Calkenyl), alkynyl (Such as nyl, tetralinyl, and 9- to 11-membered heterobicyclyl. C. alkynyl), aryl (such as phenyl), heteroalkyl, heteroalk 0445 Optionally, R', R'", R. R. R. R. and R' of enyl, heteroalkynyl, heteroaryl (such as aromatic 4- to formula (XIV) are further substituted. Suitable substituents 7-membered heterocycle) or halogen moieties. are alkyl. Such as C. alkyl, alkene. Such as such as C US 2014/0243254 A1 Aug. 28, 2014

alkene, alkine, such as such as Calkine, aryl. Such as alkyl, aryl, alkaryl, aralkyl, halogen, nitro. —SOH, phenyl, heteroalkyl, heteroalkene, heteroalkine, heteroaryl —SONHR, amino, ammonium, carboxyl, POH, and Such as aromatic 4- to 7-membered heterocycle, or halogen OPOH, moieties. 0460 R. R', and Rare independently selected from 0446. In the sub-structure —(SP)-L-D of formula (XIV) the group consisting of hydrogen, alkyl, and aryl. the moiety L is of formula (XIVa): 0461). In the sub-structure —(SP)-L-D of formula (XV) the moiety L is of formula (XVa):

(XIVa)

O i R3 R3a (XVa) N N1 R*, R R la O R4a

0447 wherein 0448 the dashed line indicates attachment to D of for mula (XIV), and R', R', R,R,R,R, RandR of formula (XIVa) are used as defined in formula (XIV). 0449 Optionally, L of formula (XIV) is further substi tuted. Suitable substituents are alkyl (such as C. alkyl). 0462 wherein alkenyl (Such as Coalkenyl), alkynyl (such as C2-alkynyl), 0463 the dashed line indicates attachment to D of for aryl (such as phenyl), heteroalkyl, heteroalkenyl, heteroalky mula (XV), and nyl, heteroaryl (Such as aromatic 4- to 7-membered hetero 0464) R', R, R and R of formula (XVa) are used as cycle) or halogen moieties. defined in formula (XV). 0450 Preferably, one of R or R' of formula (XIV) is H. 0465 Optionally, Lof formula (XV) is further substituted. 0451 Yet another preferred reversible prodrug linker moi Suitable Substituents are alkyl (Such as C. alkyl), alkenyl ety L is described in U.S. Pat. No. 7,585,837. Therefore, the (such as C. alkenyl), alkynyl (such as C. alkynyl), aryl following sub-structure of the general formula (XV) is a (such as phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, preferred embodiment for —(SP)-L-D for the water-soluble heteroaryl (such as aromatic 4 to 7 membered heterocycle) or carrier-linked prodrug of the present invention according to halogen moieties. formula (I): 0466. Yet another preferred reversible prodrug linker moi ety L is described in the international application WO-A 2002/089789. Therefore, the following sub-structure of the

(XV) general formula (XVI) is a preferred embodiment for —(SP) -L-D for the water-soluble carrier-linked prodrug of the present invention according to formula (I):

(XVI) — spy--(Y O R R5 Y. X--D, 0452 wherein the dashed line indicates attachment to a O R. R. moiety Hyp of formula (I), which moiety Hyp of for Air mula (I) is connected to m Sub-structures of formula (XV), 0453 D is connected through a functional group of D to 0467 wherein the dashed line indicates attachment to a the rest of the sub-structure of formula (XV), wherein moiety Hyp of formula (I), which moiety Hyp of for Such functional group is selected from amine, carboxyl, mula (I) is connected to m Sub-structures of formula phosphate, hydroxyl and mercapto, (XVI), 0454 the moiety 4 (SP), is attached to any one of R', 0468. D is connected through a functional group of D to R. R., and R; and the rest of the sub-structure of formula (XVI), 0455 wherein D, SP, X, R', R, R and R in formula 0469 and wherein SP, X, D, X, Ar. L. Y.Y., y, R. R. (XV) have the following meaning: R. R. and R of formula (XVI) have the following 0456 D is an aromatic amine-comprising biologically mean1ng: active moiety D, 0470 D is a biologically active moiety, 0457 SP is the spacer moiety SP of formula (I), 0471) SP is the spacer moiety SP of formula (I), 0458 x is 0 or 1, 0472 x is 0 or 1, 0459 R' and R are independently selected from the 0473 y is 0 or 1, group consisting of hydrogen, alkyl, alkoxy, alkoxy 0474 L is a bifunctional linking group, US 2014/0243254 A1 Aug. 28, 2014 36

0475 Y and Y are independently O, S or NR", 0491 and wherein SP, X, D. L. Y. and p of formula 0476 R'' are independently selected from the group (XVIII) have the following meaning: consisting of hydrogen, C- alkyls, C-12 branched 0492 D is a heteroaromatic amine-comprising biologi alkyls, C.s cycloalkyls, C. Substituted alkyls, Cs cally active moiety, Substituted cycloalkyls, aryls, Substituted aryls, aralkyls, 0493 SP is the spacer moiety SP of formula (I), C. heteroalkyls, Substituted C. heteroalkyls, C. 0494 x is 0 or 1, alkoxy, phenoxy, and C. heteroalkoxy, 0495 Y is O, S, or NR, 0477 Ar is a moiety which when included in formula 0496 p is 0 or 1, (XVI) forms a multisubstituted aromatic hydrocarbon or 0497 L is a bifunctional linker, such as, for example, a multi-substituted heterocyclic group, NH(CHCHO) (CH), NR , NH(CHCHO) 0478 X is a chemical bond or a moiety that is actively C(O)— —NH(CRRs).OC(O)— —C(O)(CRRs) transported into a target cell, a hydrophobic moiety, or a NHC(O)(CRR) (NR, C(O)O(CH), O , combination thereof. —C(O)(CRRs)..NR , - C(O)NH(CHCHO), 0479. Yet another preferred reversible prodrug linker moi (CH2)NR , —C(O)C)—(CH2CH2O)NR . ety L is described in the international application WO-A —C(O)NH(CRRs).O , —C(O)O(CRRs).O. 2001/47562. Therefore, the following sub-structure of the - C(O)NH(CHCHO), , general formula (XVII) is a preferred embodiment for —(SP) -L-D for the water-soluble carrier-linked prodrug of the present invention according to formula (I):

(XVII) - its ---0-1l--DO

0480 wherein the dashed line indicates attachment to a moiety Hyp of formula (I), which moiety Hyp of for mula (I) is connected to m Sub-structures of formula (XVII), 0498 R. R. R. R. R., and Rs are independently 0481 Disconnected through an amine group of D to the Selected from the group consisting of hydrogen, C. rest of the sub-structure of formula (XVII), alkyls, C. branched alkyls, C.s cycloalkyls, C. Sub 0482 and wherein SP, X, D, Land Ar of formula (XVII) stituted alkyls, C.s substituted cycloalkyls, aryls. Sub have the following meaning: stituted aryls, aralkyls, C. heteroalkyls, Substituted 0483 D is an amine-comprising biologically active C. heteroalkyls, C. alkoxy, phenoxy and C. het moiety comprising NH, eroalkoxy, 0484 SP is the spacer moiety SP of formula (I), 0499 R is selected from the group consisting of hydro gen, Calkyls, C. branched alkyls, C.s cycloalkyls, 0485 x is 0 or 1, C. Substituted alkyls, C.s substituted cycloalkyls, 0486 L is a covalent linkage, preferably a hydrolyti aryls, substituted aryls, aralkyls, C. heteroalkyls. Sub cally stable linkage, stituted Cheteroalkyls, Calkoxy, phenoxy and C. 0487. Ar is an aromatic group. heteroalkoxy, NO, haloalkyl and halogen, 0488 Yet another preferred reversible prodrug linker moi 0500 m and q are selected independently from each ety L is described in U.S. Pat. No. 7,393.953 B2. Therefore, other and each is a positive integer. the following sub-structure of the general formula (XVIII) is 0501. In yet another preferred embodiment the sub-struc a preferred embodiment for —(SP)-L-D for the water ture —(SP)-L-D of formula (I) for the water-soluble carrier soluble carrier-linked prodrug of the present invention linked prodrug of the present invention is given in formula according to formula (I): (XIX):

(XVIII) Y (XIX) H-SP-L) D,

0489 wherein the dashed line indicates attachment to a moiety Hyp of formula (I), which moiety Hyp of for 0502 wherein the dashed line indicates attachment to a mula (I) is connected to m Sub-structures of formula moiety Hyp of formula (I), which moiety Hyp of for (XVIII), mula (I) is connected to m Sub-structures of formula 0490 D is connected through a heteroaromatic amine (XIX), group of D to the rest of the sub-structure of formula 0503 D is connected through a carboxyl group of D to (XVIII), the rest of the sub-structure —(SP)-L- of formula (I) by US 2014/0243254 A1 Aug. 28, 2014 37

forming a carboxylic ester comprising O, and wherein SPX, D, R, R. R. Rand n of formula (XIX) have the (XX) following meaning: 0504 D is a carboxyl-comprising biologically active ---SP--W-O-D, moiety, (0505 SP is the spacer moiety SP of formula (I), 0506 x is 0 or 1, 0522 wherein the dashed line indicates attachment to a (0507) R' is selected from the group of unsubstituted moiety Hyp of formula (I), which moiety Hyp of for alkyl; substituted alkyl; unsubstituted phenyl; substi mula (I) is connected to m Sub-structures of formula tuted phenyl; unsubstituted naphthyl; substituted naph (XX), thyl; unsubstituted indenyl; substituted indenyl; unsub 0523 D is connected through a carboxyl group of D to stituted indanyl; substituted indanyl; unsubstituted the rest of the sub-structure of formula (XX) by forming tetralinyl; Substituted tetralinyl; unsubstituted Co a carboxylic ester comprising O. cycloalkyl; Substituted Co cycloalkyl; unsubstituted 0524 and wherein SP, X, D, and W of formula (XX) 4- to 7-membered heterocyclyl; substituted 4- to have the following meaning: 7-membered heterocyclyl; unsubstituted 9- to 11-mem 0525 D is a carboxyl-comprising biologically active bered heterobicyclyl; and substituted 9- to 11-mem moiety, bered heterobicyclyl: 0526 SP represents the spacer moiety SP of formula (I), 0527 x is 0 or 1: 0508 R is selected from H, unsubstituted alkyl, and 0528 W is selected from linear Cls alkyl. substituted alkyl: 0529 Preferably, a carrier moiety of the water-soluble (0509 R and R are independently selected from the carrier-linked prodrug of formula (I) is connected to at least 6 group consisting of H, unsubstituted alkyl, and Substi moieties L (either directly or indirectly), such as to 6, 7, 8, 9. tuted alkyl: 10, 11, 12, 13, 14, 15, 16, or 17 moieties L (either directly or 0510) n is 0 or 1, indirectly). More preferably, a carrier moiety of the water soluble carrier-linked prodrug of formula (I) is connected to (0511) optionally, RandR are joined together with the 8, 12, 16 or 20 moieties L (either directly or indirectly). atoms to which they are attached to form a ring A, 0530 Preferably, all moieties L of formula (I) are the 0512 A is selected from the group consisting of Co SaC. cycloalkyl, 4- to 7-membered aliphatic heterocyclyl; 0531. A water-soluble carrier-linked prodrug of formula and 9- to 11-membered aliphatic heterobicyclyl, (I) comprises biologically active moieties D which are pref wherein A is unsubstituted or substituted. erably selected from the group of oligopeptides, polypep 0513 Preferably, R of formula (XIX) is C alkyl or tides, proteins, oligonucleotides, and Small molecule biologi Substituted C. alkyl, more preferably C. alkyl or Substi cally active moieties. The corresponding drugs may comprise tuted C alkyl. one or more functional groups selected from the group com 0514 More preferably, R' of formula (XIX) is selected prising amine, hydroxyl, carboxyl, phosphate, and mercapto. from methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, A drug may be conjugated to a moiety L through a linkage sec-butyl, t-butyl, and benzyl. formed by an amine. Such as an aliphatic or aromatic amine, hydroxyl. Such as an aliphatic or aromatic hydroxyl, car 0515 Preferably, R of formula (XIX) is H. boxyl, phosphate, or mercapto group provided by the drug. 0516 Preferably, R of formula (XIX) is H, C alkyl or 0532 Suitable aromatic amine-containing drugs are, for Substituted C. alkyl, more preferably C. alkyl or Substi example, (-)-Carbovir, (t)-Hymenin, (t)-Norcisapride, (+)- tuted Calkyl. More preferably, R is selected from methyl, Picumeterol, (R)-Aminoglutethimide, (R)-Clenbuterol, (S)- ethyl, n-propyl, isopropyl. n-butyl, isobutyl, sec-butyl, t-bu Aminoglutethimide, (S)-Clenbuterol, 6-p-aminophenylala tyl, and benzyl. nine-angiotensin II, 10'-Demethoxystreptonigrin, 17-Aminogeldanamycin, 1-Aminoacridine, 1-DeaZaad 0517 More preferably, R of formula (XIX) is H. enine, 1-NA-PP 1, 1-NM-PP 1, 2,7-Diaminoacridine, 2,7- 0518. Preferably, R of formula (XIX) is s H, C, alkyl or Dimethylproflavine, 2-Amino-6(5H)-phenanthridinone, Substituted C. alkyl, more preferably C alkyl or substi 2-Aminoacridine, 2-amino-Carbanilide, 2-Aminohistamine, tuted C, alkyl. More preferably, R is selected from methyl, 2-Aminoperimidine, 2'-AMP 2-Chloroadenosine, 2-Deox ethyl, n-propyl, isopropyl. n-butyl, isobutyl, sec-butyl, t-bu yxylotubercidin, 2-Sulfanilamidoimidazole, 3,4-Diami tyl, and benzyl. nocoumarin, 3'-Amino-4'-methoxyflavone, 3-Aminoacri 0519 More preferably, R of formula (XIX) is H. dine, 3-Aminopicolinic acid, 3-Deazaguanine, 4-Aminoflavone, 4-Aminopyridine, 5'-ADP 5-Aminoacri 0520. In another preferred embodiment, R' and R of for dine, 5-amino-DL-Tryptophan, 5-Aminonicotinamide, mula (XIX) are joined together with the atoms to which they 5'-AMP, 5'-ATP 5-Chlorodeoxycytidine, 5'-CMP 5-Dim are attached to form a ring A, wherein A is selected from the ethylamiloride, 5'-GDP, 5'-GMP, 5'-GTP 5-Iodotubercidin, group consisting of cyclopropane, cyclobutane, cyclopen 5-Methylcytosine, 6-Aminoflavone, 6-Aminophenanthri tane, cyclohexane, and cycloheptane. dine, 6-Aminothymine, 6-Benzylthioguanine, 6-Chlorota 0521. In yet another preferred embodiment the sub-struc crine, 6-Iodoamiloride, 7,8-Dihydroneopterin, 7-Ami ture —(SP)-L-D of formula (I) for the water-soluble carrier nonimetazepam, 7-Methoxytacrine, 7-Methyltacrine, linked prodrug of the present invention is given in formula 9-Deazaguanine, 9-Phenethyladenine, Abacavir, Acadesine, (XX): Acediasulfone, Acefurtiamine, Acetyl coenzyme A, Aciclo US 2014/0243254 A1 Aug. 28, 2014

Vir, Actimid, Actinomycin, Acyclovir, Adefovir, Adenallene, Fursultiamine, Furyltriazine, Ganciclovir, Gancyclovir, Gas Adenine, Adenophostin A, Adenosine, Adenosine mono tracid, Gemcitabine, Giracodazole, Gloximonam, Glybuthia phosphate, Adenosine triphosphate, Adenosylhomocysteine, Zol, GSK3B Inhibitor XII, GSK3BInhibitor XII, Guanine, Aditeren, Afloqualone, Alamifovir, Albofungin, AlfuZosin, Guanine arabinoside, Guanosine, Hexyl PABA, Hydroxym Allithiamine, Alpiropride, Amanozine, Ambasilide, ethylclenbuterol, Hydroxyprocaine, Hydroxytriamterene Ambucaine, Amdoxovir, Ameltolide, Amethopterin, Sulfate, Ibacitabine, Iclaprim, Imanixil, Imiquimod, Indano Amfenac, Amflutizole, Amicycline, Amidapsone, Amifam cine, Iobenzamic acid, Iocetamic acid, Iomeglamic acid, pridine, Amiloride, Aminacrine, Aminoacridine, Aminoan Iomeglamicacid, Ipidacrine, Iramine, Irsogladine, Isatorib tipyrine, Aminobenzoate, Aminogenistein, Aminoglutethim ine, Isobutamben, Isoritmon, IsoSepiapterin, Ketoclen ide, Aminohippurate, Aminoisatin, Aminometradine, buterol, Ketotrexate, Kopexil, Lamivudine, Lamotrigin, Aminonimetazepam, Aminophenylalanine, Aminopotenti Lamotrigine, Lamtidine, Lappaconine, Lavendamycin, dine, Aminopterin, Aminopurvalanol A, Aminoquinuride, L-Cytidine, Lenalidomide, Leucinocaine, Leucovorin, L-g- Aminosalicylic Acid, Amiphenazole, Amiphenosine, Ami Methylene-10-deazaminopterin, Linifanib, Lintopride, Sometradine, Amisulpride, Amiterol, AmlexanoX, Ammelin, Lisadimate, Lobucavir, Lodenosine, Lomeguatrib, Lometr Amonafide, Amoxecaine, Amphenidone, Amphethinile, exol, Loxoribine, L-S-Adenosylmethionine, Mabuterol, Amphotalide, Amprenavir, Ampurine, Amrinone, AMT, Medeyol, Melarsenoxyd, Melarsoprol B, Mesalazine, Amthamine, Amtizole, Angustmycin A, Anileridine, Apad Metabutethamine, Metabutoxycaine, Metahexamide, Meta enoson, Apraclonidine, Apricitabine, Arafluorocytosine, Zosin, Methioprim, Methotrexate, Methylanthranilate, Aramine, Arazide, Aristeromycin, Arprinocid, Ascamycin, Metioprim, Metoclopramide, Metoprine, Minoxidil, Mirabe Ascensil, Aspiculamycin, Atolide, AZabon, AZacitidine, AZa gron, Mitomycin, Mivobulin, Mocetinostat, Monocain, line B, AZamulin, AZanidazole, AZepexole, Aztreonam, Baq Mosapride, Mutamycin, N-(p-Aminophenethyl)spiroperi uiloprim. Basedol, Batanopride, b-D-Adenosine, Bemitra dol, N6-2-(4-aminophenyeethyladenosine Role, NAD+, dine, Benfotiamine, Bentiamine, BenZamil, Benzocaine, NADH, NADH2, NADP+, NADPH2, Naepaine, Naminterol, Betoxycaine, Binodenoson, Biopterin, Bisbentiamine, Blas Naretin, Nebidrazine, NECA, Nelarabine, Nelzarabine, ticidin, Bleomycin, Bleomycin A1, Bleomycin A2, Bleomy Neolamin, Neotropine, Nepafenac, Nerisopam, Neurofort, cin A5, Bleomycin A6, Bleomycin DMA2, Brodimoprim, Nifurprazine, Nimustine, Nitrine, N-Methyltetrahydro folic Bromfenac, Bromobuterol, Bromopride, Bropirimine, Buci acid, Nolatrexed, Nomifensine, Norcisapride, N-Propionylp clovir, BunaZosin, Butyrylthiamine disulfide, Cadeguomy rocainamide, N-Sulfanilylnorfloxacin, o-Aminophenylala cin, cAMP, Candicidin, Capadenoson, Carbanilide, Carbod nine, Octotiamine, Olamufloxacin, Ormetoprim, Orthocaine, ine, Carbovir, Carbutamide, Carumonam, CDP-dipalmitin, Oximonam, Oxybuprocaine, p-Aminoantipyrine, p-Ami Cefcapenepivoxil, Cefclidin, Cefdaloxime, Cefdinir, Cefdi nobenzoate, p-Amino-D-phenylalanine, Pancopride, toren, Cefenpidone, Cefepime, Cefetamet, Cefetecol, Parsalmide, Pasdrazide, Pathocidine, Pelitrexol, Pemetrexed, Cefixime, Cefluprenam, Cefnmatilen, Cefnmenoxime, Cefodi Penciclovir, Peplomycin, Peralopride, Phenamil, Phenazone, Zime, Cefoselis, Cefotaxime, Cefotiam, Cefozopran, Ce?po Phenazopyridine, Phenyl p-aminobenzoate, Phenyl-PAS doxime, Cefauinome, Cefrom, Ceftazidime, Cefteram, Cef Tebamin, Phleomycin D1, Pibutidine, Picumeterol, Piraz tibuten, Ceftiofur, Ceftiolene, Ceftioxide, Ceftizoxime, monam, Piridocaine, Piritrexim, Porfiromycin, Pralatrexate, Ceftobiprole, Ceftriaxone, CefuZonam, Centazolone, Ceto Pramipexole, Prazobind, Prazosin, Preladenant, Procaina tiamine, c0MP. Chloroprocaine, Cidofovir, Cifostodine, mide, Procaine, Proflavine, Proparacaine, Propoxycaine, Cipamfylline, Cisapride, Cladribine, Clafanone, Claforan, Prosultiamine, Prucalopride, Pseudoisocytidine, Psicofura Clebopride, Clenbuterol, Clenproperol, Clofarabine, Clorsu nine, Pteridoxamine, Pteroyltriglutamic acid, Pyramine, lon, Coelenteramine, Coenzyme A, Colchicamid, Coumarin Pyrimethamine, Questiomycin, Quinelorane, Racivir, 10, Coviracil, Crotonoside, Cyclobut A, Cyclobut G, Cyclo Regadenoson, Renoquid, Renzapride, Residuimod, Resor clenbuterol, Cyclotiamine, Cytallene, Cytarabine, Cytarazid, cein, Retigabine, Reverset, Riluzole, Rociclovir, Rufocromo Cytidine, Cytidine diphosphate, Cytidoline, CytosineD-(+)- mycin, S-Adenosylmethionine, Sangivamycin, Sapropterin, Neopterin, Dactinomycin, D-Amethopterin, dAMP, Damvar, S-Doxazosin, Sepiapterine, Silversulfadiazine, Sinefungin, Daniquidone, Dapsone, Daptomycin, Daraprim, Darunavir, Sipatrigine, Sparfloxacin, Sparsomycin, Stearyl-CoA, Stear DATHF, Dazopride, dCMP, dCTP, Debromohymenialdisine, ylsulfamide, Streptonigrin, Succisulfone, Sulfa Decitabine, Declopramide, Deisopropylhydroxyatrazine, monomethoxine, Sulamserod, Sulfabromomethazine, Sul Delafloxacin, Delfantrine, Denavir, Deoxyadenosine, facetamide, Sulfachlorpyridazine, Sulfachrysoidine, Deoxy-ATP, Deoxycytidine, Deoxyguanosine, Dephosphoc Sulfaclomide, Sulfaclorazole, Sulfaclozine, Sulfacytine, Sul oenzyme A, Dequalinium, Desbutylbumetanide, Desciclovir, fadiasulfone, Sulfadiazine, Sulfadicramide, Sulfadimethox Desoxyminoxidil, dGMP, dGTP, Diacethiamine. Diami ine, Sulfadimidine, Sulfadoxine, Sulfaethoxypyridazine, Sul noacridine, Diaveridine, Dichlorobenzamil, Dichlo faguanidine, Sulfaguanole, Sulfalene, Sulfamerazine, romethotrexate, Dichlorophenarsine, Dideoxycytidine, Sulfamethazine, Sulfamethizole, Sulfamethoxazole, Sul Dihydrobiopterin, Dihydrofolic acid, Dimethialium, Dime famethoxydiazine, Sulfamethoxypyridazine, Sulfametomi thocaine, Dimethyl methotrexate, Dinalin, DL-5,6,7,8-Tet dine, Sulfametopyrazine, Sulfametrole, Sulfanilamide, Sul rahydrofolic acid, DL-Methotrexate, Dobupride, Dovitinib, fanilamidoimidazole, Sulfanilylglycine, Sulfaperin, Doxazosin, Draflazine, Edatrexate, Elpetrigine, Elvucitab Sulfaphenazole, Sulfaproxyline, Sulfapyrazole, Sulfapyri ine, Emtricitabine, Entecavir, Enviradene, Epcitabine, dine, Sulfasomizole, Sulfasymazine, Sulfathiadiazole, Sulfa Epiroprim, Eritadenine, Etanterol, Ethacridine, Ethaden, Eth troxazole, Sulfatrozole, Sulfisomidine, Sulfisoxazole, Tace ylisopropylamiloride, Etoprine, EtoxaZene, Etravirine, dinaline, Tacrine, Talampanel, Talipexole, Talisomycin A, Etriciguat, FAD, Famciclovir, Fazarabine, Fenamol, Feprat Tenofovir, Tenofovir disoproxil, Terazosin, Tetrahydrobiop set, Fiacitabine, Flucytosine, Fludara, Fludarabine, Fluocy terinm, Tetrahydrofolic acid, Tetroxoprim, Tezacitabine, tosine, Folic acid, Formycin A, Fosamprenavir, Furalazine, Thiamine. Thiazosulfone. Thioguanine, Tiamiprine, Tige US 2014/0243254 A1 Aug. 28, 2014 39 monam, Timirdine, Tinoridine, TiodaZosin, Tirapazamine, 90Y-DOTAGA-Substance P. LARG(Me)9 MS-10, Tiviciclovir, Tocladesine, Trancopal, Triacanthine, Triam D-TYR1ARG(Me)9] MS-10, D-TYR1AzaGLY7, ARG terene, Triapine, Triciribine, Trimazosin, Trimethoprim, Tri (Me)9] MS-10, D-TYR1 MS-10, Psi(CH2NH)TPG4Van metrexate, Tritoqualine, Troxacitabine, Tubercidin comycin Aglycon, TRP19 MS-10, 111 IN Pentetreotide, 5'-diphosphate, Tuvatidine, Tyrphostin AG 1112, Valacyclo 13-Deoxyadriamycin Hydrochloride, 17-Aminogeldanamy vir, Valganciclovir, Valopicitabine, Valtorcitabine, Velna cin, 19-O-Methylgeldanamycin, 1-Methyl-D-Tryptophan, crine, Vengicide, Veradoline, Vidarabine, Viroxime, Vita 21-Aminoepothilone B, 2-Aminoaristeromycin, 2-Aminon berin, Zalcitabine, Zhengguangmycin B2, ZinviroXime, eplanocin A, 3-Chloroprocainamide, 3-Deazaadenosine, Zorbamycin, Zoxazolamine, (t)-Saxitoxin, 2-Aminoperimi 3-Matida, 4-Aminosalicylic Acid, 4-Chlorophenylthio dine, 6-Formylpterin, 8-13-Neurotensin, 8-Thioguanosine, 9-Deazaguanosine, 9-Desarginine-bradykinin, a4-10-Corti DADME-Immucillin-A, 5,4'-Diepiarbekacin, 5'-Homonepl cotropin, Afamelanotide, Agmatine, Alarelin, Ambazone, anocin A, 5-Aminosalicylic Acid, 8(R)-Fluoroidarubicin Amiloride, Aminopterine, Ampyrimine, Angiotensin, Angio Hydrochloride, 99MTC-C(RGDFK*)2Hynic, 9-Ami tensin I. Angiotensin II, Antibiotic O-129, Antipain, Arginine, nocamptothecin, A-42867 Pseudoaglycone, Abacavir Succi Argiprestocin, Astressin, Atriopeptin III, Aviptadil, Benzyl nate, Abacavir Sulfate, Abanoquil Mesilate, Abarelix, isothiourea, Betacyamine, Bisindolylmaleimide IX, Bivaliru Acadesine, Acriflavine, Acyclovir, Acyclovir Elaidate, Acy din, Blasticidin S. Bleomycin B2, Bombesin 14, Buformin, clovir Oleate, Acyline, Adefovir, Adefovir Dipivoxil, Ademe Camostat, Cariporide, Carperitide, Cecropin P1, Cetrorelix, tionine Tosylate Sulfate, Adenallene, Adenophostin A, Cilengitide, Creapure, Cyanoginosin LR, Cyanoviridin RR, Adenophostin B, Adenosine, Aerothricin 1, Aerothricin 16, Dalargine, Damvar, Deazaminopterin, Defensin HNP 1. Aerothricin 41, Aerothricin 45, Aerothricin 5, Aerothricin 50, Deslorelin, Desmopressin, DeZaguanine, Dichloromethotr Aerothricin 55, Afloqualone, Ageliferin Diacetate, Ageliferin exate, Dihydrostreptomycin, Dimaprit, Dimethylamiloride, Dihydrochloride, Aladapcin, Alamifovir, Alatrofloxacin Mesilate, Alendronic Acid Sodium Salt, Alestramustine, DiminaZene, DL-Methotrexate, D-Methotrexate, Ebrotidine, Alfuzosin Hydrochloride, Aliskiren Fumarate. Alogliptin Edatrexate, Eel Thyrocalcitonin, Elastatinal, Elcatonin, Benzoate, Alpha-Methylnorepinephrine, Alpha-Methyltryp Enterostatin, Enviomycin, Eptifibatide, Ethylisopropy tophan, Altemecidin, Alvespimycin Hydrochloride, Amanta lamiloride, Etilamide, Etoprine, Famotidine, Flupirtine, Fur dine Hydrochloride, Ambasilide, Ambazone, Ambroxol terene, Galanin, Galegin, Ghrelin, Glucagon, Gonadoliberin Nitrate, Amdoxovir, Ameltolide, Amelubant, Amezinium A, Guanethidine, Guanfacine, Guanoxan, Guanylthiourea, Methylsulfate, Amfenac Sodium, Amidox, Amifostine Gusperimus, Hexamidine. Histatin 5. Histrelin, Homoargin Hydrate, Amikacin, Amiloride Hydrochloride, Aminocandin, ine, Icatibant, Imetit, Insulinotropin, Isocaramidine, Kallidin Aminoglutethimide, Aminoguanidine, Aminolevulinic Acid 10, Kemptide, Ketotrexate, Kiotorphin, Lactoferricin, Lami Hexyl Ester, Aminolevulinic Acid Methyl Ester, Amisul fiban, L-Bradykinin, Leucoverin, Leucovorin A, Leupeptin, pride, Amlodipine, Amlodipine Besylate, Amoxanox, Amox Leuprolide, Lometrexol, Lutrelin, m-Chlorophenylbigu icillin Pulsys. Amphotericin B, Ampicillin Sodium, anide, Melagatran, Melanotan II, Melanotropin, Melittin, Amprenavir, Ampydin, Amrinone, Amrubicin Hydrochlo Metformin, Methotrexate dimethyl ester, Methotrexate ride, Amselamine Hydrobromide, Amthamine, Anakinra, monohydrate, Methoxtrexate, Methylisothiourea, Meto Anamorelin Hydrochloride, Anatibant Mesilate, Angiopeptin prine, Miacalcin, MIBG, Minoxidil, MitoguaZone, Mivobu Acetate, Anisperimus, Antagonist-G, Antide, Antide-1. lin, Mivobulin isethionate, Moroxydine, Nafarelin, Neotine, Antide-2, Antide-3, Antileukinate, Apadenoson, Apixaban, Nesiritide, Netropsin, Neurotensin, N-Methyltetrahydro Aplonidine Hydrochloride, Apoptozole 1, Apoptozole 2, folate, Nociceptin, Nolatrexed, Novastan, Panamidin, Patho Apoptozole 3, Apricitabine, Arbekacin, Arbekacin Sulfate, cidine, Pebac, Peldesine, Pelitrexol, Pemetrexed, Pentami Arborcandin A, Arborcandin B, Arborcandin C, Arborcandin dine, Peramivir, Phenformine, Phenylbiguanide, Piggalanin, D. Arborcandin E, Arborcandin F, Argatroban Monohydrate, Pimagedine, Piritrexim, Pitressin, Porcine angiotensinogen, Argimesna, Arginine Butyrate, Argiotoxin-636, Armodafinil, Porcine gastrin-releasing hormone, Porcine neuropeptide Y. Arotinolol Hydrochloride, Arterolane Maleate, Aspoxicillin, Porcine PHI, Pralatrexate, Protein Humanin, Proteinase Atenolol, Atosiban, Atreleuton, AVorelin, AZacytidine, AZa inhibitor E 64, Pyrimethamin, Quinespar, Ratatriopeptin, Rat lanstat, AZaromycin SC, AZelnidipine, AZetirelin, AZodicar atriopeptin, Residuimod, Ribamidine, Rimorphin, Saralasin, bonamide, AZOxybacilin, AZtreonam, Aztreonam L-Lysine, Saxitoxin, Sermorelin, S-Ethylisothiourea, Spantide, Stalli AZumamide A, Baclofen, Bactobolin, Balapiravir Hydro mycin, Stilbamidine, Streptomycin A. Substance P free acid, chloride, Balhimycin, Barusiban, Batracylin, Belactin A, Sulfaguanidine, Synthetic LH-releasing hormone, Tallimus Belactosin A, Belactosin C, Benanomicin B, Benexate Cyclo tine, Teprotide, Tetracosactide, Tetrahydrobiopterin, Tetrahy dextrin, Benzocaine, Besifloxacin Hydrochloride, Beta drofolic acid, Thrombin receptor-activating peptide-14, Thy Amyloid (12-20), Binodenoson, Bleomycin A2 Sulfate, mopentin, Tioguanin, Tiotidine, Tirapazamine, Triamteren, Boceprevir, Bogorol A, Boholmycin, Brasilicardin A, Trimetrexate, Tryptorelin, Tuberactinomycin B, Tuftsin, Ure Bremelanotide, Brivanib Alaninate, Brivaracetam, Brodi pearl, Viomycidin, Viprovex, Vitamin M, Xenopsin, Zan moprim, Bromfenac Sodium, Bromhexine Hydrochloride, amivir, Zeocin, Ziconotide, Zoladex. Brostallicin Hydrochloride, Bunazosin Hydrochloride, 0533 Suitable drugs with an amine group may be selected Buserelin Acetate, Butabindide, Butamidine, Buteranol, from the group consisting of Aphidicolin Glycinate, Cabin 1, Calcium-Like Peptide 1, Calcium-Like Peptide 2, Cetrorelix Acetate, Picumeterol Fumarate, (-)-Draflazine, Cambrescidin 800, Cambrescidin 816, Cambrescidin 830, (-)-Indocarbazostatin B, (+)-(23.24)-Dihydrodiscoder Cambrescidin 844, Camostat, Canfosamide Hydrochloride, mollide, (+)-(R)-Pramipexole, (R)-(+)-Amlodipine, (R)-(+)- Capadenoson, Capeserod Hydrochloride, Capravirine, Terazosin, (R)-Ganciclovir Cyclic Phosphonate, (R)-Sufi CapraZamycin A, CapraZamycin B, CapraZamycin C, nosine, (R)-Zacopride, (S)-(-)-Norketamine, (S)- CapraZamycin E. CapraZamycin F. Capromorelin, Carafiban Oxiracetam, (S)-Sufinosine, (S)-Zacopride Hydrochloride, Maleate, Carbachol, Carbamazepine, Carbetocin, Carbovir, US 2014/0243254 A1 Aug. 28, 2014 40

Carboxyamidotriazole, Cariporide Hydrochloride, Caris Etravirine, Etriciguat. Exalamide. Examorelin, Exatecan bamate, Carpipramine, Carumonam Sodium, Caspofungin Mesilate, Ezatiostat Hydrochloride, Famciclovir, Famoti Acetate, Cefaclor, Cefcanel Daloxate Hydrochloride, Cef dine, Famotidine Bismuth Citrate, Favipiravir, Feglymycin, capene Pivoxil Hydrochloride, Cefdaloxime, Cefdaloxime Felbamate, Fenleuton, Fidarestat, Fidexaban, Filaminast, Pentexil Tosilate, Cefdinir, Cefditoren Pivoxil, Cefepime, Filarizone, Fingolimod Hydrochloride, Flucytosine, Fludara Cefetamet Pivoxil, Cefetecol, Cefixime, Cefluprenam, Cef bine Phosphate, Fluorobenzyltriamterene, Fluorominoxidil, matilen Hydrochloride Hydrate, Cefinenoxime Hydrochlo Fluoroneplanocin A. Flupiritine Maleate, Fluvirucin B2, Flu ride, Cefninox Sodium, Cefodizime, Cefodizime Sodium, voxamine Maleate, Folinic Acid, Fortimicin A, Fosam Cefoselis Sulfate, Cefotaxime Sodium, Cefotetan Disodium, prenavir Calcium, Fosamprenavir Sodium, Fosfomycin Cefotiam Hexetil, Cefotiam Hexetil Hydrochloride, Cefo Trometamol, Fradafiban, Freselestat, Frovatriptan, tiam Hydrochloride, Cefoxitin, Cefozopran, Cefozopran Fudosteine, Furamidine, G1 Peptide, Gabadur, Gabapentin, Hydrochloride, Ce?pirome, Cefpodoxime Proxetil, Cef Gabexate Mesilate, Galarubicin Hydrochloride, Galmic, Gal prozil, Cefprozil Monohydrate, Cefauinome, Ceftaroline, non, Ganciclovir, Ganciclovir Elaidic Acid, Ganciclovir Ceftazidime, Cefteram Pivoxil, Ceftibuten, Ceftobiprole, Monophosphate, Ganciclovir Sodium, Ganirelix, Ganirelix Ceftobiprole Medorcaril, CeftraZonal Bopentil, CeftraZonal Acetate, Garomefrine Hydrochloride, Gemcitabine, Gemcit Sodium, Ceftriaxone Sodium, Ceftrizoxime Alapivoxil, abine Elaidate, Gemifloxacin Mesilate, Gilatide, Girodazole, Cefuroxime, CefuroximeAxetil, Cefuroxime Pivoxetil, Cen Glaspimod, Glucosamine Sulfate, Gludopa, Glutathione tanamycin, Cephalexin Monohydrate, Ceranapril, Ceruletide Monoethylester, Glutathione Monoisopropylester, Glycine Diethylamine, Cetefloxacin, Chlorofusin, Chloroorienticin Proline-Melphalan, Glycopin, Glycothiohexide alpha, Golo A, Chloroorienticin B, Chlorotetain, Cibrostatin 1, Cidofovir, timod, Goserelin, Growth Factor Antagonist-116, Growth Cilastatin Sodium, Cilengitide, Cimaterol, Cinitapride Hormone Releasing Peptid 2, Guanabenz Acetate, Guanadrel Hydrogen Tartrate, Cipamfylline, Circinamide, Cisapride Sulfate, Guanethidine Monosulfate, Guanfacine Hydrochlo Hydrate, Cispentacin, Citicoline, Citrullimycine A, Cladrib ride, Gusperimus Hydrochloride, Halovir A. Halovir B. ine, Clitocine, Clofarabine, Clopidogrel Sulfate, Compound Halovir C. Halovir D. Halovir E. Hayumicin B, Hayumicin 3.01029, Coumamidine Gammal, Coumamidine Gamma2, C1, Hayumicin C2, Hayumicin D, Helvecardin A, Helvecar Cromoglycate Lisetil Hydrochloride, Cycallene, Cyclic-Ci din B, Hepavir B, Heptaminol AMP Amidate, Hexa-D-Argi dofovir, Cycloserine, Cyclotheonamide A, Cyclothialidine, nine, Hexadecyl Cidofovir, Hexadecyloxypropyl-Cidofovir, Cygalovir, Cypemycin, CySmethynil, Cystamidin A, Cysta Histamine Dihydrochloride. Histaprodifen, Histrelin, Histre mine, Cystazosin, Cystocin, Cytarabine, Cytarabine Ocfos lin Acetate, Human Angiotensin II, Hydrostatin A. Hydroxy fate, Cytaramycin, Cytochlor, Cytomodulin, Dabigatran, akalone, Hydroxyurea, Hypeptin, Ibutamoren Mesilate, Icati Dabigatran Etexilate, Dacopafant, Dactimicin, Dactinomy bant Acetate, Iclaprim, Icofungipen, Idarubicin cin, Dactylocycline A, Dactylocycline B, DADME-Immuci Hydrochloride, Ilatreotide, Ilonidap, Imetit, Imidafenacin, lin-G, Dalargin, Danegaptide Hydrochloride, Dapropterin Imidazenil, Imiquimod, Immunosine, Impentamine, Incyc Dihydrochloride, Dapsone, Darbufelone Mesilate, Darifena linide, Indanocine, Indantadol Hydrochloride, Indoxam, cin Hydrobromide, Darinaparsin, Darunavir, Daunorubicin, Inogatran, Intrifiban, Iobenguane 131I]. Iodorubidazone (P), Davasaicin, Davunetide, Debrisoquine Sulfate, Decahydro Iotriside, Isepamicin Sulfate, Isobatzelline A, Isobatzelline B. moenomycin A, Decaplanin, Deferoxamine, Degarelix Isobatzelline C, Isobatzelline D, Isobutyramide, Isodoxoru Acetate, Delafloxacin, Delta-Aminolevulinic Acid Hydro bicin, Isopropamide Iodide, Ispinesib Mesylate, Istaroxime, chloride, Deltibant, Denagliptin Hydrochloride, Denibulin Janthinomycin A, Janthinomycin B, Janthinomycin C, Jas Hydrochloride, Denufosol Tetrasodium, Deoxymethylsper pine B, Kahalalide F, Kaitocephalin, Kanamycin, Karnami gualin, Deoxynegamycin, Deoxyvariolin B. Desacetylvin cin B1, Katanosin A, Katanosin B. Kistamicin A, L-4-Oxal blastinehydrazide/Folate Conjugate, Des-F-Sitagliptin, Des ysine, Labetalol Hydrochloride, Labradimil, Lagatide, glugastrin Tromethamine, Deslorelin, Desmopressin Lamifiban, Lamivudine, Lamotrigine, Lanicemine 2CS)-Hy Acetate, Detiviciclovir Diacetate, Dexelvucitabine, Dexibu droxysuccinate, Lanicemine Hydrochloride, Lanomycin, profen Lysine, Dextroamphetamine Sulfate, Dezinamide, Larazotide Acetate, Lazabemide Hydrochloride, L-Dopa Dezocitidine, Diadenosine Tetraphosphate, Diaveridine, Methyl Ester Hydrochloride, L-Dopamide, Lecirelin, Lena Dichlorobenzoprim, Dicloguamine Maleate, Didemnin X. lidomide, Lenampicillin Hydrochloride, Leucettamine A, Didemnin Y. Dideoxycytidine, Difurazone, Dilevalol, Dil Leucovorin Calcium, Leuprolide Acetate, Leurubicin, Leus evalol Hydrochloride, Disermolide, Disopyramide Phos troducsin A, LeuStroducsin B. Leustroducsin C. Leustroduc phate, DI-VAL-L-DC, Docosyl Cidofovir, Dolastatin 14, sin H. Levetiracetam, Levodopa, Levodopa 3-O-Glucoside, Dolastatin C, Donitriptan Hydrochloride, Donitriptan Mesi Levodopa 4-O-Glucoside, Levoleucovorin Calcium, L-Histi late, Dovitinib Lactate. Doxazosin Mesylate, Doxorubicin dinol, L-Homothiocitrulline, Liblomycin, Linagliptin, Lini Hydrochloride, Doxycycline Hyclate, D-Penicillamine, fanib, Lintopride, Lirexapride, Lirimilast, Lisinopril, Draflazine, Droxidopa, DTPA-Adenosylcobalamin, Ebroti L-Lysine-D-Amphetamine Dimesylate, Lobophorin A, dine, Ecenofloxacin Hydrochloride, Efegatran Sulfate Lobucavir, Lodenosine, Loloatin B, Lomeguatrib, Lometr Hydrate, Eflornithine Hydrochloride, Eglumegad Hydrate, exol, Lonafarnib, Loracarbef Hydrate, Loviride, Loxoribine, Eicosyl Cidofovir, Elacytarabine, Elastatinal B, Elastatinal C. L-Simexonyl Homocysteine, L-Thiocitrulline, Lymphostin, Elpetrigine, Elvucitabine, Emtricitabine, Enalkiren, Enig Lysobactin, Mabuterol Hydrochloride, Makaluvamine A, mol, Eniporide Mesilate, Entecavir, Entinostat, Epinastine Makaluvamine A, Makaluvamine B, Makaluvamine C, Hydrochloride, Epiroprim, Epirubicin Hydrochloride, Epi Managlinat Dialanetil, Matristatin A2, Melagatran, Melano thalon, Epofolate, Epostatin, Epsilon Aminocaproic Acid, tan II, Memantine Hydrochloride, Memno-Peptide A, Mep Eremomycin, Eribulin Mesylate, Erucamide, Esafloxacine robamate, Meriolin-3, Mersacidin, Metaraminol, Metazosin, Hydrochloride, Eslicarbazepine Acetate, Etaquine, Ethanola Metformin Hydrochloride, Methotrexate, Methyl Bestatin, mine, Ethylthio-DADME-Immucillin-A, Ethynylcytidine, Methyldopa, Methylthio-DADME-Immucillin-A, Metoclo US 2014/0243254 A1 Aug. 28, 2014 pramide Hydrochloride, Metyrosine, Mexiletine Hydrochlo B', Pyloricidin B, Pyradizomycin, Pyrazinamide, Pyrazi ride, Micafungin Sodium, Midaxifylline, Mideplanin, noylguanidine, Pyriferone, Pyrimethamine, Quinelorane Midoriamin, Milacamide Tartrate, Milacemide-2H, Mil Hydrochloride, R-(+)-Aminoindane, Ralfinamide, Ramopla nacipran Hydrochloride, Minamestane, Minocycline Hydro nin A1, Ramoplanin A2, Ramoplanin A3. Ramorelix, Ravi chloride, Minoxidil, Mirabegron, Mitomycin, MivaZerol, domycin N-oxide, Razaxaban Hydrochloride, Reblastatin, Mivobulin Isethionate, Mizoribine, Mocetinostat Dihydro Regadenoson, Relcovaptan, Remacemide Hydrochloride, bromide, Modafinil, Modafinil Sulfone, Moenomycin A Residuimod, Restricticin, Retaspimycin Hydrochloride, Chloride Bismuth Salt, Mofegiline, Mofegiline Hydrochlo Retigabine Hydrochloride, Rhodopeptin C1, Rhodopeptin ride, Monamidocin, Monodansyl Cadaverine, Montirelin C2, Rhodopeptin C3, Rhodopeptin C4, Rhodostreptomycin Tetrahydrate, Mosapride Citrate, Moxilubant, Moxilubant A, Rhodostreptomycin B. Ribavirin, Ribavirin Eicosenate Maleate, Mozenavir Mesilate, M-Phenylene Ethynylene, cis, Ribavirin Eicosenate trans, Ribavirin Elaidate, Ribavirin Muraminomicin A, Muraminomicin B, Muraminomicin C, Oleate, Rilmazafone Hydrochloride Dihydrate, Riluzole, MuraminomicinD, Muraminomicin E1, Muraminomicin E2, Rimacalib Hydrochloride, Rimeporide Hydrochloride, Rio Muraminomicin F. Muraminomicin G, Muraminomicin H, ciguat, Ritipenem Acoxil, RobalZotan Hydrochloride, Robal Muraminomicin I, Muraminomicin Z1, Muraminomicin Z2, Zotan Tartrate Hydrate, Rociclovir, Romurtide, Rotigaptide, Muraminomicin Z3, Muraminomicin Z4, Muramyl Dipep Roxifiban Acetate, Ruboxyl, Rufinamide, Rumycin 1, Rumy tide C. Mureidomycin A. Mureidomycin B. Mureidomycin cin 2, Sabarubicin Hydrochloride, Sabiporide Mesilate, Safi C. Mureidomycin D. Mycestericin E. Myriocin, Nafamostat namide Mesilate, Safingol, Sagamacin, Sampatrilat, Sampir Mesylate, Nafarelin Acetate, Naglivan, Namitecan, Napsa tine, Saprisartan, Saquinavir, Saquinavir Mesilate, gatran, Nebostinel, Nebracetam Fumarate, Neldazosin, Sardomizide Hydrochloride, Sardomozide, Saussureamine Nelzarabine, Nemonoxacin, Neomycin B-Hexaarginine C, Saxagliptin, Secobatzelline A, Secobatzelline B, Seglitide, Conjugate, Neomycin-Acridine, Nepafenac, Nepicastat Selank, Seletracetam, Semapimod Hydrochloride, Senica Hydrochloride, Neramexane Hydrochloride, Neridronic poc, Sepimostat Mesilate, Seproxetine, Seraspenide, Seve Acid, Netamiftide Trifluoroacetate, Netilmicin Sulfate, lamer Carbonate. Sevelamer Hydrochloride, Shepherdin, Nocathiacin I, Nocathiacin II, Nocathiacin III, Nocathiacin Sibrafiban, Silodosin, Silver Sulfadiazine, Sipatrigine, Sita IV, NO-Gabapentin, Nolatrexed Hydrochloride, NO-Me floxacin Hydrate, Sitagliptin Phosphate Monohydrate, S-Ni salamine, Noraristeromycin, Nuvanil. 06-Benzylguanine, trosoglutathione, Sofigatran, Sonedenoson, Sotirimod, Spar Ocimumoside A, Octacosamicin A, Octacosamicin B, Oct floxacin, Sperabillin A, Sperabillin B. Sperabillin C, reother, Octreotide Acetate, Oglufanide Disodium, Olamu Sperabillin D, Sphingofungin F. Spinorphin, Spisulosine, floxacin, Olamufloxacin Mesilate, Olcegepant, Olradipine Squalamine Lactate, Streptomycin, Styloguanidine, Sub Hydrochloride, Omaciclovir, Ombrabulin, Ombrabulin stance P(8-11), Sufinosine, Sulcephalosporin, Sulfostin, Sul Hydrochloride, Onnamide A, Opiorphin, Orbofiban Acetate, phazocine, Sultamicilline Tosylate, Sunflower Trypsin Orienticin A, Orienticin B, Orienticin C, Orienticin D, Orita Inhibitor-1, Surfen, Synadenol, Synguanol, Tabimorelin, vancin, Oseltamivir Carboxylate, Oseltamivir Tacedinaline, Tacrine Hydrochloride, Tageflar, Talabostat, 0534 Phosphate, Otamixaban, Otenabant Hydrochloride, Talaglumetad Hydrochloride, Talampanel, Talipexole Dihy Ovothiol A, Oxazofurin, Oxcarbazepine, Oxiglutatione drochloride, Tallimustine Hydrochloride, Talopterin, Taltire Sodium, Oxiracetam, Oxolide, Oxynor, Oxyphenarsine, lin, Tanespimycin, Tanogitran, Targinine, Technetium Ozarelix, Pachymedusa Dacnicolor Tryptophyllin-1, Paecil (99MTC) Depreotide, Teicoplanin-A2-1, Teicoplanin-A2-2, aminol, Pafuramidine Maleate, Palau.Amine, Paldimycin B, Teicoplanin-A2-3, Teicoplanin-A2-3, Teicoplanin-A2-5, Pamidronate Sodium, Pancopride, Papuamide A, Papuamide Telavancin Hydrochloride, Telinavir, Temozolomide, B, Papuamide C, Papuamide D, Parasin I, Paromomycin, Temurtide, Tenidap, Tenidap Sodium, Tenofovir, Tenofovir Pasireotide, Paulomycin, Paulomycin A2, Paulomycin B, DF, Terazosin Hydrochloride, Tetracosyl Cidofovir, Tetracy Paulomycin C, Paulomycin D. Paulomycin E. Paulomycin F, cline Hydrochloride, Tetrafibricin, Texenomycin A, Tezacit PaZufloxacin, Pazufloxacin Mesilate, PEG-Vancomycin, abine, TGP. Thioacet, Thiothio. Thrazarine, Thymoctonan, Pelagiomicin C, Peldesine, Pelitrexol, Pemetrexed Diso Thymopentin, Tiamdipine, Tigecycline, Tilarginine Hydro dium, Penciclovir, Penicillin G Procaine, Pentamidine Glu chloride, Timirdine Diethanesulfonate, Timodepressin, Tipi conate, Pentamidine Isethionate, Pentamidine Lactate, Pep farnib, TNF-Alpha Protease Enzyme Inhibitor, Tobramycin, lomycin, Peramivir, Perphanazine 4-Aminobutyrate, Tocamide Hydrochloride, Tokaramide A, Tomopenem, Phakellistatin 5, PHE-ARG-Beta-Naphthylamide, Phenter Topostatin, Torcitabine, Tosufloxacin, Tosufloxacin Tosilate, mine, Phortress, Phospholine, Pibutidine Hydrochloride, Tranexamic Acid, Trantinterol Hydrochloride, Tranyl Pimeloylanilide O-Aminoanilide, Piracetam, Pirarubicin, cypromine Sulfate, Trelanserin, Tresperimus Triflutate, Tri Pivampicillin, Pixantrone Maleate, Pluraflavin A, Pluraflavin chomycin A, Triciribine, Triciribine Phosphate, Trientine B, Plusbacin A1, Plusbacin A2, Plusbacin A3, Plusbacin A4, Hydrochloride, Trimazosin Hydrochloride, Trimetrexate Plusbacin B1, Plusbacin B2, Plusbacin B3, Plusbacin B4, Glucuronate, Trimexautide, Trimidox, Trovafloxacin, Trova PMEO-5-ME-DAPY. Pneumocandin A0, Pneumocandin floxacin Hydrate, Trovafloxacin Hydrochloride Mesylate, BO, Pneumocandin BO 2-Phosphate. Pneumocandin D0, Trovafloxacin Mesilate, Troxacitabine, Trybizine Hydro Polaprezinc, Polydiscamide A, Polymer Bound Human Leu chloride, Tubastrine, Tuftsin, Tyroservatide, Tyrphostin 47. kocyte Elastase Inhibitor, Poststatin, PPI17-24, Pradimicin E, Ubenimex, Valacyclovir, Valganciclovir Hydrochloride, Val Pradimicin FA-2, Pralatrexate, Pramipexole Hydrochloride, nemulin, Valomaciclovir Stearate, Valonomycin A, Valopic Pranedipine Tartrate, Prazosin Hydrochloride, Prefolic A. itabine, Valpromide, Valrocemide, Vamicamide, Vancomycin Pregabalin, Preladenant, Primaquine Phosphate, Probestin, Hydrochloride, Vancoresmycin, Vapitadine Hydrochloride, Procainamide Hydrochloride, Procaine Hydrochloride, Pro Varespladib, Varespladib Methyl, Varespladib Mofetil, Vel Diazepam, Prostatin, Prucalopride, Prucalopride Hydrochlo nacrine Maleate, Venorphin, Vigabatrin, Vilazodone Hydro ride, Prucalopride Succinate, Pseudomycin A", Pseudomycin chloride, Vindesine, Viramidine Hydrochloride, Viranamy US 2014/0243254 A1 Aug. 28, 2014 42 cin-B, Vitamin B3, W Peptide, Xemilofiban, Xylocydine, 3-Bromomethcathinone, 4.5-Dianilinophthalimide, 4-Hy Zanamivir, Zileuton, Zoniporide Hydrochloride, Zorubicin droxyatomoxetine, 5-Methylurapidil, 7-Oxostaurosporine, Hydrochloride, ACTH, adenosine deaminase, agallsidase, 99 mTc-c(RGDfK*)2HYNIC, A-42867 pseudoaglycone, albumin, alfa-1 antitrypsin (AAT), alfa-1 proteinase inhibitor Abacavir Succinate, Abacavir Sulfate, Abarelix, Acarbose, (API), alglucosidase, alteplase, anistreplase, ancrod serine Acebutolol hydrochloride, Aceclofenac, Acyline, Adaphos protease, antibodies (monoclonal or polyclonal and frag tin, Adaprolol maleate, Adaprolol oxalate, Adecypenol, ments or fusions), antithrombin III, antitrypsins, aprotinin, Adrogolide hydrochloride, Aglaiastatin C, Alchemix, Alini asparaginases, biphalin, bone-morphogenic proteins, calcito dine, Alkasar-18, Alminoprofen, Alniditan, alpha-Methylepi nin (salmon), collagenase, DNase, endorphins, enfuVirtide, nephrine, Alprafenone hydrochloride, Alprenolol hydrochlo enkephalins, erythropoietins, factor VIIa, factor VIII, factor ride, AlprenoXime hydrochloride. Altromycin A, Altromycin VIIIa, factor IX, fibrinolysin, fusion proteins, follicle-stimu C, Alvespimycin hydrochloride, Ambroxol nitrate, Amfeb lating hormones, granulocyte colony stimulating factor utamone hydrochloride, Ami begron hydrochloride, Amifos (G-CSF), galactosidase, glucagon, glucagon-like peptides tine hydrate, Amineptine, Aminocandin, Aminochinol, Ami like GLP-1, glucocerebrosidase, granulocyte macrophage tivir, Amlodipine, Amlodipine besylate. Amocarzine, colony stimulating factor (GM-CSF), chorionic gonadotro Amodiaquine. Amosulalol hydrochloride, Amoxapine, pin (hCG), hemoglobins, hepatitis B vaccines, hirudin, hyalu Amsacrine, Anabasine hydrochloride, Anisperimus, Antide ronidases, idurnonidase, immune globulins, influenza vac 1, Aranidipine, Araprofen, Arbutamine hydrochloride, cines, interleukines (1 alfa, 1 beta, 2, 3, 4, 6, 10, 11, 12), IL-1 Ardeemin, Arformoterol tartrate, Argatroban monohydrate, receptor antagonist (rhIL-lra), insulins, interferons (alfa 2a, Argiopine, Arotinolol hydrochloride, Asperlicin E, Atenolol. alfa 2b, alfa 2c, beta 1 a, beta 1b, gamma 1a, gamma 1b). Atevirdine mesylate, AZathioprine, AZelnidipine, AZepi keratinocyte growth factor (KGF), lactase, leuprolide, nostatin, Balamapimod, Balhimycin, Balofloxacin, Balof levothyroxine, luteinizing hormone, lyme vaccine, natriuretic loxacin dihydrate, Bambuterol, Bamirastine hydrate, Banox peptide, pancrelipase, papain, parathyroid hormone, PDGF, antrone, Baogongteng A, Barixibat, Barnidipine pepsin, phospholipase-activating protein (PLAP), platelet hydrochloride, Batoprazine, Batzelline A, Batzelline B, Bat activating factor alcetylhydrolase (PAF-AH), prolactin, pro Zelline C. Becampanel, Bederocin, Bedoradrine sulfate, tein C, octreotide, secretin, sermorelin, Superoxide dismutase Befunolol hydrochloride, Belactin B, Belotecan hydrochlo (SOD). Somatropins (growth hormone). Somatostatin, Strep ride, Benazepril hydrochloride, Bendroflumethiazide, Beni tokinase, Sucrase, tetanus toxin fragment, tilactase, throm dipine hydrochloride, Berlafenone hydrochloride, Betaxolol bins, thymosin, thyroid stimulating hormone, thyrothropin, hydrochloride, Bevantolol hydrochloride, Biemnidin, Bife transforming growth factors, tumor necrosis factor (TNF). melane hydrochloride, Binospirone mesylate, Bioxalomycin TNF receptor-IgG Fc, tissue plasminogen activator (tPA), alpha 1, Bis(7)-cognitin, Bisantrene hydrochloride, Bisnafide transferrin, TSH, urate oxidase, urokinase, Fab (fragment, mesilate, Bisoprolol fumarate, Bitolterol mesylate, Bleomy antigen-binding), F(ab')2 fragments, Fc (fragment, crystalli cin A2 sulfate, Boholmycin, Bopindolol, Bosutinib, Brinaz Zable), pFc fragment, Fv (fragment, variable), ScFv (single arone, Brinzolamide, Bulaquine, Bumetanide, Buteranol, chain variable fragment), di-schv/diabodies, bi-specific Butofilolol, Cadrofloxacin hydrochloride, Caldaret hydrate, T-cell engager, CDRS (complementarity determining Calindol Dihydrochloride, Capridine beta, Carmoterol regions), single-domain antibodies (sdABS/Nanobodies), hydrochloride, Carteolol hydrochloride, Carvedilol, Caspo heavy chains (C. B. e. Y, u) or heavy chain fragments, light fungin acetate, Ceftaroline fosamil acetate, Ceftizoxime chains (W, K) or light chain fragments, VH fragments (variable sodium, Ceftobiprole, Celiprolol hydrochloride, Cerebro region of the heavy chain), VL fragments (variable region of crast, Ceruletide diethylamine, Cevipabulin, Chinoin-169, the light chain), VHH fragments, VNAR fragments, shark Chloptosin, Chlordiazepoxide hydrochloride, Chloroorienti derived antibody fragments and affinity scaffold proteins, cin A, Chloroorienticin B, Cilazapril, Cilnidipine, Ciluprevir, Kunitz domain-derived affinity scaffold proteins, centyrin Cimaterol, Cinacalcet hydrochloride, Cinnamycin, Ciprof derived affinity scaffold proteins, ubiquitin-derived affinity loxacin hydrochloride, Ciprofloxacin silver salt, Clevidipine scaffold proteins, lipocalin-derived affinity scaffold proteins, butyrate, Clitocine, Clopenphendioxan, Cloranolol hydro ankyrin-derived affinity scaffold proteins, Versabodies (dis chloride, Clozapine, Conantokin-R, Conophylline, Crisinatol ulfide-rich affinity scaffold proteins), fibronectin-derived mesilate, Cronidipine, Dabelotine mesilate, Dabigatran, affinity scaffold proteins, cameloid-derived antibody frag Dabigatran etexilate, Dalbavancin, Dapivirine, Dapropterin ments and affinity scaffold proteins, llama-derived antibody dihydrochloride, Dasantafil. Debromoshermilamine, Deca fragments and affinity Scaffold proteins, transferrin-derived planin, Degarelix acetate, Delapril hydrochloride, Delavird affinity Scaffold proteins, Squash-type protease inhibitors ine mesilate, Delfaprazine hydrochloride, Delucemine with cysteine-knot scaffold-derived affinity scaffold proteins. hydrochloride, Demethylallosamidin, Demexiptiline hydro 0535 Suitable secondary amine-containing drugs may be chloride, Denopamine, Deoxymethylspergualin, Deoxysper selected from the group consisting of (-)-3-O-Acetylspecta gualin Hydrochloride, Desacetylvinblastinehydrazide/folate line hydrochloride, (-)-3-O-tert-Boc-spectaline hydrochlo conjugate. Desbutyl benflumetol, Desbutylhalofantrine ride, (-)-Cicloprolol, (-)-Norchloro-18Ffluoro-homoepi hydrochloride, Desferri-salmycin A, Desferri-salmycin B, batidine, (-)-Salbutamol hydrochloride, (-) Salmeterol, Desferri-salmycin C, Desferri-salmycin D. Desipramine (+)-(S)-Hydroxychloroquine, (+)-Isamoltan, (+)-R-Prami hydrochloride, Desloratadine, Dexfenfluramine hydrochlo pexole, (R)-(+)-Amlodipine, (R)-Clevidipine, (R)-NSP-307, ride, Dexketoprofen meglumine, Dexmethylphenidate (R)-Teludipine, (R)-Thionisoxetine, (S)-Clevidipine, (S)-N- hydrochloride, Dexniguldipine hydrochloride, Dexsotalol, Desmethyltrimebutine, (S)- Noremopamil, 99TcDemobe Diazepinomicin, Dichlorobenzoprim, Diclofenac potassium, sin 4. Glu10.Nle17.Nle30-Pancreatic polypeptide(2-36), Diclofenac sodium, Diclofenac Zinc salt, Diethylnorsper Nle17.Nle30-Pancreatic polypeptide(2-36), psiCH2NH mine, Dihydrexidine, Dilevalol, Dilevalol hydrochloride, Tpg4Vancomycin aglycon, 15bbeta-Methoxyardeemin, Dinapsoline, Dinoxyline, Dipivefrine hydrochloride, Disco US 2014/0243254 A1 Aug. 28, 2014

dermide, Discodermide acetate, Discorhabdin D, Discorhab Meclofenamate sodium, Mefenamic acid, Mefloquine hydro din P. Discorhabdin S, Discorhabdin T. Discorhabdin U, Dob chloride, Melagatran, Melogliptin, Meluadrine, Meluadrine utamine hydrochloride, Dobutamine phosphate, tartrate, Memoquin, Mepindolol sulfate, Mepindolol trans Dopexamine, Dopexamine hydrochloride, Doripenem, Dor dermal patch, Meropenem, Methamphetamine hydrochlo Zolamide hydrochloride, d-Pseudoephedrine hydrochloride, ride, Methoctramine, Methyclothiazide, Methylhistaprod Droximavir, Duloxetine hydrochloride, Duocarmycin A, ifen, Methylphenidate hydrochloride, Metipranolol, Duocarmycin B1, Duocarmycin B2, Duocarmycin C1, Duo Metolazone, Metoprolol fumarate, Metoprolol succinate, carmycin C2, Dynemicin A. Dynemicin C. Ebanicline, Ect Metoprolol tartrate, Mezacopride, Michellamine B. Microcin einascidin 1560, Ecteinascidin 722, Ecteinascidin 729, Ect J25, Micronomicin sulfate, Midafotel, Milacemide-2H, einascidin 736, Ecteinascidin 745, Ecteinascidin 770, Minaprine hydrochloride, Mirabegron, Mitomycin, Mitox Ecteinascidin 875, Efaroxan, Efegatran sulfate hydrate, Efe antrone hydrochloride, Mivobulin isethionate, Modipafant, pristin, Efonidipine hydrochloride ethanol, Elagolix sodium, Moexipril hydrochloride, Moexiprilat, Montirelin tetrahy Elansolid C1, Elarofiban, Elbanizine, Elgodipine hydrochlo drate, Moranolin, Motesanib diphosphate, Moxifloxacin ride, Elinafide mesilate, Elinogrel potassium, Elnadipine, hydrochloride, Moxonidine hydrochloride hydrate, Murami Enalapril maleate, Enalapril nitrate, Enalaprilat, EnaZadrem, nomicin I, Mureidomycin E, Mureidomycin F. Mureidomy Enkastin (D), Enkastin (D), Enkastin (D), Enkastin AD, cins, N1,N8-Bisnorcymserine, Nadolol, Naproxen pipera Enkastin AE, Enkastin ID, Enkastin IE, Enkastin VD, Enkas Zine, Napsamycin A, Napsamycin B, Napsamycin C, tin VE, Enoxacin, Epibatidine, Epostatin, Eremomycin, Napsamycin D. Nardeterol, N-demethylated sildenafil. Ersentilide, Ersentilide hydrochloride, Ertapenem sodium, Nebivolol, Nemonapride, Neomycin-acridine, Neratinib, Esculeogenin A, Esculeoside A, Esmolol hydrochloride, Netilmicin sulfate, Nicardipine hydrochloride, Nifedipine, Esperamicin A1, Etamsylate, Ethoxy-idaZOXan, Eugenodilol. Nifekalant hydrochloride, Niguldipine hydrochloride, Nilva Ezlopitant, Falnidamol, Fargilitazar, Fasobegron hydrochlo dipine, Nimodipine, Nipradillol, Nisoldipine, Nitracrine dihy ride, Fasudil hydrochloride, Felodipine, Fenoldopam mesi drochloride hydrate, Nitrendipine, Nitrofenac, Nitroso-nife late, Fenoterol hydrobromide, Fepradinol, Ferroquine, Fer dipine, Noberastine, Noberastine citrate, NO-ciprofloxacin, ulinolol, Finafloxacin hydrochloride, Flecamide acetate, N-Octyl-beta-valienamine, Nolomirole hydrochloride, Nor Florbetaben, Florbetapir F 18, Flufenoxine, Flumezapine, floxacin, Norsegoline, Nortopixantrone hydrochloride, Fluodipine, Fluoxetine hydrochloride, Fluparoxan, Flupir Nortriptyline hydrochloride, N-tert butyl isoquine, tine maleate, Foetidine 1, Foetidine 2, Folinic acid, Formot Oberadillol, Oberadilol monoethyl maleate, Odanacatib, erol fumarate. Forodesine hydrochloride, Fosaprepitant Olanzapine, Olanzapine pamoate, Olradipine hydrochloride, dimeglumine, Fosopamine, Frovatriptan, Furnidipine, Furo Ontazolast, OPC-17083, Orbifloxacin, Orciprenaline sul semide, Gaboxadol, Gadobenic acid dimeglumine salt, phate, Orienticin A. Orienticin B. Orienticin C, Oritavancin, Gadopentetate dimeglumine, Gadoterate meglumine, Galac Osemozotan hydrochloride, Osutidine, Otenabant hydro tomycin I, Galactomycin II, Garenoxacin mesilate, Gati chloride, Ovothiol B, Oxprenolol hydrochloride, Ozenoxa floxacin, Gefitinib, Glucolanomycin, Glutapyrone, Gos cin, Pafenolol, Palau'amine, Palindore fumarate, Panobin ogliptin hydrochloride, Grepafloxacin hydrochloride, ostat, Parodilol hemifumarate, Parogrelil hydrochloride, Gypsetin, Halofuginone hydrobromide, Helvecardin A, Paroxetine, Paroxetine ascorbate, Paroxetine camsilate, Par Helvecardin B, Herquline B, Hesperadin, Himastatin, Hispi oxetine hydrochloride, Paroxetine mesilate, Pazelliptine tri dospermidin, Homoepibatidine, Hydrochlorothiazide, hydrochloride, Pazelliptine trihydrochloride monohydrate, Hydroflumethiazide, Hydroxychloroquine sulfate, Ibopam Pelitinib, Pelitrexol, Penbutolol sulfate, Pentostatin, Peplo ine, IdaZOXanhydrochloride, Iganidipine hydrochloride, Imi mycin, Perindopril, Perzinfotel, Phendioxan, Pibutidine dapril, Imidapril hydrochloride, Imidazoacridinone, Imiso hydrochloride, Picumeterol fumarate, Pindolol, Pirbuterol pasem manganese, Immepip, Immepyr, Incadronate, hydrochloride, Pittsburgh Compound B, Pixantrone maleate, Indacaterol, Indantadol hydrochloride, Indeloxazine hydro Plerixafor hydrochloride, Polyglutamate camptothecin, chloride, Indolmycin, Inogatran, Intoplicine, Iofetamine Pozanicline hydrochloride, Pradimicin A, Pradimicin B, hydrochloride I-123. Iptakalim hydrochloride, Isavuconazo Pradimicin D, Pradimicin FA-1, Pradimicin FL, Pradimicin nium chloride hydrochloride, Isepamicin Sulfate, Isofagom FS, Pradimicin L. Pradimicin S. Pradofloxacin, Pramipexole ine tartrate, Isoquine, Ispronicline, Isradipine, Iturelix, Kai hydrochloride, Pranedipine tartrate, Pranidipine, Prefolic A. tocephalin, Ketamine hydrochloride, Kopsinine, Premafloxacin, Premafloxacin hydrochloride, Premafloxacin Korupensamine A, Korupensamine B. Korupensamine C, magnesium, Primaquine phosphate, Prisotinol, Procaterol Kosinostatin, Labedipinedilol A, Labedipinedilol B, Labe Hydrochloride Hemihydrate, Propafenone hydrochloride, talol hydrochloride, Labradimil, Lacidipine, Ladasten, Propranolol hydrochloride, Protriptyline hydrochloride, Ladostigil tartrate, Lagatide, Landiolol, Lapatinib ditosylate, Proxodolol, Pumaprazole, Pyrindamycin A. Pyrindamycin B, Lenapenem hydrochloride, Lenapenem hydrochloride Quinapril hydrochloride, Quinpramine, rac-Debromoflustra hydrate, Lerisetron, Leucovorin calcium, LeVobetaxolol mine E. Radezolid, Rafabegron, Ralfinamide, Ramipril, hydrochloride, Levobunolol hydrochloride, Levoleucovorin Rasagiline mesilate, Razupenem, Reboxetine mesilate, Repi calcium, Levonebivolol, Liblomycin, Linaprazan, Lisinopril, notan, Repinotan hydrochloride, Reproterol hydrochloride, Litoxetine, Lobenzarit sodium, Lodamin, Lofexidine hydro Retaspimycin hydrochloride, Retigabine hydrochloride, chloride, Lomefloxacin hydrochloride, Lorcaserin, Rhodostreptomycin A. Rhodostreptomycin B. Rifabutin, Ril Lotrafiban, Loviride, Lubazodone hydrochloride, Lumira menidine dihydrogen phosphate, Rimoterol hydrobromide, coxib, Mabuterol hydrochloride, Makaluvamine D. Makalu Risotilide, Rivanicline, Robenacoxib, Rolapitant hydrochlo vamine E. Makaluvamine F, Makaluvone, Manidipine hydro ride, Safinamide mesilate, Sagandipine, Salbostatin, Salbuta chloride, Manifaxine hydrochloride, Manzamine B. mol nitrate, Salbutamol sulfate, Salmaterol, Salmeterol Xin Manzamine D. Maprotiline hydrochloride, Maropitant, Mas afoate, Sarizotan hydrochloride, Saussureamine C, nidipine hydrochloride, Mecamylamine hydrochloride, Sazetidine-A, Selodenoson, Sertraline, Sertraline hydrochlo US 2014/0243254 A1 Aug. 28, 2014 44 ride, Setazindol, Sezolamide hydrochloride, Shishijimicin A, pothilone D, 11-Keto-Beta-Boswellic Acid, 12-Methylthio Shishijimicin B, Shishijimicin C, Sibanomicin, Sibenadet vinblastine dihydrochloride, 13-Deoxyadriamycin hydro hydrochloride, Silodosin, Sitamaquine hydrochloride, Sive chloride, 14alpha-Lipoyl andrographolide, 14beta lestat sodium hydrate, Sofinicline, Solabegron hydrochlo Hydroxydocetaxel-1,14-acetonide, 14beta ride, Solpecainol hydrochloride, Soraprazan, Sotalol hydro Hydroxytaxotere, 14-C-Methyltriptolide, chloride, Sparfloxacin, Spermine dialdehyde, Spirapril, 14-Demethylmycoticin A, 14-Hydroxyclarithromycin, Spiroquinazoline, Squalamine lactate, Streptomycin, 14-Isobutanoylandrographolide, 14-Pivaloylandrogra Stressin1-A, Sumanirole maleate, Suprofenac 1, Suprofenac pholide, 15-Methylepothilone B, 16-Methyloxazolomycin, 2, Suprofenac 3, Suronacrine maleate, Tafamidis meglumine, 17-Aminogeldanamycin, 17beta-Hydroxywortmannin, Tafenoquine Succinate, Talarozole, Talibegron, Talibegron 18, 19-Dehydrobuprenorphine hydrochloride, 18-Hydroxy hydrochloride, Talniflumate, Talotrexin, Taltobulin, Talu coronaridine, 19-O-Demethylscytophycin C, 19-O-Meth dipine hydrochloride, Tamsulosin hydrochloride, Tanespi ylgeldanamycin, 1alpha,25-Dihydroxyvitamin D3-23.26 mycin, Tanogitran, Tauropyrone, Tazopsine, Tecalcet hydro lactone, 1alpha-Hydroxyvitamin D4.1-Oxorapamycin, chloride, Tecastemizole, Technetium (99mTc) apcitide, 21-Aminoepothilone B, 22-Ene-25-oxavitamin D, 22-OX Technetium (99mTc) bicisate, Telatinib, Telavancin hydro acalcitriol, 24(S)-Ocotillol, 24-Deoxyascomycin, 25-Anhy chloride, Temacrazine mesilate, Temafloxacin hydrochlo drocimigenol-3-O-beta-D-Xylopyranoside, 26-Fluoroe ride, Temocapril hydrochloride, Terbutaline sulfate, pothilone, 2-Aminoaristeromycin, 2-Aminoneplanocin A, Terodiline hydrochloride, Tertatolol hydrochloride, Tetra 2-Methoxyestradiol. 2'-Palmitoylpaclitaxel, 3,5-Dicaf caine hydrochloride, Tetrahydrodercitin 1, Tetrindole, feoylquinic acid, 3,7a-Diepialexine, 36-Dihydroisorollini Tezampanel. Thiamet-G, Thiofedrine, Tiamdipine, Tiameni astatin 1.3-Allyl farnesol, 3-Bromodiosmine, 3-Chlo dine, Tianeptine sodium, Tiapafant, Tienoxolol hydrochlo rodioSmine, 3-DeaZaadenosine, 3-Epimaxacalcitol. 4.6- ride, Tigecycline, Tilisolol hydrochloride, Timolol hemihy diene-Cer. 41-Demethylhomooligomycin B, drate, Timolol maleate, Tinazoline hydrohloride, Tirofiban 44-Homooligomycin B, 4-Chlorophenylthio-DADMe-im hydrochloride, Tizanidine hydrochloride, Toborinone, Tolfe mucillin-A, 4-Demethylepothilone B, 4'-Ethynylstavudine, namic acid, Tomatine, Tomoxetine hydrochloride, Topix 4"-Hydroxymevastatin lactone, 5(R)-Hydroxytriptolide, antrone hydrochloride, Torasemide, Trabectedin, Trandola 5,4'-Diepiarbekacin, 5,6-Dehydroascomycin, 5'-Epiequise pril, Trandolaprilat, Trantinterol hydrochloride, Treprostinil tin, 5-Ethylthioribose, 5-N-Acetyl-15balpha-hy diethanolamine, Tresperimus triflutate, Triacetyl dynemicin droxyardeemin, 5-Phenylthioacyclouridine, 5-Thiae C, Trientine hydrochloride, Trifluproxim, Trimetazidine, Tri pothilone, 5Z-7-OxoZeaenol, 6alpha-7-Epipaclitaxel, metrexate glucuronate, Trombodipine, Troxipide, Tulathro 6alpha-FluorourSodeoxycholic acid, 6'-Homoneplanocin A, mycin A, Tulathromycin B, Tulobuterol hydrochloride, Ufe 6-Hydroxyscytophycin B, 6-O-mPEG4-Nalbupine, 6-O- namate, Ulifloxacin, Ulimorelin, Uncialamycin, Urapidil, mPEGS-Nalbuphine, 7,7a-Diepialexine, 7-Deoxytaxol. Utibapril, Utibaprilat, Vabicaserin hydrochloride, Vancomy 8(R)-Fluoroidarubicin hydrochloride, 9,11-Dehydrocortex cin hydrochloride, Vandetanib, Vanidipinedilol, Vaminolol, olone 17alpha-butyrate, 9.9-Dihydrotaxol. 9-18FFluoro Vapitadine hydrochloride, Varenicline tartrate, Varlitinib, propyl-(+)-dihydrotetrabenazine, 99 mTc-c(RGDfK*) Vatalanib succinate, Vatanidipine, Vatanidipine hydrochlo 2HYNIC, 9-Aminocamptothecin, 9-Hydroxyrisperidone, ride, Vestipitant mesylate, Vicenistatin, Vildagliptin, Vilox A-42867 pseudoaglycone, Abacavir Succinate, Abacavir Sul azine hydrochloride, Vofopiitant hydrochloride, Voglibose, fate, Abaperidone hydrochloride, Abarelix, Abietaquinone Voreloxin, Xamoterol fumarate, Ximelagatran, Yttrium-90 methide, Abiraterone, Acadesine, Acarbose, Acaterin, Ace edotreotide, Zabicipril hydrochloride, Zabiciprilat hydro butolol hydrochloride, Acemannan, Aceneuramic acid chloride, Zabofloxacin hydrochloride, Zanapezil fumarate, Sodium salt, Achimillic Acids, Achimillicic Acid a Lactone, Zelandopam hydrochloride, Zilpaterol, Zolmitriptan. Aciclovir, Aclarubicin, Actinoplanone A, Actinoplanone B. 0536 Suitable drugs containing aliphatic hydroxyl groups Aculeacin Agamma, Acyline, Adamantyl globotriaosylcera are, for example, (-)-(2R*,3R*,11bS*)-Dihydrotetrabena mide, Adaprolol maleate, Adaprolol Oxalate, Adecypenol, zine, (-)-(2R*.3S*.11bR*)-Dihydrotetrabenazine, (-)-2-(2- Adelmidrol, Ademetionine tosylate Sulfate, Adenophostin A, Bromohexadecanoyl)paclitaxel, (-)-4',5'-Didemethoxypi Adenophostin B. Adenosine, Adlupulon, AdXanthromycin A, cropodophyllin, (-)-4'-Demethoxypicropodophyllin, (-)-9- Aerothricin 1, Aerothricin 16, Aerothricin 41, Aerothricin 45, Dehydrogalanthaminium bromide, (-)-Calicheamicinone, Aerothricin 5, Aerothricin 50, Aerothricin 55, Afeletecan (-)-Clcloprolol, (-)-Indocarbazostatin B, (-)-Kendomycin, hydrochloride, Agelasphin 517. Agelasphin 564, Aglaiastatin (-)-Kolavenol, (-)-Salmeterol, (+)-(2R*.3R*.11bS*)-Dihy A, Aglaiastatin B, Aglaiastatin C, Aglepristone, Albacona drotetrabenazine, (+)-(2R*,3S*,11bR*)-Dihydrotetrabena Zole, Albifylline, Albithiazolium bromide, Albocycline K3, zine, (+)-(S)-Hydroxychloroquine, (+)-23,24-Dihydrodisco Alclometasone dipropionate, Alcuronium chloride, Aldecal dermolide, (+)-Almuheptolide A, (+)-AZacalanolide A, (+)- mycin, Alemcinal, Alendronate sodium, Alfacalcidol, Alisa Cystothiazole B, (+)-Dihydrocalanolide A, (+)-Etorphine, mycin, Aliskiren fumarate, Alkasar-18, Almokalant, alpha (+)-Hemipalmitoylcarnitinium, (+)-Indocarbazostatin, (+)- C-Galactosylceramide, alpha-Galactosylceramide, alpha Isamoltan, (+)- SCH-351448, (+)-Sotalol, (E)-p-Couma Galactosylceramide-BODIPY, alpha-Lactosylceramide, roylquinic acid, (R)-Almokalant, (R)-Bicalutamide, (R)-Dix alpha-Methylepinephrine, alpha-Methylnorepinephrine, yrazine dihydrochloride, (R)-Sulfinosine, (S)-Almokalant, Alprafenone hydrochloride, Alprenolol hydrochloride, (S)-Methylmaltrexone bromide, (S)-Oxiracetam, (S)-Sulfi Alprostadil. Altemicidin, Altorhyrtin C. Altromycin A. Altro nosine, (Z)-Indenaprost, 125I-Iodomethylycaconitine, 8 mycin B. Altromycin C. Altromycin D. Altromycins, Gingerol, Arg(Me)9 MS-10, D-Tyrl, Arg(Me)9] MS-10, Alvespimycin hydrochloride, Alvocidib hydrochloride, D-TyrlAZaCly7. Arg(Me)9 MS-10, D-Tyr 1 MS-10, Amarogentin, AmbroXol nitrate, Amdoxovir, Amelometa N-MeIle4-cyclosporin, psiCH2NHITpg4Vancomycin Sone, Amibegron hydrochloride, Amikacin, Aminocandin, aglycon, Trp 19 MS-10, 111 In-Pentetreotide, 11-Hydroxye Ammocidin A, Amosulalol Hydrochloride, Amphidinolide E. US 2014/0243254 A1 Aug. 28, 2014

Amphidinolide T1, Amphinidin A, Amphotericin B, cin H, Carbovir, Caribaeolin, Caribaeoside, Carisbamate, Amprenavir, Amrubicin Hydrochloride, Amycolamicin, Carmoterol hydrochloride, Carpesterol, Carquinostatin A, Amycomycin, Anandamide, Andenallene, ANDREA-1, Carsatirin, Carteolol hydrochloride, Carteramine A, Carvas Androstanolone, Androxolutamide, Anecortave acetate, tatin, Carvedilol, Caspofungin acetate, Castanospermine, Anguinomycin C, Anguinomycin D. Anidulafungin, Ankino Cefbuperazone sodium, Cefcanel, Cefonicid sodium, Cefos mycin, Annamycin, Annocherimolin, Antheliatin, Antide, elis sulfate, Celgosivir, Celikalim, Celiprolol hydrochloride, Antide-1, Antide-2, Antide-3, Antiflammin-1, Antiflammin Cephalostatin 1, Cephalostatin 2, Cephalostatin 3, Cepha 3. Apadenoson, Apaziquone, Aphidicolin, Aphidicolin Gly lostatin 4, Cephalostatin 7, Cephalostatin 8, Cephalostatin 9. cinate, ApicularenA, Apicularen B, Aplaviroc hydrochloride, Ceramidastin, Cerebroside A, Cerebroside B, Cerebroside C, Apricitabine, Aragusterol A, Aragusterol C, Aranorosin, Ara Cerebroside D, Cerivastatin sodium, Ceruletide diethy norosinol A, Aranorosinol B, Aranose, Arbekacin, Arbekacin lamine, Cethromycin, Cetrorelix Acetate, Chackol, Cha sulfate, Arborcandin A, Arborcandin B, Arborcandin C, etoatrosin A, Chafuroside, Chenodeoxycholic acid, Cheto Arborcandin D, Arborcandin E, Arborcandin F, Arbutamine cin, Chinoin-169, Chloptosin, ChloraZicomycin, hydrochloride, Archazolid A, Archazolid B, Arformoterol Chlorofusin, Chlorogentisylquinone, Chloroorienticin A, tartrate, Arimoclomol maleate, Arisostatin A, Arisugacin A, Chloroorienticin B, Chlortalidone, Cholerae Autoinducer-1, Arotinolol hydrochloride, Artelinate, Arteminolide A, Choline alfoscerate, Clclesonide, Cidofovir, Cimaterol, Arteminolide B, Arteminolide C, Arteminolide D, Artilide Cimetropium bromide, Cinatrin A, Cinatrin B, Cinatrin C1, fumarate, Arundifungin, Ascosteroside, Asiatic acid, Asiati Cinatrin C2, Cinatrin C3, Cinnabaramide A, Cinolazepam, coside, Asimadoline, Asperlicin B, Asperlicin E, Assamicin I. Ciprokiren, Citicoline, Citreamicin-eta, Citropeptin, Citrulli Assamicin II, Astromicin Sulfate, Atazanavir Sulfate, mycine A, Cladribine, Clarithromycin, Clavaric acid, Cla Atenolol, Atigliflozin, Atorvastatin, Atorvastatin calcium, Varinone, Clavulanate potassium, ClaZosentan, Clevudine, Atorvastatin-Aliskiren, Atosiban, Atovaquone, Atrinositol, Clidinium bromide, Clindamycin hydrochloride, Clitocine, Auristatin E. Aurothioglucose, Australifungin, Australine, Clobenoside, Clofarabine, Clopithepin, Cloranolol hydro Avicenol A, Avicequinone A, Avicin D, Avicin G, AVorelin, chloride, Cocositol, Collabomycin A, Coleneuramide, Axitirome, AZacitidine, AZaromycin SC, Azithromycin, Coleophomone B, Colestimide, Colforsin, Colforsin Azithromycin Copper Complex, Bactobolin, Bafilomycin Al, daproate hydrochloride, Colletoic acid, Colupulon, Conage Bafilomycin Cl, Baicalin, Balhimycin, Bambuterol, nin, Coniferol Alcohol, Coniosetin, Conocurvone, Conophyl Baogongteng A, Barixibat, Barusiban, Basifungin, Becate line, Contignasterol, Contortumine hydrochloride, Contu carin, Beciparcil. Beclometasone dipropionate. Becocal lakin G. Coproverdine, Correolide, Cortexolone 17alpha cidiol, Bedoradrine sulfate. Befloxatone. Befunolol hydro propionate, Corynecandin, Cositecan, Costatolide, chloride, Begacestat, Belactin B, Belotecan hydrochloride, Coumamidine Gammal, Coumamidine Gamma2, Crassi Beloxepin, BenanomicinA, Benanomicin B, Benexate cyclo cauline A, Crellastatin A, Crisinatol mesilate, Cromakalim, dextrin, Bengazole A, Bengazole B, Beraprost sodium, Ber Crossoptine A, Crossoptine B, Curtisian D. Curvularol, vastatin, Beta-Boswellic Acid, beta-Hydroxy beta-methylbu Cyclamenol, Cyclandelate, Cyclipostin A, Cyclohexanediol. tyrate, Betamethasone butyrate propionate, Betamethasone Cyclomarin A, Cyclooctatin, Cycloplatam, Cyclosporin A, dipropionate, Beta-Sialosylcholesterol Sodium Salt, Betax Cyclosporin J. Cyclothialidine, Cygalovir, Cypemycin, Cys olol hydrochloride, Bevantolol hydrochloride, Biapenem, tocin, Cystothiazole C, Cystothiazole D, Cystothiazole F. Bicalutamide, Bimatoprost, Bimoclomol, Bimoclomol 1-ox Cytallene, Cytarabine, Cytaramycin, Cytoblastin, Cytocha ide, Bimosiamose, Binodenoson, Biperiden, Bipranol hydro lasin B, Cytochlor, Cytogenin, Cytosporic acid, Cytostatin, chloride, Bisabosqual A, Bisabosqual B, Bisabosqual C. Cytotrienin I, Cytotrienin II, Cytotrienin III, Cytotrienin IV. Bisabosqual D, Bisoprolol fumarate, Bitolterol mesylate, Cytoxazone, DACH-Pt(II)-bis-ascorbate, Dacinostat, Dac Bleomycin A2 sulfate, Bogorol A, Bohemine, Boholmycin, timicin, Dactylfungin A, Dactylfungin B. Dactylocycline A, Bolinaquinone, Borrellidin, Bosentan, Brasilicardin A, Bra Dactylocycline B, Dactylorhin B, DADMe-Immucillin-G, silinolide A, Brasilinolide B, Brecanavir, Breflate, Breynin A, DADMe-Immucillin-H, Dalbavancin, Dalfopristin mesilate, Breynin B. Brivanib, Brivudine, Bromocriptine mesilate, Dalvastatin, Dapagliflozin, Daphnodorin B. Dapitant, Bromperidol, Brovincamine fumarate, Bryostatin 1, Bryosta Dapropterin dihydrochloride, Darunavir, Dasantafil. Dasat tin 10, Bryostatin 11, Bryostatin 12, Bryostatin 13, Bryostatin inib, Daunorubicin, Davunetide, Decahydromoenomycin A, 9, Budesonide, Bungeolic acid, Buprenorphine hemiadipate, Decaplanin, Decarestrictine C, Decarestrictine D, Decatro Buprenorphine hydrochloride, Buprenorphine-Val-carbam micin A, Decatromicin B, Decitabine, Decursinol, Defer ate, Buserelin acetate, Butalactin, Buteranol, Butixocort, iprone, Deflazacort, Deforolimus, Degarelix acetate, Butofilolol, Butorphanol tartrate, Byssochlamysol, Cabazi Dehydelone, Dehydrodolastatin-13, Dehydroilludin M, taxel, Cabin 1, Cadralazine, Calanolide A, Calanolide B, Cal Delafloxacin, Delaminomycin A, Delaminomycin B, bistrin A, Calbistrin B, Calbistrin C, Calbistrin D. Calcipot Delaminomycin C, Delimotecan sodium, delta-Tocopherol riol, Calcitriol, Calcium-like peptide 1, Caloporoside B, glucoside, Deltibant, Demethimmunomycin, Demethomy Caloporoside C, Caloporoside D, Caloporoside E. Caloporo cin, Demethylallosamidin, Demethylasterriguinone B-1, side F, Calphostin B, Calphostin D. Calteridol calcium, Cam Denopamine, Denufosol tetrasodium, Deoxyenterocin, brescidin 800, Cambrescidin 816, Cambrescidin 830, Cam Deoxylaidlomycin, Deoxymulundocandin, Deoxynojirimy brescidin 844, Camiglibose, Campestanol ascorbyl cin, Deoxyspergualin Hydrochloride, Deprodone propionate, phosphate, Canadensol, Canagliflozin, Candelalide B, Can Desacetyleleutherobin, Desacetylravidomycin N-oxide, delalide C, Cangrelor tetrasodium, Canrenoate potassium, Desacetylvinblastinehydrazide, Desacetylvinblastinehy Canventol, Capadenoson, Capecitabine, CapraZamycin A, drazide/folate conjugate, Desbutylbenflumetol, Desbutylha CapraZamycin B, CapraZamycin C, CapraZamycin E, lofantrine hydrochloride, Desferri-danoxamine, Desferri CapraZamycin F. Capridine beta, Carabersat, Carbazoma nordanoxamine, Desferri-salmycin A, Desferri-salmycin B, durin A, Carbazomadurin B, Carbazomycin G, Carbazomy Desferri-salmycin C, Desferri-salmycin D. Desisobutyrylci US 2014/0243254 A1 Aug. 28, 2014 46 clesonide, Deslorelin, Desmethyleleutherobin, Desmin-370, P, Fingolimod hydrochloride, Finrozole, Flomoxef Sodium, Desogestrel, Desoxyepothilone B. Desoxyepothilone F. Des Flopristin, Floxuridine, Fluconazole, Fludarabine phosphate, oxylaulimalide, Desvenlafaxine Succinate, Dexamethasone, Fludelone, Fludeoxyglucose (18F), Flumecinol, Flunisolide, Dexamethasone beloxil, Dexamethasone cipecilate, Dexam Flunoprost, Fluocinonide, Fluoroindolocarbazole A. Fluor ethasone Palmitate, Dexamethasone sodium phosphate, Dex oindolocarbazole B, Fluoroindolocarbazole C, Fluoronepl anabinol, Dexelvucitabine, Dexylosylbenanomycin A, DHA anocin A. Fluostatin B, Flupentixolhydrochloride, Fluphena paclitaxel, Diadenosine tetraphosphate, Dictyostatin 1, zine hydrochloride, Flurithromycin, Fluticasone furoate, Didemnin X, DidemninY. Dideoxyinosine, Dienogest, Diep Fluticasone propionate, Flutropium Bromide, Fluvastatin oxin-sigma, Diflomotecan, Digalactosyldiacylglycerol, sodium, Fluvirucin B2, Foetidine 1, Foetidine 2, Fonda Digoxin, Diheteropeptin, Dihydro-alpha-ergokryptine mesy parinux sodium, Formamicin, Formestane, Formosyn A, For late, Dihydrocostatolide, Dihydroeponemycin, Dihydroer moterol fumarate. Forodesine hydrochloride, Fosteabine gotamine mesylate, Dihydrogranaticin B, Dihydroheptapre sodium hydrate, Frederine, Fucoxanthin, Fudosteine, Fula nol, Dihydroisosteviol, Dilevalol, Dilevalol hydrochloride, dectin component A3, Fuladectin component A4, Fulves Dilimapimod, Dimelamol, Dimethandrolone, Dimethylcur trant, Fumagalone, Furaquinocin A, Furaquinocin B, Fusa cumin, di-mPEGS-Atazanavir, Dinaphine, Dioncoquinone candin A, Fusacandin B, Fuscoside B, Fusidate silver, A, Dioncoquinone B, Dioxolane thymine nucleoside, Dipera Fusidienol, Gabusectin, Gabusectin methyl ester, mycin, Dipivefrine hydrochloride, Dipyridamole, Dipy Gadobutrol, Gadocoletic acid trisodium salt, Gadomelitol, ridamole beta-cyclodextrin complex, Dicquafosol tetraso Gadoterate meglumine, Gadoteridol, Galactomycin I, Galac dium, Dirithromycin, Discodermide, Discodermide acetate, tomycin II, Galactosyllactose, Galamustine hydrochloride, Disermolide, Disodium cromproxate, Disodium lettusate, Galantamine hydrobromide, Galarubicin hydrochloride, Disorazol E1, Docetaxel, Docosanol, Docosyl cidofovir, Galocitabine, Ganaxolone, Ganciclovir, Ganciclovir elaidic Dofequidar fumarate, Dolastatin 13, Doramectin, Doranida acid, Ganciclovir monophosphate, Ganciclovir Sodium, Zole, Doretinel, Doripenem, Dorrigocin A, Dorrigocin B, Ganefromycin Alpha, Ganefromycin Beta, Ganglioside Doxefazepam, Doxercalciferol, Doxifluridine, Doxorubicin GM1, Ganirelix, Ganirelix acetate, Ganoderic acid X, Hydrochloride, Doxorubicin, Morpholinyl, DoxoTam 12, Garomefrine hydrochloride, Garveatin E, Garveatin F, Gem Doxycycline hyclate, Dridocamide, Droxidopa, Droximavir, citabine, Gemcitabine elaidate, Gemeprost, Genaconazole, Drupangtonine, DTPA-adenosylcobalamin, Duramycin, Genipin, Gestrinone, Gilatide, Gimatecan, Girodazole, Glau Dutomycin, Ecdysterone, Ecomustine, Ecraprost, Ecteinas cocalyxin A, Glemanserin, Glenvastatin, Glidobactin PF-1, cidin 1560, Ecteinascidin 722, Ecteinascidin 729, Ecteinas Glucarolactam potassium, Glucolanomycin, Glucolipsin A, cidin 736, Ecteinascidin 757, Edotecarin, Edotreotide Glucolipsin B. Glucopiericidinol A1, Glucopiericidinol A2, yttrium, Eicosyl cidofovir, Elacytarabine, Elansolid C1, Glucosamine Sulfate, Glufosfamide, Glycopin, Glycopyrro Eldecalcitol, Eleutherobin, Eleutheroside B, Eliprodil, nium bromide, Glycothiohexide alpha, Glycyrrhizinic acid, Elisapterosin B, Elocalcitol, Elomotecan hydrochloride, Gomphostenin, Goodyeroside A, Goodyeroside B. Gora Eltanolone, Elvitegravir, Elvucitabine, Emakalim, Embe latide, Goserelin, Granaticin B. Griseusin C. Gypsetin, conazole, Embelin, Emestrin C, Emtricitabine, Enalkiren, Halistatin 1, Halistatin 2, Halistatin 3, Halobetasol propi Enfumafungin, Englerin A, Enigmol, Enkastin (D), Enkastin onate, Halofantrine hydrochloride, Halofuginone hydrobro AD, Enkastin AE, Enkastin ID, Enkastin IE, Enkastin VD, mide, Halometasone, Haloperidol, Halopredone Acetate, Enkastin VE, Enocitabine, Enoloxone, Enpiperate, Enprostil, Halovir A, Halovir B, Halovir C, Halovir D, Halovir E. Halx Enrasentan, Entecavir, ent-Estriol, Eperezolid, Eperezolid azone, Haperforin F. Haperforine A, Haperforine B1, N-oxide, Epervudine, Epicochlioquinone A, Epidoxoform, Hatomamicin, Hatomarubigin C, Hatomarubigin D. Hattalin, Epirubicin hydrochloride, Epispongiadiol, Epocarbazolin A, Hayumicin A, Hayumicin B. Hayumicin C1, Hayumicin C2, Epocarbazolin B, Epofolate, Epolactaene, Eponemycin, Epo Hayumicin D. Hederacolchiside E. Heliquinomycin, Helve prostenol sodium, Epothilone A, Epothilone A N-oxide, cardin A, Helvecardin B, Heptaminol AMP Amidate, Hepte Epothilone B N-oxide, Epothilone E. Epoxomicin, lidic acid chlorohydrin, Hexadecyl cidofovir, Hexadecylox Epoxyvibsanin B, Eptaloprost, Eptastatin Sodium, Eptastig ypropyl-cidofovir, Hexafluorocalcitriol, Hidrosmin, mine Tartrate, Erabulenol B, Erectumin A, Eremomycin, Himastatin, Hispitolide C. Hispitolide D. Histrelin, Histrelin Eremophyllene A, Ergotamine tartrate, Eribulin mesilate, acetate, Homorisedronate, Hyaluronate sodium, Hydrocorti Eriocalyxin B, Eritoran tetrasodium, Ersentilide, Ersentilide Sone Aceponate, Hydrostatin A, Hydroxychloroquine Sulfate, hydrochloride, Ertapenem sodium, Eryloside A, Eryloside F. Hydroxymycotrienin A. Hydroxymycotrienin B, Hydroxy Erythritol, Erythrodiol, Erythromycin, Erythromycin Acis phoslactomycin B, Hydroxyzine hydrochloride, Hypeptin, trate, Erythromycin Salnacedin, Erythromycin stinoprate, Hyperoside, Hypocholamide, Hypocholaride, Ibandronic Esculeogenin A, Esculeoside A, Esmolol hydrochloride, acid monosodium salt monohydrate, Ibutilide fumarate, Espatropate hydrate, Esperatrucin, Estetrol, Estradiol, Estra Icariin, Icatibant acetate, Idarubicin hydrochloride, Ide diol acetate, Estren, Estriol, Ethanolamine, Ethchlorvynol, benone, Idremcinal, Ifenprodil, Ilatreotide, Iliparcil, Ethinylestradiol, Ethylthio-DADMe-immucillin-A, Ethynyl Ilonidap, Iloprost, Imipenem, Immunosine, Implitapide, cytidine, Etidronic acid disodium salt, Etiprednol dicloac Incyclinide, Indacaterol, Indianaprost (S), Indinavir Sulfate, etate, Etonogestrel, Etoposide, Etoposide phosphate diso Indomethacin-Simvastatin, Indynaprost, Ingenol mebutate, dium salt, Eugenodilol, Eugenosedin A, Euphodendroidin D, Inophyllum B, Inophyllum P. Inosiplex, Integracide A, Inte Evernimicin, Everolimus, Exatecan mesilate, EZetimibe, gracide B, Integracin B, Integramycin, Integrastatin A, EZetimibe glucuronide, Faerieflungin A, Faerieflungin B, Iobitridol, Iodixanol, Iodorubidazone (p). Iofratol, Iohexyl, Faropenem medoxomil, Faropenem Sodium, Fasobegron Iomeprol, Iopamidol, Iopentol, Iopromide, Iotriside, Iotrol, hydrochlorid, Fattiviracin A1, Febradinol, Febuprol, Fenot Ioversol, Ioxilan, Ipratropium bromide, Iralukast, Iralukast erol hydrobromide, Ferulinolol, Fesoterodine fumarate, Fex Sodium, IrciniastatinA, Irciniastatin B, Irinotecan hydrochlo ofenadine hydrochloride, Fidaxomicin, Filibuvir, Fimbrigal ride, Irofulven, Isalmadol, Isavuconazole, Isavuconazonium US 2014/0243254 A1 Aug. 28, 2014 47 chloride hydrochloride, Isepamicin sulfate, Isodoxorubicin, A2, Microcolin A, Micronomicin sulfate, Midecamycin Isoeleutherobin A, Isofagomine tartrate, Isofloxythepin, Iso acetate, Mideplanin, Mifepristone, Miglitol, Miglustat, homohalichondrin B, Isosorbide 5-mononitrate, IsoSpongia Milataxel, Milbemycin alpha-9, Milrinone Lactate, Miner diol, Isoxazoledehydelone, Isoxazolefludelone, Itavastatin val, Minocycline hydrochloride, Minodronate, Miporamicin, calcium, Itrocinonide, Ixabepilone, Jadomycin B, Janthino Mipragoside, Mirabegron, Mirodenafil hydrochloride, Mis mycin A, Janthinomycin B. Janthinomycin C, Jorumycin, akinolide, Misoprostol, Mitemcinal fumarate, Mitoxantrone Kadsuphilin C, Kahalalide F, Kaitocephalin, Kanamycin, hydrochloride, Mizoribine, Modecamide, Modithromycin, Kanglemycin A, Kansuinin B, kappa-Conotoxin P VIIA, Moenomycin A chloride bismuth salt, Mometasone furoate, Karalicin, Katanosin A, Katanosin B. Khafrefungin, Kifun Momordin Ic, Monamidocin, Monlicin A, Monogalactosyl ensine, Kigamicin A, Kigamicin B. Kigamicin C, Kigamicin diacylglycerol, Monohydroxyethylrutoside, Monophospho D. Kigamicin E. Kigamicinone, Kijimicin, Kinsenoside, ryl lipid A. Montelukast sodium, Morphine Glucuronide, Kobifuranone B, Kobin, Kodaistatin A, Kodaistatin B, Morphine hydrochloride, Morphine sulfate, Motexafin gado Kodaistatin C, Kodaistatin D. Kosinostatin, Kuehneromycin linium, Motexafin lutetium, Moxidectin, Mozenavir mesi A. Kurasoin B. Kynostatin-227. Kynostatin-272, Labe late, Multiforisin A, Mumbaistatin, Mupirocin, Muramino dipinedilol A, Labedipinedilol B, Labetalol hydrochloride, micin A, Muraminomicin B. Muraminomicin C, Labradimil, Lactonamycin, Lactosylphenyl trolox, Ladirubi MuraminomicinD, Muraminomicin E1, Muraminomicin E2, cin, Lagatide, Laherradurin, Lamivudine, Landiolol, Lan Muraminomicin F. Muraminomicin G, Muraminomicin H, reotide acetate, Lanthiopeptin, Larotaxel dihydrate, Lasi Muraminomicin I, Muraminomicin Z1, Muraminomicin Z2, navir, LaSonolide A, Latanoprost, Latrunculin S. Muraminomicin Z3, Muraminomicin Z4, Muramyl dipeptide Lavanduquinocin, Lecirelin, LedaZerol, Leinamycin, C. Mureidomycin A, Mureidomycin B. Mureidomycin C, Lemuteporphin, Lenapenem hydrochloride, Lenapenem Mureidomycin D. Mureidomycin E. Mureidomycins, Myca hydrochloride hydrate, Leptocillin, Leptofuranin.A, Leptofu lamide A, Mycaperoxide A, Mycaperoxide B, Mycestericin ranin B. Lersivirine, Lestaurtinib, Leuprolide acetate, Leuru E. Mycolactone A, Mycolactone B. Myrciacitrin I, Myrci bicin, LeuStroducsin A, LeuStroducsin B. Leustroducsin C, acitrin II, Myrciaphenone B. Myrocin C, Mytolbillinol, Leustroducsin H. Levalbuterol hydrochloride, Levobetaxolol N4-Hexadecyl-dC-AZT, N-9-Oxadecyl-6-methyl-DGJ, hydrochloride, Levobunolol hydrochloride, Levodopa 3-O- N-Acetylsperamycin A1, N-Acetylsperamycin A1B, N-Ace glucoside, Levodopa 4-O-glucoside, Levodropropizine, tylsperamycin A2, Nadifloxacin, Nadolol, Nafarelin acetate, Levonadifloxacin arginine salt, Levonebivolol, Levonorg Naftopidil, Nafuredin, Nafuredin-gamma, Nagstatin, Nalbu estrel, Lexacalcitol, L-Histidinol, Liblomycin, Licorice-sa phine hydrochloride, Nalfurafine hydrochloride, Nalmefene, ponin C2, Lificiguat, Limaprost alfadex, Linaprazan, Linde Naloxone hydrochloride, Naltrexone hydrochloride, Naltrin rol A, Lipiarmycin B3, Lipiarmycin B4, Lipo-isocarbacyclin dole, Namitecan, Napsamycin A, Napsamycin B, Napsamy methyl ester Clinprost, Liquiritin apioside, Lisofylline, cin C, Napsamycin D. Nardeterol, Naroparcil, Navuridine, Lobatamide C. Lobatamide F, Lobophorin A, Lobophorin B, N-Cyclopentyl-tazopsine, Nebivolol, Nectrisine, Nelda Lobucavir, Lodenafil. Lodenosine, Lonaprisan, Longestin, Zosin, Nelfinavir mesilate, Nelivaptan, Nelzarabine, Nemi Loperamide hydrochloride, Lopinavir, Lorazepam, fitide ditriflutate, Nemorubicin, Neocimicigenoside A, Neo Lorimetazepam, Lornoxicam, Losartan, Losartan potassium, cimicigenoside B, Neolaulimalide, Neomycin B-arginine Losigamone, Loteprednoletabonate, Lovastatin, Loxoribine, conjugate, Neomycin-acridine, Neotripterifordin, Nepadu L-threitol ceramide, L-threo-C6-pyridinium-ceramide-bro tant, Neparensinol A, Neridronic acid, Neristatin 1, Nesbuvir, mide, Lubeluzole, Lubiprostone, Lumefantrine, Luminacin Netilmicin sulfate, Netivudine, Neu5Ac2en, Ngercheumicin D. Lupulone, Lurtotecan, Lu-TeX bis(gluconate), Lysobactin, A, Ngercheumicin B, N-hexacosanol, Nifekalant hydrochlo Mabuterol hydrochloride, Macquarimycin B. Macrocarpin ride, Nileprost beta-cyclodextrin clathrate, Nipradolol, Nitro B, Macrolactine M, Madecassic acid, Madecassoside, Mad pravastatin, N-Nonyl-deoxygalactojirimycin, Nocathiacin I. indoline A, Madindoline B. Manifaxine hydrochloride, Man No.cathiacin II, No.cathiacin III, No.cathiacin IV, N-Octyl itimus, Mannopeptimycin alpha, Mannopeptimycin beta, beta-valienamine, NO-hydrocortisone, Noladin ether, Mannopeptimycin delta, Mannopeptimycin epsilon, Man Noraristeromycin, Norelgestromin, Norethisterone, Norm nopeptimycin gamma, Manoalide, Manumycin A. Manumy ethyljiadifenin, Nortopixantrone hydrochloride, Nostocyclo cin B. Manumycin C. Manumycin E. Manumycin F. Manu peptide M1, Nothramicin, NO-Ursodeoxycholic acid, N-Re mycin G. Manzamine A. Manzamine D. Manzamine E. tinoyl-D-glucosamine, Nubiotic 2, Nutlin-2, Obelmycin H, Manzamine F, Maribavir, Marimastat, Maslinic acid, Mat Oberadillol, Oberadilol Monoethyl Maleate, Obeticholic acid, teuorienate A, Matteuorienate B, Matteuorienate C, Mazin Ocimumoside A, Ocimumoside B, Octacosamicin A, Octa dol, Mazokalim, Mefloquine hydrochloride, Megovalicin A, cosamicin B, Octreotide Acetate, O-Demethylchlorothricin, Megovalicin B. Megovalicin C, Megovalicin D. Megovalicin Odiparcil, Oenothein B, Okicenone, Oleanolic acid, Oleoyl G. Megovalicin H, Meloxicam, Meluadrine, Meluadrine tar L-Valinol amide, Olmesartan, Olmesartan medoxomil, trate, Memno-peptide A, Mepenzolate bromide, Mepindolol Olpadronic acid sodium salt, Omaciclovir, Ombrabulin, sulfate, Mepindolol transdermal patch, Meropenem, Met Ombrabulin hydrochloride, Onnamide A, Opiorphin, araminol, Metesind glucuronate, Methanobactin, Meth Opipramol hydrochloride, Orciprenaline sulphate, Orienticin oxatone, Methscopolamine bromide, Methyl bestatin, Meth A, Orienticin B, Orienticin C, Orienticin D, Oritavancin, ylnaltrexone bromide, Methylprednisolone, Orniplabin, Ornoprostil, Ortataxel, Orthosomycin A, Ortho Methylprednisolone aceponate, Methylprednisolone sulep somycin B, Orthosomycin C, Orthosomycin D. Orthosomy tanate, Methyltestosterone, Methylthio-DADMe-immucil cin E, Orthosomycin F. Orthosomycin G, Orthosomycin H, lin-A, Methysergide maleate, Metildigoxin, Metipranolol, Ospemifene, Osutidine, Ovalicin, Oxandrolone, Oxaspirol A, Metoprolol Fumarate, Metoprolol succinate, Metoprolol tar Oxaspirol B, Oxazepam, Oxazofurin, Oxeclosporin, Oxirac trate, Metrifonate, Metronidazole, Micacocidin A, Micacoci etam Oxitropium bromide, Oxolide, Oxprenolol hydrochlo din B, Micafungin sodium, MichigaZone, Microbisporicin ride, Oxybutynin chloride, Oxycodone hydrochloride, Oxy US 2014/0243254 A1 Aug. 28, 2014 48 morphazole dihydrochloride, Oxymorphone hydrochloride, Rhodostreptomycin B. Ribavirin, Ribavirin eicosenate cis, Oxymorphone-Val-carbamate, Oxynor, Oxyphencyclimine Ribavirin eicosenate trans, Ribavirin elaidate, Ribavirinole hydrochloride, Ozarelix, Pachastrissamine, Pachymedusa ate, Rifabutin, Rifalazil, Rifamexil, Rifampicin, Rifapentine, dacnicolor Tryptophyllin-1, Paciforgine, Paclitaxel, Pacli Rifaximin, Rilmakalim hemihydrate, Rimexolone, Rimot taxel ceribate, Paecilaminol, Paeciloquinone D. Pafenolol. erol hydrobromide, Risedronate sodium, Ritipenem acoxil, Palau'amine, Paldimycin B, Palinavir, Palmidrol, Palosuran Ritonavir, Rivastigmine tartrate, Rivenprost, Rocagloic acid, Sulfate, Pamapimod, Pamaqueside, Pamidronate Sodium Pan Rocuronium bromide, Rofleponide, Rofleponide palmitate, amesine hydrochloride, Pancratistatin disodium phosphate, Rohitukine, Rokitamycin, Rolliniastatin 1, Romurtide, Pancratistatin-3,4-cyclic phosphate Sodium salt, Panipenem, Rosaprostol sodium, Roscovitine, Roselipin 1A, Roselipin Pantethine, Papuamide A, Papuamide B, Papuamide C. Pap 1B, Roselipin2A, Roselipin2B, Rostafuroxine, Rosuvastatin uamide D, Papyracillic acid, Paraherquamide G. Parasin I, calcium, Rosuvastatin Sodium, Rotigaptide, Roxatidine bis Paricalcitol, Parodilol Hemifumarate, Paromomycin, Parthe muth citrate, Roxithromycin, Rubiginone A1, Rubiginone nin, Parvisporin B, Patellazole A, Patellazole B, Patellazole A2, Rubiginone B1, Rubiginone C1, Rubitecan, Ruboxyl, C, Patupilone, Pauciflorine A, Pauciflorine B, Paulomycin, Rugatocenone B. Rumycin 1, Rumycin 2, Sabarubicin hydro Paulomycin A2, Paulomycin B, Paulomycin C, Paulomycin chloride, Safingol, Saishin N. Sakyomicin A, Sakyomicin E, D, Paulomycin E, Paulomycin F. PEG40000-Paclitaxel, Salbostatin, Salbutamol nitrate, Salbutamol sulfate, Salicyli PEG5000-Paclitaxel, PEG-conjugated camptothecin, PEG halamide A, Salicylihalamide B, Salinamide A, Salinospora Vancomycin, Peloruside A, Penasterol, Penbutolol sulfate, mide A, Saliphenylhalamide, Salmaterol, Salmeterol xin Penciclovir, Penicillide, Pentostatin, Peplomycin, Pepluanin afoate, Samaderine X, Sanfetrinem, Sanfetrinem cilexetil, A. Peramivir, Percyduinnin, Periciazine, Perillyl alcohol, Sanfetrinem sodium, Sanglifehrin A, Sanglifehrin B, San Perphenazine, Persin, Petrosaspongiolide M. Phaseolinone, glifehrin C, Sanglifehrin D. Sapacitabine, Saquinavir, Phenochalasin A, Phenochalasin B. Philinopside A, Phomac Saquinavir mesilate, Sarcophytol A, Sarcophytol B, Sarican tin A, Phomactin B, Phomactin E, Phomactin F. Phomactin G, din, Saussureamine D. Saussureamine E. Saxagliptin, Saze Phomoidride A, Phomopsichalasin, Phorboxazole A, Phor tidine-A, Schizandrin, Scopinast fumarate, Scopolamine, boxazole B. Phospholine, Phosphostim, Picumeterol fuma Scyphostatin, Secalciferol, Secobatzelline A, Secobatzelline rate, Pimecrolimus, Pimilprost, Pindolol, Pinitol, Pipalamy B, Secoisolariciresinol diglucoside, Securioside A, Securio cin, Pipenzolate bromide, Pipotiazine, Pirarubicin, Pirbuterol side B, Selamectin, Selank, Selodenoson, Semagacestat, hydrochloride, Pirmenol hydrochloride, Pironetin, Piroxi Semduramicin, Semorphone hydrochloride, Seocalcitol, cam, Pladienolide A, Pladienolide B, Pladienolide C, Pladi Seprilose, Sergliflozin etabonate, Serofendic acid, Sessilo enolide D. Pladienolide E. Plantagoside, Plaunotol, Pliti side, Setamycin, Setazindol, Shepherdin, Shishijimicin A, depsin, Pluraflavin A, Pluraflavin B, Pluraflavin E, Plusbacin Shishijimicin B, Shishijimicin C, Sialosylcholesterol-Alpha A1, Plusbacin A2, PlusbacinA3, Plusbacin A4, Plusbacin B1, Sodium Salt, Sibanomicin, Sibiskoside, Silodosin, Silten Plusbacin B2, Plusbacin B3, Plusbacin B4, Pneumocandin Zepine, Silychristin, Simotaxel, Simvastatin, Sitostanol A0, Pneumocandin BO, Pneumocandin BO 2-phosphate, ascorbyl phosphate, Siwenmycin, Sizofuran, Smilagenin, Pneumocandin D0, Podophyllotoxin, Poldine metilsulfate, Socorromycin, Sodium cromoglycate, Sodium oxybate, Polyestradiol phosphate, Polyketomycin, Polymer bound Solabegron hydrochloride, Solidagenon, Solpecainol hydro human leukocyte elastase inhibitor, Popolohuanone E. Posa chloride, Sonedenoson, Soraprazan, Sorbicillactone A, conazole, PosiZolid, Potassium embelate, Pradimicin A, Sorivudine, so-Simvastatin-6-one, Sotalol hydrochloride, Pradimicin B, Pradimicin D, Pradimicin E, Pradimicin FA-1, Sparoxomycin A1, Sparoxomycin A2, Sperabillin A, Spera Pradimicin FA-2, Pradimicin FL, Pradimicin FS ((+)-enanti billin B. Sperabillin C, Sperabillin D. Sphingofungin F, omer), Pradimicin L. Pradimicin Q, Pradimicin S. Pradimicin Spinorphin, Spiralizone B, Spirocardin A, Spirocardin B, T1, Pradimicin T2, Prasterone, Prednicarbate, Prednisolone, Spiruchostatin A, Spiruchostatin B, Spisulosine, Spongia Prednisolone acetate, Prednisolone farnesylate, Prednisone, diol, Spongistatin 1, Spongistatin 3, Spongistatin 4, Spong Preussin, Pristinamycin IIA, Probestin, Procaterol Hydro istatin 5, Spongistatin 6, Spongistatin 7. Spongistatin 8, chloride Hemihydrate, Procyclidine hydrochloride, Prolylm Spongistatin 9, Sporeamicin A, Sporeamicin B, Squalamine eridamycin, Propafenone hydrochloride, Propeptin T. Pro lactate, Squalestatin I, Stachybocin A, Stachybocin B, pranolol hydrochloride, Prostanit, Prostatin, Prostratin, Stachybocin C, Stachybotrin C, Stachybotrydial, Staplabin, Prostratin succinate, Proxodolol, Pseudoephedrine hydro Starrhizin, Stavudine, Stelleramacrin A, Stelleramacrin B, chloride, Pseudohypericin, Pseudomycin A", Pseudomycin Sterenin A, Streptomycin, Styloguanidine, Suberosenol A, B'. Purpuromycin, Purvalanol A. Pycnanthuquinone A. Pyc Sufotidine bismuth citrate, Sugammadex sodium, Sulfi nanthuquinone B, Pyloricidin B, Pyripyropene A. Pyripyro nosine, Sulfircin C, Sulopenem, Sulopenem etzadroxil, Sul pene B, Pyripyropene C, Pyripyropene D. Pyrrocidine A, phoquinovosyldiacylglycerol, Sulprostone, Sulukast, Sun Pyrrocidine B, Pyrrolosporin A, Quartromicin A1, Quartro flower trypsin inhibitor-1, Suplatast tosilate, Suronacrine micin A2, Quartromicin A3. Quartromicin D1, Quartromicin maleate, Swiftiapregnene, Synadenol, Synguanol, Syriacusin D2, Quartromicin D3, Quetiapine fumarate, Quinidine, Qui B, Syzygiol, Tacalcitol, Tacapenem pivoxil, Taccalonolide E. noxapeptin C, Rafabegron, Raluridine, Rameswaralide, Tacrolimus, Tafluprost, Takanawaene A, Takanawaene B. Ramoplanin A1, Ramoplanin A2, Ramoplanin A3. Ramo Takanawaene C, Talibegron, Talibegron hydrochloride, relix, Ranimustine, Ranolazine, Rapamycin, Ravidomycin Tamandarin A, Tamandarin B, Tamolarizine Hydrochloride, N-oxide, Ravuconazole, Razupenem, Reblastatin, Regad Tanespimycin, TAP-doxorubicin, Taurohyodeoxycholic enoson, Relcovaptan, Remikiren mesilate, Remiprostol, acid, Tautomycin, Taxuspain D, Taxuyunnanine, Tazopsine, Remogliflozin etabonate, Repandiol, Reproterol hydrochlo Tebipenem, Tebipenem cilexetyl, Tebipenem pivoxil, Tecad ride, Residuimod, Resorthiomycin, Retapamulin, Retaspi enoson, Teicoplanin-A2-1, Teicoplanin-A2-2, Teicoplanin mycin hydrochloride, Revatropate, Reveromycin A. Rhodi A2-3, Teicoplanin-A2-5, Telavancin hydrochloride, Telbivu ocyanoside A, Rhodiocyanoside B, Rhodostreptomycin A, dine, Telinavir, Telithromycin, Temazepam, Temiverine, US 2014/0243254 A1 Aug. 28, 2014 49

Temiverine hydrochloride hydrate, Tempol, Temsirolimus, (+)-Etorphine, (+)-Indoc arbazo statin, (+)-SCH-351448, Temurtide, Tenidap, Teniposide, Tenoxicam, Tenuifoliside A, (R)-Gossypol, (S)-(+)-Curcuphenol, (S)-Methylmaltrexone Tenuifoliside B, Tenuifoliside C, Tenuifoliside D, Terbutaline bromide, 8-Gingerol, Arg(Me)9 MS-10, D-Tyr1, Arg sulfate, Terestigmine tartrate, Terfenadine, Teriflunomide, (Me)9 MS-10, D-Tyr1AZaGly7, Arg(Me)9 MS-10, D-Tyr Terlakiren, Ternatin, Terreulactone A, Terreulactone B, Ter 1 MS-10, psiCH2NHITpg4Vancomycin aglycon, Trp 19 reulactone C, Terreulactone D, Tertatolol hydrochloride, MS-10, 13-Deoxyadriamycin hydrochloride, 14-Meth Tesetaxel, Testosterone glucoside, Tetracosylcidofovir, Tet oxymetopon, 14-Phenylpropoxymetopon, 18, 19-Dehy racycline hydrochloride, Tetrafibricin, Tetrahydrocortisol, drobuprenorphine hydrochloride, 2,12-Dimethyleurotinone, Tetrahydroechinocandin B, Tetrahydroswertianolin, Tetrahy 2'-Hydroxymatteucinol, 2-Methoxyestradiol, 2-Methyleuro droxyquinone, Tetromycin A, Tetromycin B, Tetronothiodin, tinone, 3.5-Dicaffeoylquinic acid, 3-Bromodiosmetine, TeXenomycin A, Tezacitabine, Tezosentan, TeZosentan diso 3-Bromodiosmine, 3-Chlorodiosmetime, 3-Chlorodiosmine, dium, Thenorphine. Theopederin D. Theoperidin E, Theo 4,7,8-Trihydroxyisoflavone, 4-Aminosalicylic acid, 4-Hy phylline rutoside. Thermozymocidin, Thiamet-G, Thiam droxyatomoxetine, 4-Iodopropofol. 5-Iodofredericamycin A, phenicol. Thiarubrine E. Thiarubrine F. Thiarubrine G. 5Z-7-Oxozeaenol, 6-Carboxygenistein, 6-O-mPEG4-Nal Thiarubrine H, Thiazinotrienomycin B. Thiazohalostatin, bupine, 6-O-mPEG5-Nalbuphine, 7-Methylcapillarisin, Thielocin, Thiofedrine. Thiomarinol, Thiomarinol B, Thiom 8(R)-Fluoroidarubicin hydrochloride, 8.9-Dehydroasco arinol C, Thiomarinol D, Thiomarinol E. Thiomarinol F. chlorin, 8-Carboxy-iso-iantheran A, 8-Paradol, 8-Prenylapi Thioviridamide. Thioxamycin, Thrazarine, Thymallene, genin, 8-Prenylmaringenin, 9-HydroxycrisamicinA, A-42867 Thymectacin, Tibolone, Tidembersat, Tienoxolol hydrochlo pseudoaglycone, Abarelix, Acacetin, Aclarubicin, Acolb ride, Tigecycline, Tilisolol hydrochloride, Timolol hemihy ifene hydrochloride, Acotiamide hydrochloride hydrate, drate, Timolol maleate, Tiotropium bromide, Tipranavir, Acrovestone, Actinoplanone A, Actinoplanone B. Aculeacin Tiqueside, Tisocalcitate, Tixocortol buryrate propionate, Agamma, Adaphostin, Adarotene, AdXanthromycin A, Aero Toborinone, Tobramycin, Toloxatone, Tolvaptan, Tolytoxin, thricin 1, Aerothricin 16, Aerothricin 41, Aerothricin 45, Tomatine, Tomeglovir, Tonabersat, Topixantrone hydrochlo Aerothricin 50, Aerothricin 55, Ajulemic acid, Alchemix, ride, Topotecan Acetate, Topotecane Hydrochloride, Torcit Aldifen, alpha-Mangostin, alpha-Methylepinephrine, alpha abine, Torezolid, Toripristone, Tosagestin, Tosedostat, Tra Methylnorepinephrine, Alpha-Peltatin, Altromycin A. Altro bectedin, Tradecamide, Tramadol hydrochloride, Tramadol N-oxide, Trantinterol hydrochloride, Travoprost, Traxo mycin B. Altromycin C. Altromycin D. Altromycins, Alvi prodil, Traxoprodil mesylate, Trecadrine, Trecetilide fuma mopan hydrate, Alvocidib hydrochloride, Amamistatin A, rate, Treprostinil diethanolamine, Treprostinil Sodium, Amamistatin B, Amarogentin, Amelubant, Amidox, Ami Trewiasine, Triamcinolone acetonide, Triamcinolone hexac nocandin, Amodiaquine, Amoxicillin trihydrate, Amrubicin etonide, Trichodimerol, Trichomycin A, Trichostatin D, Tric Hydrochloride, Amurensin H. Anguillosporal, Anidulafun iferol, Triciribine, Triciribine phosphate, Trifluridine, Trihex gin, Ankinomycin, Annamycin, Annulin C, Antimycin A11, yphenidyl hydrochloride, Trilostane, TrimaZosin Antimycin A12, Antimycin A13, Antimycin A14, Antimycin hydrochloride, Trimegestone, Trimoprostil, Tripterifordin, A15, Antimycin A16, Apicularen A, Apicularen B, Apigenin, Tripterin, Tripterinin, Triptolide, Troxacitabine, Tsukubamy Apomine, Apomorphine hydrochloride, Arbidol, Arbutamine cin A, Tubelactomicin A, Tuberactomycin B, Tuberactomy hydrochloride, Arformoterol tartrate, Artepillin C, Arzox cin D, Tuberactomycin E. Tubingensin B, Tuftsin, Tulathro ifene hydrochloride, Aspoxicillin, Atalaphillidine, Atal mycin A, Tulathromycin B, Tulobuterol hydrochloride, aphillinine, Atraric acid, AVorelin, AXitirome, AZaresveratrol, Turbostatin 1, Turbostatin 2, Turbostatin 3, Turbostatin 4, AZatoxin, AZepinostatin, Baicalein, Baicalin, Balhimycin, Tyroservatide, Ubenimex, Ukrain, Uncarinic acid A. Uncar Balsalazide disodium, Banoxantrone, BaZedoxifene acetate, inic acid B, Uncialamycin, Unoprostone, Unoprostone iso Bazedoxifene hydrochloride, Bedoradrine sulfate, Benadros propyl ester, Ursodeoxycholic acid, Ustilipid A, Ustilipid B, tin, Benanomicin A, Benanomicin B. Benastatin A, Benasta tin B, Benastatin C, Benastatin D, Benzbromarone, Bere Ustilipid C, Uvalol, Valganciclovir hydrochloride, Valnemu frine, Berupipam maleate, beta-Mangostin, Biemnidin, lin, Valonomycin A, Valopicitabine, Valrubicin, Vancomycin Biochanin A, Bioxalomycin alpha 1, Bioxalomycin alpha2. hydrochloride, Vancoresmycin, Vanidipinedilol, Vaminolol. Bismuth subsalicylate, Bisphenol, Bix, Bizelesin, Bogorol A, Variapeptin, Veinamitol, Velnacrine Maleate, Velusetrag, Brandisianin A, Brandisianin B, Brandisianin C, Brasilicar Venlafaxine hydrochloride, Venlafaxine N-oxide, Ver din A, Brevifolin carboxylic acid, Breynin A, Breynin B, misporin, Vernakalant hydrochloride, Verticillatine, Viceni Bromotopsentin, Buflomedil pyridoxalphosphate, Buprenor statin, Vildagliptin, Vincristine Sulfate, Vindesine, Vin phine hydrochloride, Buserelin acetate. Butein, Buteranol, flunine, Vinfosiltine sulfate, Vinleucinol, Vinorelbine, Butorphan, Butorphanol tartrate, Calebin A, Calocoumarin Vinylamycin, Viduidacin, Viramidine Hydrochloride, A, Caloporoside D, Caloporoside E. Caloporoside F. Viranamycin-A, Viranamycin-B, Viscosin, Vitilevuamide, Calphostin A, Calphostin B, Calphostin C, Calphostin D, Voclosporin, Voglibose, Volinanserin, Volpristin, Voricona Calphostin I, Capillarisin, CapsaZepine, Carbazomadurin A, Zole, Woodorien, Xamoterol Fumarate, Xanthofulvin, Xeno Carbazomadurin B, Carbetocin, Carbidopa, Carmoterol Vulene A, Xylocydine, Yohimbine, Zahavin B, Zalcitabine, hydrochloride, Caspofungin acetate, Cassigalol A, Cefetecol, Zampanolide, Zanamivir, Zankiren, Zanoterone, Zaragozic CefoperaZone sodium, Ce?piramide sodium, Cefprozil, Cef acid D3, Z-Eleutherobin, Zidovudine, Zilascorb (2H), Zil prozil monohydrate, Cetrorelix Acetate, Chaetoatrosin A, paterol, Zoledronic acid monohydrate, Zorubicin hydrochlo Chafuroside, Chloroorienticin A, Chloroorienticin B, Chon ride, ZoSuquidar trihydrochloride, Zotarolimus, Zoticasone dramide A, Chondramide B, Chondramide C, Cinnatriacetin propionate, Zuclopenthixol hydrochloride. A, Cinnatriacetin B, cis-6-Shogaol, Citpressine I, Citreami 0537 Suitable drugs containing aromatic hydroxyl groups cin-Alpha, Citreamicin-eta, Citrusinine-I, Clausenamine A, are, for example, (-)-cis-Resorcylide, (-)-Indocarbazostatin Combretastatin A-1, Combretastatin A-2, Combretastatin B, (-)-Salmeterol, (-)-Subersic acid, (+)-alpha-Viniferin, A-3, Combretastatin B-1, Combretastatin B-2, Combretasta US 2014/0243254 A1 Aug. 28, 2014 50 tin B-3, Combretastatin B-4, Combretastatin D-1, Combret ide, Indacaterol, Indanocine, Integracin A, Integracin B, Inte astatin D-2, Complestatin, Coniferol Alcohol, Conophylline, gracin C, Integramycin, Integrastatin A, Integrastatin B, Corynecandin, Cosalane, Crisamicin C, Crobenetine, Crobe Intoplicine, Iodochlorhydroxyquin, Iododiflunisal, Iodoru netine hydrochloride, Curtisian A. Curtisian B, Curtisian D, bidazone (p), Iolopride (123I), Ioxipride, Iralukast, Iralukast Cyanidin Chloride Monohydrate, Cyclocommunol, Cyclo Sodium, Irciniastatin A, Irciniastatin B, Isalmadol, Isoba proparadicicol, Cyclotheonamide A, Cyclothialidine, Cyr Vachalcone, Isodoxorubicin, Iso-iantheran A, Isoliquiritige tominetin, Cytogenin, Cytosporone B, Cytotrienin I, Cytot nin, Isomolpan Hydrochloride, Isoquine, Isovanihuperzine rienin II, Dactylocycline A, Dactylocycline B. Dalargin, A, Jadomycin B, Jasplakinolide, Kadsuphilin C, Kaitocepha Dalbavancin, Damunacantal, Daphnodorin A, Daphnodorin lin, Kampanol A, Kampanol B, Kanglemycin A, Kapurimy B. Daphnodorin C ((-)-enantiomer), Darbufelone, Dar cin A1, Kapurimycin A3, Kapurimycin A3. Kehokorin D, bufelone mesilate, Daunorubicin, Daurichromenic acid, Kehokorin E. Kigamicin A, Kigamicin B. Kigamicin C, Davidigenin, Deacetyl moxisylyte hydrochloride, Decapla Kigamicin D. Kigamicin E. Kigamicinone, Kistamicin A, nin, Decyl gallate, Deferasirox, Dehydrozingerone, Del Klainetin A, Klainetin B, Kodaistatin A, Kodaistatin B, phinidin, Denopamine, Deoxymulundocandin, Dersalazine, Kodaistatin C, Kodaistatin D. Korupensamine A, Korupen Desacetylravidomycin N-oxide, Desglugastrin samine B. Korupensamine C, Korupensamine D. Kosinosta tromethamine, Deslorelin, Desmopressin acetate, DeSven tin, Labetalol hydrochloride, Laccaridione A, Lactonamycin, lafaxine Succinate, Dexanabinol, Dextrorphan, Dexylosyl Lactosylphenyltrolox, Ladirubicin, Lamellarin alpha 20-sul benanomycin A, D-Fluviabactin, Diazaphilonic acid, Diaz fate Sodium salt, Lamifiban, Lanreotide acetate, LaSofox epinomicin, Dieckol, Diflunisal, Dihydrexidine, ifene, LaSofoxifene tartrate, Latamoxef sodium, L-Chicoric Dihydroavenanthramide D, Dihydrogranaticin B, Dihydro acid, L-Dopamide, Lecirelin, LedaZerol, Leuprolide acetate, honokiol B, Dihydroraloxifene, Dilevalol, Dilevalol hydro Leurubicin, Levalbuterol hydrochloride, Levodopa, chloride, Dinapsoline, Dinoxyline, Dioncoquinone A, Dion Levodopa 3-O-glucoside, Levodopa 4-O-glucoside, Levor coquinone B, Dipotassium gossypolate, Dobutamine phanol tartrate, L-Fluviabactin, Lipiarmycin B3, Lipiarmy hydrochloride, Dobutamine Phosphate, Dopexamine, cin B4, Liquiritin apioside, Lithospermic acid B magnesium Dopexamine hydrochloride, Dosmalfate, Doxorubicin salt, Lobatamide C, Lobatamide F, Loloatin B, Luminacin D, Hydrochloride, Doxorubicin, Morpholinyl, DoxoTam 12, Luteolin, Macrocarpin A, Macrocarpin B. Makaluvamine D. Doxycycline hyclate, Dronabinol, Droxidopa, Duocarmycin Makaluvamine E. Malonoben, Maltolyl p-coumarate, Man B1, Duocarmycin B2, Duocarmycin C1, Duocarmycin C2, nopeptimycin beta, Manzamine F, Marinopyrrole A, Marme Dutomycin, Dynemicin A, Dynemicin C, Econazole Sul lin, Masoprocol, Mastprom, Matteuorienate A. Matteuo fosalicylate, Ecopipam, Ecteinascidin 1560, Ecteinascidin rienate B. Matteuorienate C, Medicarpin, Melevodopa 722, Ecteinascidin 729, Ecteinascidin 736, Ecteinascidin hydrochloride, Mellein, Meluadrine, Meluadrine tartrate, 745, Ecteinascidin 757, Ecteinascidin 770, Ecteinascidin Memno-peptide A, Meptazinol hydrochloride, Mesalazine, 875, Edotecarin, Edotreotide yttrium, Eflucimibe, Eflumast, Metaraminol, Methanobactin, Methyl gallate, Methyldopa, Elansolid C1, Eldacimibe, Ellagic acid-4-gallate, Elliptinium Methylmaltrexone bromide, Metirosine, Micacocidin A, acetate, Elsibucol, Eltrombopag olamine, Emodin, Enaza Micacocidin B. Micafungin sodium, Michellamine B, Mide drem, Enofelast, Entacapone, ent-Estriol, Epidoxoform, Epi planin, Mimopezil, Minocycline hydrochloride, Miprox gallocatechin-3-gallate, Epirubicin hydrochloride, Eplivan ifene, Mitoxantrone hydrochloride, MivaZerol, Modecamide, serin, Eplivanserin fumarate, Eplivanserin mesilate, Mollugin, Monohydroxyethylrutoside. Morphine Glucu Epocarbazolin A, Epocarbazolin B, Eprotirome, Eptazocine ronide, Morphine hydrochloride, Morphine sulfate, Moxife hydrobromide, Erabulenol A, Erabulenol B, Eremomycin, tin hydrogen maleate, Mumbaistatin, Mureidomycin A, Estetrol, Estradiol, Estriol, Etalocib sodium, Etamsylate, Mureidomycin B. Mureidomycin C, Mureidomycin D, Ethinylestradiol, Ethyl gallate, Etoposide, Eurotinone, Eux Mureidomycin E, Mureidomycin F. Mureidomycins, Myco anthone, Evernimicin, Exifone, EZetimibe, Fadolmidine phenolate Mofetil, Mycophenolic acid sodium salt, Myrci hydrochloride, Feglymycin, Fenoldopam mesilate, Fenoterol acitrin I, Myrciacitrin II, Myrciaphenone B. Myriceric acid A. hydrobromide, Fidaxomicin, Fidexaban, Fluostatin A. Flu Mytolbilin, Mytolbilin acid, Mytolbilin acid methyl ester, ostatin B, Foetidine 1, Foetidine2, Folipastatin, Formobactin, Mytolbillinol, Naamidine A, Nabilone, N-Acetylcolchinol, Formoterol fumarate, Fosopamine, Frederine, Fulvestrant, Nafarelin acetate, Nalbuphine hydrochloride, Nalfurafine Furaquinocin A, Furaquinocin B, Fusacandin A, Fusacandin hydrochloride, N-Allylsecoboldine, Nalmefene, Naloxone B. Fusidienol, Galactomycin I, Galactomycin II, Galarubicin hydrochloride, Naltrexone hydrochloride, Naltrindole, Nap hydrochloride, Galocitabine, Gambogic acid, gamma-Man samycin A, Napsamycin B, Napsamycin C, Napsamycin D, gostin, gamma-Tocotrienol, Ganirelix, Ganirelix acetate, Nardeterol, N-Cyclopentyl-tazopsine, Nebicapone, Nelfi Garvalone C. Garveatin E, Garveatin F, Genistein-7-phos navir mesilate, Nemorubicin, Neparensinol A, Neparensinol phate, Gigantol, Gilvusmycin, Glucopiericidinol A1, Glu B, Neparensinol C, Nerfilin I, Nicanartine, Nitecapone, copiericidinol A2, Gludopa, Glycothiohexide alpha, Goser Nocardione A, Nocathiacin I, Nocathiacin III, Nocathiacin elin, Granaticin B. Griseusin C, Hatomarubigin A, IV, NO-Mesalamine, Nordamunacantal, Nostocyclopeptide Hatomarubigin B. Hatomarubigin C, Hatomarubigin D, M1. Nothramicin, N-tert butyl isoquine, Obelmycin H, Hayumicin A, Hayumicin B. Hayumicin C1, Hayumicin C2, Ochromycinone, Octyl gallate, Odapipam acetate, O-Dem Hayumicin D. Helicquinomycin, Helvecardin A, Helvecardin ethylchlorothricin, O-Demethylmunrrayafoline A, B, Hericenal A, Hericenal B, Hericenal C, Hidrosmin, His Oenothein B, Okicenone, Olanzapine pamoate, Olcegepant, trelin, Histrelin acetate, Hongoquercin A, Hongoquercin B, Olsalazine sodium, Onjixanthone I, Onjixanthone II, Honokiol diepoxide, Honokiol diepoxide, Human angio Oolonghomobisflavan A, Oolonghomobisflavan C, Orci tensin II, Hydromorphone methiodide, Hymenistatin 1, prenaline sulphate. Orienticin A. Orienticin B. Orienticin C, Hypeptin, Hypericin, Hyperoside, Icariin, Idarubicin hydro Orienticin D. Oritavancin, Orniplabin, Orthosomycin A, chloride, Idronoxil, Ifenprodil, Imidazoacridinone, Incyclin Orthosomycin B, Orthosomycin C, Orthosomycin D, Ortho US 2014/0243254 A1 Aug. 28, 2014 somycin E, Orthosomycin F. Orthosomycin G, Orthosomy Tokaramide A, Tolcapone, Tolterodine Tartrate, Topotecan cin H, Osutidine, Oximidine III, Oxymetazoline hydrochlo Acetate, Topotecane Hydrochloride, Topsentine B1, Trabect ride, Oxymorphazole dihydrochloride, Oxymorphone edin, trans-Resveratrol, Traxoprodil, Traxoprodil mesylate, hydrochloride, Oxyphenarsine, Ozarelix, Paeciloquinine A, Trimidox, Triphendiol, Troglitazone, Tubastrine, Tubulysin Paeciloquinine D, Paeciloquinone B, Paeciloquinone D. Pan A, Tubulysin B, Tubulysin C, Tucaresol, Tyropeptin A10. cratistatin-3,4-cyclic phosphate Sodium salt, Pannorin, Pap Tyropeptin A6, Tyropeptin A9, Tyroservatide, Tyrphostin 47. uamide A, Papuamide B, Papuamide C, Papuamide D, Parac Uncarinic acid A, Uncarinic acid B, Uncialamycin, Valrubi etamol, Parvisporin B. PEG-Vancomycin, Penicillide, cin, Vancomycin hydrochloride, Veinamitol, Venorphin, Ver Pentazocine hydrochloride, Pepticinnamin E, Phaffiaol, ticillatine, Vexibinol, Vialinin B, Vinaxanthone, W Peptide, Wiedendiol A, Wiedendiol B, Woodorien, Xamoterol Fuma Phakellistatin 7, Phakellistatin 8, Phakellistatin9, Phenocha rate, Xanthoangelol E., Xanthofulvin, Xanthomegnin, Xipa lasin A, Phentolamine mesilate, Phlorofucofuroeckol, Pho mide, Yatakemycin, Zelandopam hydrochloride, Zorubicin mopsichalasin, Phthalascidin, Physostigmine Salicylate, hydrochloride. Piceatannol, Pidobenzone, Pinocembrin, Pipendoxifene, Pirarubicin, Pittsburgh Compound B, Platencin, Platensimy 0538 Suitable drugs with a carboxyl group may be be cin, Pluraflavin A, Pluraflavin B, Pluraflavin E, Pneumocan selected from the list containing (-)-Subersic acid, (+)- din A0, Pneumocandin BO, Pneumocandin BO 2-phosphate, Deoxoartelinic acid, (+)-Hemipalmitoylcarnitinium, (+)-In Pneumocandin D0, Polyestradiol phosphate, Polyketomycin, dobufen, (+)-SCH-351448, (E)-p-Coumaroylquinic acid, Popolohuanone E. Pradimicin A, Pradimicin B, Pradimicin (Z)-Indenaprost, 111 In-DTPA-Prol,Tyr4 bombesin, 90Y D, Pradimicin E, Pradimicin FA-1, Pradimicin FA-2, DOTAGA-substance P. psiCH2NHITpg4Vancomycin Pradimicin FL, Pradimicin FS ((+)-enantiomer), Pradimicin aglycon, 111 In-Pentetreotide, 11-Keto-Beta-Boswellic Acid, L., Pradimicin Q, Pradimicin S. Pradimicin T1, Pradimicin 15-Methoxypinusolidic acid, 1-Methyl-D-tryptophan, 3.5- T2, Prinaberel, Probucol, Procaterol Hydrochloride Hemihy Dicaffeoylquinic acid, 3-MATIDA, 3-O-Acetyloleanolic drate, Propofol, Propyl gallate, Protocatechuic acid, Proto acid, 4-Aminosalicylic acid, 6alpha-FluorourSodeoxycholic catechuic aldehyde, Pseudohypericin, Purpuromycin, Pyrin acid, 6-Carboxygenistein, 7-Chlorokynurenic acid, 8-Car damycin A. Pyrindamycin B, Quercetin-3-O-methyl ether, boxy-iso-iantheran A, 99 mTc-c(RGDfK*)2HYNIC, Quinagolide hydrochloride, Quinobene, rac-Apogossy A-42867 pseudoaglycone, Aceclofenac, Acemetacin, Ace polone, Rac-Tolterodine, Raloxifene hydrochloride, neuramic acid sodium salt, Acetyl-11-Keto-Beta-Boswellic Ramoplanin A1, Ramoplanin A2, Ramoplanin A3. Ramo Acid, Acetyl-Beta-Boswellic Acid, Acetylcysteine, Achimil relix, Ravidomycin N-oxide, Rawsonol, Reblastatin, Repro lic Acids, Acipimox, Acitazanolast, Acrivastine, Actarit, Ada terol hydrochloride, Resobene, Resorthiomycin, Retaspimy palene, Adarotene, Ademetionine tosylate Sulfate, AdXan cin hydrochloride, Rhodiocyanoside B, thromycin A, Ajulemic acid, Alacepril, Aladapcin, Rhododaurichromanic acid A, Rifabutin, Rifalazil, Aleglitazar, Alitretinoin, Alminoprofen, Alogliptin benzoate, Rifamexil, Rifampicin, Rifapentine, Rifaximin, Rimoterol alpha-Linolenic acid, alpha-Lipoic acid, alpha-Methyltryp hydrobromide, Riodoxol, Rohitukine, Rotigaptide, Rotigo tophan, Alprostadil. Altemicidin, Alutacenoic acid B, Alvi tine, Roxindole Mesilate, Ruboxyl, Rufigallol, Rumycin 1, mopan hydrate, Amiglumide, Amineptine, Aminocaproic Rumycin 2, Russuphelin A, Sabarubicin hydrochloride, Sain acid, Aminolevulinic acid hydrochloride, Amlexanox, topin, Saintopin E. Sakyomicin A, Sakyomicin E. Salazopy Amoxicillin trihydrate, Amphotericin B, Amsilarotene, ridazin, Salbutamol nitrate, Salbutamol sulfate, Salcaprozic Anakinra, Antiflammin-1, Antiflammin-2, Antiflammin-3, acid sodium salt, Salicylazobenzoic acid, Salicylihalamide A, Apalcillin Sodium, Aplaviroc hydrochloride, Argatroban Salicylihalamide B, Saliphenylhalamide, Salmaterol, Salme monohydrate, Argimesna, Artelinate, Artepillin C, Artesu terolxinafoate, Saloxin, Salvianolic acid L. Sampatrilat, San nate, Arundifungin, Ascosteroside, Asiatic acid, Aspirin, glifehrin A, Sanglifehrin B, Sanglifehrin C, Sanglifehrin D, Aspoxicillin, Assamicin I. Assamicin II, Ataluren, Atorvasta Saptomycin D. Sapurimycin, Saricandin, Secoisolaricires tin, Atorvastatin calcium, Atrasentan, AZaromycin SC, AZe inol diglucoside, Seglitide, Semorphone hydrochloride, laic Acid, AZepinostatin, AZilsartan, AZOxybacilin, AZtre Shishijimicin A, Shishijimicin B, Shishijimicin C, Sibenadet onam, Aztreonam L-lysine, AZumamide E. Baclofen, hydrochloride, Silychristin, Sinomenine, Sivifene, Siwen Bafilomycin C1, Baicalin, Balhimycin, Balofloxacin, Balof mycin, Sootepenseone, Spinorphin, Spinosulfate A, Spino loxacin dihydrate, Balsalazide disodium, Bamirastine sulfate B, Spiroximicin, Stachybocin A, Stachybocin B, hydrate, Belactosin A, Belactosin C, Benanomicin A, Bena Stachybocin C, Stachybotrin C, Stachybotrydial, Staplabin, nomicin B, Benastatin A, Benastatin B, Benazepril hydro Sterenin A, Sterenin C, Sterenin D. Streptopyrrole. Succino chloride, Benthocyanin A, Bepotastine besilate, Beraprost bucol, Sulfasalazine, Sulphazocine, Susalimod, Symbio sodium, Besifloxacin hydrochloride, Beta-Boswellic Acid, imine, Syriacusin A, Syriacusin B, Syriacusin C, Tageflar, beta-Hydroxy beta-methylbutyrate, Betamipron, Beta-Sialo Taiwanhomoflavone A, TAP-doxorubicin, Tapentadol hydro sylcholesterol Sodium Salt, Bevirimat, Bexarotene, Bezafi chloride, Taramanon A, Tazofelone, Tazopsine, Tebufelone, brate, Biapenem, Bilastine, Bimosiamose, Bindarit, Bin Technetium Tc 99m depreotide, Teicoplanin-A2-1, Teicopla floxacin, Biphenyl-indanone A, Boc-Belactosin A, nin-A2-2. Teicoplanin-A2-3, Teicoplanin-A2-3, Teicopla Borrellidin, Brasilicardin A, Brasilinolide A, Bremelanotide, nin-A2-5, Telavancin hydrochloride, Temoporfin, Tenipo Brevifolin carboxylic acid, Bucillamine, Bumetanide, Bun side, Tenuifoliside A, Tenuifoliside B, Tenuifoliside C, geolic acid, Buprenorphine hemiadipate, Buprenorphine Terbutaline sulfate, Terprenin, Tetracycline hydrochloride, Val-carbamate, Butibufen, Butoctamide hemisuccinate, Tetragalloylquinic acid, Tetrahydrocurcumin, Tetrahydro ButyZamide, Cabin 1, Cadrofloxacin hydrochloride, Calbis echinocandin B, Tetrahydroswertianolin, Thenorphine, trin A, Calbistrin B, Calbistrin C, Calbistrin D, Calcium-like Theophylline rutoside. Thiazinotrienomycin B. Thiazinot peptide 1, Calcium-like peptide 2, Caloporoside B, Caloporo rienomycin F. Thiazinotrienomycin G. Thielavin G. Thielo side C, Caloporoside D, Caloporoside E. Caloporoside F. cin B3, Thymopentin, Tigecycline, Tipelukast, Tocotrienol, Calpinactam, Calteridol calcium, Camprofen, Candesartan, US 2014/0243254 A1 Aug. 28, 2014 52

Candoxatril, Candoxatrilat, Canfosfamide hydrochloride, hydrochloride, Fleroxacin, Flobufen, Flomoxef Sodium, Canrenoate potassium, CapraZamycin A, CapraZamycin B, Flunoprost, Flunoxaprofen, Flurbiprofen, Fluvastatin CapraZamycin C, CapraZamycin E. CapraZamycin F. Capto Sodium, Folinic acid, Fondaparinux sodium, Fosfosal, pril, Carbidopa, Carmoxirole hydrochloride, Carprofen, Fradafiban, Frusemide, Fudosteine. Furprofen, G1 peptide, Cefaclor, Cefalexin monohydrate, Cefbuperazone sodium, Gabadur, Gabapentin, Gabapentin enacarbil, Gabusectin, Cefcanel, Cefdaloxime, Cefdinir, Cefetecol, Cefixime, Cef Gadobenic acid dimeglumine salt, Gadobutrol, Gadocoletic matilenhydrochloride hydrate, Cefnmenoxime hydrochloride, acid trisodium salt, Gadodenterate, Gadomelitol, Gadopen Cefninox sodium, Cefodizime, Cefonicid sodium, Cefopera tetate dimeglumine, Gadoterate meglumine, Gadoteridol. Zone sodium, Cefoselis sulfate, Cefotiam hydrochloride, Gambogic acid, Gamendazole, Gamma-Linolenic Acid, Cefoxitin, Ce?pimizole sodium, Ce?piramide sodium, Cef Ganefromycin Alpha, Ganefromycin Beta, Ganglioside prozil, Cefprozil monohydrate, Ceftaroline fosamil acetate, GM1, Ganoderic acid X, Garenoxacin mesilate, Gastrazole, Ceftazidime, Ceftibuten, Ceftobiprole, Cefuroxime, Cer Gatifloxacin, Gemfibrozil, Gemifloxacin mesilate, Gemopat anapril, Cerivastatin sodium, Ceruletide diethylamine, Cet rilat, Gilatide, Gimatecan, Giripladib, Glaspimod, Glucaro efloxacin, Cetirizine hydrochloride, Chenodeoxycholic acid, lactam potassium, Gludopa, Glutathione Monoethyl Ester, Chinoin-169, Chlorambucil, Chloroorienticin A, Chloroori Glutathione Monoisopropyl Ester, Glycine-proline-Mel enticin B, Choline fenofibrate, Choline thioctate, Chrolacto phalan, Glycopin, Glycyrrhizinic acid, Golotimod, Goody mycin, Cilastatin Sodium, CilaZapril, Cilengitide, Cilomilast, eroside B. Goralatide, Grepafloxacin hydrochloride, GS-143, Ciluprevir, Cinaciguat, Cinalukast, Cinatrin A, Cinatrin B, Haterumadioxin A, Haterumadioxin B, Helvecardin A, Cinatrin C1, Cinatrin C2, Cinatrin C3, Cinnatriacetin A, Cin Helvecardin B, Heptelidic acid chlorohydrin, Hericenal A. natriacetin B, Ciprofibrate, Ciprofloxacin hydrochloride, Cir Hericenal B, Hericenal C. Homoindanomycin, Hongoquer cinamide, Cispentacin, Citrullimycine A, Clavaric acid, Cla cin A, Hongoquercin B. Human angiotensin II, Hyaluronate Vulanate potassium, Clinofibrate, Clopidogrel Sulfate, Sodium, Hydrostatin A, Ibuprofen, Icatibant acetate, Icofun Colletoic acid, Complestatin, Conagenin, Cosalane, Creatine gipen, Idrapril, Ifetroban, Ilepatril, Iloprost, Imidapril, Imi phosphate, Cyclocreatine, Cycloplatam, Cyclothialidine, dapril hydrochloride, Imiglitazar, Imipenem, Indianaprost Cytomodulin, Cytosporic acid, Dabigatran, Daglutril, Dalar (S), Indanomycin, Indeglitazar, Indobufen, Indole-3-propi gin, Dalbavancin, Danegaptide hydrochloride, Danofloxacin, onic acid, Indometacin, Indomethacintrometamol, Indoxam, Darinaparsin, Darusentan, Daurichromenic acid, Davu Indynaprost, Inogatran, Inosiplex, Iododiflunisal, Iodofiltic netide, Decahydromoenomycin A, Decaplanin, Decatromi acid-123.I. Iodostearic Acid, Iralukast, Iralukast Sodium, cin A, Decatromicin B. Deferasirox, Delafloxacin, Delapril Isalsteine, Isobongkrekic acid, Isotretinoin, Itavastatin cal Hydrochloride, Deltibant, Deoxylaidlomycin, Deoxynega cium, Itriglumide, Kaitocephalin, Kanglemycin A, Kapuri mycin, Dersalazine, Desacetylvinblastinehydrazide/folate mycin A1, Kapurimycin A3. Ketoprofen, Ketoprofen lysine, conjugate, Desferri-danoxamine, Desferri-nordanoxamine, Desglugastrin tromethamine, Desmin-370, Dexibuprofen, Ketorolac, Ketorolac tromethamine, Khafrefungin, Kijimi Dexibuprofen lysine, Dexketoprofen, Dexketoprofen cho cin, Kistamicin A, L-4-Oxalysine, Labradimil, Lamectacin, line, Dexketoprofen D.L-lysine, Dexketoprofen lysine, Lamifiban, Lanthiopeptin, Lapaquistat acetate, LaraZotide Dexketoprofen meglumine, Dexketoprofen trometamol. acetate, Laropiprant, Latamoxef sodium, L-Chicoric acid, Dexloxiglumide, Dexpemedolac, dextro-Ciprofibrate, Dexy Lenapenem hydrochloride, Lenapenem hydrochloride losylbenanomycin A, Diacerein, Diazaphilonic acid, Di-Cal hydrate, Levocabastine hydrochloride, Levocetirizine dihy ciphor, Difenoxin, Diflunisal, Dihydroavenanthramide D, drochloride, levo-Ciprofibrate, Levodopa, Levodopa 3-O- Dihydrogranaticin B, Dihydroisosteviol, Dihydrolipoic acid, glucoside, Levodopa 4-O-glucoside, Levofloxacin, Disalazine, Disila-bexarotene, Disodium cromproxate, Diso Levonadifloxacin arginine salt, L-Homothiocitrulline, dium lettusate, Doqualast, Doripenem, Dormitroban, Dorri Licofelone, Licorice-Saponin C2, Lidorestat, Limaprostalfa gocin A, Dorrigocin B, Droxidopa, DTPA-adenosylcobal dex, Limazocic, Linoleic acid 18:2W6-cis, 9-cis, Linotroban, amin, Duramycin, Dynemicin A, Ecabet Sodium, Lintitript, Lipohexin, Lisinopril, Lithium Succinate, Lithos Ecenofloxacin hydrochloride, Econazole Sulfosalicylate, permic acid B magnesium salt, Loloatin B, Lomefloxacin Edetic acid, Edotreotide yttrium, Efletirizine, Eflornithine hydrochloride, Lometrexol, Longestin, Lonidamine, Lora hydrochloride, Eglumetadhydrate, Elansolid C1, Elarofiban, carbef hydrate, Lorglumide, Lotrafiban, Loxiglumide, Elastatinal B, Elastatinal C, Elsibucol, Eltrombopagolamine, L-Simexonyl homocysteine, L-Thiocitrulline, Lubiprostone, Elvitegravir, Emricasan, Enalapril maleate, Enalapril nitrate, Lumiracoxib, Lu-TeX bis(gluconate), Lysinated-betulonic Enalaprilat, Enfumafungin, Enkastin (D), Enkastin AD, acid, Lysine acetylsalicylate, Macrocarpin B. Madecassic Enkastin AE, Enkastin ID, Enkastin IE, Enkastin VD, Enkas acid, Maracenin A1, Maracenin A2, Maracenin B1, Marace tin VE, Enoloxone, Enoxacin, Enrasentan, Enrofloxacin, nin B2, Maracenin C1, Maracenin C2, Maracenin D1, Epalrestat, Epidioxymanadic acid A, Epidioxymanadic acid Maracenin D2, Marbofloxacin, Maslinic acid, Matristatin B, Epithalon, Epofolate, Epoprostenol sodium, Epostatin, A1, Matristatin A2, Matteuorienate A, Matteuorienate B, Matteuorienate C, Mebrofenin, Meclinertant, Mefenamic Epristeride, Eprosartan mesilate, Eprotirome, Eptaloprost, acid, Melagatran, Memno-peptide A, Meptazinol-Val-car Eptastatin Sodium, Eptastigmine Tartrate, Eptifibatide, bamate, Meropenem, Mersacidin, Mesalazine, Metesind glu Erdosteine, Eremomycin, Ertapenem sodium, Ertiprotafib, curonate, Methanobactin, Methotrexate, Methoxatin, Meth Eryloside F. Esafloxacin Hydrochloride, Esonarimod, yldopa, Methylenolactocin, Methylhomoindanomycin, Etacrynic acid, Etalocib sodium, Etodolac, Etretin, Eva Metiapril, Metirosine, Micacocidin A, Micacocidin B, tanepag, Evernimicin, Exisulind, EZetimibe glucuronide, Midafotel, Midoriamin, Milrinone Lactate, Minerval, Mipi Fandofloxacin hydrochloride, Faranoxi, Farglitazar, troban, Mispyric acid, Mixanpril, Moenomycin A chloride 0539 Faropenem sodium, Fasobegron hydrochloride, bismuth salt, Moexipril hydrochloride, Moexiprilat, Mof Febuxostat, Feglymycin, Felbinac, Felbinac Lysine Salt, Fen eZolac, Momordin Ic, Monamidocin, Monoethanolamine bufen, Fexofenadine hydrochloride, Fidexaban, Finafloxacin oleate, Montelukast sodium, Morphine Glucuronide, Moxi US 2014/0243254 A1 Aug. 28, 2014 floxacin hydrochloride, Mumbaistatin, Mupirocin, Muragli caprozic acid sodium salt, Salicylazobenzoic acid, S-Allylm tazar, Muraminomicin A, Muraminomicin B. Muraminomi ercaptocaptopril, Salmisteine, Salvianolic acid L. Samix cin C, Muraminomicin D, Muraminomicin E1, ogrel, Sampatrilat, Sanfetrinem, Sanfetrinem Sodium, Muraminomicin E2, Muraminomicin F. Muraminomicin G, Sapurimycin, Sarpogrelate hydrochloride, Saussureamine A, Muraminomicin H, Muraminomicin I, Muraminomicin Z1, Saussureamine B, Saussureamine C, Saussureamine D. Sau Muraminomicin Z2, Muraminomicin Z3, Muraminomicin ssureamine E. Scabronine G. Scopadulcic acid B, Securio Z4, Mureidomycin A, Mureidomycin B. Mureidomycin C, side A, Securioside B, Selank, Semduramicin, Seocalcitol, Mureidomycin D, Mureidomycin E, Mureidomycin F. Mure Seratrodast, Serofendic acid, Sessiloside. Shepherdin, Sialo idomycins, Mycaperoxide A, Mycaperoxide B, Mycestericin sylcholesterol-Alpha Sodium Salt, Sitafloxacin hydrate, E. Mycophenolic acid sodium salt, Myriceric acid A. Mytol S-Nitrosocaptopril, S-Nitrosoglutathione, Sodelglitazar, Sodium cromoglycate, Sodium oxybate, Sofalcone, Solabe bilin acid, Nadifloxacin, Nafagrel hydrochloride, Nafagrel gron hydrochloride, Sorbicillactone A, Sparfloxacin, Sphin hydrochloride hemihydrate, Nagstatin, Napirimus, Napsa gofungin F. Spinorphin, Spirapril, Spiriprostil, Spiroglumide, gatran, Napsamycin A, Napsamycin B, Napsamycin C, Nap Spiroximicin, Squalestatin I, Stachybocin A, Stachybocin B, samycin D. Nateglinide, Naveglitazar, Nebostinel, Nemon Stachybocin C, Staplabin, Starrhizin, Sterenin D. Subtilopen oxacin, Neu5Ac2en, Niacin, Niglizin, Nileprost beta tadecanoic acid, Succinobucol, Sufotidine bismuth citrate, cyclodextrin clathrate, Nooglutil, Norfloxacin, Norfloxacin Sugammadex sodium, SulfaSalazine, Sulindac, Sulopenem, Succinil, Obeticholic acid, Octacosamicin A, Octacosamicin Sulukast, Sunflower trypsin inhibitor-1, Susalimod, Tafami B, O-Demethylchlorothricin, Ofloxacin, Olamufloxacin, dis meglumine, Tageflar, Talaglumetad hydrochloride, Tali Olamufloxacin mesilate, Olanzapine pamoate, Oleanolic begron, Talibegron hydrochloride, Talopterin, Taltobulin, acid, Olmesartan, Olopatadine Hydrochloride, Olsalazine Tamibarotene, Tanogitran, Tanomastat, TAP-doxorubicin, sodium, Omapatrilat, Onnamide A, OPC-17083, Opiorphin, Tarenflurbil, Targinine, Tazarotenic Acid, Tebipenem, Teico Orbifloxacin, Oreganic acid, Orienticin A. Orienticin B, Ori planin-A2-1, Teicoplanin-A2-2, Teicoplanin-A2-3, Teicopla enticin C, Orienticin D. Oritavancin, Orniplabin, Oseltamivir nin-A2-5, Telavancin hydrochloride, Telmesteine, Telmisar carboxylate, Ovothiol A, Ovothiol B, Ovothiol C, Oxaprozin, tan, Temafloxacin hydrochloride, Temocapril hydrochloride, Oxeglitazar, Oxiglutatione sodium, Oxymorphone-Val-car Temurtide, Tenosal, Terbogrel, Terestigmine tartrate, Terikal bamate, Oxynor, OZagrel hydrochloride, Ozenoxacin, Pac ant fumarate, Tesaglitazar, Tetomilast, Tetradecylselenoace timibe, Padoporfin, Paeciloquinone B, Paeciloquinone D. tic acid, Tetrafibricin, Tetragalloylquinic acid, Tetrahydro Paldimycin B, Palovarotene, Panipenem, Parasin I, Parinaric echinocandin B, Tetronothiodin, Tezampanel, acid, Paulomycin, Paulomycin A2, Paulomycin B, Paulomy Thermozymocidin, Thiazohalostatin, Thielavin G. Thielocin, cin C, Paulomycin D. Paulomycin E, Paulomycin F. PaZu Thielocin B3. Thiofoscarnet, Thioxamycin, Thrazarine, Thy floxacin, PaZufloxacin mesilate, Pefloxacin, PEG-vancomy mic humoral factor gamma-2, Thymopentin, Tiagabine cin, Pelagiomicin C, Peliglitazar, Pelitrexol, Pelretin, hydrochloride, Tibenelast, Ticolubant, Tilarginine hydro Penasterol, Penicillamine, Peramivir, Perindopril, PG-camp chloride, Tiliquinatine, Timodepressin, Tipelukast, Tiplasi tothecin, Phomallenic acid C, Phomoidride A, Phomoidride B. Phosphinic cyclocreatine, Phosphosalsalate, Physostig nin, Tirofiban hydrochloride, Tisartan, Tolfenamic acid, Tol metin, Tolrestatin, Tomopenem, ToSufloxacin, ToSufloxacin mine salicylate, Pibaxizine, Pidotimod, Piraxostat, Piret Tosilate, Trandolapril, Trandolaprilat, Tranexamic acid, Tra anide, Pirfenoxone, Pirprofen, Pivagabine, Pixantrone male nilast, Treprostinil diethanolamine, Treprostinil sodium, Tre ate, Plakotenin, Platencin, Platensimycin, Plevitrexed, tinoin, Triacetylshikimic acid, Trichomycin A, Triflusal, Tri Pluraflavin E, Plusbacin A1, Plusbacin A2, Plusbacin A3, mexautide, Trimoprostil, Tripterin, Tropesin, Trovafloxacin, Plusbacin A4, Plusbacin B1, Plusbacin B2, Plusbacin B3, Trovafloxacin hydrate, Trovafloxacin hydrochloride mesy Plusbacin B4, Polyalthidin, Pomisartan, Ponalrestat, Poststa late, Trovafloxacin mesilate, Tubelactomicin A, Tuberacto tin, PPI17-24, Pradimicin A, Pradimicin B, Pradimicin D, mycin D, Tuberactomycin E. Tubulysin A, Tubulysin B, Pradimicin E, Pradimicin FA-1, Pradimicin FA-2, Pradimicin FL, Pradimicin FS ((+)-enantiomer), Pradimicin L. Pradimi Tubulysin C, Tucaresol, Tuftsin, Turbinaric acid, Tyroser cin Q, Pradimicin S. Pradimicin T1, Pradimicin T2, Pradof Vatide, Ubenimex, Ulifloxacin, Uncarinic acid A, Uncarinic loxacin, Pralatrexate, Pranoprofen, Prefolic A. Pregabalin, acid B, Unoprostone, Ursodeoxycholic acid, Ursolic acid Premafloxacin, Premafloxacin hydrochloride, Prezatide cop phosphate, Utibapril, Utibaprilat, Vadimezan, Valonomycin per acetate, Proamipide, Probenecid, Probestin, Procysteine, A. Valproate Semisodium, Valproic acid, Valsartan, Vanco Proglumide, Propagermanium, Propofol hemisuccinate, mycin hydrochloride, Varespladib, Vebufloxacin, Vedapro Prostatin, Prostratin succinate, Protocatechuic acid, Proto fen, Veliflapon, Verlukast, Vinaxanthone, Vicquidacin, Virana porphyrin 1X gallium(III) complex, Prulifloxacin, Pruli mycin-A, Viscosin, Vitilevuamide, Voreloxin, W Peptide, floxacin Hydrochloride, Prulifloxacin Mesylate, Pseudomy Xanthofulvin, Zabicipril Hydrochloride, Zabiciprilat Hydro cin A", Pseudomycin B". Pycnanthuquinone A, chloride, Zabofloxacin hydrochloride, Zaltoprofen, Zan Pycnanthuquinone B, Pyloricidin B, Pyridazomycin, Pyrro amivir, Zaragozic acid D3, Zenarestat, Zofenoprilat, Zofeno losporin A, Quiflapon Sodium, Quinapril hydrochloride, prilat arginine, Zolasartan, Zonampanel. Quinlukast, Rafabegron, Ragaglitazar, Raltitrexed, Rama 0540 Suitable drugs with a phosphate group may be troban, Ramipril, Raxofelast, Razupenem, Rebamipide bis selected fromt the group consisting of Adenophostin A, muth citrate tetramethyledamine, Rebamipide bismuth L-tar Adenophostin B, Atrinositol, Buflomedil pyridoxalphos trate tetramethyledamine, Repaglinide, Resobene, phate, Cytostatin, Fludarabine phosphate, Fosfluconazole, Reveromycin A, Rhododaurichromanic acid A. Ridogrel, Fosfonochlorin, Fosfosal, Fosopamine, Fosquidone, Fos Robenacoxib, Rocagloic acid, Rolafagrel, RomaZarit, tamatinib, Ganciclovir monophosphate, Genistein-7-phos Romurtide, Rosaprostol Sodium, Rosuvastatin calcium, phate, Hydroxyphoslactomycin B. Leustroducsin A, Leustro Rosuvastatin sodium, Rufloxacin Gluconate, Rufloxacin ducsin B. Leustroducsin C. LeuStroducsin H. Mangafodipir hydrochloride, Rumycin 1, Rumycin 2, Salazopyridazin, Sal trisodium, Menadiol sodium diphosphate, Miproxifene phos US 2014/0243254 A1 Aug. 28, 2014 54 phate, Monophosphoryl lipid A. Phospholine, Phosphosal functional groups to yield carrier-linker conjugate reagents. salate, Pneumocandin BO 2-phosphate, Tafluposide, Tricir To such carrier-linker conjugate reagents are Subsequently ibine phosphate, Ursolic acid phosphate. drugs coupled. Alternatively, a drug may first be coupled to a 0541 Suitable drugs with a thiol group may be selected linker reagent and Subsequently, the biologically active moi fromt the group consisting of Acetylcysteine, Antileukinate, ety-linker reagent is coupled to the carrier. Argimesna, Bucillamine, Butixocort, Captopril, Dihydroli 0551 Another aspect of the present invention is a pharma poic acid, Gemopatrilat, Glutathione monoethyl ester, Glu ceutical composition comprising the water-soluble carrier tathione monoisopropyl ester, Midoriamin, Omapatrilat, linked prodrugs of the present invention or a pharmaceutical Ovothiol A, Ovothiol B, Ovothiol C, Penicillamine, Rebim salt thereof and optionally one or more pharmaceutically astat, Shepherdin, Zofenoprilat, Zofenoprilat arginine. acceptable excipients. 0542. Another aspect of the present invention is a method 0552. The pharmaceutical composition is further of synthesing the water-soluble carrier-linked prodrugs of the described in the following paragraphs. present invention. A preferred process for the preparation of a 0553. The pharmaceutical composition comprising the water-soluble carrier-linked prodrug acording to the present water-soluble carrier-linked prodrug of the present invention invention is as follows: may be provided as a liquid composition or as a dry compo 0543. A preferred starting material is a methoxy-PEG sition. Suitable methods of drying are, for example, spray amine with the PEG mono reagent having a molecular weight drying and lyophilization (freeze-drying). A preferred ranging from 0.2 to 160 kDa. To such PEG amine, lysine method of drying is lyophilization. residues are coupled sequentially to form the hyperbranched 0554 Preferably, the water-soluble carrier-linked prodrug polymer carrier. It is understood that the lysines can be par is sufficiently dosed in the composition to provide atherapeu tially or fully protected by protective groups during the cou tically and/or diagnostically effective amount of the drug, in pling steps and that also the final hyperbranched polymer particular for at least one day in one application. More pref carrier may contain protective groups. A preferred building erably, one application of the pharmaceutical composition block is bis-boc lysine. comprising the water-soluble carrier-linked prodrug is suffi 0544 Alternatively, instead of sequential additions of cient for at least two days. Such as three days, four days, five lysine residues, a hyperbranched poly-lysine moiety may be days, six days, or is sufficiently dosed for at least one week, assembled first and subsequently coupled to the PEG amine Such as for one week, two weeks, three weeks, four weeks, reagent. Such polylysine may be obtained by batch conden five weeks, six weeks, seven weeks, eight weeks, three sation or by means of sequential assembly using protected months, four months, five months or six months. lysine building blocks. 0555. In one embodiment, the pharmaceutical composi 0545 For example it may be desirable to obtain hyper tion comprises more than one water-soluble carrier-linked branched polymer carrier carrying 16 amino groups, conse prodrug of the present invention. Said one or more water quently fifteen lysines would be attached to a PEG mono soluble carrier-linked prodrugs may comprise different amine reversible prodrug linker moieties having different or the 0546. In another embodiment, the PEG reagent may be a same half-lives, may comprise different biologically active methoxy-PEG-carboxylate. In this case the dendritic moi moieties, and/or may comprise different water-soluble carrier eties may be generated from glutamic or aspartic acid, and the moieties. resulting hyperbranched polymer carrier would carry a num 0556. The pharmaceutical composition of water-soluble ber of terminal carboxy groups. carrier-linked prodrug according to the present invention 0547 Alternatively, instead of sequential additions of preferably contains one or more excipients. glutamic or aspartic acid residues, a hyperbranched poly 0557. Excipients may be categorized as buffering agents, glutamate or poly-aspartate moiety may be assembled first isotonicity modifiers, preservatives, stabilizers, anti-adsorp and Subsequently coupled to the PEG mono carboxy reagent. tion agents, oxidation protection agents, viscosifiers/viscos Such polyglutamate or -aspartate may be obtained by batch ity enhancing agents, or other auxiliary agents. In some cases, condensation or by means of sequential assembly using cor these ingredients may have dual or triple functions. The phar responding protected amino acid building blocks. maceutical compositions of water-soluble carrier-linked pro 0548. In yet another embodiment, an oligo- or polyglyc drugs according to the present invention preferably contain erol may be converted into a corresponding poly-amine com one or more excipients, selected from the groups consisting prising a glycerol condensation product core. Such polyglyc of: erol-derived poly-amine may be coupled to a PEG mono 0558 (i) Buffering agents: physiologically tolerated buff carboxy reagent to yield a hyperbranched polymer carrier ers to maintain pH in a desired range, such as Sodium according to the invention. It is understood that carboxy phosphate, bicarbonate. Succinate, histidine, citrate and groups may be activated to enhance their reactivity. For acetate, Sulphate, nitrate, chloride, pyruvate. Antacids such instance, the carboxy group may be converted into a chloride as Mg(OH) or ZnCO may be also used. Buffering capac or an active ester. ity may be adjusted to match the conditions most sensitive 0549. It is also understood that all or a fraction of the to pH stability hyperbranched polymer carrier's reactive functional groups 0559 (ii) Isotonicity modifiers: to minimize pain that can may be present in a free form, as salts or conjugated to result from cell damage due to osmotic pressure differ protecting or activating groups. Due to practical reasons, the ences at the injection depot. Glycerin and sodium chloride hyperbranched polymer carrier reagent's number of branches are examples. Effective concentrations can be determined per carrier will be in a range of for example 4 to 7, more by osmometry using an assumed osmolality of 285-315 preferable 6 to 7, even more preferably approximately seven. mOsmol/kg for serum 0550 Functional groups of the carrier are then used for 0560 (iii) Preservatives and/or antimicrobials: multidose coupling linker reagents comprising Suitable complementary parenteral preparations require the addition of preserva US 2014/0243254 A1 Aug. 28, 2014 55

tives at a sufficient concentration to minimize risk of removal. For this purpose Sugars and polyols may be used patients becoming infected upon injection and correspond but corresponding positive effects have also been observed ing regulatory requirements have been established. Typical for Surfactants, amino acids, non-aqueous solvents, and preservatives include m-cresol, phenol, methylparaben, other peptides. Trehalose is particulary efficient at reduc ethylparaben, propylparaben, butylparaben, chlorobu ing moisture-induced aggregation and also improves ther tanol, benzyl alcohol, phenylmercuric nitrate, thimerosol, mal stability potentially caused by exposure of protein Sorbic acid, potassium Sorbate, benzoic acid, chlorocresol, hydrophobic groups to water. Mannitol and Sucrose may and benzalkonium chloride also be used, either as solely of cryoprotectant or in com 0561 (iv) Stabilizers: Stabilization is achieved by bination with each other where higher ratios of mannitol: strengthening of the protein-Stabilizing forces, by destabi Sucrose are known to enhance physical stability of a lyo lization of the denatured state, or by direct binding of philized cake. Mannitol may also be combined with excipients to the protein. Stabilizers may be amino acids trehalose. Trehalose may also be combined with sorbitol or Such as alanine, arginine, aspartic acid, glycine, histidine, sorbitol used as the sole protectant. Starch or starch deriva lysine, proline, Sugars such as glucose. Sucrose, trehalose, tives may also be used polyols such as glycerol, mannitol, Sorbitol, salts such as 0564 (vii) Oxidation protection agents: antioxidants such potassium phosphate, Sodium Sulphate, chelating agents as ascorbic acid, ectoine, methionine, glutathione, mono Such as EDTA, hexaphosphate, ligands Such as divalent thioglycerol, morin, polyethylenimine (PET), propyl gal metal ions (Zinc, calcium, etc.), other salts or organic mol late, vitamin E, chelating agents such aus citric acid, ecules such as phenolic derivatives. In addition, oligomers EDTA, hexaphosphate, thioglycolic acid or polymers such as cyclodextrins, dextran, dendrimers, 0565 (viii) Spreading or diffusing agent: modifies the per PEG or PVP or protamine or HSA may be used meability of connective tissue through the hydrolysis of components of the extracellular matrix in the intrastitial 0562 (v) Anti-adsorption agents: Mainly ionic or non space Such as but not limited to hyaluronic acid, a polysac ionic Surfactants or other proteins or soluble polymers are charide found in the intercellular space of connective tis used to coat or adsorb competitively to the inner surface of Sue. A spreading agent such as but not limited to hyalu the composition’s or composition's container. Suitable ronidase temporarily decreases the Viscosity of the Surfactants are e.g., alkyl Sulfates. Such as ammonium lau extracellular matrix and promotes diffusion of injected ryl sulfate and sodium lauryl sulfate; alkyl ether sulfates, drugs. Such as Sodium laureth Sulfate and sodium myreth Sulfate; Sulfonates Such as dioctyl Sodium sulfoSuccinates, perfluo 0566 (ix) Other auxiliary agents: Such as wetting agents, rooctanesulfonates, perfluorobutanesulfonates, alkylben Viscosity modifiers, antibiotics, hyaluronidase. Acids and Zene Sulfonates; phosphates, such as alkylaryl ether phos bases such as hydrochloric acid and sodium hydroxide are phates and alkyl ether phosphates; carboxylates, such as auxiliary agents necessary for pH adjustment during manu fatty acid salts (soaps) or Sodium Stearate, sodium lauroyl facture. sarcosinate, perfluorononanoate, perfluorooctanoate; 0567. In a general embodiment the pharmaceutical com octenidine dihydrochloride; quaternary ammonium cat position comprising the water-soluble carrier-linked pro ions such as cetyl trimethylammonium bromide, cetyl tri drugs of the present invention in either dry or liquid form may methylammonium chloride, cetylpyridinium chloride, be provided as a single or multiple dose composition. polyethoxylated tallow amine, benzalkonium chloride, 0568. In one embodiment of the present invention, the benzethonium chloride, 5-bromo-5-nitor-1,3-dioxane, liquid or dry pharmaceutical composition comprising the dimethyldioctadecylammonium chloride, dioctade water-soluble carrier-linked prodrug is provided as a single cyldimethylammonium bromide, Zwitterionics, such as dose, meaning that the container in which it is Supplied con 3-(3-cholamidopropyedimethylammonio-1-propane tains one pharmaceutical dose in case of therapeutically Sulfonate, cocamidopropyl hydroxysultaine, amino acids, active drugs. imino acids, cocamidopropyl betaine, lecithin; fatty alco 0569. Alternatively, in one embodiment, the liquid or dry hols, such as cetyl alcohol, Stearyl alcohol, cetostearyl pharmaceutical composition comprising the water-soluble alcohol, oleyl alcohol; polyoxyethylene glycol alkyl carrier-linked prodrug is a multiple dose composition, mean ethers, such as octaethylene glycol monododecyl ether, ing that the container in which it is Supplied contains more pentaethylene glycol monododecyl ether, polyoxypropy than one therapeutic dose in case of therapeutically active lene glycol alkyl ethers; glucoside alkyl ethers, such as drugs, i.e., a multiple dose composition contains at least 2 decyl glucoside, lauryl glucoside, octyl glucoside; poly doses. Such multiple dose composition of water-soluble car oxyethylene glycol octylphenol ethers such as Triton rier-linked prodrug can either be used for different patients in X-100; polyoxyethylene glycol alkylphenol ethers such as need thereof or can be used for one patient, wherein the nonoxynol-9, glycerol alkyl esters such as glyceryl laurate; remaining doses are stored after the application of the first polyoxyethylene glycol Sorbitan alkyl esters such as dose until needed. polysorbates; sorbitan alkyl esters; cocamide MEA and 0570. In another aspect of the present invention the phar cocamide DEA; dodecyl dimethylamine oxide: block maceutical composition is in a container. Suitable containers copolymers of polyethylene glycol and polypropylene gly for liquid or dry compositions are, for example, Syringes, col, such as poloxamers (Pluronic F-68), PEG dodecyl vials, vials with stopper and seal, ampouls, and cartridges. In ether (Brij 35), polysorbate 20 and 80; other anti-absorp particular, the liquid or dry composition comprising the tion agents are dextran, polyethylene glycol, PEG-polyhis water-soluble carrier-linked prodrug according to the present tidine, BSA and HSA and gelatines. Chosen concentration invention is provided in a syringe. If the pharmaceutical com and type of excipient depends on the effect to be avoided position comprising the water-soluble carrier-linked prodrug but typically a monolayer of surfactant is formed at the is a dry pharmaceutical composition the container preferably interface just above the CMC value is a dual-chamber Syringe. In such embodiment, said dry 0563 (vi) Lyo- and/or cryoprotectants: During freeze- or pharmaceutical composition is provided in a first chamber of spray drying, excipients may counteract the destabilizing the dual-chamber Syringe and reconstitution Solution is pro effects caused by hydrogen bond breaking and water vided in the second chamber of the dual-chamber syringe. US 2014/0243254 A1 Aug. 28, 2014 56

0571 Prior to applying the dry composition of water drug of the present invention, and optionally one or more soluble carrier-linked prodrug to a patient in need thereof, the pharmaceutically acceptable excipients. dry composition is reconstituted. Reconstitution can take 0579. Another aspect of the present invention is the place in the container in which the dry composition of water method of manufacturing a dry composition of water-soluble soluble carrier-linked prodrug is provided. Such as in a vial, carrier-linked prodrug. In one embodiment, such dry compo Syringe, dual-chamber Syringe, ampoule, and cartridge. sition is obtainable by Reconstitution is done by adding a predefined amount of (i) admixing the water-soluble carrier-linked prodrug with reconstitution Solution to the dry composition. Reconstitution one or more excipients, solutions are sterile liquids, such as water or buffer, which (ii) transfering amounts equivalent to single or multiple doses may contain further additives, such as preservatives and/or into a suitable container, antimicrobials, such as, for example, benzylalcohol and (iii) drying the composition in said container, and cresol. Preferably, the reconstitution solution is sterile water. (iv) sealing the container. When a dry composition is reconstituted, it is referred to as a 0580 Suitable containers are vials, syringes, dual-cham “reconstituted pharmaceutical composition” or “reconsti ber Syringes, ampoules, and cartridges. tuted composition'. 0581 Another aspect of the present invention is a kit of 0572 An additional aspect of the present invention relates parts. to the method of administration of a reconstituted or liquid 0582. If the administration device is simply a hypodermic pharmaceutical composition comprising the water-soluble Syringe then the kit may comprise the Syringe, a needle and a carrier-linked prodrug of the present invention. The pharma container comprising the dry pharmaceutical composition of ceutical composition comprising water-soluble carrier-linked water-soluble carrier-linked prodrug suitable for use with the prodrug may be administered by methods of inhalation, injec Syringe and a second container comprising the reconstitution tion or infusion, including intradermal, Subcutaneous, intra Solution. muscular, intravenous, intraosseous, and intraperitoneal. 0583. If the pharmaceutical composition is a liquid com Preferably, the pharmaceutical composition comprising position then the kit may comprise the Syringe, a needle and water-soluble carrier-linked prodrug is administered Subcu a container comprising the liquid composition of water taneously. soluble carrier-linked prodrug suitable for use with the 0573. The preferred method of administration for dry Syringe. pharmaceutical compositions comprising the water-soluble 0584. In more preferred embodiments, the injection carrier-linked prodrugs of the present invention is via inhala device is other than a simple hypodermic syringe and so the tion. separate container with reconstituted or liquid water-soluble 0574. Therefore, in a preferred embodiment, the present carrier-linked prodrug is adapted to engage with the injection invention relates to a water-soluble carrier-linked prodrug or device such that in use the liquid composition in the container a pharmaceutically acceptable salt thereof of the present is in fluid connection with the outlet of the injection device. invention or a pharmaceutical composition of the present Examples of administration devices include but are not lim invention, for use as medicament for topical, enteral admin ited to hypodermic syringes and pen injector devices. Particu istration, parenteral administration, inhalation, injection, larly preferred injection devices are the peninjectors in which orinfusion, intraarticular, intradermal, Subcutaneous, intra case the container is a cartridge, preferably a disposable car muscular, intravenous, intraosseous, and intraperitoneal, tridge. Optionally, the kit of parts comprises a safety device intrathecal, intracapsular, intraorbital, intracardiac, transtra for the needle which can be used to cap or cover the needle cheal, Subcuticular, intraarticular, Subcapsular, Subarachnoid, after use to prevent injury. intraspinal, intraventricular or intrasternal administration. 0585. A preferred kit of parts comprises a needle and a (0575. Therefore, in another preferred embodiment, the container containing the composition according to the present present invention relates to a water-soluble carrier-linked pro invention and optionally further containing a reconstitution drug or a pharmaceutically acceptable salt thereof of the Solution, the container being adapted for use with the needle. present invention or a pharmaceutical composition of the Preferably, the container is a dual-chamber syringe. present invention, wherein such water-soluble carrier-linked 0586. In another aspect, the invention provides a cartridge prodrug or pharmaceutically acceptable salt thereof or phar comprising a pharmaceutical composition of water-soluble maceutical composition is suitable to be administered to a carrier-linked prodrug as hereinbefore described for use with patient via topical, enteral or parenteral administration and by a pen injector device. The cartridge may contain a single dose methods of external application, inhalation, injection or infu or multiplicity of doses of the water-soluble carrier-linked Sion, including intraarticular, intradermal, Subcutaneous, prodrug. intramuscular, intravenous, intraosseous, and intraperitoneal, 0587 Yet another aspect of the present invention is a intrathecal, intracapsular, intraorbital, intracardiac, transtra water-soluble carrier-linked prodrug of the present invention cheal, Subcuticular, intraarticular, Subcapsular, Subarachnoid, or a pharmaceutically acceptable salt thereof, or a pharma intraspinal, intraventricular and intrasternal application. ceutical composition of the present invention for use as a medicament and/or diagnostic. 0576 A further aspect is a method of preparing a recon 0588. In another embodiment, the present invention stituted composition comprising a therapeutically effective relates to the use of a water-soluble carrier-linked prodrug of amount of water-soluble carrier-linked prodrug of the present the present invention or a pharmaceutically acceptable salt invention, and optionally one or more pharmaceutically thereof, or a pharmaceutical composition of the present acceptable excipients, the method comprising the step of invention for the preparation of a medicament and/or diag 0577 contactingglnep the pharmaceutical compositionp com nostic. prising water-soluble carrier-linked prodrug of the 0589. It is understood, that the disease that can be treated present invention with a reconstitution solution. and/or diagnosed a water-soluble carrier-linked prodrug of 0578. Another aspect is a reconstituted pharmaceutical the present invention or a pharmaceutically acceptable salt composition comprising a diagnostically and/or therapeuti thereof, or a pharmaceutical composition of the present cally effective amount of the water-soluble carrier-linked pro invention depends on the active agent. A water-soluble car US 2014/0243254 A1 Aug. 28, 2014 57 rier-linked prodrug with an active agent moiety which has to low physiological compatibility, are not directly Suitable anti-cancer activity, like Doxorubicin, is typically adminis for use in pharmaceuticals but which can be used, for tered to a cancer patient. Analogously, a water-soluble car example, as intermediates for chemical reactions or for the rier-linked prodrug with an active agent moiety which has preparation of pharmaceutically acceptable salts. anti-inflammatory activity, like aminosalicylic acid, is typi 0591. Yet another aspect of the present invention is a cally administered to a patient which suffers from an inflam method of treating, controlling, delaying or preventing in a matory disease, like rheumatoid arthritis, IBD or Morbus mammalian patient, preferably in a human, in need of the Crohn. Analogously, a water-soluble carrier-linked prodrug treatment of one or more conditions comprising administer with an active agent moiety which has neurological activity is ing to said patient a diagnostically and/or therapeutically typically administered to a patient Suffering from a neurologi effective amount of a water-soluble carrier-linked prodrug of cal disease like Alzheimer's disease or Parkinson's disease. the present invention or a pharmaceutically acceptable salt Analogously, a water-soluble carrier-linked prodrug with an thereof, or a pharmaceutical composition of the present active agent moiety which has anti-infective activity, like invention. Gancyclovir, is typically administered to a patient Suffering from a infectious disease like bacterial, viral, protozoal or Operative Examples fungal infection. 0592. The subject matter of the present invention is eluci 0590. In case the water-soluble carrier-linked prodrugs dated in more detail below, using examples, without any according to the invention contain one or more acidic or basic intention that the subject matter of the invention should be groups, the invention also comprises their corresponding confined to these exemplary embodiments. pharmaceutically or toxicologically acceptable salts, in par ticular their pharmaceutically utilizable salts. Thus, the Materials and Methods water-soluble carrier-linked prodrugs according to the inven 0593 Paliperidone was purchased from Carbon Scientific tion which contain acidic groups can be used according to the Co., Ltd, London, UK. 40 kDa methoxy (polyethylene gly invention, for example, as alkali metal salts, alkaline earth col)-ethyl amine was obtained from Chirotech Technology Ltd, Cambridge, UK. C.co-Bis-amino-PEG 20 kDa was metal salts or as ammonium salts. More precise examples of obtained from Rapp Polymere, Tubingen, Germany. All other Such salts include Sodium salts, potassium salts, calcium salts, chemicals were purchased from Sigma-ALDRICH Chemie magnesium salts or salts with ammonia or organic amines GmbH, Taufkirchen, Germany. Such as, for example, ethylamine, ethanolamine, triethanola 0594 RP-HPLC purification: mine or amino acids. Water-soluble carrier-linked prodrugs 0595 RP-HPLC was done on a 100x20 or a 100x40 mm according to the invention which contain one or more basic C18 ReproSil-Pur 3000DS-3 5u column (Dr. Maisch, groups, i.e. groups which can be protonated, can be present Ammerbuch, Germany) connected to a Waters 600 HPLC and can be used according to the invention in the form of their System and Waters 2487 Absorbance detector. Linear gradi addition salts with inorganic or organic acids. Examples for ents of solution A (0.1% TFA in HO) and solution B (0.1% Suitable acids include hydrogen chloride, hydrogen bromide, TFA in acetonitrile or 0.1% TFA in 2/1 (v/v) methanol/iso phosphoric acid, Sulfuric acid, nitric acid, methanesulfonic propanol) were used. HPLC fractions containing product acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, were lyophilized. Alternatively, if the HCl salt of the purified oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic product was desired, TFA was replaced by 0.01% HCl (v/v, acid, benzoic acid, formic acid, propionic acid, pivalic acid, 37% HCl) in solution A and solution B. diethylacetic acid, malonic acid. Succinic acid, pimelic acid, 0596 LC-MS Analytics: fumaric acid, maleic acid, malic acid, Sulfaminic acid, phe 0597 Ultra performance liquid chromatography-electron nylpropionic acid, gluconic acid, ascorbic acid, isonicotinic spray ionization mass spectrometry (UPLC-ESI-MS) was acid, citric acid, adipic acid, and other acids known to the performed on a Waters Acquity Ultra Performance LC instru person skilled in the art. If the water-soluble carrier-linked ment connected to a Thermo scientific LTQ Orbitrap Discov prodrugs according to the invention simultaneously contain ery instrument and spectra were, if necessary, interpreted by acidic and basic groups in the molecule, the invention also Thermo scientific software xcalibur. M/Z signals correspond includes, in addition to the salt forms mentioned, inner salts or ing to the most abundant isotope are given. betaines (Zwitterions). The respective salts can be obtained by Example 1 customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or Synthesis of Branched Paliperidone Building Block inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present Synthesis of Intermediate 1 a invention also includes all salts of the prodrugs which, owing 0598

la O O

N / O-N O US 2014/0243254 A1 Aug. 28, 2014 58

0599 5.35 g glutaric anhydride and 2.84 mL pyridine were added to a solution of 2.00 g paliperidone in 30 mL DCM (dry, mol. sieve). The reaction mixture was allowed to stir for 3 d at RT. Volatiles were removed and the resulting mixture was diluted with ACN/water 1/1 and acidified with acetic acid until pH reached about 4. 1a was purified by RP-HPLC. 0600 Yield: 1.60 g (2.77 mmol, 60%, HCl salt). 0601 MS: m/z 541.2=M+H" (MW calculated=540.7) Synthesis of Intermediate 1b 0602

1b ---O O O CO or

0603) 1a (1.50 g, 2.77 mmol) was dissolved in 40 mL 0604 Yield: 1.25 g (TFA salt, 1.66 mmol, 60%). DCM (dry, mol. sieve). DCC (1.72g, 8.32 mmol), N-hydroxy succinimide (1.60 g, 13.87 mmol) and a catalytic amount of 0605 MS: m/z 638.25-M+H" (MW calculated=637.67) DMAP was added and mixture was stirred for 3 h at RT. Precipitate was filtered off and the solvent was removed under Synthesis of Intermediate 1c reduced pressure. Residue was dissolved with ACN/water 1/1 and acidified with acetic acid until pH reached about 4.1b was purified by RP-HPLC. 0606

O OH

O H N n

N O HN CO O ---,

O l US 2014/0243254 A1 Aug. 28, 2014 59

0607 A solution of L-lysine (19 mg.0.13 mmol) in 2.5 mL 0.5M sodium borate buffer pH 8.5 was given to a solution of 1b (TFA salt, 300 mg, 0.40 mmol) in 5 mL DMSO. Mixture was stirred for 60 min at RT. Solution was acidified with acetic acid to a pH of approx. 4 and diluted with water and acetonitrile. 1c was purified by RP-HPLC. 0608. Yield: 125 mg (HCl salt, 0.10 mmol, 74%). 0609 MS: m/z. 1191.55=M+H" (MW calculated=1191. 35) Synthesis of Intermediate 1d 0610 1d F

F F

F F

O O O O

O --- N' w H N n

N F N O HN

I O O --- O

O- N Nn

N F N O

O-N

0611 1c (bis HCl salt, 196 mg, 0.155 mmol) was dis- Example 2 solved in 12 mL DCM (anhydrous, mol. sieve). Bis(pen Synthesis of 40 kD PEG-Lys Carrier Building Block tafluorophenyl) carbonate (MW 394 g/mol. 122 mg, 0.310 mmol) and sym-collidine (205 uL. 1.55 mmol) were added Synthesis of Intermediate 2a and mixture was stirred for 16 hat RT. Product was precipi 0615 tated from reaction mixture by adding 30 mL MTBE (puriss., p.a. D99.5%) and separated by centrifugation. Precipitate 2a was redissolved in DCM and precipitation procedure was HN1 boc repeated. Precipitate was redissolved in DCM and volatiles were removed in vacuo (waterbath at 20°C.). Product 1d was O dried by means of lyophilizer. 1. N-nonpi 0612 Yield: 185 mg (88%) O

0613 MS: m/z 1357.52=M+H" (MW calculated=1357. boc N1 40) H 0614 Pfp ester of 1d is partially hydrolyzed under LCMS --900 conditions. A purity of 95% (LCMS, 215 nm) was confirmed 0616 40 kDa methoxy (polyethylene glycol)-ethyl amine after derivatization of 1d with 1-dodecylamine. For derivati 2a (MW ca. 40000 g/mol, 200 mg, 5umol) is reacted with Zation purpose 0.1 mg 1d is reacted with 0.3 mg 1-dodecy Boc-Lys(Boc)-OSu (22 mg, 50 umol) in 2 mL of Isopropanol lamine for 5 min at RT in DCM and analyzed by means of (anhydrous) and DIEA (17 uL. 100 umol) under stirring for LCMS. 30 min at RT. US 2014/0243254 A1 Aug. 28, 2014 60

0617 Product is precipitated by dilution with 15 mL. 0619 Diamine 2b is obtained by stirring 2a (MW ca. MTBE (-20°C.). Product is centrifuged, washed twice with 40000 g/mol, 120 mg. 3 umol) in 1 ml methanol and 2 ml 4N MTBE and dried. HCl in dioxane at RT for 15 min. After evaporation of vola Synthesis of Intermediate 2b tiles product 2b can be used in the next step without further 0618 purification. 2b NH2 O Example 3 1. O

O Synthesis of Carrier Linked Prodruge 40 kD PEG-Trilysine-Tetrapaliperidone NH2 I-900 0620

3 N-O

N N u?' - : N

S^-n -O NH O N

O F N

O Sa ChrN

N H H N a N N O F NH O ----- NS O N 2 N N O F

I-900 US 2014/0243254 A1 Aug. 28, 2014

0621 Diamine 2b (MW ca. 40000 g/mol, 120 mg. 3 phate, 3 mM EDTA, 0.01% Tween-20, 1.4 mL). Sample was mmol) is reacted with intermediate 1d (27 mg, 20 mmol) in 1 incubated at 37° C. At various time points aliquots were mL of NMP (anhydrous, mol. sieve) and DIEA (17 uL. 100 analyzed by UPLC and the amount of released paliperidone mmol) under stirring for 6 hat RT. Mixture is acidified with was plotted against time. Drug release was found to follow acetic acid and diluted with ACN and water, followed by first order kinetics. Curve fitting software was used to deter purification of compound 3 by RP-HPLC. mine half life time of drug release from the conjugate. A paliperidone release half life time of 5.5 d was obtained. Example 4 Abbreviations: Synthesis of Carrier Linked Prodrug 0626. ACN acetonitrile C.co-Bis(lysyl-dipaliperidone) 20 kD PEG Boc t-butyloxycarbonyl 0622 DCC N,N'-dicyclohexylcarbodiimide 4 N O

O F

N

Sa irN 's-n-r NH O O H on N pi O --N-soO H N a

N C.C.O F NS O 2 n-225

0623 O.co-Bis-amino-PEG 20 kDa Diamine (MW 24 DCM dichloromethane kDa, 60 mg, 2.5umol) was reacted with intermediate 1d (13 DIEA diisopropylethylamine mg, 9.7 umol) in 2 mL of DCM (anhydrous, mol. sieve) and DMAP dimethylamino-pyridine DIEA (4 uL, 19 umol) under stirring for 16 hat RT. Mixture DMSO dimethylsulfoxide was quenched by addition of 1-dodecylamine (2 mg), acidi eq Stoichiometric equivalent fied with acetic acid and diluted with ACN and water, fol LCMS mass spectrometry-coupled liquid chromatography lowed by purification of compound 4 (main peak, 215 nm) by MS mass spectrum RP-HPLC. Combined HPLC fractions (40 mL) were mixed MTBE Methyl tert-butyl ether with water (30 mL) and 0.5 M sodium phosphate pH 7.4 (4 MW molecular mass mL). The mixture was extracted with DCM (25 mL, 3x) and combined organic phases were washed with brine (20 mL) NHS N-hydroxy succinimide and dried over NaSO and evaporated under reduced pres NMP N-methyl-2-pyrrolidone sure. Yield: 29 mg PEG poly(ethylene glycol) 0624. A uniform material was obtained according to RP-HPLC reversed-phase high performance liquid chroma UPLC analytics, eluting at 3.35 min (Waters BEH300 C18 tography column, 2.1 x50mm, 1.7 um particle size, flow 0.25 mL/min, RT room temperature lineargradient 0-70% B in 4 min, mobile phase A: 0.05%TFA TFA trifluoroacetic acid in water, mobile phase B: 0.04% TFA in acetonitrile). 0627. While this invention has been described in conjunc tion with the specific embodiments outlined above, it is evi Example 5 dent that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, the pre Drug Release Kinetics from PEG Conjugate 4 ferred embodiments of the invention as set forth above are intended to be illustrative, not limiting. Various changes may 0625 Conjugate 4 (2 mg) was dissolved in acetonitrile be made without departing from the spirit and scope of the (100 ul) and mixed with pH 7.4 buffer (60 mM sodium phos inventions as defined in the following claims. US 2014/0243254 A1 Aug. 28, 2014 62

SEQUENCE LISTING

<16O is NUMBER OF SEO ID NOS : 15

<210s, SEQ ID NO 1 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 1

Ala Ala Ala Ala Ser Ser Ala Ser Ser Ala Ser Ser Ser Ser Ser Ala 1. 5 1O 15

Ala Ala Ser Ala 2O

<210s, SEQ ID NO 2 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 2

Ala Ala Ser Ala Ala Ala Ser Ser Ala Ala Ala Ser Ala Ala Ala Ala 1. 5 1O 15

Ser Ala Ser Ser 2O

<210s, SEQ ID NO 3 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 3

Ala Ser Ala Ser Ala Ser Ala Ser Ala Ser Ala Ser Ser Ala Ala Ser 1. 5 1O 15

Ala Ala Ser Ala 2O

<210s, SEQ ID NO 4 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 4

Ser Ala Ala Ser Ser Ser Ala Ser Ser Ser Ser Ala Ala Ser Ser Ala 1. 5 1O 15

Ser Ala Ala Ala 2O US 2014/0243254 A1 Aug. 28, 2014 63

- Continued

<210s, SEQ ID NO 5 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 5

Ser Ser Ser Ser Ala Ala Ser Ala Ala Ser Ala Ala Ala Ala Ala Ser 1. 5 1O 15

Ser Ser Ala Ser 2O

<210s, SEQ ID NO 6 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 6

Ser Ser Ala Ser Ser Ser Ala Ala Ser Ser Ser Ala Ser Ser Ser Ser 1. 5 1O 15

Ala Ser Ala Ala 2O

<210s, SEQ ID NO 7 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OO > SEQUENCE: 7

Ser Ala Ser Ala Ser Ala Ser Ala Ser Ala Ser Ala Ala Ser Ser Ala 1. 5 1O 15

Ser Ser Ala Ser 2O

<210s, SEQ ID NO 8 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 8

Ala Ser Ser Ala Ala Ala Ser Ala Ala Ala Ala Ser Ser Ala Ala Ser 1. 5 1O 15

Ala Ser Ser Ser 2O US 2014/0243254 A1 Aug. 28, 2014 64

- Continued

<210s, SEQ ID NO 9 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 9

Ala Ser Pro Ala Ala Pro Ala Pro Ala Ser Pro Ala Ala Pro Ala Pro 1. 5 1O 15

Ser Ala Pro Ala 2O

<210s, SEQ ID NO 10 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 10

Ala Ala Pro Ala Ser Pro Ala Pro Ala Ala Pro Ser Ala Pro Ala Pro 1. 5 1O 15

Ala Ala Pro Ser 2O

<210s, SEQ ID NO 11 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 11

Ala Pro Ser Ser Pro Ser Pro Ser Ala Pro Ser Ser Pro Ser Pro Ala 1. 5 1O 15

Ser Pro Ser Ser 2O

<210s, SEQ ID NO 12 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 12

Ser Ser Pro Ser Ala Pro Ser Pro Ser Ser Pro Ala Ser Pro Ser Pro 1. 5 1O 15

Ser Ser Pro Ala 2O US 2014/0243254 A1 Aug. 28, 2014

- Continued

<210s, SEQ ID NO 13 &211s LENGTH: 24 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 13

Ala Ala Ser Pro Ala Ala Pro Ser Ala Pro Pro Ala Ala Ala Ser Pro 1. 5 1O 15

Ala Ala Pro Ser Ala Pro Pro Ala 2O

<210s, SEQ ID NO 14 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 14

Ala Ser Ala Ala Ala Pro Ala Ala Ala Ser Ala Ala Ala Ser Ala Pro 1. 5 1O 15

Ser Ala Ala Ala 2O

<210s, SEQ ID NO 15 &211s LENGTH: 2O 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: polymer cassette

<4 OOs, SEQUENCE: 15

Ser Ala Pro Ser Ser Pro Ser Pro Ser Ala Pro Ser Ser Pro Ser Pro 1. 5 1O 15

Ala Ser Pro Ser 2O

1-14. (canceled) each n is independently an integer from 2 to 200, and 15. A water-soluble carrier-linked prodrug of formula (I), each x is independently 0 or 1. or a pharmaceutically acceptable salt thereof, 16. The water-soluable carrier-linked prodrug, or the phar ((D-L-(SP } } Hyp-}-POL-Hyp--(-(SP)-L-D), (I), maceutically acceptable salt thereof, as claimed in claim 15, wherein wherein each n is independently and integer from 2 to 16. Hyp,-POL-Hyp form a carrier moiety, and 17. The water-soluble carrier-linked prodrug, or the phar wherein maceutically acceptable salt thereof, as claimed in claim 15, POL is a polymeric moiety having a molecular weight wherein each L is independently a traceless prodrug linker ranging from 0.2 moiety. kDa to 160 kDa, 18. The water-soluble carrier-linked prodrug, or the phar each Hyp is independently a hyperbranched moiety, maceutically acceptable salt thereof, as claimed in claim 15, each SP is independently a spacer moiety, wherein the moiety POL comprises a PEG-based polymer. each L is independently a reversible prodrug linker moi 19. The water-soluble carrier-linked prodrug, or the phar ety, maceutically acceptable salt thereof, as claimed in claim 15, each D is independently a biologically active moiety, wherein the moiety POL comprises a linear PEG-based poly m is 0 or 1, C. US 2014/0243254 A1 Aug. 28, 2014 66

20. The water-soluble carrier-linked prodrug, or the phar tyric acid), nonadecadiaminobutyric acid), lysine, dilysine, maceutically acceptable salt thereof, as claimed in claim 15, trilysine, tetralysine, pentalysine, hexylysine, heptalysine, wherein the moiety POL is a polypeptide. octalysine, nonalysine, decalysine, undecalysine, dodecal 21. The water-soluble carrier-linked prodrug, or the phar ysine, tridecalysine, tetradecalysine, pentadecalysine, hexa maceutically acceptable salt thereof, as claimed in claim 15, decalysine, heptadecalysine, octadecalysine, nonadecal wherein if m informula (I) is 0, POL comprises a structure ysine, oligolysines, triornithine, tetraornithine, of the formula pentaornithine, hexaornithine, heptaornithine, octaornithine, nonaornithine, decaornithine, undecaornithine, dodecaorni wherein thine, tridecaornithine, tetradecaornithine, pentadecaorni n is 1, 2, 3, or 4, thine, hexadecaomithine, heptadecaomithine, octadecaorni p is an integer from 5 to 2000, thine, nonadecaornithine, tridiaminobutyric acid, X2 is a functional group covalently linked to Hyp, and tetradiaminobutyric acid, pentadiaminobutyric acid, hexadi X1 is selected from H, CH and CHs; and aminobutyric acid, heptadiaminobutyric acid, octadiami wherein if m informula (I) is 1, POL comprises a structure nobutyric acid, nonadiaminobutyric acid, decadiaminobu of the formula tyric acid, undecadiaminobutyric acid, dodecadiaminobutyric acid, tridecadiaminobutyric acid, tet radecadiaminobutyric acid, pentadecadiaminobutyric acid, wherein hexadecadiaminobutyric acid, heptadecadiaminobutyric n1 and n2 are independently 1, 2, 3, or 4. acid, octadecadiaminobutyric acid, and nonadecadiaminobu p is an integer from 5 to 2000, and tyric acid. X and X’ are independently a functional group covalently linked to Hyp. 25. The water-soluble carrier-linked prodrug, or the phar maceutically acceptable salt thereof, as claimed in claim 22, 22. The water-soluble carrier-linked prodrug, or the phar wherein the polycarboxylate is selected from the group con maceutically acceptable salt thereof, as claimed in claim 15, sisting of di(glutamic acid), tri(glutamic acid), tetra(glutamic wherein each moiety Hyp independently comprises a moiety acid), penta(glutamic acid), hexa(glutamic acid), hepta selected from the group consisting of: (glutamic acid), octa(glutamic acid), nona (glutamic acid), a polyalcohol in bound form comprising at least 2 hydroxyl decac glutamic acid), undecaglutamic acid), dodeca groups: (glutamic acid), tridecacglutamic acid), tetradecacglutamie a polyamine in bound form comprising at least 2 amine acid), pentadecaglutamic acid), hexadecac glutamic acid), groups; and heptadecac glutamic acid), octadecacglutamic acid), nona a polycarboxylate in bound form comprising at least 2 decac glutamic acid), di(aspartic acid), tri(aspartic acid), tetra carboxylate groups. (aspartic acid), penta(aspartic acid), hexacaspartic acid), hep ta(aspartic acid), octa(aspartic acid), nona (aspartic acid), 23. The water-soluble carrier-linked prodrug, or the phar decacaspartic acid), undecacaspartic acid), dodecacaspartic maceutically acceptable salt thereof, as claimed in claim 22, acid), tridecacaspartic acid), tetradecacaspartic acid), penta wherein the polyalcohol is selected from the group consisting decacaspartic acid), hexadecacaspartic acid), heptadeca?as of glycerol, pentaerythritol, dipentaerythritol, tripentaeryth partic acid), octadecacaspartic acid), nonadecacaspartic acid), ritol, hexaglycerine. Sucrose, Sorbitol, fructose, mannitol, polyethyleneimines, and polyvinylamines. glucose, cellulose, amyloses, starches, hydroxyalkyl starches, polyvinylalcohols, dextrans, and hyualuronans. 26. The water-soluble carrier-linked prodrug, or the phar 24. The water-soluble carrier-linked prodrug, or the phar maceutically acceptable salt thereof, as claimed in claim 15, maceutically acceptable salt thereof, as claimed in claim 22, wherein each Hyp independently has a molecular weight wherein the polyamine is selected from the group consisting ranging from 0.1 to 4 kDa. of ornithine, diornithine, triornithine, tetraornithine, pentaor 27. The water-soluble carrier-linked prodrug, or the phar nithine, hexaornithine, heptaornithine, octaornithine, nonaor maceutically acceptable salt thereof, as claimed in claim 15, nithine, decaornithine, undecaornithine, dodecaornithine, wherein each Hyp independently has a molecular weight tridecaornithine, tetradecaornithine, pentadecaornithine, ranging from 0.4 to 4 kDa. hexadecaornithine, heptadecaomithine, octadecaornithine, nonadecaornithine, diaminobutyric acid, di(diaminobutyric 28. The water-soluble carrier-linked prodrug, or the phar acid), tri(diaminobutyric acid), tetra(diaminobutyric acid), maceutically acceptable salt thereof, as claimed in claim 15, penta(diaminobutyric acid), hexa(diaminobutyric acid), hep wherein each Hyp independently comprises, in bound form, ta(diaminobutyric acid), octa(diaminobutyric acid), nonadi trilysine, heptalysine or pentadecalysine. aminobutyric acid), decadiaminobutyric acid), undecadi 29. The water-soluble carrier-linked prodrug or the phar aminobutyric acid), dodecacdiaminobutyric acid), trideca maceutically acceptable salt thereof, as claimed in claim 15, (diaminobutyric acid), tetradecac diaminobutyric acid), wherein m is 0, and the sub-structure POL-Hyp is selected pentadecacdiaminobutyric acid), hexadecacdiaminobutyric from one of the following sub-structures (v), (vi), (vii) and acid), heptadecadiaminobutyric acid), octadecadiaminobu (viii): US 2014/0243254 A1 Aug. 28, 2014 67

(v)

NH

O

HN

O 1. N-n onp O

(vi) H HN w /

NH O

NH US 2014/0243254 A1 Aug. 28, 2014 68

-continued (vii)

(viii)

US 2014/0243254 A1 Aug. 28, 2014 69

wherein enteral, parenteral, inhalation, injection, infusion, intraarticu dashed lines indicate attachment to sub-structures —(SP) lar, intradermal, Subcutaneous, intramuscular, intravenous, -L-D of formula (I), intraosseous, intraperitoneal, intrathecal, intracapsular, p is an integer from 5 to 2000, and intraorbital, intracardiac, transtracheal, Subcuticular, intraar q is an integer of from 0 to 15. ticular, Subcapsular, Subarachnoid, intraspinal, intraventricu 30. The water-soluble carrier-linked prodrug, or the phar lar and intrasternal administration. maceutically acceptable salt thereof, as claimed in claim 15, 34. A method of treating, controlling, delaying or prevent wherein m is 0. ing in a mammalian patient in need of the treatment of one or 31. A pharmaceutical composition comprising the water more conditions comprising administering to said patient a soluble carrier-linked prodrug or the pharmaceutically diagnostically and/or therapeutically effective amount of the acceptable salt thereofas claimed in claim 15, and optionally pharmaceutical composition of claim 31. one or more excipients. 35. The method of claim 34, wherein the administration of 32. A method of treating, controlling, delaying or prevent the pharmaceutical composition is selected from the group ing in a mammalian patient in need of the treatment of one or consisting of topical, enteral, parenteral, inhalation, injection, more conditions comprising administering to said patient a infusion, intraarticular, intradermal, Subcutaneous, intramus diagnostically and/or therapeutically effective amount of the cular, intravenous, intraosseous, intraperitoneal, intrathecal, water-soluble protein carrier-linked prodrug, or a pharmaceu intracapsular, intraorbital, intracardiac, transtracheal, Subcu tically acceptable salt thereof, as claimed in claim 15. ticular, intraarticular, Subcapsular, Subarachnoid, intraspinal, 33. The method of claim 32, wherein administration of the intraventricular and intrasternal administration. prodrug is selected from the group consisting of topical, k k k k k