US 20140296257A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0296257 A1 Hersel et al. (43) Pub. Date: Oct. 2, 2014

(54) HIGH-LOADING WATER-SOLUABLE Publication Classification CARRIER-LINKED PRODRUGS (51) Int. Cl. A 6LX3/59 (2006.01) A613 L/428 (2006.01) (75) Inventors: Ulrich Hersel, Heidelberg (DE): A647/48 (2006.01) Guillaume Maitro, Mannheim (DE); (52) U.S. Cl. Harald Rau, Dossenheim (DE); Dirk CPC ...... A61 K3I/519 (2013.01); A61K47/48215 Vetter, Heidelberg (DE) (2013.01); A61 K3I/428 (2013.01) USPC ...... 514/259.41: 548/163; 544/282: 514/367 (73) Assignee: Ascendis Pharma A/S, Hellerup (DK) (57) ABSTRACT The present invention relates to water-soluble carrier-linked prodrugs of formula (I), wherein B, A and Hyp form the (21) Appl. No.: 14/237,429 carrier, B is a branching core, each A is independently a poly(ethylene glycol)-based polymeric chain, each Hyp is (22) PCT Filed: Aug. 10, 2012 independently a branched moiety, each SP is independently a spacer moiety, each L is independently a reversible prodrug (86). PCT No.: PCT/EP2012/065731 linker moiety, each D is independently a biologically active S371 (c)(1), moiety, each X is independently 0 or 1, each m is indepen (2), (4) Date: May 13, 2014 dently an integer of from 2 to 64, n is an integer from 3 to 32: or the pharmaceutically acceptable salt thereof. It further (30) Foreign Application Priority Data relates to pharmaceutical compositions comprising said water-soluble carrier-linked prodrugs, their use as medica Aug. 12, 2011 (EP) ...... 11177405.5 ment or diagnostic, and methods of treatment. US 2014/02962.57 A1 Oct. 2, 2014

HGH-LOADING WATER-SOLUABLE 0009. A major drawback of predominantly enzymatic CARRIER-LINKED PRODRUGS cleavage is interpatient variability. Enzyme levels may differ significantly between individuals resulting in biological 0001. The present application claims priority from PCT variation of prodrug activation by the enzymatic cleavage. Patent Application No. PCT/EP2012/065731 filed on Aug. The enzyme levels may also vary depending on the site of 10, 2012, which claims priority from German Patent Appli administration. For instance it is known that in the case of cation No. EP 11177405.5 filed on Aug. 12, 2011, the disclo Subcutaneous injection, certain areas of the body yield more sures of which are incorporated herein by reference in their predictable therapeutic effects than others. To reduce this entirety. unpredictable effect, non-enzymatic cleavage or intramo lecular catalysis is of particular interest. FIELD OF THE INVENTION 0010. Therefore, enzyme-independent autocatalytic 0002. It is noted that citation or identification of any docu cleavage of carrier and drug is preferred. In most cases this is ment in this application is not an admission that such docu achieved by an appropriately designed linker moiety between ment is available as prior art to the present invention. the carrier and the drug, which is directly attached to a func 0003 Drugs frequently exhibit short plasma half-life due tional group of a drug via covalent bond. to renal and receptor-mediated clearance, aggregation, pro 0011. A number of such enzyme-independent prodrugs teolytic degradation, poor bioavailability and physical prop suitable for different classes of biologically active moieties erties which preclude efficient formulations. This is highly are known in the art. Examples can be found in the interna undesirable as it leads to the need for frequent and repeated tional patent applications WO-A 2005/099768, WO-A 2006/ administration of the drug, resulting in increased costs and 13565869, WO-A 2009/095479, and WO-A 2011/012722. inconvenience for the patient. 0012 Typically, carrier-linked prodrugs have a stoichiom 0004 One mechanism for enhancing the availability of etry of one drug molecule conjugated to one carrier moiety. drugs is by conjugating them with derivatizing compounds, However, for many medical applications such stoichiometry which include, for example, poly(ethylene glycol) (PEG) and is disadvantageous as large Volumes of Such conjugates poly(propylene glycol). Some of the benefits recognized would have to be applied to a patient to ensure a high enough include lowered immunogenicity and antigenicity, increased dose of drug, causing undue pain and possibly requiring duration of action, and altered pharmacokinetic properties increased amounts of time for the administration process and (Veronese, F. M.. “Enzymes for Human Therapy: Surface thus increasing the costs of the treatment. In Such situations, Structure Modifications.” Chimica Oggi, 7:53-56, 1989). carrier-linked prodrugs in which more than one drug moiety 0005 To enhance physicochemical or pharmacokinetic is conjugated to a carrier molecule might be better Suited as properties of a drug in vivo, drugs can be bound to carriers in they provide a higher drug loading and thus require Smaller a non-covalent way, using physicochemical formulations of Volumes of the pharmaceutical composition to be adminis drug-solvent-carrier mixtures. However, the non-covalent tered to a patient. approach requires a highly efficient drug encapsulation to 0013 Patent U.S. Pat. No. 7,744,861 B2 discloses multi prevent uncontrolled, burst-type release of the drug. Restrain arm prodrugs in which at least three arms extend from a ing the diffusion of an unbound, water Soluble drug molecule branching core and each of these arms carries one drug moi requires strong van der Waals contacts, frequently mediated ety. Similarly, WO-A 2010/019233 discloses multi-arm pro through hydrophobic moieties. Many conformationally sen drugs of which each arm of a carrier moiety is conjugated to sitive drugs, such as proteins or peptides, are rendered dys one drug moiety. Despite the multi-arm backbone structure, functional during the encapsulation process and/or during Such carrier-linked prodrugs still have a relatively low drug Subsequent storage of the encapsulated drug. In addition, load. Such amino-containing drugs readily undergo side reactions 0014 More carrier-linked prodrugs with two polymer with carrier degradation products. Furthermore, dependence based arms are disclosed in WO-A 2008/034119, wherein of the release mechanism of the drug upon biodegradation each arm is attached to a drug moiety, diagnostic agent or may cause interpatient variability. targeting moiety. 0006 Alternatively, the drugs may be conjugated to a car 00.15 Prodrugs of the anti-malaria drug artelinic acid are rier via a transient linker molecule, resulting in carrier-linked disclosed in U.S. Pat. No. 6,461,603 B2. The polymeric pro prodrugs. This approach is applied to various classes of mol drugs are also based on a backbone moiety from which arms ecules, from So-called Small molecules, through natural prod extend which each carry one drug moiety at their terminus. ucts up to larger peptides and proteins. 0016. Another approach to high-loading carrier-linked 0007 Prodrug activation may occur by enzymatic or non prodrugs involves the use of dendrimers. Dendrimers are enzymatic cleavage of the bond between the carrier and the repeatedly branched, roughly spherical, large molecules. drug molecule, or a sequential combination of both, i.e. an Dendrimers have been used to non-covalently embed drug enzymatic step followed by a non-enzymatic rearrangement. 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 (0017 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. In an NO-donors through the reaction with NO gas. The dendrim in-vivo environment, esterases or amidases are typically ers released NO over a period of 60 days. However, this present and the esterases and amidases may cause significant approach does not allow for the adjustment of release speed as catalytic acceleration of the kinetics of hydrolysis from two no reversible prodrug linkers have been used to attach the NO fold up to several orders of magnitude. Therefore, the cleav to the termini of the dendrimer and this approach is also not age is predominantly controlled by the enzymatic reaction. transferable to other drug moieties. US 2014/02962.57 A1 Oct. 2, 2014

0018 US 2010/0160299 A1 discloses dendrimers to eties. In addition, the poly(ethylene glycol)-based (PEG which therapeutic agents for the reduction and/or elimination based) polymeric chain allows for increased water-solubility. of pain are connected in a reversible manner. Similarly, WO-A 2010/075423 discloses modular dendrimer platforms DETAILED DESCRIPTION OF EMBODIMENTS suitable for the delivery of therapeutic agents, for example. 0036. It is to be understood that the figures and descrip 0019. However, dendrimers typically exhibit a low degree tions of the present invention have been simplified to illustrate of water-solubility. When poorly water-soluble drug moieties elements that are relevant for a clear understanding of the are coupled to the functional groups of Such dendrimers the present invention, while eliminating, for purposes of clarity, resulting conjugates are even less water-soluble. Therefore, many other elements which are conventional in this art. Those although dendrimers provide a high drug loading, their appli of ordinary skill in the art will recognize that other elements cability for prodrug approaches is limited. are desirable for implementing the present invention. How 0020. It is noted that in this disclosure and particularly in ever, because Such elements are well known in the art, and the claims and/or paragraphs, terms such as "comprises'. because they do not facilitate a better understanding of the “comprised', 'comprising and the like can have the meaning present invention, a discussion of Such elements is not pro attributed to it in U.S. Patent law; e.g., they can mean vided herein. “includes”, “included”, “including, and the like; and that 0037. 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 0038. 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 0039. The terms “drug”, “biologically active molecule', a basic or novel characteristic of the invention. “biologically active moiety”, “biologically active agent'. 0021. 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. 0040 “Biologically active moiety D' means the part of a SUMMARY OF THE INVENTION biologically active moiety-reversible prodrug linker conju 0022. Therefore, there is a need to provide novel water gate or the part of a biologically active moiety-reversible soluble carrier-linked prodrugs that at least partially over prodrug linker-carrier conjugate, which results after cleavage come the above-mentioned shortcomings. This object is in a drug D-H of known biological activity. 0041 Amine-containing biologically active moiety' or achieved with a water-soluble carrier-linked prodrug 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 I cally active moiety-reversible prodrug linker-carrier conju B-A-Hyp-e-SP--L-D)), (I) gate (active agent) of (known) biological activity, and which part of the drug comprises at least one amine or hydroxyl group, respectively. 0023 wherein 0042. In addition, the subterm “aromatic amine-contain 0024 B, A and Hyp form a carrier moiety, and wherein ing' means that the respective biologically active moiety D 0025 B is a branching core, and analogously the corresponding drug D-H contains at least 0026 each A is independently a poly(ethylene gly one aromatic fragment which is Substituted with at least one col)-based polymeric chain, amino group. The Subterm “aliphatic amine-containing 0027 each Hyp is independently a branched moiety, means that the respective biologically active moiety D and 0028 each SP is independently a spacer moiety, analogously the corresponding drug D-H contains at least one aliphatic fragment which is substituted with at least one 0029 each L is independently a reversible prodrug amino group. Without further specification the term “amine linker moiety, containing is used generically and refers to aliphatic and 0030 each D is independently a biologically active aromatic amine-containing moieties. moiety, 0043. The subterm “aromatic hydroxyl-containing 0031 each x is independently 0 or 1, means that the respective moiety D and analogously the cor 0032 each m is independently an integer of from 2 to responding drug D-H contains at least one aromatic fragment, 64, which is substituted with at least one hydroxyl group. The 0033 n is an integer from 3 to 32: Subterm “aliphatic hydroxyl-containing means that the 0034 or a pharmaceutically acceptable salt thereof. hydroxyl group of the respective moiety D and analogously 0035. It was now surprisingly found that such water the corresponding drug D-H is connected to an aliphatic soluble carrier-linked prodrug can be used as a Sustained fragment. Without further specification the term “hydroxyl release dosage form of biologically active moieties with a containing is used generically and refers to aliphatic and high drug loading due to the presence of the branched moi aromatic hydroxyl-containing moieties. US 2014/02962.57 A1 Oct. 2, 2014

0044) “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 0045 Targeting moieties are moieties that when present in that bind specifically to a receptor preferentially expressed on a molecule. Such as for example in a prodrug, allow prefer the Surface of tumor cells or on an infectious organism, anti ential localization of Such larger molecule in specific target microbial and other drugs designed to fit into the binding areas of the organism to which it has been administered. Such pocket of a particular receptor based on the crystal structure specific target areas might be organs, certain cell types or of the receptor or other cell Surface protein, ligands of tumor subcellular compartments. “Preferential localization” means antigens or other molecules preferentially expressed on the that at least 10%, preferably at least 20% and more preferably Surface of tumor cells, or fragments of any of these molecules. at least 30% of the biologically active moieties administered Examples of tumor-specific antigens that can function as to a patient reach said specific target areas. targeting moieties include extracellular epitopes of a member 0046 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, 0047 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 0048 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 0051. 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 0.052 The phrases “in bound form”, “connected to’, and tensin, “moiety” refer to sub-structures which are part of a molecule. 0049 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 0050. 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: 0053 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 0054) 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(s), carrier(s) combinatorial libraries, growth factors, such as EGF, FGF, and/or any optional spacer moiety/moieties. insulin, and insulin-like growth factors, and homologous 0055. The terms “reversible prodrug linker” or “transient polypeptides. Somatostatin and its analogs, transferrin, lipo prodrug linker” refer to linker 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 tins, 6-opioid receptor ligands, cholecystokinin A receptor ranging from, for example, one hour to three months. On the ligands, ligands specific for angiotensin AT1 or AT2 recep other hand, stable or permanent linkers have stable or perma US 2014/02962.57 A1 Oct. 2, 2014

nent linkages, which are typically non-cleavable permanent from other types of reactions or interactions of one or more of bonds, meaning that they have a half-life of at least six months the pharmaceutically acceptable excipients. Accordingly, the under physiological conditions (aqueous buffer at pH 7.4, 37° pharmaceutical compositions of the present invention C.). encompass any composition obtainable by admixing a water 0056. A “traceless prodrug linker refers to a prodrug soluble carrier-linked prodrug of the present invention and linker from which a drug is released in its free form, meaning optionally one or more pharmaceutically acceptable excipi that upon release from the promoiety the drug does not con entS. tain any traces of the promoiety. “Non-biologically active 0065. The term “excipient” refers to a diluent, adjuvant, or linker” means a linker which does not show the pharmaco vehicle with which the water-soluble carrier-linked prodrug logical effects of the drug (D-H) derived from the biologically is administered. Such pharmaceutical excipient can be sterile active moiety. liquids, such as water and oils, including those of petroleum, 0057 The term “polymer describes a molecule compris animal, vegetable or synthetic origin, including but not lim ing, in particular consisting of, repeating structural units con ited to peanut oil, soybean oil, mineral oil, Sesame oil and the nected by chemical bonds in a linear, circular, branched, like. Water is a preferred excipient when the pharmaceutical crosslinked or dendrimeric way or a combination thereof, composition is administered orally. Saline and aqueous dex which can be of synthetic or biological origin or a combina trose are preferred excipients when the pharmaceutical com tion of both. It is understood, that e.g. capping moieties may position is administered intravenously. Saline Solutions and be present in a polymer. aqueous dextrose and glycerol Solutions are preferably 0058. The term “polymeric' refers to a moiety comprising employed as liquid excipients for injectable solutions. Suit one or more polymer. able pharmaceutical excipients include starch, glucose, lac 0059. The term “poly(ethylene glycol)-based polymeric tose, Sucrose, mannitol, trehalose, gelatin, malt, rice, flour, chain' or “PEG-based polymeric chain” refers to a polymer chalk, silica gel, Sodium Stearate, glycerol monostearate, talc, chain comprising at least 10% by weight, preferably at least Sodium chloride, dried skim milk, glycerol, propylene, gly 25%, more preferably at least 50% by weight, even more col, water, ethanol and the like. The composition, if desired, preferably at least 80% by weight poly(ethylene glycol). It is can also contain minor amounts of wetting or emulsifying understood that a PEG-based polymeric chain may be termi agents, pH buffering agents, like, for example, acetate. Suc nated in case of branched chains and/or or interrupted by alkyl cinate, tris, carbonate, phosphate, HEPES (4-(2-hydroxy oraryl groups and optionally be substituted with heteroatoms ethyl)-1-piperazineethanesulfonic acid), MES (2-(N-mor and/or functional groups. pholino)ethanesulfonic acid), or can contain detergents, like 0060. The terms “spacer”, “spacer group”, “spacer mol Tween, poloxamers, poloxamines, CHAPS, Igepal, or amino ecule', and 'spacer moiety are used interchangeably and acids like, for example, glycine, lysine, or histidine. These refer to any moiety Suitable for connecting two moieties, such compositions can take the form of Solutions, Suspensions, as Clso alkyl, Clso alkenyl or Clso alkinyl, which moiety is emulsions, tablets, pills, capsules, powders, Sustained-release optionally interrupted by one or more groups selected from formulations and the like. The composition can beformulated —NH-, -N (C. alkyl)-, —O— —S , —C(O)—, as a Suppository, with traditional binders and excipients such —C(O)NH , —C(O)N(C. alkyl)-, —O—C(O)—, as triglycerides. Oral formulation can include standard —S(O)— —S(O). , 4- to 7-membered heterocyclyl phe excipients such as pharmaceutical grades of mannitol, lac nyl and naphthyl. tose, starch, magnesium Stearate, Sodium saccharine, cellu 0061. The term “terminus’ refers to the last carbon atom lose, magnesium carbonate, etc. Examples of Suitable phar or heteroatom of a linear or branched chain comprising, in maceutical excipients are described in “Remington's particular consisting of carbon atoms or heteroatoms, i.e. to a Pharmaceutical Sciences” by E. W. Martin. Such composi carbon or heteroatom which is connected to exactly one other tions will contain a diagnostically and/or therapeutically carbon or heteroatom. effective amount of the a water-soluble carrier-linked pro 0062. The term “branched moiety” refers to a moiety com drug, preferably in purified form, together with a suitable prising at least one branching point. Such branching point amount of excipient so as to provide the form for proper comprises, for example, an at least 3-fold Substituted car administration to the patient. The formulation should suit the bocycle, an at least 3-fold substituted heterocycle, a tertiary mode of administration. carbon atom, a quaternary carbon atom or a tertiary nitrogen 0066. The term “pharmaceutically acceptable” means atOm. approved by a regulatory agency Such as the EMEA (Europe) 0063 A carbocycle and heterocycle may be substituted by and/or the FDA (US) and/or any other national regulatory Co alkyl, optionally interrupted or terminated by heteroa agency for use in animals, preferably in humans. toms or functional groups selected from the group consisting 0067 "Dry composition” means that the pharmaceutical of-O-, -S. , N(R), C(O), C(O)N(R), and N(R)C(O), composition comprising water-soluble carrier-linked pro wherein R is hydrogen or a Coalkyl chain, which is option drug according to the present invention is provided in a dry ally interrupted or terminated by one or more of the above form in a container. Suitable methods for drying are spray mentioned atoms or groups which further have a hydrogen as drying and lyophilization (freeze-drying). Such dry compo terminal atom. sition of water-soluble carrier-linked prodrug has a residual 0064 "Pharmaceutical composition” or “composition' water content of a maximum of 10%, preferably less than 5% means a composition comprising 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. orindirectly, from combination, complexation or aggregation 0068 “Lyophilized composition” means that the pharma of any two or more of the ingredients, or from dissociation of ceutical composition comprising water-soluble carrier-linked one or more of the pharmaceutically acceptable excipients, or prodrug was first frozen and Subsequently Subjected to water US 2014/02962.57 A1 Oct. 2, 2014 reduction by means of reduced pressure. This terminology atom(s) of a C- alkynyl carbon may be replaced by a Sub does not exclude additional drying steps which may occur in stituent as indicated herein. The term C alkynyl is defined the manufacturing process prior to filling the composition accordingly. into the final container. 0078 “Clso alkenyl” means a branched or unbranched 0069 “Lyophilization' (freeze-drying) is a dehydration alkenyl chain having 2 to 50 carbon atoms (unsubstituted process, characterized by freezing a composition and then Clso alkenyl), e.g. if present at the end of a molecule: reducing the Surrounding pressure and, optionally, adding -CH=CH, -CH=CH-CH, -CH-CH=CH, heat to allow the frozen water in the composition to sublime -CH=CH-CH CH-CH=CH-CH=CH, or e.g. directly from the solid phase to gas. Typically, the sublimed —CH=CH , when two moieties of a molecule are linked water is collected by desublimation. by the alkenyl group. Optionally, one or more hydrogenatom 0070 The term “functional group' refers to a specific (s) of a Clso alkenyl carbon may be replaced by a substituent group of atoms within molecules that can undergo character as further specified. Accordingly, the term “alkenyl relates to istic chemical reactions. Examples of functional groups are a carbon chain with at least one carbon double bond. Option hydroxyl, carbonyl, aldehyde, carboxyl, ester, ketal, ally, one or more triple bonds may occur. The term "Cs hemiketal, acetal, hemiacetal, primary/secondary/tertiary alkenyl' is defined accordingly. amine, cyanate, disulfide, Sulfhydryl, Sulfonyl and phosphate 0079. “Clso alkynyl means a branched or unbranched groups. alkynyl chain having 2 to 50 carbon atoms (unsubstituted 0071. If a functional group is coupled to another func Clso alkynyl), e.g. if present at the end of a molecule: tional group, the resulting chemical structure is referred to as -C=CH, -CH C=CH, CH-CH C=CH, CH “linkage'. For example, the reaction of an amine functional C=C CH, or e.g. —C=C when two moieties of a mol group with a carboxyl functional group results in an amide ecule are linked by the alkynyl group. Optionally, one or more linkage. Further examples for linkages are ester, ether, ketal, hydrogen atom(s) of a C-so alkynyl carbon may be replaced acetal, secondary/tertiary amine, carboxamide, Sulfide and by a substituent as further specified. Accordingly, the term disulfide linkages. “alkynyl relates to a carbon chain with at least one carbon 0072 “Alkyl means a straight-chain or branched carbon triple bond. Optionally, one or more double bonds may occur. chain (unsubstituted alkyl). Optionally, one or more hydro 0080) “C., cycloalkyl” or “C., cycloalkyl ring” means a gen atoms of an alkyl carbon may be replaced by a substitu cyclic alkyl chain having 3 to 7 carbon atoms, which may ent. In general, a preferred alkyl is C alkyl. have carbon-carbon double bonds being at least partially satu 0073 "Ca alkyl means an alkyl chain having 1 to 4 rated (unsubstituted C-7 cycloalkyl), e.g. cyclopropyl. carbon atoms (unsubstituted C. alkyl), e.g. if present at the cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohep end of a molecule: methyl, ethyl, n-propyl, isopropyl. n-butyl, tyl. Optionally, one or more hydrogenatom(s) of a cycloalkyl isobutyl, sec-butyl tert-butyl, or e.g. —CH2—, —CH2— carbon may be replaced by a Substituent as indicated herein. CH , —CH(CH)—, CH-CH-CH , CH The term "C., cycloalkyl” or “C., cycloalkyl ring” also (CHS)— —C(CH) , when two moieties of a molecule includes bridged bicycles like norbonane (norbonanyl) or are linked by the alkyl group (also referred to as C. alky norbonene (norbonenyl). Accordingly, "Cs cycloalkyl lene). Optionally, one or more hydrogen atom(s) of a Ca means a cycloalkyl having 3 to 5 carbon atoms. Accordingly, alkyl carbon may be replaced by a Substituent as indicated “Clio cycloalkyl means a cycloalkyl having 3 to 10 carbon herein. Accordingly, “Clso alkyl means an alkyl chain hav atOmS. ing 1 to 50 carbon atoms. I0081. "Halogen' means fluoro, chloro, bromo or iodo. It is 0074 "C. alkyl” means an alkyl chain having 1-6 carbon generally preferred that halogen is fluoro or chloro. atoms, e.g. if present at the end of a molecule: C. alkyl, I0082 “4 to 7 membered heterocyclyl or “4 to 7 mem methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, Sec-bu bered heterocycle” means a ring with 4, 5, 6 or 7 ring atoms tyl, tert-butyl, n-pentyl, n-hexyl, or e.g. —CH2—, —CH2— that may contain up to the maximum number of double bonds CH2—, —CH(CH)—, C(CH2) , CH-CH (aromatic or non-aromatic ring which is fully, partially or CH , —CH(CHs)— —C(CH) , when two moieties un-saturated) wherein at least one ring atom up to 4 ring of a molecule are linked by the alkyl group (also referred to as atoms are replaced by a heteroatom selected from the group C. alkylene). One or more hydrogenatom(s) of a C- alkyl consisting of Sulfur (including —S(O)— —S(O) ), oxy carbon may be replaced by a Substituent as indicated herein. gen and nitrogen (including=N(O)—) and wherein the ring The terms Cls alkyl or Cs alkylene are defined accord is linked to the rest of the molecule via a carbon or nitrogen ingly. atom (unsubstituted 4 to 7 membered heterocyclyl). For the 0075 "Calkenyl' means an alkenyl chain having 2 to 6 sake of completeness it is indicated that in Some embodiments carbon atoms, e.g. if present at the end of a molecule: of the present invention, 4 to 7 membered heterocyclyl has to -CH=CH, -CH=CH-CH, CH-CH=CH, fulfill additional requirements. Examples for a 4 to 7 mem -CH=CH-CH CH-CH=CH-CH=CH, or e.g. bered heterocycles are azetidine, oxetane, thietane, furan, —CH=CH , when two moieties of a molecule are linked thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyra by the alkenyl group. One or more hydrogenatom(s) of a C Zole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, alkenyl carbon may be replaced by a Substituent as indicated thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, herein. thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrroli 0076. The term C alkenyl is defined accordingly. dine, imidazolidine, pyrazolidine, oxazolidine, isoxazoli 0077 "C. alkynyl” means an alkynyl chain having 2 to 6 dine, thiazolidine, isothiazolidine, thiadiazolidine, Sulfolane, carbon atoms, e.g. if present at the end of a molecule: pyran, dihydropyran, tetrahydropyran, imidazolidine, pyri -C=CH, -CH C=CH, CH, CH, C=CH, CH dine, pyridazine, pyrazine, pyrimidine, piperazine, piperi C=C CH, or e.g. —C=C when two moieties of a mol dine, morpholine, tetrazole, triazole, triazolidine, tetrazoli ecule are linked by the alkynyl group. One or more hydrogen dine, diazepane, azepine or homopiperazine. Optionally, one US 2014/02962.57 A1 Oct. 2, 2014 or more hydrogen atom(s) of a 4 to 7 membered heterocyclyl N(R')S(O)N(R') , S: , N(R') , may be replaced by a substituent. –OC(O)R''', N(R)C(O) , N(R)S(O) I0083) “8 to 11 membered heterobicyclyl” or “8 to 11 mem , N(R')S(O) , N(R')C(O)O , bered heterobicycle” means a heterocyclic system of two N(R''')C(O)N(R') , and OC(O)N rings with 8 to 11 ring atoms, where at least one ring atom is (RI Rhila), shared by both rings and that may contain up to the maximum I0090 T is selected from the group consisting of phe number of double bonds (aromatic or non-aromatic ring nyl, naphthyl, indenyl, indanyl, tetralinyl, Co which is fully, partially or un-saturated) wherein at least one cycloalkyl, 4- to 7-membered heterocyclyl, and 9- to ring atom up to 6 ring atoms are replaced by a heteroatom 11-membered heterobicyclyl, wherein T is option Selected from the group consisting of sulfur (including ally substituted with one or more R', which are the —S(O)— —S(O) ), oxygen and nitrogen (including same or different, =N(O)—) and wherein the ring is linked to the rest of the (0091) R' is halogen, CN, oxo (=O), COOR'', molecule via a carbon or nitrogenatom (unsubstituted 8 to 11 OR 12, C(O)R12, C(O)N(R2R12), S(O)N membered heterobicyclyl). Examples for a 8 to 11 membered (Rb12Rb12a), S(O)N(R2R12), S(O).R'', S(O) heterobicycle are indole, indoline, benzofuran, ben Rb12, N(R12)SO)N(R2R12), SR 12, Zothiophene, benzoxazole, benzisoxazole, benzothiazole, N(Rb12Rb2a), NO, OC(O)R’ 12N(R12)C(O)R12, benzisothiazole, benzimidazole, benzimidazoline, quinoline, N(R12)SO).R. 12, N(R12)SO)R12, N(R12)C quinazoline, dihydroquinazoline, quinoline, dihydroquino (OOR 12, N(R12)C(O)N(Rb12Rb12b), OC(O)N 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 0092 Rb11, Rhila, Rb12, Rb12a, R2 are indepen rings like 1,4-dioxa-8-azaspiro4.5 decane or bridged 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. 0093. The term “interrupted' means that between two car I0084. The term “aliphatic' means fully saturated. bons a group is inserted or that at the end of the carbon chain I0085. 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 I0094. 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 0095. In the following section the invention is described in —NH ) is inserted. further detail. I0086) In general the term "substituted” preferably refers to 0096. 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, CN, COOR, OR, C(O)R, C(O)N(RR), S(O)N (R'R''), S(O)N(R'R''), S(O).R., S(O)R, N(R)s (O)N(R9"R9), SR 9, N(R'R'98), NO, OC(O)R’, B-A-Hyp-et-SP--L-D)), (I) N(R)C(O)R’9, N(R)S(O).R., N(R)S(O)R’, N(R)C(O)OR, N(R9)C(O)N(R9"R9), OC(O)N 0097 wherein (R'R''), T". Clso alkyl, C, so alkenyl, and Clso alkynyl, 0.098 B, A and Hyp form a carrier moiety, and wherein I0087 wherein T". Clso alkyl, Clso alkenyl, and Clso I0099 B is a branching core, alkynyl are optionally substituted with one or more R', 10100 each A is independently a poly(ethylene gly which are the same or different, and wherein Clso alkyl: col)-based polymeric chain, C2-so alkenyl; and C2-so alkynyl are optionally inter 10101 each Hyp is independently a branched moiety, rupted by one or more groups selected from the group 10102 each SP is independently a spacer moiety, (0103) each L is independently a reversible prodrug linker moiety, I0104 each D is independently a biologically active moiety, I0105 each x is independently 0 or 1, I0106 eachm is independently an integer of from 2 to (R11) : and OC(O)N(R'R'' 1a); 64, I0088) R', R', R'' are independently selected from I0107 n is an integer from 3 to 32: the group consisting of H; T'; and Clso alkyl: Clso 0108) or a pharmaceutically acceptable salt thereof. alkenyl; and Clso alkynyl, 0109 The moieties A of the water-soluble carrier-linked I0089 wherein T. Clso alkyl, Clso alkenyl, and prodrug of formula (I) may be the same or different. Prefer Clso alkynyl are optionally substituted with one or ably all moieties A of formula (I) are the same. more R', which are the same or different, and 0110. The moieties Hyp of the water-soluble carrier wherein Clso alkyl: Clso alkenyl; and Clso alkynyl linked prodrug of formula (I) may be the same or different. are optionally interrupted by one or more groups Preferably all moieties Hyp of formula (I) are the same. selected from the group consisting of T, C(O)O , 0111. The moieties SP of the water-soluble carrier-linked —O , —C(O) , —C(O)N(R') , S(O)N prodrug of formula (I) may be the same or different. Prefer (R') , S(O)N(R')-, -S(O). , S(O), ably all moieties SP of formula (I) are the same. US 2014/02962.57 A1 Oct. 2, 2014

0112. The moieties L of the water-soluble carrier-linked 0.125. In a preferred embodiment, the branching core B prodrug of formula (I) may be the same or different. Prefer comprises, preferably consists of pentaerythritol. ably all moieties L of formula (I) are the same. 0.126 Preferably, each A of formula (I) individually con 0113. The moieties D of the water-soluble carrier-linked sists of a linear PEG-based chain, of which one terminus is prodrug of formula (I) may be the same or different. Prefer connected to B and the other terminus is connected to a ably all moieties D of formula (I) are the same. moiety Hyp. It is understood that each moiety A offormula (I) 0114. Each n of the water-soluble carrier-linked prodrug may independently optionally be terminated in case of a of formula (I) may be the same or different. Preferably all n of branched PEG-based chain and/or may optionally be inter formula (I) are the same. rupted in case of a branched or linear PEG-based chain by 0115 Each x of the water-soluble carrier-linked prodrug alkyl or aryl groups and may optionally be substituted with of formula (I) may be the same or different. Preferably all x of heteroatoms and/or functional groups. formula (I) are the same. I0127. According to the present invention, each A and each 0116 Preferably, all n. x and all moieties A. Hyp, SP, L, D Hyp may be selected independently from the other moieties A of the water-soluble carrier-linked prodrug of formula (I) are and Hyp of formula (I). Preferably, all moieties A of formula the same. (I) are the same and all moieties Hyp of formula (I) are the 0117. It is understood that m is equal to or less than the SaC. number of functional groups of Hyp of formula (I). I0128. According to the present invention, each sub-struc 0118 Preferably, m is an integer from 2 to 32, more pref ture A-Hyp of formula (I) may be independently the same or erably from 2 to 24, more preferably from 2 to 12, more a different sub-structure A-Hyp. In a preferred embodiment, preferably m is 2, 3, 4, 5, 6, 7, 8, 9, or 10, and even more all sub-structures A-Hyp of formula (I) are the same. preferably m is 2, 3, 4, 5, 6, 7, or 8. Most preferably, m is 2. I0129. Preferably, each moiety A of formula (I) is con 0119. In a preferred embodiment, the branching core B of nected to B through a permanent linkage. formula (I) comprises, preferably consists of a moiety 0.130. According to the invention, n is an integer from 3 to selected from: 32. Preferably, n is an integer from 3 to 16, more preferably in I0120 a polyalcohol comprising at least 2 hydroxyl is an integer from 4 to 8 and most preferably n is 4. groups (preferably further comprising a functional I0131. In a preferred embodiment n is 4 and m is 2. group, which is preferably an additional amino group or 0.132. In one embodiment, each moiety A is independently a carboxylic acid group, more preferably an additional selected from linear and branched poly(ethylene glycol)- carboxylic acid group), based polymeric chains. Preferably, each A is independently I0121 preferably B is selected from glycerol, pen a linear poly(ethylene glycol)-based polymeric chain. taerythritol, dipentaerythritol, tripentaerythritol, hexag 0.133 Preferably, each A is independently selected from lycerine. Sucrose, Sorbitol, fructose, mannitol, glucose, the formula cellulose, amyloses, starches, hydroxyalkyl starches, polyvinylalcohols, dextranes, and hyualuronans, 0.122 or a polyamine comprising at least 2 amine 0.134 wherein groups (preferably further comprising a functional 0.135 n1 and n2 are independently 1, 2, 3, or 4, prefer group, which is preferably an additional hydroxyl group ably n1 and n2 are independently 1, 2, or 3, more pref or a carboxylic acid group, more preferably a carboxylic erably 2 or 3: acid group), 0.136 p is an integer from 5 to 2000, preferably p is an I0123 preferably selected from ornithine, diornithine, integer from 10 to 1000, more preferably from 20 to triornithine, tetraomithine, pentaornithine, hexaorni 1000, more preferably, 50 to 1000 and more preferably p thine, heptaornithine, octaornithine, nonaornithine, is an integer from 100 to 1000; and decaornithine, undecaornithine, dodecaornithine, tride 0.137 X3 is a chemical bond or linkage group caornithine, tetradecaornithine, pentadecaornithine, covalently linked to B, and hexadecaornithine, heptadecaornithine, octadecaorni 0.138 X2 is a chemical bond or linkage group thine, nonadecaornithine, diaminobutyric acid, di(di covalently linked to Hyp. aminobutyric acid), tri(diaminobutyric acid), tetra(di 0.139 Preferably, each linkage between a moiety A and a aminobutyric acid), penta(diaminobutyric acid), hexa moiety Hyp of formula (I) is a permanent linkage, more (diaminobutyric acid), hepta(diaminobutyric acid), octa preferably a permanent linkage comprising, preferably con (diaminobutyric acid), nona (diaminobutyric acid), deca sisting of a linkage group selected from amine, amide, car (diaminobutyric acid), undecacdiaminobutyric acid), bamate, thioether, or ether groups, and most preferably each dodecacdiaminobutyric acid), tridecacdiaminobutyric permanent linkage between A and Hyp of formula (I) is an acid), tetradecacdiaminobutyric acid), pentadecadiami amide linkage, i.e. X2 is an amide linkage (-NH nobutyric acid), hexadecadiaminobutyric acid), hepta (C=O)—). decadiaminobutyric acid), octadecacdiaminobutyric 0140. In a preferred embodiment, a sub-structure B-(A), acid), nonadecac diaminobutyric acid), lysine, dilysine, of formula (I) is a multi-arm PEG derivative as, for instance, trilysine, tetralysine, pentalysine, hexalysine, heptal detailed in the products list of JenKem Technology, USA ysine, octalysine, nonalysine, decalysine, undecalysine, (accessed by download from http://jenkemusa.net/pegprod dodecalysine, tridecalysine, tetradecalysine, pentade ucts2.aspx on Mar. 8, 2011), such as a 4-arm-PEG derivative, calysine, hexadecalysine, heptadecalysine, octadecal in particular comprising a pentaerythritol core, an 8-arm ysine, nonadecalysine, oligolysines, polyethylene PEG derivative comprising a hexaglycerin core, and an imines, and polyvinylamines; 8-arm-PEG derivative comprising a tripentaerythritol core. 0.124 wherein the polyalcohol or polyamine is in bound Most preferred are sub-structures B-(A) of formula (I) com form. prising, in particular consisting of moieties selected from: US 2014/02962.57 A1 Oct. 2, 2014

0141 a 4-arm PEG Amine comprising a pentaerythritol 0159. In a preferred embodiment, a moiety Hyp of the COC water-soluble carrier-linked prodrug of formula (I) com prises, preferably consists of a moiety selected from 0.160 a polyalcohol in bound form comprising at least 2 hydroxyl groups (preferably further comprising a func tional group, which is preferably an additional hydroxyl group or a carboxylic acid group, more preferably an 0142 with n ranging from 400 to 2000; additional hydroxyl group), 0143 a 4-arm PEG Carboxyl comprising a pentaerythritol 0.161 preferably selected from glycerol, pentaerythri COC tol, dipentaerythritol, tripentaerythritol, hexaglycerine, Sucrose, Sorbitol, fructose, mannitol, glucose, cellulose, amyloses, starches, hydroxyalkyl starches, polyvinylal O cohols, dextranes, and hyualuronans, 0162 or a polyamine in bound form comprising at least 2 amine groups (preferably further comprising a func tional group, which is preferably an additional amine 0144 with n ranging from 400 to 2000; group or a carboxylic acid group, more preferably a 0145 an 8-arm PEG Amine comprising a hexaglycerin carboxylic acid group), COC 0.163 preferably selected from ornithine, diornithine, triornithine, tetraornithine, pentaornithine, hexaorni thine, heptaornithine, octaornithine, nonaornithine, R-(-CH-O--CHCHO-H-CHCH-NHls decaornithine, undecaornithine, dodecaornithine, tride caornithine, tetradecaornithine, pentadecaornithine, hexadecaornithine, heptadecaornithine, octadecaorni 0146 with n ranging from 400 to 2000 and thine, nonadecaornithine, diaminobutyric acid, di(di 0147 R-hexaglycerin core structure; aminobutyric acid), tri(diaminobutyric acid), tetra(di 0148 an 8-arm PEG Carboxyl comprising a hexaglycerin aminobutyric acid), penta(diaminobutyric acid), hexa (diaminobutyric acid), hepta(diaminobutyric acid), octa COC (diaminobutyric acid), nona (diaminobutyric acid), deca (diaminobutyric acid), undecacdiaminobutyric acid), O dodecacdiaminobutyric acid), tridecacdiaminobutyric acid), tetradecacdiaminobutyric acid), pentadecac diami R--CH-O--CHCH-O-, -CH-C-OHis nobutyric acid), hexadecadiaminobutyric acid), hepta decadiaminobutyric acid), octadecacdiaminobutyric acid), nonadecac diaminobutyric acid), lysine, dilysine, 0149 with n ranging from 400 to 2000 and trilysine, tetralysine, pentalysine, hexalysine, heptal 0150 R-hexaglycerin core structure; ysine, octalysine, nonalysine, decalysine, undecalysine, 0151 an 8-arm PEG Amine comprising a tripentaerythri dodecalysine, tridecalysine, tetradecalysine, pentade tol core: calysine, hexadecalysine, heptadecalysine, octadecal ysine, nonadecalysine, oligolysines, triornithine, tet raornithine, pentaornithine, hexaornithine, heptaornithine, octaornithine, nonaornithine, decaorni thine, undecaornithine, dodecaornithine, tridecaorni thine, tetradecaornithine, pentadecaornithine, hexade 0152 with n ranging from 400 to 2000 caornithine, heptadecaornithine, octadecaornithine, 0153 and R=tripentaerythritol core structure; nonadecaornithine, tridiaminobutyric acid, tetradiami 0154 and an 8-arm PEG Carboxyl comprising a tripen nobutyric acid, pentadiaminobutyric acid, hexadiami taerythritol core: nobutyric acid, heptadiaminobutyric acid, octadiami nobutyric acid, nonadiaminobutyric acid, decadiaminobutyric acid, undecadiaminobutyric acid, O dodecadiaminobutyric acid, tridecadiaminobutyric acid, tetradecadiaminobutyric acid, pentadecadiami nobutyric acid, hexadecadiaminobutyric acid, hepta decadiaminobutyric acid, octadecadiaminobutyric acid, nonadecadiaminobutyric acid, (O155 with n ranging from 400 to 2000 and 0.164 or a polycarboxylate in bound form comprising at 0156 R=tripentaerythritol core structure; least 2 carboxylate groups (preferably further compris O157 each in bound form. ing a functional group, which is preferably an additional 0158. In a preferred embodiment, the molecular weight of amino group or a carboxylic acid group, more preferably the sub-structure B-(A), of formula (I) ranges from 1 kDa to an additional carboxylic acid group), 160 kDa, more preferably from 1 kDa to 80 kDa and even 0.165 preferably selected from di(glutamic acid), tri more preferably from 10 kDa to 40 kDa. It is understood that (glutamic acid), tetra (glutamic acid), penta(glutamic the terminal amine groups or carboxyl groups, respectively, acid), hexa(glutamic acid), hepta(glutamic acid), octa are used for conjugation to Hyp of formula (I). (glutamic acid), nona (glutamic acid), decac glutamic US 2014/02962.57 A1 Oct. 2, 2014

acid), undecaglutamic acid), dodecacglutamic acid), and a moiety L of formula (I) may independently be director tridecacglutamic acid), tetradecaglutamic acid), penta indirect through a moiety SP. Preferably, all linkages between decac glutamic acid), hexadecaglutamic acid), hepta a moiety Hyp and a moiety L of formula (I) are either director decac glutamic acid), octadecacglutamic acid), nonadeca indirect through a moiety SP. (glutamic acid), di(aspartic acid), tri(aspartic acid), tetra 0170 In a preferred embodiment, a moiety Hyp of formula (aspartic acid), penta(aspartic acid), hexacaspartic acid), (I) is connected to a moiety SP (if x of formula (I) is 1) or to hepta(aspartic acid), octa(aspartic acid), nona (aspartic a moiety L (if X of formula (I) is 0) through a linkage group acid), decacaspartic acid), undecacaspartic acid), dodeca selected from amide, carbamate, ester, ether, amine or thio (aspartic acid), tridecacaspartic acid), tetradecacaspartic ether; preferably, a moiety Hyp of formula (I) is connected to acid), pentadecacaspartic acid), hexadecacaspartic acid), a moiety SP (if x of formula (I) is 1) or to a moiety L (if x of heptadecacaspartic acid), octadecacaspartic acid), nona formula (I) is 0) through a linkage group selected from amide, decacaspartic acid), polyethyleneimines, and polyviny thioether or ether, even more preferably through an amide lamines. group. 0166 In a preferred embodiment, a moiety Hyp is selected 0171 Optionally, a functional group of Hyp which is not from the group comprising, in particular consisting of, in connected to a moiety SP or a moiety L of formula (I) may be bound form, dilysine, trilysine, tetralysine, pentalysine, capped with a suitable capping reagent or may optionally be hexalysine, heptalysine, octalysine, nonalysine, decalysine, connected to at least one targeting moiety, in particular undecalysine, dodecalysine, tridecalysine, tetradecalysine, through permanent linkages. Preferably, all functional groups pentadecalysine, hexadecalysine, heptadecalysine, octade of a moiety Hyp of formula (I) are connected to a moiety L or calysine, nonadecalysine, triornithine, tetraornithine, pen SP. Targeting moieties, if present, may be conjugated to Hyp taornithine, hexaornithine, heptaornithine, octaornithine, either directly or indirectly through spacer moieties. nonaornithine, decaornithine, undecaornithine, dodecaorni 0172 Examples of suitable capping moieties are linear, thine, tridecaornithine, tetradecaornithine, pentadecaorni branched or cyclic Cls alkyl groups. thine, hexadecaornithine, heptadecaornithine, octadecaorni 0173. In one embodiment, each moiety Hyp of formula (I) thine, nonadecaornithine, tridiaminobutyric acid, is directly or indirectly connected to at least two moieties L. tetradiaminobutyric acid, pentadiaminobutyric acid, hexadi Such as to at least three moieties L., to at least four moieties L aminobutyric acid, heptadiaminobutyric acid, octadiami or to at least five moieties L. nobutyric acid, nonadiaminobutyric acid, decadiaminobu 0.174. In a further preferred embodiment, each branched tyric acid, undecadiaminobutyric acid, moiety Hyp has at least 1 branching and is conjugated to at dodecadiaminobutyric acid, tridecadiaminobutyric acid, tet least 2 moieties L (either directly or indirectly) and has at radecadiaminobutyric acid, pentadecadiaminobutyric acid, most 63 branchings and is at most conjugated to 64 moieties hexadecadiaminobutyric acid, heptadecadiaminobutyric L (either directly or indirectly). More preferably each acid, octadecadiaminobutyric acid, nonadecadiaminobutyric branched moiety Hyp has at least 1 branching and is conju acid, di(glutamic acid), tri(glutamic acid), tetra(glutamic gated to at least 2 moieties L (either directly or indirectly) and acid), penta(glutamic acid), hexacglutamic acid), hepta has at most 31 branchings and is at most conjugated to 32 (glutamic acid), octa(glutamic acid), nona (glutamic acid), moieties L (either directly or indirectly). decac glutamic acid), undecaglutamic acid), dodeca 0.175. A moiety SP of formula (I) is a spacer moiety con (glutamic acid), tridecacglutamic acid), tetradecacglutamic necting a moiety Hyp to a moiety L of formula (I). acid), pentadecacglutamic acid), hexadeca?glutamic acid), (0176 Preferably, SP is selected from COOR'; OR': C(O) heptadecac glutamic acid), octadecacglutamic acid), nona R': C(O)N(R'R''); S(O)N(R'R''); S(O)N(R'R''); S(O) decac glutamic acid), di(aspartic acid), tri(aspartic acid), tetra R'; S(O)R'; N(R)S(O)N(R'R''); SR'; N(R'R''); OC(O) (aspartic acid), penta(aspartic acid), hexacaspartic acid), hep R'; N(R')C(O)R'': N(R')S(O).R'; N(R')S(O)R'; N(R')C ta(aspartic acid), octa(aspartic acid), nona (aspartic acid), (O)OR'': N(R')C(O)N(R'R''); OC(O)N(R'R''); T. C. decacaspartic acid), undecacaspartic acid), dodecacaspartic alkyl, C2-soalkenyl; and C2-so alkynyl, acid), tridecacaspartic acid), tetradecacaspartic acid), penta 0177 wherein T. Clso alkyl, C-so alkenyl, and C-so decacaspartic acid), hexadecacaspartic acid), heptadeca?as alkynyl are optionally substituted with one or more R. partic acid), octadecacaspartic acid), nonadecacaspartic acid), which are the same or different, polyethyleneimines, and low-molecular weight PEI. 0.178 and wherein Clso alkyl: Clso alkenyl; and Clso 0167 More preferably, a moiety Hyp is selected from the alkynyl are optionally interrupted by one or more groups group comprising, more preferably consisting of in bound Selected from the group consisting of-T-, —C(O)C)—; form, trilysine, tetralysine, pentalysine, hexalysine, heptal -O-; C(O)–: –C(O)N(R)-; –S(O)N(R)–: ysine, octalysine, nonalysine, decalysine, undecalysine, —S(O)N(R)-; –S(O) ; – S(O)–: N(R)S(O) dodecalysine, tridecalysine, tetradecalysine, pentadecal N(R)-; S : N(R)-; OC(O)R’; N(R) ysine, hexadecalysine, and heptadecalysine, even more pref C(O) : N(R)S(O) : N(R)S(O) ; N(R)C erably a moiety Hyp of formula (I) comprises, preferably (O)O ; N(R)C(O)N(R) ; and OC(O)N consists of, in bound form, trilysine, heptalysine or pentade (RR): calysine. (0179 R', R', Rare independently selected from the 0.168. In a preferred embodiment, Hyp has a molecular group consisting of H.T. and Clso alkyl, C2-soalkenyl: weight of from 0.1 kDa to 4kDa, in particular of from 0.2 kDa and C2-so alkynyl, to 2 kDa. 0180 wherein T. Clso alkyl, Clso alkenyl, and Clso 0169. According to formula (I), a moiety Hyp of formula alkynyl are optionally substituted with one or more R. (I) is connected to m moieties L., either directly (if x of which are the same or different, formula (I) is 0) or indirectly through SP (if x of formula (I) is 0181 and wherein Clso alkyl, Clso alkenyl; and C-so 1). It is understood that each linkage between a moiety Hyp alkynyl are optionally interrupted by one or more groups US 2014/02962.57 A1 Oct. 2, 2014

Selected from the group consisting of T. —C(O)C)—; the sub-structure shown in formula (II) or (III) by form - O -; C(O) ; –C(O)N(R) ; –S(O)N(R)-; ing a O (C=O) N. ; O-(C=S) N. ; —S(O)N(R)-; –S(O) ; – S(O)–: N(R)S(O) S—(C=O) N—; or —S (C=S) N— linkage, N(R)-; S : N(R)-; OC(O)R: N(R)C (0191 SP is the spacer moiety SP of formula (I), (O) ; N(R)S(O) : N(R)S(O) ; N(R)C 0.192 x is 0 or 1, (O)O ; N(R)C(O)N(R); and OC(O)N(RR): (0193 Y and Y are each independently O, S or NR6, 0182 T is selected from the group consisting of phenyl: (0194 Y, is O or S, naphthyl; indenyl; indanyl, tetralinyl; Co cycloalkyl, (0195 Y is O, NR6, or C(R7)(R8)- 4- to 7-membered heterocyclyl; or 9- to 11-membered (0196) Y is O or S, heterobicyclyl, wherein T is optionally substituted with (0197) each of R2 and R3 is a moiety selected from the one or more R, which are the same or different; group consisting of hydrogen, Substituted or unsubsti 0183 R’ is halogen; CN; oxo (=O); COOR: OR; tuted linear, branched or cyclical alkyl or heteroalkyl C(O)R: C(O)N(RR), S(O)N(R'R''); S(O)N groups, aryls, Substituted aryls, Substituted or unsubsti (R'R''); S(O).R.: S(O)R; N(R)S(O)N(R'R''); tuted heteroaryls, cyano groups, nitro groups, halogens, SR; N(R'R''); NO; OC(O)R: N(R)C(O)R“; N(R) carboxy groups, carboxyalkyl groups, alkylcarbonyl S(O).R.: N(R)S(O)R’; N(R)C(O)OR; N(R)C groups and carboxamidoalkyl groups, (O)N(R'R''); OC(O)N(R'R''); or C alkyl, wherein 0198 R4 is selected from the group consisting of hydro C. alkyl is optionally substituted with one or more gen, Substituted or unsubstituted linear, branched or halogen, which are the same or different; cyclical alkyls or heteroalkyls, aryls, Substituted aryls, (0184 R. R. R. R. Rare independently selected substituted or unsubstituted heteroaryl, substituted or from the group consisting of H; and C alkyl, wherein unsubstituted linear, branched or cyclical alkoxys. Sub C. alkyl is optionally Substituted with one or more stituted or unsubstituted linear, branched or cyclical het halogen, which are the same or different. eroalkyloxys, aryloxys or heteroaryloxys, cyano groups 0185. A moiety L of formula (I) may be chosen depending and halogens, on the one or more functional groups present in the corre- 0199 R6 is selected from hydrogen, substituted or sponding drug of a biologically active moiety D of formula unsubstituted linear, branched or cyclical alkyls or het (I). Suitable moieties L are known to the person skilled in the eroalkyls, aryls, Substituted aryls and Substituted or art and examples are given in the following sections. unsubstituted heteroaryls, 0186. In a preferred embodiment, a moiety L of formula 0200 R7 and R8 are each independently selected from (I) is a traceless prodrug linker. Preferably, all moieties L of the group consisting of hydrogen, Substituted or unsub formula (I) are traceless prodrug linkers. stituted linear, branched or cyclical alkyls or het 0187. A preferred reversible prodrug linker moiety for eroalkyls, aryls, Substituted aryls, Substituted or unsub amine-comprising drugs is described in WO-A 2005/099768. stituted heteroaryls, carboxyalkyl groups, alkylcarbonyl Therefore, the following sub-structures selected from the groups, carboxamidoalkyl groups, cyano groups, and general formulae (II) and (III) are preferred embodiments for halogens, —(SP)-L-D for the water-soluble carrier-linked prodrug of 0201 W is selected from substituted or unsubstituted the present invention according to formula (I): linear, branched or cyclical alkyls, aryls, Substituted aryls, substituted or unsubstituted linear, branched or cyclical heteroalkyls, substituted or unsubstituted het (II) eroaryls, 0202) Nu is a nucleophile, R4 X 0203 m is zero or a positive integer, and Y (SP), Ys 0204 Aris a multi-substituted aromatic hydrocarbon or X-y O Y D multi-substituted aromatic heterocycle. 2 3 0205 Another suitable reversible prodrug linker moiety Nu-W-Y Air R3 for amine-comprising drugs is described in WO-A 2006/ (III) 136586. Accordingly, the following sub-structures selected from the general formulas (IV), (V) and (VI) are preferred embodiments for —(SP)-L-D for the water-soluble carrier R4) (SP), linked prodrug of the present invention according to formula YX-Y, O R2 Y-I-DYs (I): Nu-W-Y Air R3 s (IV) R7 R5 0188 wherein the dashed line indicates attachment to a R2-O mo1ety Hyp of formula (I), which moiety Hyp of for- R8 R6 R4 O mula (I) is connected to m Sub-structures of formula (s) (II) and/or (III), and N D, (0189 SP, X, Y, Y, Y.Y.Y., R2, R3, R4, Nu, W. m. R12 R1O (SP), and D of formulas (II) and (III) have the following mean- R3-O ing: 0.190 D is an amine-comprising biologically active R11 R9 moiety D of formula (I) which is attached to the rest of US 2014/02962.57 A1 Oct. 2, 2014 11

-continued (V) (VII)

2 R1 -H-SP N X X R7 (SP), R31 X s Nx R2 R2a : O s

0215 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 (VII); E) (0216) the moiety (SP)- is attached to any one of R', (VI) R'', R,R,R,R, X, and X; and 0217 wherein SP, x, D, X, XI, X, R', R, R2, R2, R, and R' of formula (VII) have the following meaning: 0218 D is a primary amine- or secondary amine-com (SP), R5 prising biologically active moiety D; 0219. SP is the spacer moiety SP of formula (I); 0220 x is 0 or 1: R8 R6 R4 0221 X is C(R'R''); N(R). O: C(RR) C(RR): C(RR) C(RR): C(RR) N(R); N(R) C - I - (RR): C(RR). O: or O C(R'R''); 0222 X is C; or S(O); 0223 X is C(R7, R7); or C(R7, R7), C(R,R); 0224 R", R1a, R°, R2, R, R3a, R, R4, R5, R5, R, R7, E) R", R. Rare independently selected from the group consisting of H; and C alkyl; 0206 wherein the dashed line indicates attachment to a 0225 optionally, one or more of the pairs R''/R“, R'/ R, R/R, R/R, R7/R form a chemical bond; moiety Hyp of formula (I), which moiety Hyp of for 0226) optionally, one or more of the pairs R/R". mula (I) is connected to m Sub-structures of formula (s) R/R2, R/R, R/R, R7/R7, R/R are joined (IV), (V) and/or (VI), and together with the atom to which they are attached to form 0207 wherein SP, x, R2, R3, R4, R5, R6, R7, R8, R9, a C-7 cycloalkyl or 4- to 7-membered heterocyclyl; R10, R11, R12 and D of formulas (IV), (V) and (VI) 0227 optionally, one or more of the pairs R/R, R/R, have the following meaning: R"/R, R/R, R/R, R/Rare joined together with the atoms to which they are attached to form a ring A: 0208 D is an amine-comprising biologically active 0228) optionally, R/R are joined together with the moiety D of formula (I), nitrogen atom to which they are attached to form a 4- to (0209 SP is the spacer moiety SP of formula (I), 7-membered heterocycle; 0229 A is selected from the group consisting of phenyl, 0210 x is 0 or 1, naphthyl, indenyl, indanyl, tetralinyl, Co cycloalkyl, 0211 Y1 is O, S, NR6, succinimide, maleimide, an 4- to 7-membered heterocyclyl, and 9- to 11-membered unsaturated carbon-carbon bond, or any heteroatom heterobicyclyl. containing a free electron pair or Y1 is absent, 0230. In the sub-structure —(SP)-L-D of formula (VII) the moiety L is of formula (VIIa): 0212 R2 and R3 are selected independently from hydrogen, acyl groups, and protecting groups for hydroxyl groups; (VIIa) R3a 0213 R4 to R12 are selected independently from R1 R1a hydrogen, Substituted or non-substituted linear, branched or cyclical alkyl or heteroalkyl, aryls, substi tuted aryls, substituted or non-substituted heteroaryls, -Sks-skR2 R2a . s cyano, nitro, halogen, carboxy, and carboxamide. 0214) Another suitable reversible prodrug linker moiety 0231 wherein for primary amine- or secondary amine-comprising drugs is 0232 the dashed line indicates attachment to D of for described in WO-A2009/095479. Accordingly, the following mula (VII), and sub-structure of the general formula (VII) is a preferred 0233 X, X, X, R', R', R, R2, R, and R of for embodiment for —(SPX)-L-D for the water-soluble carrier mula (VIIa) are defined as in formula (VII). linked prodrug of the present invention according to formula 0234 Optionally, Linformula (VII) is further substituted, (I): provided that the hydrogen marked with the asterisk in for US 2014/02962.57 A1 Oct. 2, 2014

mula (VII) is not replaced by a substituent. Preferably, the one 0242 Preferred moieties L according to formula (VII) are or more further optional substituents are independently selected from the group consisting of: selected from the group consisting of halogen, CN, COOR,

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, 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), OC(O)N(RR).T.C. so alkyl, C-soalkenyl, and Clso alky nyl, 0235 wherein T. Clso alkyl, Clso alkenyl, and C-so alkynyl are optionally substituted with one or more R', which are the same or different, and wherein Clso alkyl; C2-so alkenyl; and C2-so alkynyl are optionally inter rupted by one or more groups selected from the group consisting of T. —C(O)O——O——C(O)——C(O) N(R') :- S(O)N(R') :- S(O)N(R') :- S(O)

(R' IRI (); 0236 R. R. Rare independently selected from the group consisting of H.T. and Clso alkyl, C2-soalkenyl: and C2-so alkynyl, 0237 wherein T. Clso alkyl, C-soalkenyl, and C-so alkynyl are optionally substituted with one or more R', which are the same or different, and wherein Clso alkyl, C2-so alkenyl; and C2-so alkynyl are optionally interrupted by one or more groups selected from the group consisting of T. —C(O)C)— —O—,

nyl, naphthyl, indenyl, indanyl, tetralinyl, Co cycloalkyl, 4- to 7-membered heterocyclyl, and 9- to 11-membered heterobicyclyl, wherein T is optionally substituted with one or more R', which are the same or different, 0239) R' is halogen, CN, oxo (=O), COOR, OR2, C(O)R2, C(O)N(R'R'2), S(O)N(R'R'2), S(O)N(R'R''), S(O).R', S(O)R', N(R')S(O)N (R2R12), SR 12, N(R12R12), NO, OC(O)R', N(R')C(O)R'2, N(R')S(O).R2, N(R')S(O) R12a, N(R'2)C(O)OR2, N(R12)C(O)N(R2R12), OC(O)N(R'R'''), or Calkyl, wherein C alkyl is optionally substituted with one or more halogen, which are the same or different, 0240 R'', R'', R', R''", 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. 0241 The term “interrupted' means that between two car bons a group is inserted or at the end of the carbon chain between the carbon and hydrogen. US 2014/02962.57 A1 Oct. 2, 2014 13

-continued -continued O R1 Rla '', NHR US 2014/02962.57 A1 Oct. 2, 2014 14

-continued 0248. Even more preferred moieties L according to for mula (VII) are selected from the group consisting of

0243 wherein ', s H* 0244 dashed lines indicate attachment to D of formula

(VII), w 0245 R is H or C alkyl, 0246 Y is NH, O or S, 0247 and R', R, R2, R2, R,R,R, X, X, X? have the meaning as indicated in formula (VII). US 2014/02962.57 A1 Oct. 2, 2014 15

-continued -continued

US 2014/02962.57 A1 Oct. 2, 2014 16

-continued -continued

US 2014/02962.57 A1 Oct. 2, 2014 17

-continued -continued

H N X VN 1. O

NH O H N VN X US 2014/02962.57 A1 Oct. 2, 2014 18

-continued -continued

H* E A.

SR

O E

US 2014/02962.57 A1 Oct. 2, 2014 19

-continued -continued SR

0249 wherein 0250 dashed lines indicate attachment to D of formula (VII), and 0251 R is Hor Calkyl 0252. 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 (VIII):

(VIII) RI R1a D ---SP X

O s

0253 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 (VIII), (0254) the moiety (SP)- is attached to any one of R', R', and X; and 0255 wherein SP, X, D.X. R', and R'' of formula (VIII) have the following meaning: 0256 D is a primary amine- or secondary amine-com prising biologically active moiety D, 0257 SP is the spacer moiety SP of formula (I); 0258 x is 0 or 1: 0259 X is H or Clso alkyl, optionally interrupted by one or more groups selected from —NH , —C(Ca alkyl)—, —O , —C(O)—or —C(O)NH , 0260 R and R'' are independently selected from the group consisting of H and C-C alkyl, 0261 Optionally, the sub-structure of formula (VIII) is further substituted. US 2014/02962.57 A1 Oct. 2, 2014 20

0262. In the sub-structure —(SP)-L-D of formula (VIII) -continued the moiety L is of formula (VIIIa): (VIIIcb)

(VIIIa) N

0268 Another preferred reversible prodrug linker moiety L for aromatic amine-comprising drugs is described in WO 2011/012721. Therefore, the following sub-structure of the general formula (IX) is a preferred embodiment for —(SP)- 0263 wherein L-D for the water-soluble carrier-linked prodrug of the 0264 the dashed line indicates attachment to D of for present invention according to formula (I): mula (VIII) and 0265 X, R' and R' of formula (VIIIa) are defined as in (IX) formula (VIII). O D 0266 More preferably, L of the sub-structure of formula — esp., R2 ls x21 X (VIII) comprises one of the fragments of formulas (VIIIb) or (VIIIc), wherein the dashed line marked with an asterisk R2a O indicates attachment to D by forming an amide bond with the aromatic amino group of D and the unmarked dashed line 0269 wherein the dashed line indicates attachment to a indicates attachment to the rest of L of formula (VIII) and moiety Hyp of formula (I), which moiety Hyp of for wherein the structures of formulas (VIIIb) and (VIIIc) are mula (I) is connected to m Sub-structures of formula optionally further substituted: (IX), 0270 D is connected to the rest of the sub-structure of formula (IX) through an aromatic amine group of D by

A. w (VIIIb) forming an amide bond, w F w w (0271 the moiety (SP)- is attached to any one of R, S&f O : R’, X', and X; and F w 0272 wherein D, SP, X, X', X, R, and R' in formula O (IX) have the following meaning: (VIIIc) F w 0273 D is an aromatic amine-comprising biologically w p & w active moiety D, Yx N w : (0274 SP is the spacer moiety SP of formula (I), P H w 0275 x is 0 or 1, O (0276 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 0267 More preferably, L of the sub-structure of formula bered heterobicyclyl, (VIII) comprises one of the fragments of formulas (VIIIba), (0277 X is a chemical bond or selected from C(RR), (VIIIca), or (VIIIcb), wherein the dashed line marked with an N(R), O, C(RR) C(RR), C(RR) N(R), asterisk indicates attachment to D of formula (VIII) by form N(R) C(R'R''), C(RR) O, and O C(RR), ing an amide bond with the aromatic amino group of D and 0278 wherein in case X" is a cyclic fragment, X is a the unmarked dashed line indicates attachment to the rest of L chemical bond, C(RR), N(R) or O, of formula (VIII): (0279 optionally, in case X" is a cyclic fragment and X is C(RR), the order of the X' fragment and the X fragment within the sub-structure —(SP)-L-D shown in (VIIIba) formula (IX) may be changed, 0280 R', RandR are independently selected from the , N x group consisting of H, C, alkyl and N(R'R''), -> ^o w: (0281) R'", R. R. R. R* and Rare independently w O O Selected from the group consisting of H, and C alkyl, 0282 optionally, one of the pairs R/R, R/R, R*/ (VIIIca) R" are joined to form a 4- to 7-membered at least par tially saturated heterocycle, N x (0283 R is C(O)R, ux 1sH w : 0284 R is C alkyl, and w O O 0285) optionally, one of the pairs R''/R, R/R or R"/R' form a chemical bond. US 2014/02962.57 A1 Oct. 2, 2014

0286 Optionally, the sub-structure —(SP)-L-D of for 0297 D is connected through an aromatic amine group mula (IX) is further substituted. of D to the rest of the sub-structure of formula (X) by (0287. In the sub-structure —(SP)-L-D of formula (IX) forming an amide bond, the moiety L is of formula (IXa): (0298 the moiety (SP)- is attached to any one of R, X', and X; and (IXa) 0299 wherein D, SP, X, X', X, R, and R in formula O , (X) have the following meaning: 0300 D is an aromatic amine-comprising biologically 2 X w active moiety D, RS 1. x21 '', 0301 SP is the spacer moiety SP of formula (I), R2a O s 0302 x is 0 or 1, 0303 X is C(R'R'') or a cyclic fragment selected from C-7 cycloalkyl, 4 to 7 membered heterocyclyl phenyl, 0288 wherein naphthyl, indenyl, indanyl, tetralinyl, and 9 to 11 mem 0289 the dashed line indicates attachment to D of for bered heterobicyclyl, mula (IX), and (0304 wherein in case X" is a cyclic fragment, said 0290 X', X, R, and R* of formula (IXa) are used as cyclic fragment is incorporated into —(SP)-L-D of for defined in formula (IX). mula (X) via two adjacent ring atoms and the ring atom 0291 More preferably, the moiety L according to formula of X", which is adjacent to the carbonatom of the amide (IX) is selected from the following formulas: bond, is also a carbon atom, 0305 X is a chemical bond or selected from C(RR), N(R), O, C(RR) C(RR), C(RR) N(R), O O N(R) C(R'R''), C(RR) O, and O C(RR), (0306 wherein in case X" is a cyclic fragment, X is a chemical bond, C(RR), N(R) or O, *s-s-s-sa (0307 optionally, in case X" is a cyclic fragment and X O O is C(RR), the order of the X' fragment and the X fragment within the sub-structure —(SP)-L-D shown in formula (X) may be changed and the cyclic fragment is incorporated into the sub-structure —(SP)-L-D of for s--> mula (X) via two adjacent ring atoms, O R1 0308) R', RandR are independently selected from the group consisting of H, C, alkyl and N(RR), O N O 0309 R', R. R. R* and R are independently R2 lu Selected from the group consisting of H, and C alkyl, 0310 R is C(O)R, 0311 R is C alkyl, 0312 optionally, one of the pairs R'/R', R/R“ or 0292 wherein the dashed line indicates attachment to D R"/R" form a chemical bond, provided that the hydro of formula (IX), and gen marked with the asterisk in formula (X) is not 0293 R' and Rare used as defined in formula (IX). replaced by the moiety (SP)- of formula (X). 0294 Preferably, in formula (IX) R', R. R. R. R. 0313. In the sub-structure —(SP)-L-D of formula (X) the and Rare independently selected from the group consisting moiety L is of formula (Xa): of H, and C alkyl. 0295) Another preferred reversible prodrug linker moiety L for aromatic amine-comprising drugs is described in WO (Xa) 2011/012722. Therefore, the following sub-structure of the O , general formula (X) is a preferred embodiment for —(SP)- R2 l X --> L-D for the water-soluble carrier-linked prodrug of the s x21 , present invention according to formula (I): H' O s

(X) 0314 wherein O 0315 the dashed line indicates attachment to D of for D mula (X), and — esp. Rulx21 0316 X, X, and R of formula (Xa) are used as H' O s defined in formula (X). 0317 Optionally, the moiety L of formula (X) is further substituted. 0296 wherein the dashed line indicates attachment to a 0318 More preferably, the moiety L according to formula moiety Hyp of formula (I), which moiety Hyp of for (X) is selected from the group consisting of formulas (i) mula (I) is connected to m Sub-structures of formula (X), through (XXix): US 2014/02962.57 A1 Oct. 2, 2014 22

-continued (x)

(xi)

(xii)

(xiii)

(xiv)

(xv)

(ix) (xvii) US 2014/02962.57 A1 Oct. 2, 2014 23

-continued -continued

(xvii) (xxiv) R2 O H*---\ H O E (XXv) R2 O \ H (xviii) H*--- O w

(xxvi)

(xvix) (xxvii) R2 | O V A.

H*---y R Ra s (xxviii) R2 i O V p (XX)

H*---O R1 R1a O (xxix) O O H R2n N lus F 4 R1 R1a (xxi) 0319 wherein the dashed line indicates attachment to D, and 0320 R', R', R. R. and R are used as defined in formula (X). 0321. 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 L and D. By consequence, D and L of formula (X) are connected (chemically bound) by an amide fragment (xxii) of the general structure Y' C(O) N(R) Y.Y' indicates the remaining parts of the sub-structure of formula (X) andY indicates the aromatic fragment of D. R is a Substituent, Such as C. alkyl or preferably hydrogen. 0322. As indicated above, X" of formula (X) may also be 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 (xxiii) 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 together with the aromatic amino group of D forms an amide bond. 0323 Preferably, L of formula (X) is defined as follows: 0324 X is C(R'R''), cyclohexyl, phenyl, pyridinyl, norbonenyl, furanyl, pyrrolyl or thienyl, US 2014/02962.57 A1 Oct. 2, 2014 24

0325 wherein in case X" is a cyclic fragment, said -continued cyclic fragment is incorporated into L of formula (X) via (viii) two adjacent ring atoms; 0326 X is a chemical bond or selected from C(RR), N(R), O, C(RR) O or C(RR) C(R'R''); 0327 R', RandR are independently selected from H, Calkyl and N(RR): 0328 R', R. R* and Rare independently selected from Hand C alkyl; (ix) 0329 R is C alkyl: 0330 R is C(O)R; 0331 R is C alkyl: 0332 More preferably, L of formula (X) is selected from:

(i) (x)

(ii)

(xi)

(iii)

(iv)

(xii) O

(v) O O ? R2 ?'

? s R-, H* A. f O1. N 2

O O (vi) H* H A. (xiii) R N f R2 i O N V M s N N H* H* 1. A.

(vii) ? s

(xiv) US 2014/02962.57 A1 Oct. 2, 2014 25

-continued -continued

(xv) (xxii)

r -N, O H* (xvii) (xxiii)

(xvii) (xxiv) R2 O V H A. N N Hs 1 A. O E (XXv) R2 O V H (xviii) N N Hs 1 r F O p

(xxvi)

(xvix) (xxvii) R2 O V H w N N Hs 1 r O R1 R1a s (xxviii) R2 O V H p (XX) Hs 1 N r N O O R1 R1a (xxix) O O H A. is-lus2 M H* RI R1a F

(xxi) 0333 wherein the dashed line indicates attachment to D, 0334 R is C(O)R, and 0335) R', R', R, R and R are independently from each other C. alkyl. 033.6 L of formula (X) is substituted with one moiety (SP)- and preferably said substitution occurs at R, i.e. preferably R’ is substituted with one moiety (SP)- US 2014/02962.57 A1 Oct. 2, 2014 26

0337 Yet another preferred reversible prodrug linker moi nyl are optionally Substituted with one or more halogen, ety L for hydroxyl-comprising drugs is described in WO which is/are the same of different, 2011/012721. Therefore, the following sub-structure of the 0354) T is phenyl, naphthyl, azulenyl, indenyl, inda general formula (XI) is a preferred embodiment for —(SP)- nyl, C-7 cycloalkyl, 3- to 7-membered heterocyclyl, or L-D for the water-soluble carrier-linked prodrug of the 8- to 11-membered heterobicyclyl, wherein T', is present invention according to formula (I): optionally substituted with one or more R", which is/are the same or different, 0355 R7 is halogen, CN, COOR, OR, C(O)R, C(O) (XI) N(RR), S(O)N(RR), S(O)N(RR), S(O).R. S(O)R, N(R)S(O)N(RR), SR, N(RR), NO, ---SP--Z'-O-D, OC(O)R, N(R)C(O)R, N(R)S(O),R, N(R)S(O) R8, N(R)C(O)OR8, N(R)C(O)N(RR), OC(O)N (RR), oxo (=O), where the ring is at least partially 0338 wherein the dashed line indicates attachment to a Saturated, Co alkyl, C- alkenyl, or C2-alkynyl, moiety Hyp of formula (I), which moiety Hyp of for wherein Ce alkyl, C- alkenyl, and C- alkynyl are mula (I) is connected to m Sub-structures of formula optionally substituted with one or more R, which is/are (XI), the same or different, 0339 D is connected through a hydroxyl group of D to 0356. R. R. Rare independently selected from the the rest of the sub-structure of formula (XI), and group consisting of H. C. alkyl, C2-alkenyl, and C2 (0340 wherein D, SP, x and Z' in formula (XI) have the alkynyl, wherein Calkyl, Calkenyl, and C- alky following meaning: nyl are optionally substituted with one or more R', 0341. D is a hydroxyl-comprising biologically active which is/are the same of different, moiety D comprising O. 0357 R. R'' are independently selected from the (0342. SP is the spacer moiety SP of formula (I), group consisting of halogen, CN, C(O)R'', C(O)CR'', 0343 x is 0 or 1, OR'', C(O)R'', C(O)N(R'R''), S(O)N(R'R''), (0344) Z” is the moiety -L- of formula (I) and is X” C S(O)N(R'R''), S(O).R'', S(O)R'', N(R'')S(O)N (O), X-O-C(O), X-S(O), X-C(S), X-O-S (R' laR1b). SR'', N(R'R''), NO, OC(O)R' l, N(R') (O) X S(O)N(R'), X-CH(OR), X C(OR) C(O)R'', N(R)SOR, N(R')S(O)R'', N(R)C (OR), XO C(O)N(R'), XO P(=O)CH)O, X P (O)N(R'R''), N(R')C(O)OR'', and OC(O)N (—O)(OR)O, X P(=O)(SH)O, X P(=O)(SR) (R' IRI la), O, X P(=O)(OR), X P(—S)(OH)O, X P 0358 R'', R''", R'' are independently selected from (—S)(OR")O, X P(—S)(OH)N(R'), X P(—S) the group consisting of H. C. alkyl, Calkenyl, and (OR')N(R), X P(=O)(OH)N(R') or X P(=O) C- alkynyl, wherein C alkyl, Calkenyl, and C (OR)N(R), alkynyl are optionally substituted with one or more halo (0345) R', Rare independently selected from the group gen, which is/are the same of different, and consisting of Calkyl; or R' and Rjointly form a C alkylene bridging group, 10359 wherein (SP)- of formula (XI) is covalently (0346 X" is (X')-(X'), attached to X'. 0347 m1, m2 are independently 0 or 1, 0360 Preferably, Z is X C(O), X C(O)C, or X' S 0348 X is T', (O). More preferably, Z is X C(O) or X'C(O)O. Even (0349 X" is a branched or unbranched Co alkylene more preferably, Z is X” C(O). group which is unsubstituted or substituted with one or 0361 Preferably, X is unsubstituted. more R, which is/are the same or different, 0362 Preferably, m1 is 0 and m2 is 1. 0350 R is halogen, CN, C(O)R,C(O)OR, OR, C(O) 0363 Preferably, X is C(R'R)CH, wherein R and R. R, C(O)N(RR), S(O)N(RR), S(O)N(RR), are independently selected from the group consisting of H S(O).R., S(O)R, N(R)S(O)N(R'R''), SR, and Calkyl, provided that at least one of R', R is other than N(RR), NO, OC(O)R, N(R)C(O)R, N(R) H, or (CH), wherein n is 3, 4, 5, 6, 7 or 8. SOR, N(R)S(O)R“, N(R)C(O)N(RR), N(R) C(O)OR, OC(O)N(RR), or T, (0364) Preferably, the moiety (SP)- of formula (XI) is 10351 R. R. Rare independently selected from the covalently attached to X" via an amide group. group consisting of H. T. C. alkyl, C2a alkenyl, and 0365. In yet another preferred embodiment the sub-struc C2-alkynyl, wherein Calkyl, C2-alkenyl, and C2 ture —(SP)-L-D of formula (I) for the water-soluble carrier alkynyl are optionally substituted with one or more R. linked prodrug of the present invention is of formula (XII): which is/are the same of different, 0352 R is halogen, CN, C(O)R,C(O)OR, OR, C(O) R°, C(O)N(RR), S(O)N(RR), S(O)N(RR), (XII) S(O).R, S(O)R, N(R)S(O)N(RR), SR, O N(RR), NO, OC(O)R, N(R)C(O)R, N(R) R3 R? D, SOR, N(R)S(O)R, N(R)C(O)N(RoR), N(R) C(O)OR or OC(O)N(RR), ---SP- N 0353 R. R. Rare independently selected from the R R2a iii. group consisting of H. C. alkyl, C2-alkenyl, and C2 alkynyl, wherein Ce alkyl, C- alkenyl, and C- alky US 2014/02962.57 A1 Oct. 2, 2014 27

0366 wherein the dashed line indicates attachment to a

moiety Hyp of formula (I), which moiety Hyp of for (XIII) mula (I) is connected to m Sub-structures of formula (XII), 0367 D is connected through an aromatic hydroxyl group of D to the rest of the sub-structure of formula (XII) by forming a carbamate group, SP- H. 0368 the moiety +(SP)- is attached to any one of R', R, R2, R, and R; and 0369 wherein D, SP, x, R. R. R. R. R. and m in formula (XII) have the following meaning: 0382 wherein the dashed line indicates attachment to a 0370 D is an aromatic hydroxyl-comprising biologi moiety Hyp of formula (I), which moiety Hyp of for cally active moiety D, mula (I) is connected to m Sub-structures of formula 0371 SP is the spacer moiety SP of formula (I), (XIII), 0383 D is connected through an aliphatic amine group 0372 x is 0 or 1, of D to the rest of the sub-structure of formula (XIII) by 0373) R' is selected from the group consisting of Ca forming an amide group, alkyl, heteroalkyl, C., cycloalkyl, and (0384) the moiety (SP)- is attached to any one of R', R. R. R. R. R. R', and X'; and 0385 wherein D, SP, X, X, R', R,R,R,R, R and R" in formula (XIII) have the following meaning: R3 R2 0386 D is an aromatic amine-comprising biologically active moiety D, (0387 SP is the spacer moiety SP of formula (I), R R2a iii. 0388 x is 0 or 1, 0389 X is selected from O, S or CH R' 0390 R and R'' are independently selected from H, OH, CH, 0374 each R, each R', R, R are independently 0391 R, R, R and R“ are independently selected selected from hydrogen, substituted or non-substituted from Hand C alkyl, linear, branched or cyclic C alkyl or heteroalkyl, 0392 R, R are independently selected from H. C. alkyl, and R. 0375 m is 2, 3 or 4. 0393 R is selected from 0376. In the sub-structure —(SP)-L-D of formula (XII) the moiety L is of formula (XIIa):

(XIIa)

0377 wherein 0378 the dashed line indicates attachment to D of for mula (XII), and 0379 R', each R, each R', R, R and m of formula (XIIa) are used as defined in formula (XII). 0380 Optionally, Lof formula (XII) is further substituted. 0381. 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 given in formula (XIII): US 2014/02962.57 A1 Oct. 2, 2014 28

-continued (XIV) O R R3 R3a y N R D SP- - s R Ra R4a

0404 wherein the dashed line indicates attachment to a NH2. moiety Hyp of formula (I), which moiety Hyp of for mula (I) is connected to m Sub-structures of formula (XIV), NH 0405 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, 0394 Preferably, one of the pair R/R of formula (XIII) is Hand the other one is selected from R. (0406) the moiety (SP)- is attached to any one of R', R'', R,R,R,R, and R; and 0395 Preferably, one of R/R of formula (XIII) is H. 0407 wherein D, SP, x, R,R,R,R,R,R,R and 0396 Optionally, one or more of the pairs R/R, R/R', R" in formula (XIV) have the following meaning: R/R' of formula (XIII) may independently form one or more 0408 D is an aromatic amine-comprising biologically cyclic fragment(s) selected from C-7 cycloalkyl, 4- to active moiety D, 7-membered heterocyclyl, and 9- to 11-membered heterobi 04.09 SP is the spacer moiety SP of formula (I), cyclyl. 0410 x is 0 or 1: 0411) R', R'", R. R. R, R and R* are indepen 0397 Optionally, R. R. RandR of formula (XIII) are dently selected from Hand C alkyl. further substituted. Suitable substituents are alkyl (such as 0412 Optionally, any two of R', R', R. R. R. Rand C. alkyl), alkenyl (such as C. alkenyl), alkynyl (such as R“ of formula (XIV) may independently form one or more C. alkynyl), aryl (such as phenyl), heteroalkyl, heteroalk cyclic fragment(s) selected from C, cycloalkyl, 4- to enyl, heteroalkynyl, heteroaryl (such as aromatic 4- to 7-membered heterocyclyl phenyl, naphthyl, indenyl, inda 7-membered heterocycle) or halogen moieties. nyl, tetralinyl, and 9- to 11-membered heterobicyclyl. 0398. In the sub-structure —(SP)-L-D of formula (XIII) 0413 Optionally, R', R'", R. R. R. R. and R' of the moiety L is of formula (XIIIa): formula (XIV) are further substituted. Suitable substituents are alkyl, such as C. alkyl, alkene, such as such as C. alkene, alkine, such as Such as Calkine, aryl. Such as (XIIIa) phenyl, heteroalkyl, heteroalkene, heteroalkine, heteroaryl R R4a Such as aromatic 4- to 7-membered heterocycle, or halogen n N 1 moieties. R3 0414. In the sub-structure —(SP)-L-D of formula (XIV) R3a the moiety L is of formula (XIVa): R2 (XIVa) R2a O i R3 R3a -> N R*, R Ra , R4a 0399 wherein 0400 the dashed line indicates attachment to D of for 0415 wherein mula (XIII), and 0416 the dashed line indicates attachment to D of for (0401 X, R', R. R. R. R, R and R of formula mula (XIV), and (XIIIa) are used as defined in formula (XIII). 0417 R', R', R,R,R,R, R and R of formula (XIVa) are used as defined in formula (XIV). 0402 Optionally, L of formula (XIII) is further substi 0418 Optionally, L of formula (XIV) is further substi tuted. Suitable Substituents are alkyl (such as C. alkyl). tuted. Suitable Substituents are alkyl (such as C. alkyl). alkenyl (Such as Coalkenyl), alkynyl (such as C2-alkynyl), alkenyl (Such as Coalkenyl), alkynyl (such as C2-alkynyl), aryl (such as phenyl), heteroalkyl, heteroalkenyl, heteroalky aryl (such as phenyl), heteroalkyl, heteroalkenyl, heteroalky nyl, heteroaryl (Such as aromatic 4- to 7-membered hetero nyl, heteroaryl (Such as aromatic 4- to 7-membered hetero cycle) or halogen moieties. cycle) or halogen moieties. 0403. In yet another preferred embodiment the sub-struc 0419 Preferably, one of R or R“ of formula (XIV) is H. ture —(SP)-L-D of formula (I) for the water-soluble carrier 0420 Yet another preferred reversible prodrug linker moi linked prodrug of the present invention is of formula (XIV): ety L is described in U.S. Pat. No. 7,585,837. Therefore, the US 2014/02962.57 A1 Oct. 2, 2014 29 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): 0435 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) — esp-l-KY O R R5 Y. 0421 wherein the dashed line indicates attachment to a X--D, moiety Hyp of formula (I), which moiety Hyp of for mula (I) is connected to m Sub-structures of formula OR (XV), 0422 D is connected through a functional group of D to the rest of the sub-structure of formula (XV), wherein 0436 wherein the dashed line indicates attachment to a Such functional group is selected from amine, carboxyl, moiety Hyp of formula (I), which moiety Hyp of for phosphate, hydroxyl and mercapto, mula (I) is connected to m Sub-structures of formula 10423 the moiety (SP)- is attached to any one of R', (XVI), R. R., and R; and 0437 D is connected through a functional group of D to 0424 wherein D, SP, X, R', R, R and R' in formula the rest of the sub-structure of formula (XVI), (XV) have the following meaning: 0438 and wherein SP, X, D, X, Ar, L. Y.Y., y, R. R. 0425 D is an aromatic amine-comprising biologically R. R. and R of formula (XVI) have the following active moiety D, meaning: 0426 SP is the spacer moiety SP of formula (I), 0439 D is a biologically active moiety, 0427 x is 0 or 1, 0440 SP is the spacer moiety SP of formula (I), 0428 R' and R are independently selected from the 0441 x is 0 or 1, group consisting of hydrogen, alkyl, alkoxy, alkoxy 0442 y is 0or 1, alkyl, aryl, alkaryl, aralkyl, halogen, nitro. —SOH, 0443 L is a bifunctional linking group, —SONHR, amino, ammonium, carboxyl, POH, and 0444 Y and Y are independently O, S or NR", OPOH, 0445 R7 are independently selected from the group 0429 R. R., and Rare independently selected from consisting of hydrogen, C. alkyls, C-12 branched the group consisting of hydrogen, alkyl, and aryl. alkyls, C.s cycloalkyls, C. Substituted alkyls, Cs Substituted cycloalkyls, aryls, Substituted aryls, aralkyls, 0430. In the sub-structure —(SP)-L-D of formula (XV) C. heteroalkyls, Substituted C. heteroalkyls, C. the moiety L is of formula (XVa): alkoxy, phenoxy, and C. heteroalkoxy, 0446 Ar is a moiety which when included in formula

(XVa) (XVI) forms a multisubstituted aromatic hydrocarbon or a multi-substituted heterocyclic group, 0447 X is a chemical bond or a moiety that is actively transported into a target cell, a hydrophobic moiety, or a combination thereof. 0448. Yet another preferred reversible prodrug linker moi ety L is described in the international application WO-A 2001/47562. Therefore, the following sub-structure of the 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): 0431 wherein 0432 the dashed line indicates attachment to D of for mula (XV), and (XVII) 0433 R', R, R and R of formula (XVa) are used as O defined in formula (XV). 0434 Optionally, L of formula (XV) is further substituted. -its---0-1l--D. Suitable Substituents are alkyl (Such as C. alkyl), alkenyl (such as C- alkenyl), alkynyl (such as C. alkynyl), aryl US 2014/02962.57 A1 Oct. 2, 2014 30

0449 wherein the dashed line indicates attachment to a -continued moiety Hyp of formula (I), which moiety Hyp of for mula (I) is connected to m Sub-structures of formula (XVII), 0450 Disconnected through an amine group of D to the rest of the sub-structure of formula (XVII), 0451 and wherein SP, X, D, Land Ar of formula (XVII) have the following meaning: 0467 R. R. R. Rs. R-7 and Rs are independently 0452 D is an amine-comprising biologically active selected from the group consisting of hydrogen, C. moiety comprising NH, alkyls, C. branched alkyls, C.s cycloalkyls, C. Sub 0453 SP is the spacer moiety SP of formula (I), stituted alkyls, C.s substituted cycloalkyls, aryls, Sub 0454 x is 0 or 1, stituted aryls, aralkyls, C. heteroalkyls, Substituted 0455 L is a covalent linkage, preferably a hydrolyti C. heteroalkyls, Ce alkoxy, phenoxy and C. het cally stable linkage, eroalkoxy, 0468 R is selected from the group consisting of hydro 0456 Ar is an aromatic group. gen, Calkyls, C. branched alkyls, C.s cycloalkyls, 0457. Yet another preferred reversible prodrug linker moi C. Substituted alkyls, C.s substituted cycloalkyls, ety L is described in U.S. Pat. No. 7,393.953 B2. Therefore, aryls, Substituted aryls, aralkyls, C. heteroalkyls, Sub the following sub-structure of the general formula (XVIII) is stituted Cheteroalkyls, Calkoxy, phenoxy and C. a preferred embodiment for —(SP)-L-D for the water heteroalkoxy, NO, haloalkyl and halogen, soluble carrier-linked prodrug of the present invention 0469 m and q are selected independently from each according to formula (I): other and each is a positive integer. 0470. In yet another preferred embodiment the sub-struc ture —(SP)-L-D of formula (I) for the water-soluble carrier (XVIII) linked prodrug of the present invention is given in formula Y (XIX): ---SP--L D,

(XIX)

0458 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 (XVIII), 0459 D is connected through a heteroaromatic amine 0471 wherein the dashed line indicates attachment to a group of D to the rest of the sub-structure of formula moiety Hyp of formula (I), which moiety Hyp of for (XVIII), mula (I) is connected to m Sub-structures of formula 0460 and wherein SP, X, D. L. Y. and p of formula (XIX), (XVIII) have the following meaning: 0472. D is connected through a carboxyl group of D to 0461 D is a heteroaromatic amine-comprising biologi the rest of the sub-structure —(SP)-L- of formula (I) by cally active moiety, forming a carboxylic ester comprising O. 0473 and wherein SP, X, D, R, R. R. R. and n of 0462 SP is the spacer moiety SP of formula (I), formula (XIX) have the following meaning: 0463 x is 0 or 1, 0474 D is a carboxyl-comprising biologically active 0464 Y is O, S, or NR, moiety, 0465 p is 0 or 1, 0475 SP is the spacer moiety SP of formula (I), 0476 x is 0 or 1, 0466 L is a bifunctional linker, such as, for example, 0477) R' is selected from the group of unsubstituted alkyl; substituted alkyl; unsubstituted phenyl; substi tuted phenyl; unsubstituted naphthyl; substituted naph thyl; unsubstituted indenyl; substituted indenyl; unsub stituted indanyl; substituted indanyl; unsubstituted tetralinyl; Substituted tetralinyl; unsubstituted Co cycloalkyl; Substituted Co cycloalkyl; unsubstituted 4- to 7-membered heterocyclyl; substituted 4- to 7-membered heterocyclyl; unsubstituted 9- to 11-mem bered heterobicyclyl; and substituted 9- to 11-mem bered heterobicyclyl: 0478 R is selected from H. unsubstituted alkyl, and substituted alkyl: 0479. R and R are independently selected from the group consisting of H, unsubstituted alkyl, and Substi tuted alkyl: US 2014/02962.57 A1 Oct. 2, 2014 31

0480 n is 0 or 1, (0500 Preferably, all moieties L of formula (I) are the 0481 optionally, R' and Rare joined together with the SaC. atoms to which they are attached to form a ring A, 0501. A water-soluble carrier-linked prodrug of formula 0482 A is selected from the group consisting of Co (I) comprises biologically active moieties D which are pref cycloalkyl, 4- to 7-membered aliphatic heterocyclyl; erably selected from the group of oligopeptides, polypep and 9- to 11-membered aliphatic heterobicyclyl, tides, proteins, oligonucleotides, and Small molecule biologi wherein A is unsubstituted or substituted. cally active moieties. The corresponding drugs may comprise 0483 Preferably, R' of formula (XIX) is C alkyl or one or more functional groups selected from the group com Substituted C. alkyl, more preferably C alkyl or substi prising amine, hydroxyl, carboxyl, phosphate, and mercapto. tuted C. alkyl. A drug may be conjugated to a moiety L through a linkage 0484 More preferably, R' of formula (XIX) is selected formed by an amine. Such as an aliphatic or aromatic amine, from methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, hydroxyl. Such as an aliphatic or aromatic hydroxyl, car sec-butyl, t-butyl, and benzyl. boxyl, phosphate, or mercapto group provided by the drug. 0485 Preferably, R of formula (XIX) is H. 0502 Suitable aromatic amine-containing drugs are, for 0486 Preferably, R of formula (XIX) is H, C, alkyl or example, (-)-Carbovir, (t)-Hymenin, (t)-Norcisapride, (+)- Substituted C. alkyl, more preferably C. alkyl or Substi Picumeterol, (R)-Aminoglutethimide, (R)-Clenbuterol, (S)- tuted Calkyl. More preferably, R is selected from methyl, Aminoglutethimide, (S)-Clenbuterol, 6-p-aminophenylala ethyl, n-propyl, isopropyl. n-butyl, isobutyl, sec-butyl, t-bu nine-angiotensin II, 10'-Demethoxystreptonigrin, tyl, and benzyl. 17-Aminogeldanamycin, 1-Aminoacridine, 1-DeaZaad 0487. More preferably, R of formula (XIX) is H. enine, 1-NA-PP 1, 1-NM-PP 1, 2,7-Diaminoacridine, 2,7- 0488 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 0489 More preferably, R of formula (XIX) is H. dine, 3-Aminopicolinic acid, 3-Deazaguanine, 0490. In another preferred embodiment, R' and R of for 4-Aminoflavone, 4-Aminopyridine, 5'-ADP 5-Aminoacri mula (XIX) are joined together with the atoms to which they dine, 5-amino-DL-Tryptophan, 5-Aminonicotinamide, are attached to form a ring A, wherein A is selected from the 5'-AMP, 5'-ATP 5-Chlorodeoxycytidine, 5'-CMP 5-Dim group consisting of cyclopropane, cyclobutane, cyclopen ethylamiloride, 5'-GDP, 5'-GMP, 5'-GTP 5-Iodotubercidin, tane, cyclohexane, and cycloheptane. 5-Methylcytosine, 6-Aminoflavone, 6-Aminophenanthri 0491. In yet another preferred embodiment the sub-struc dine, 6-Aminothymine, 6-Benzylthioguanine, 6-Chlorota ture —(SP)-L-D of formula (I) for the water-soluble carrier crine, 6-Iodoamiloride, 7,8-Dihydroneopterin, 7-Ami linked prodrug of the present invention is given in formula nonimetazepam, 7-Methoxytacrine, 7-Methyltacrine, (XX): 9-Deazaguanine, 9-Phenethyladenine, Abacavir, Acadesine, Acediasulfone, Acefurtiamine, Acetyl coenzyme A, Aciclo Vir, Actimid, Actinomycin, Acyclovir, Adefovir, Adenallene, (XX) Adenine, Adenophostin A, Adenosine, Adenosine mono phosphate, Adenosine triphosphate, Adenosylhomocysteine, -H-SP--W-O-D, Aditeren, Afloqualone, Alamifovir, Albofungin, AlfuZosin, Allithiamine, Alpiropride, Amanozine, Ambasilide, Ambucaine, Amdoxovir, Ameltolide, Amethopterin, Amfenac, Amflutizole, Amicycline, Amidapsone, Amifam 0492 wherein the dashed line indicates attachment to a pridine, Amiloride, Aminacrine, Aminoacridine, Aminoan moiety Hyp of formula (I), which moiety Hyp of for tipyrine, Aminobenzoate, Aminogenistein, Aminoglutethim mula (I) is connected to m Sub-structures of formula ide, Aminohippurate, Aminoisatin, Aminometradine, (XX), Aminonimetazepam, Aminophenylalanine, Aminopotenti 0493 D is connected through a carboxyl group of D to dine, Aminopterin, Aminopurvalanol A, Aminoquinuride, the rest of the sub-structure of formula (XX) by forming Aminosalicylic Acid, Amiphenazole, Amiphenosine, Ami a carboxylic ester comprising O. Sometradine, Amisulpride, Amiterol, AmlexanoX, Ammelin, 0494 and wherein SP, X, D, and W of formula (XX) Amonafide, Amoxecaine, Amphenidone, Amphethinile, have the following meaning: Amphotalide, Amprenavir, Ampurine, Amrinone, AMT, 0495 D is a carboxyl-comprising biologically active Amthamine, Amtizole, Angustmycin A, Anileridine, Apad moiety, enoson, Apraclonidine, Apricitabine, Arafluorocytosine, 0496 SP represents the spacer moiety SP of formula (I), Aramine, Arazide, Aristeromycin, Arprinocid, Ascamycin, 0497 x is 0 or 1: Ascensil, Aspiculamycin, Atolide, AZabon, AZacitidine, AZa 0498 W is selected from linear Cls alkyl. line B, AZamulin, AZanidazole, AZepexole, Aztreonam, Baq 0499 Preferably, a carrier moiety of the water-soluble uiloprim. Basedol, Batanopride, b-D-Adenosine, Bemitra carrier-linked prodrug of formula (I) is connected to at least 6 dine, Benfotiamine, Bentiamine, BenZamil, Benzocaine, moieties L (either directly or indirectly), such as to 6, 7, 8, 9. Betoxycaine, Binodenoson, Biopterin, Bisbentiamine, Blas 10, 11, 12, 13, 14, 15, 16, or 17 moieties L (either directly or ticidin, Bleomycin, Bleomycin A1, Bleomycin A2, Bleomy indirectly). More preferably, a carrier moiety of the water cin A5, Bleomycin A6, Bleomycin DMA2, Brodimoprim, soluble carrier-linked prodrug of formula (I) is connected to Bromfenac, Bromobuterol, Bromopride, Bropirimine, Buci 8, 12, 16 or 20 moieties L (either directly or indirectly). clovir, BunaZosin, Butyrylthiamine disulfide, Cadeguomy US 2014/02962.57 A1 Oct. 2, 2014 32 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, Cycotiamine, 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, Sufamonomethox Decitabine, Declopramide, Deisopropylhydroxyatrazine, ine, Sulamserod, Sulfabromomethazine, Sulfacetamide, Sul Delafloxacin, Delfantrine, Denavir, Deoxyadenosine, fachlorpyridazine, Sulfachrysoidine, Sulfaclomide, Deoxy-ATP, Deoxycytidine, Deoxyguanosine, Dephosphoc Sulfaclorazole, Sulfaclozine, Sulfacytine, Sulfadiasulfone, oenzyme A, Dequalinium, Desbutylbumetanide, Desciclovir, Sulfadiazine, Sulfadicramide, Sulfadimethoxine, Sulfadimi Desoxyminoxidil, dGMP, dGTP, Diacethiamine, Diami dine, Sulfadoxine, Sulfaethoxypyridazine, Sulfaguanidine, noacridine, Diaveridine, Dichlorobenzamil, Dichlo Sulfaguanole, Sulfalene, Sulfamerazine, Sulfamethazine, romethotrexate, Dichlorophenarsine, Dideoxycytidine, Sulfamethizole, Sulfamethoxazole, Sulfamethoxydiazine, Dihydrobiopterin, Dihydrofolic acid, Dimethialium, Dime Sulfamethoxypyridazine, Sulfametomidine, Sulfametopyra thocaine, Dimethyl methotrexate, Dinalin, DL-5,6,7,8-Tet Zine, Sulfametrole, Sulfanilamide, Sulfanilamidoimidazole, rahydrofolic acid, DL-Methotrexate, Dobupride, Dovitinib, Sulfanilylglycine, Sulfaperin, Sulfaphenazole, Sulfaproxy Doxazosin, Draflazine, Edatrexate, Elpetrigine, Elvucitab line, Sulfapyrazole, Sulfapyridine, Sulfasomizole, Sulfasy ine, Emtricitabine, Entecavir, Enviradene, Epcitabine, mazine, Sulfathiadiazole, Sulfatroxazole, Sulfatrozole, Sulfi Epiroprim, Eritadenine, Etanterol, Ethacridine, Ethaden, Eth somidine, Sulfisoxazole, Tacedinaline, Tacrine, Talampanel, ylisopropylamiloride, Etoprine, EtoxaZene, Etravirine, Talipexole, Talisomycin A, Tenofovir, Tenofovir disoproxil, Etriciguat, FAD, Famciclovir, Fazarabine, Fenamol, Feprat Terazosin, Tetrahydrobiopterinm, Tetrahydrofolic acid, set, Fiacitabine, Flucytosine, Fludara, Fludarabine, Fluocy Tetroxoprim, Tezacitabine. Thiamine. Thiazosulfone, tosine, Folic acid, Formycin A, Fosamprenavir, Furalazine, Thioguanine, Tiamiprine, Tigemonam, Timirdine, Tinori Fursultiamine, Furyltriazine, Ganciclovir, Gancyclovir, Gas dine, TiodaZosin, Tirapazamine, Tiviciclovir, Tocladesine, tracid, Gemcitabine, Giracodazole, Gloximonam, Glybuthia Trancopal, Triacanthine, Triamterene, Triapine, Triciribine, Zol, GSK 3B Inhibitor XII, GSK3BInhibitorxII, Guanine, Trimazosin, Trimethoprim, Trimetrexate, Tritoqualine, Trox Guanine arabinoside, Guanosine, Hexyl PABA, Hydroxym acitabine, Tubercidin 5'-diphosphate, Tuvatidine, Tyrphostin ethylclenbuterol, Hydroxyprocaine, Hydroxytriamterene AG 1112, Valacyclovir, Valganciclovir, Valopicitabine, Val Sulfate, Ibacitabine, Iclaprim, Imanixil, Imiquimod, Indano torcitabine, Velnacrine, Vengicide, Veradoline, Vidarabine, cine, Iobenzamic acid, Iocetamic acid, Iomeglamic acid, Viroxime, Vitaberin, Zalcitabine, Zhengguangmycin B2, Iomeglamicacid, Ipidacrine, Iramine, Irsogladine, Isatorib Zinviroxime, Zorbamycin, Zoxazolamine, (+)-Saxitoxin, ine, Isobutamben, Isoritmon, Isosepiapterin, Ketoclen 2-Aminoperimidine, 6-Formylpterin, 8-13-Neurotensin, buterol, Ketotrexate, Kopexil, Lamivudine, Lamotrigin, 8-Thioguanosine, 9-Deazaguanosine, 9-Desarginine-brady Lamotrigine, Lamtidine, Lappaconine, Lavendamycin, kinin, a4-10-Corticotropin, Afamelanotide, Agmatine, Alare L-Cytidine, Lenalidomide, Leucinocaine, Leucovorin, L-g- lin, Ambazone, Amiloride, Aminopterine, Ampyrimine, Methylene-10-deazaaminopterin, Linifanib, Lintopride, Angiotensin, Angiotensin I, Angiotensin II, Antibiotic Lisadimate, Lobucavir, Lodenosine, Lomeguatrib, Lometr O-129, Antipain, Arginine, Argiprestocin, Astressin, Atrio exol, Loxoribine, L-S-Adenosylmethionine, Mabuterol, peptin III, Aviptadil, Benzylisothiourea, Betacyamine, Bisin Medeyol, Melarsenoxyd, Melarsoprol B, Mesalazine, dolylmaleimide IX, Bivalirudin, Blasticidin S. Bleomycin Metabutethamine, Metabutoxycaine, Metahexamide, Meta B2, Bombesin 14, Buformin, Camostat, Cariporide, Carper Zosin, Methioprim, Methotrexate, Methylanthranilate, itide, Cecropin P1, Cetrorelix, Cilengitide, Creapure, Cyan Metioprim, Metoclopramide, Metoprine, Minoxidil, Mirabe oginosin LR, Cyanoviridin RR, Dalargine, Damvar, Dea gron, Mitomycin, Mivobulin, Mocetinostat, Monocain, Zaaminopterin, Defensin HNP 1, Deslorelin, Desmopressin, Mosapride, Mutamycin, N-(p-Aminophenethyl)spiroperi Dezaguanine, Dichloromethotrexate, Dihydrostreptomycin, dol, N6-2-(4-aminophenyl)ethyladenosine Role, NAD+, Dimaprit, Dimethylamiloride, Diminazene, DL-Methotrex NADH, NADH2, NADP+, NADPH2, Naepaine, Naminterol, ate, D-Methotrexate, Ebrotidine, Edatrexate, Eel Thyrocalci Naretin, Nebidrazine, NECA, Nelarabine, Nelzarabine, tonin, Elastatinal, Elcatonin, Enterostatin, Enviomycin, Epti Neolamin, Neotropine, Nepafenac, Nerisopam, Neurofort, fibatide, Ethylisopropylamiloride, Etilamide, Etoprine, Nifurprazine, Nimustine, Nitrine, N-Methyltetrahydrofolic Famotidine, Flupirtine, Furterene, Galanin, Galegin, Ghrelin, acid, Nolatrexed, Nomifensine, Norcisapride, N-Propionylp Glucagon, Gonadoliberin A, Guanethidine, Guanfacine, rocainamide, N-Sulfanilylnorfloxacin, o-Aminophenylala Guanoxan, Guanylthiourea, Gusperimus, Hexamidine, US 2014/02962.57 A1 Oct. 2, 2014

Histatin 5. Histrelin, Homoarginine, Icatibant, Imetit, Insuli Hydrate, Amikacin, Amiloride Hydrochloride, Aminocandin, notropin, Isocaramidine, Kallidin 10, Kemptide, Ketotrexate, Aminoglutethimide, Aminoguanidine, Aminolevulinic Acid Kiotorphin, Lactoferricin, Lamifiban, L-Bradykinin, Leu Hexyl Ester, Aminolevulinic Acid Methyl Ester, Amisul coverin, Leucovorin A, Leupeptin, Leuprolide, Lometrexol. pride, Amlodipine, Amlodipine Besylate, Amoxanox, Amox Lutrelin, m-Chlorophenylbiguanide, Melagatran, Melanotan icillin Pulsys. Amphotericin B, Ampicillin Sodium, II, Melanotropin, Melittin, Metformin, Methotrexate dim Amprenavir, Ampydin, Amrinone, Amrubicin Hydrochlo ethyl ester, Methotrexate monohydrate, Methoxtrexate, ride, Amselamine Hydrobromide, Amthamine, Anakinra, Methylisothiourea, Metoprine, Miacalcin, MIBG, Minoxidil, Anamorelin Hydrochloride, Anatibant Mesilate, Angiopeptin MitoguaZone, Mivobulin, Mivobulin isethionate, Moroxy Acetate, Anisperimus, Antagonist-G, Antide, Antide-1. dine, Nafarelin, Neotine, Nesiritide, Netropsin, Neurotensin, Antide-2, Antide-3, Antileukinate, Apadenoson, Apixaban, N-Methyltetrahydrofolate, Nociceptin, Nolatrexed, Novas Aplonidine Hydrochloride, Apoptozole 1, Apoptozole 2, tan, Panamidin, Pathocidine, Pebac, Peldesine, Pelitrexol, Pemetrexed, Pentamidine, Peramivir, Phenformine, Phenyl Apoptozole 3, Apricitabine, Arbekacin, Arbekacin Sulfate, biguanide, Pig galanin, Pimagedine, Piritrexim, Pitressin, Arborcandin A, Arborcandin B, Arborcandin C, Arborcandin Porcine angiotensinogen, Porcine gastrin-releasing hormone, D. Arborcandin E, Arborcandin F, Argatroban Monohydrate, Porcine neuropeptide Y, Porcine PHI, Pralatrexate, Protein Argimesna, Arginine Butyrate, Argiotoxin-636, Armodafinil, Humanin, Proteinase inhibitor E 64, Pyrimethamin, Arotinolol Hydrochloride, Arterolane Maleate, Aspoxicillin, Quinespar, Rat atriopeptin, Rat atriopeptin, Residuimod, Atenolol, Atosiban, Atreleuton, AVorelin, AZacytidine, AZa Ribamidine, Rimorphin, Saralasin, Saxitoxin, Sermorelin, lanstat, AZaromycin SC, AZelnidipine, AZetirelin, AZodicar S-Ethylisothiourea, Spantide, Stallimycin, Stilbamidine, bonamide, AZOxybacilin, AZtreonam, Aztreonam L-Lysine, Streptomycin A. Substance Pfree acid, Sulfaguanidine, Syn AZumamide A, Baclofen, Bactobolin, Balapiravir Hydro thetic LH-releasing hormone, Tallimustine, Teprotide, Tetra chloride, Balhimycin, Barusiban, Batracylin, Belactin A, cosactide, Tetrahydrobiopterin, Tetrahydrofolic acid, Throm Belactosin A, Belactosin C, Benanomicin B, Benexate Cyclo bin receptor-activating peptide-14, Thymopentin, Tioguanin, dextrin, Benzocaine, Besifloxacin Hydrochloride, Beta Tiotidine, Tirapazamine, Triamteren, Trimetrexate, Tryptore Amyloid (12-20), Binodenoson, Bleomycin A2 Sulfate, lin, Tuberactinomycin B, Tuftsin, Urepearl, Viomycidin, Boceprevir, Bogorol A, Boholmycin, Brasilicardin A, Bremelanotide, Brivanib Alaninate, Brivaracetam, Brodi Viprovex, Vitamin M, Xenopsin, Zanamivir, Zeocin, moprim, Bromfenac Sodium, Bromhexine Hydrochloride, Ziconotide, Zoladex. Brostallicin Hydrochloride, Bunazosin Hydrochloride, 0503 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, 90Y-DOTAGA-Substance P. LARG(Me)9 MS-10, Carboxyamidotriazole, Cariporide Hydrochloride, Caris D-TYR1ARG(Me)9] MS-10, D-TYR1AzaGLY7, ARG bamate, Carpipramine, Carumonam Sodium, Caspofungin (Me)9] MS-10, D-TYR1 MS-10, Psi(CH2NH)TPG4Van Acetate, Cefaclor, Cefcanel Daloxate Hydrochloride, Cef comycin Aglycon, TRP19 MS-10, 111 IN-Pentetreotide, capene Pivoxil Hydrochloride, Cefdaloxime, Cefdaloxime 13-Deoxyadriamycin Hydrochloride, 17-Aminogeldanamy Pentexil Tosilate, Cefdinir, Cefditoren Pivoxil, Cefepime, cin, 19-O-Methylgeldanamycin, 1-Methyl-D-Tryptophan, Cefetamet Pivoxil, Cefetecol, Cefixime, Cefluprenam, Cef 21-Aminoepothilone B, 2-Aminoaristeromycin, 2-Aminon matilen Hydrochloride Hydrate, Cefnmenoxime Hydrochlo eplanocin A, 3-Chloroprocainamide, 3-Deazaadenosine, ride, Cefninox Sodium, Cefodizime, Cefodizime Sodium, 3-Matida, 4-Aminosalicylic Acid, 4-Chlorophenylthio Cefoselis Sulfate, Cefotaxime Sodium, Cefotetan Disodium, DADME-Immucillin-A, 5,4'-Diepiarbekacin, 5'-Homonepl Cefotiam Hexetil, Cefotiam Hexetil Hydrochloride, Cefo anocin A, 5-Aminosalicylic Acid, 8(R)-Fluoroidarubicin tiam Hydrochloride, Cefoxitin, Cefozopran, CefoZopran Hydrochloride, 99MTC-C(RGDFK*)2Hynic, 9-Ami Hydrochloride, Ce?pirome, Cefpodoxime Proxetil, Cef nocamptothecin, A-42867 Pseudoaglycone, Abacavir Succi prozil, Cefprozil Monohydrate, Cefauinome, Ceftaroline, nate, Abacavir Sulfate, Abanoquil Mesilate, Abarelix, Ceftazidime, Cefteram Pivoxil, Ceftibuten, Ceftobiprole, Acadesine, Acriflavine, Acyclovir, Acyclovir Elaidate, Acy Ceftobiprole Medorcaril, CeftraZonal Bopentil, CeftraZonal clovir Oleate, Acyline, Adefovir, Adefovir Dipivoxil, Ademe Sodium, Ceftriaxone Sodium, Ceftrizoxime Alapivoxil, tionine Tosylate Sulfate, Adenallene, Adenophostin A, Cefuroxime, CefuroximeAxetil, Cefuroxime Pivoxetil, Cen Adenophostin B, Adenosine, Aerothricin 1, Aerothricin 16, tanamycin, Cephalexin Monohydrate, Ceranapril, Ceruletide Aerothricin 41, Aerothricin 45, Aerothricin 5, Aerothricin 50, Diethylamine, Cetefloxacin, Chlorofusin, Chloroorienticin Aerothricin 55, Afloqualone, Ageliferin Diacetate, Ageliferin A, Chloroorienticin B, Chlorotetain, Cibrostatin 1, Cidofovir, Dihydrochloride, Aladapcin, Alamifovir, Alatrofloxacin Cilastatin Sodium, Cilengitide, Cimaterol, Cinitapride Mesilate, Alendronic Acid Sodium Salt, Alestramustine, Hydrogen Tartrate, Cipamfylline, Circinamide, Cisapride Alfuzosin Hydrochloride, Aliskiren Fumarate. Alogliptin Hydrate, Cispentacin, Citicoline, Citrullimycine A, Cladrib Benzoate, Alpha-Methylnorepinephrine, Alpha-Methyltryp ine, Clitocine, Clofarabine, Clopidogrel Sulfate, Compound tophan, Altemecidin, Alvespimycin Hydrochloride, Amanta 3.01029, Coumamidine Gammal, Coumamidine Gamma2, dine Hydrochloride, Ambasilide, Ambazone, Ambroxol Cromoglycate Lisetil Hydrochloride, Cycallene, Cyclic-Ci Nitrate, Amdoxovir, Ameltolide, Amelubant, Amezinium dofovir, Cycloserine, Cyclotheonamide A, Cyclothialidine, Methylsulfate, Amfenac Sodium, Amidox, Amifostine Cygalovir, Cypemycin, CySmethynil, CyStamidin A, Cysta US 2014/02962.57 A1 Oct. 2, 2014 34 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 Etravirine, Etriciguat. Exalamide, Examorelin, Exatecan pramide Hydrochloride, Metyrosine, Mexiletine Hydrochlo Mesilate, Ezatiostat Hydrochloride, Famciclovir, Famoti ride, Micafungin Sodium, Midaxifylline, Mideplanin, dine, Famotidine Bismuth Citrate, Favipiravir, Feglymycin, Midoriamin, Milacainide Tartrate, Milacemide-2H, Mil Felbamate, Fenleuton, Fidarestat, Fidexaban, Filaminast, nacipran Hydrochloride, Minamestane, Minocycline Hydro Filarizone, Fingolimod Hydrochloride, Flucytosine, Fludara chloride, Minoxidil, Mirabegron, Mitomycin, MivaZerol, bine Phosphate, Fluorobenzyltriamterene, Fluorominoxidil, Mivobulin Isethionate, Mizoribine, Mocetinostat Dihydro Fluoroneplanocin A. Flupiritine Maleate, Fluvirucin B2, Flu bromide, Modafinil, Modafinil Sulfone, Moenomycin A voxamine Maleate, Folinic Acid, Fortimicin A, Fosam Chloride Bismuth Salt, Mofegiline, Mofegiline Hydrochlo prenavir Calcium, Fosamprenavir Sodium, Fosfomycin ride, Monamidocin, Monodansyl Cadaverine, Montirelin Trometamol, Fradafiban, Freselestat, Frovatriptan, Tetrahydrate, Mosapride Citrate, Moxilubant, Moxilubant Fudosteine, Furamidine, G1 Peptide, Gabadur, Gabapentin, Maleate, Mozenavir Mesilate, M-Phenylene Ethynylene, Gabexate Mesilate, GalarubicinHydrochloride, Galmic, Gal Muraminomicin A, Muraminomicin B, Muraminomicin C, non, Ganciclovir, Ganciclovir Elaidic Acid, Ganciclovir MuraminomicinD, Muraminomicin E1, Muraminomicin E2, Monophosphate, Ganciclovir Sodium, Ganirelix, Ganirelix Muraminomicin F. Muraminomicin G, Muraminomicin H, Acetate, Garomefrine Hydrochloride, Gemcitabine, Gemcit Muraminomicin I, Muraminomicin Z1, Muraminomicin Z2, abine Elaidate, Gemifloxacin Mesilate, Gilatide, Girodazole, Muraminomicin Z3, Muraminomicin Z4, Muramyl Dipep Glaspimod, Glucosamine Sulfate, Gludopa, Glutathione tide C. Mureidomycin A. Mureidomycin B. Mureidomycin Monoethylester, Glutathione Monoisopropylester, Glycine C. Mureidomycin D. Mycestericin E. Myriocin, Nafamostat Proline-Melphalan, Glycopin, Glycothiohexide alpha, Golo Mesylate, Nafarelin Acetate, Naglivan, Namitecan, Napsa timod, Goserelin, Growth Factor Antagonist-116, Growth gatran, Nebostinel, Nebracetam Fumarate, Neldazosin, Hormone Releasing Peptid 2, Guanabenz Acetate, Guanadrel Nelzarabine, Nemonoxacin, Neomycin B-Hexaarginine Sulfate, Guanethidine Monosulfate, Guanfacine Hydrochlo Conjugate, Neomycin-Acridine, Nepafenac, Nepicastat ride, Gusperimus Hydrochloride, Halovir A. Halovir B. Hydrochloride, Neramexane Hydrochloride, Neridronic Halovir C. Halovir D. Halovir E. Hayumicin B, Hayumicin Acid, Netamiftide Trifluoroacetate, Netilmicin Sulfate, C1, Hayumicin C2, Hayumicin D, Helvecardin A, Helvecar Nocathiacin I, Nocathiacin II, Nocathiacin III, Nocathiacin din B, Hepavir B, Heptaminol AMP Amidate, Hexa-D-Argi IV, NO-Gabapentin, Nolatrexed Hydrochloride, NO-Me nine, Hexadecyl Cidofovir, Hexadecyloxypropyl-Cidofovir, salamine, Noraristeromycin, Nuvanil, O6-Benzylguanine, Histamine Dihydrochloride. Histaprodifen, Histrelin, Histre Ocimumoside A, Octacosamicin A, Octacosamicin B, Oct US 2014/02962.57 A1 Oct. 2, 2014

reother, Octreotide Acetate, Oglufanide Disodium, Olamu fungin F. Spinorphin, Spisulosine, Squalamine Lactate, floxacin, Olamufloxacin Mesilate, Olcegepant, Olradipine Streptomycin, Styloguanidine, Substance P(8-11), Sufi Hydrochloride, Omaciclovir, Ombrabulin, Ombrabulin nosine, Sulcephalosporin, Sulfostin, Sulphazocine, Sultami Hydrochloride, Onnamide A, Opiorphin, Orbofiban Acetate, cilline Tosylate, Sunflower Trypsin Inhibitor-1, Surfen, Syn Orienticin A, Orienticin B, Orienticin C, Orienticin D, Orita adenol, Synguanol, Tabimorelin, Tacedinaline, Tacrine vancin, Oseltamivir Carboxylate, Oseltamivir Phosphate, Hydrochloride, Tageflar, Talabostat, Talaglumetad Hydro Otamixaban, Otenabant Hydrochloride. Ovothiol A, Oxazo chloride, Talampanel, Talipexole Dihydrochloride, Tallimus furin, Oxcarbazepine, Oxiglutatione Sodium, Oxiracetam, tine Hydrochloride, Talopterin, Taltirelin, Tanespimycin, Oxolide, Oxynor, Oxyphenarsine, Ozarelix, Pachymedusa Tanogitran, Targinine, Technetium (99MTC) Depreotide, Dacnicolor Tryptophyllin-1, Paecilaminol, Pafuramidine Teicoplanin-A2-1, Teicoplanin-A2-2, Teicoplanin-A2-3, Maleate, Palau.Amine, Paldimycin B, Pamidronate Sodium, Teicoplanin-A2-3, Teicoplanin-A2-5, Telavancin Hydro Pancopride, Papuamide A, Papuamide B, Papuamide C. Pap chloride, Telinavir, Temozolomide, Temurtide, Tenidap, uamide D, Parasin I, Paromomycin, Pasireotide, Paulomycin, Tenidap Sodium, Tenofovir, Tenofovir DF, Terazosin Hydro Paulomycin A2, Paulomycin B, Paulomycin C, Paulomycin chloride, Tetracosyl Cidofovir, Tetracycline Hydrochloride, D. Paulomycin E, Paulomycin F. PaZufloxacin, PaZufloxacin Tetrafibricin, Texenomycin A, Tezacitabine, TGP. Thioacet, Mesilate, PEG-Vancomycin, Pelagiomicin C, Peldesine, Thiothio. Thrazarine, Thymoctonan, Thymopentin, Tiam Pelitrexol, Pemetrexed Disodium, Penciclovir, Penicillin G dipine, Tigecycline, Tilarginine Hydrochloride, Timirdine Procaine, Pentamidine Gluconate, Pentamidine Isethionate, Diethanesulfonate, Timodepressin, Tipifarnib, TNF-Alpha Pentamidine Lactate, Peplomycin, Peramivir, Perphanazine Protease Enzyme Inhibitor, Tobramycin, Tocainide Hydro 4-Aminobutyrate, Phakellistatin 5, PHE-ARG-Beta-Naph chloride, Tokaramide A, Tomopenem, Topostatin, Torcitab thylamide, Phentermine, Phortress, Phospholine, Pibutidine ine, ToSufloxacin, ToSufloxacin Tosilate, Tranexamic Acid, Hydrochloride, Pimeloylanilide O-Aminoanilide, Piracetam, Trantinterol Hydrochloride, Tranylcypromine Sulfate, Pirarubicin, Pivampicillin, Pixantrone Maleate, Pluraflavin Trelanserin, Tresperimus Triflutate, Trichomycin A, Tricirib A, Pluraflavin B, Plusbacin A1, Plusbacin A2, Plusbacin A3, ine, Triciribine Phosphate, Trientine Hydrochloride, Trima Plusbacin A4, Plusbacin B1, Plusbacin B2, Plusbacin B3, Zosin Hydrochloride, Trimetrexate Glucuronate, Trimexau Plusbacin B4, PMEO-5-ME-DAPY, Pneumocandin A0, tide, Trimidox, Trovafloxacin, Trovafloxacin Hydrate, Pneumocandin B0, Pneumocandin B0 2-Phosphate, Pneu Trovafloxacin Hydrochloride Mesylate, Trovafloxacin Mesi mocandin D0, Polaprezinc, Polydiscamide A, Polymer late, Troxacitabine, Trybizine Hydrochloride, Tubastrine, Bound Human Leukocyte Elastase Inhibitor, Poststatin, Tuftsin, Tyroservatide, Tyrphostin 47, Ubenimex, Valacyclo PPI17-24, Pradimicin E, Pradimicin FA-2, Pralatrexate, vir, Valganciclovir Hydrochloride, Valnemulin, Valomaciclo Pramipexole Hydrochloride, Pranedipine Tartrate, Prazosin vir Stearate, Valonomycin A, Valopicitabine, Valpromide, Hydrochloride, Prefolic A. Pregabalin, Preladenant, Pri Valrocemide, Vamicamide, Vancomycin Hydrochloride, Van maquine Phosphate, Probestin, Procainamide Hydrochlo coresmycin, Vapitadine Hydrochloride, Varespladib, Varesp ride, Procaine Hydrochloride, Pro-Diazepam, Prostatin, Pru ladib Methyl, Varespladib Mofetil, Velnacrine Maleate, calopride, Prucalopride Hydrochloride, Prucalopride Venorphin, Vigabatrin, Vilazodone Hydrochloride, Vin Succinate, Pseudomycin A", Pseudomycin B", Pyloricidin B, desine, Viramidine Hydrochloride, Viranamycin-B, Vitamin Pyradizomycin, Pyrazinamide, Pyrazinoylguanidine, Pyrif B3, W Peptide, Xemilofiban, Xylocydine, Zanamivir, Zileu erone, Pyrimethamine, Quinelorane Hydrochloride, R-(+)- ton, Zoniporide Hydrochloride, Zorubicin Hydrochloride, Aminoindane, Ralfinamide, Ramoplanin A1, Ramoplanin ACTH, adenosine deaminase, agallsidase, albumin, alfa-1 A2, Ramoplanin A3. Ramorelix, Ravidomycin N-oxide, antitrypsin (AAT), alfa-1 proteinase inhibitor (API), alglu Razaxaban Hydrochloride, Reblastatin, Regadenoson, Rel cosidase, alteplase, anistreplase, ancrod serine protease, anti covaptan, Remacemide Hydrochloride, Residuimod, Restric bodies (monoclonal or polyclonal and fragments or fusions), ticin, Retaspimycin Hydrochloride, Retigabine Hydrochlo antithrombin III, antitrypsins, aprotinin, asparaginases, ride, Rhodopeptin C1, Rhodopeptin C2, Rhodopeptin C3, biphalin, bone-morphogenic proteins, calcitonin (salmon), Rhodopeptin C4, Rhodostreptomycin A, Rhodostreptomycin collagenase, DNase, endorphins, enfuVirtide, enkephalins, B, Ribavirin, Ribavirin Eicosenate cis, Ribavirin Eicosenate erythropoietins, factor VIIa, factor VIII, factor VIIIa, factor trans, Ribavirin Elaidate, Ribavirin Oleate, Rilmazafone IX, fibrinolysin, fusion proteins, follicle-stimulating hor Hydrochloride Dihydrate, Riluzole, Rimacalib Hydrochlo mones, granulocyte colony stimulating factor (G-CSF), ride, Rimeporide Hydrochloride, Riociguat, Ritipenem galactosidase, glucagon, glucagon-like peptides like GLP-1. Acoxil, RobalZotan Hydrochloride, RobalZotan Tartrate glucocerebrosidase, granulocyte macrophage colony stimu Hydrate, Rociclovir, Romurtide, Rotigaptide, Roxifiban lating factor (GM-CSF), chorionic gonadotropin (hCG), Acetate, Ruboxyl, Rufinamide, Rumycin 1, Rumycin 2, hemoglobins, hepatitis B vaccines, hirudin, hyaluronidases, Sabarubicin Hydrochloride, Sabiporide Mesilate, Safinamide idurnonidase, immune globulins, influenza vaccines, inter Mesilate, Safingol, Sagamacin, Sampatrilat, Sampirtine, leukines (1 alfa, 1 beta, 2, 3, 4, 6, 10, 11, 12), IL-1 receptor Saprisartan, Saquinavir, Saquinavir Mesilate, Sardomizide antagonist (rhIL-1 ra), insulins, interferons (alfa 2a, alfa 2b, Hydrochloride, Sardomozide, Saussureamine C. Saxagliptin, alfa 2c, beta1a, beta1b, gamma 1a, gamma 1b), keratinocyte Secobatzelline A, Secobatzelline B, Seglitide, Selank, Sele growth factor (KGF), lactase, leuprolide, levothyroxine, tracetam, Semapimod Hydrochloride, Senicapoc, Sepimostat luteinizing hormone, lyme vaccine, natriuretic peptide, pan Mesilate, Seproxetine, Seraspenide, Sevelamer Carbonate, crelipase, papain, parathyroid hormone, PDGF, pepsin, phos Sevelamer Hydrochloride. Shepherdin, Sibrafiban, Silo pholipase-activating protein (PLAP), platelet activating fac dosin, Silver Sulfadiazine, Sipatrigine, Sitafloxacin Hydrate, tor alcetylhydrolase (PAF-AH), prolactin, protein C, Sitagliptin Phosphate Monohydrate, S-Nitrosoglutathione, octreotide, Secretin, sermorelin, Superoxide dismutase Sofigatran, Sonedenoson, Sotirimod, Sparfloxacin, Sperabil (SOD). Somatropins (growth hormone). Somatostatin, Strep lin A, Sperabillin B, Sperabillin C, Sperabillin D. Sphingo tokinase, Sucrase, tetanus toxin fragment, tilactase, throm US 2014/02962.57 A1 Oct. 2, 2014 36 bins, thymosin, thyroid stimulating hormone, thyrothropin, hydrochloride, Betaxolol hydrochloride, Bevantolol hydro transforming growth factors, tumor necrosis factor (TNF). chloride, Biemnidin, Bifemelane hydrochloride, Binospirone TNF receptor-IgG Fc, tissue plasminogen activator (tPA), mesylate, Bioxalomycin alpha 1, Bis(7)-cognitin, Bisantrene transferrin, TSH, urate oxidase, urokinase, Fab (fragment, hydrochloride, Bisnafide mesilate, Bisoprolol fumarate, antigen-binding), F(ab')2 fragments, Fc (fragment, crystalli Bitolterol mesylate, Bleomycin A2 sulfate, Boholmycin, Zable), pFc fragment, Fv (fragment, variable), ScPv (single Bopindolol, Bosutinib, Brinazarone, Brinzolamide, chain variable fragment), di-schv/diabodies, bi-specific Bulaquine, Bumetanide. Buteranol, Butofilolol, Cadrofloxa T-cell engager, CDRS (complementarity determining cin hydrochloride, Caldaret hydrate, Calindol Dihydrochlo regions), single-domain antibodies (sdABS/Nanobodies), ride, Capridine beta, Carmoterol hydrochloride, Carteolol heavy chains (C. 6, e, Y, u) or heavy chain fragments, light hydrochloride, Carvedilol, Caspofungin acetate, Ceftaroline chains (W, K) or light chain fragments, VH fragments (variable fosamil acetate, Ceftizoxime sodium, Ceftobiprole, Celip region of the heavy chain), VL fragments (variable region of rolol hydrochloride, Cerebrocrast, Ceruletide diethylamine, the light chain), VHH fragments, VNAR fragments, shark Cevipabulin, Chinoin-169, Chloptosin, Chlordiazepoxide derived antibody fragments and affinity scaffold proteins, hydrochloride, Chloroorienticin A, Chloroorienticin B, Kunitz domain-derived affinity scaffold proteins, centyrin Cilazapril, Cilnidipine, Ciluprevir, Cimaterol, Cinacalcet derived affinity scaffold proteins, ubiquitin-derived affinity hydrochloride, Cinnamycin, Ciprofloxacin hydrochloride, scaffold proteins, lipocalin-derived affinity scaffold proteins, Ciprofloxacin silver salt, Clevidipine butyrate, Clitocine, ankyrin-derived affinity scaffold proteins, Versabodies (dis Clopenphendioxan, Cloranolol hydrochloride, Clozapine, ulfide-rich affinity scaffold proteins), fibronectin-derived Conantokin-R, Conophylline, Crisinatol mesilate, Cronid affinity scaffold proteins, cameloid-derived antibody frag ipine, Dabelotine mesilate, Dabigatran, Dabigatran etexilate, ments and affinity scaffold proteins, llama-derived antibody Dalbavancin, Dapivirine, Dapropterin dihydrochloride, Das fragments and affinity Scaffold proteins, transferrin-derived antafil. Debromoshermilamine, Decaplanin, Degarelix affinity Scaffold proteins, Squash-type protease inhibitors acetate, Delapril hydrochloride, Delavirdine mesilate, Del with cysteine-knot scaffold-derived affinity scaffold proteins. faprazine hydrochloride, Delucemine hydrochloride, Dem 0504 Suitable secondary amine-containing drugs may be ethylallosamidin, Demexiptiline hydrochloride, Denopam selected from the group consisting of (-)-3-O-Acetylspecta ine, Deoxymethylspergualin, Deoxyspergualin line hydrochloride, (-)-3-O-tert-Boc-spectaline hydrochlo Hydrochloride. Desacetylvinblastinehydrazide/folate conju ride, (-)-Cicloprolol, (-)-Norchloro-18Ffluoro-homoepi gate, Desbutylbenflumetol, Desbutylhalofantrine hydrochlo batidine, (-)-Salbutamol hydrochloride, (-)-Salmeterol, (+)- ride, Desferri-salmycin A, Desferri-salmycin B. Desferri-sal (S)-Hydroxychloroquine, (+)-Isamoltan, (+)-R- mycin C, Desferri-salmycin D. Desipramine hydrochloride, Pramipexole, (R)-(+)-Amlodipine, (R)-Clevidipine, (R)- Desloratadine, Dexfenfluramine hydrochloride, Dexketopro NSP-307, (R)-Teludipine, (R)-Thionisoxetine, (S)- fen meglumine, Dexmethylphenidate hydrochloride, Dex Clevidipine, (S) N— Desmethyltrimebutine, (S)- niguldipine hydrochloride, DeXSotalol, Diazepinomicin, Noremopamil, 99TcDemobesin 4, Glu10.Nle17.Nle30 Dichlorobenzoprim, Diclofenac potassium, Diclofenac Pancreatic polypeptide(2-36), Nle17.Nle30-Pancreatic sodium, Diclofenac zinc salt, Diethylnorspermine, Dihy polypeptide(2-36), psiCH2NHITpg4Vancomycin agly drexidine, Dilevalol, Dilevalol hydrochloride, Dinapsoline, con, 15bbeta-Methoxyardeemin, 3-Bromomethcathinone, Dinoxyline, Dipivefrine hydrochloride, Discodermide, Dis 4,5-Dianilinophthalimide, 4-Hydroxyatomoxetine. 5-Me codermide acetate, Discorhabdin D, Discorhabdin P. Dis thylurapidil, 7-Oxostaurosporine, 99mTc-c(RGDfK*) corhabdin S, Discorhabdin T. Discorhabdin U, Dobutamine 2HYNIC, A-42867 pseudoaglycone, Abacavir succinate, hydrochloride, Dobutamine phosphate, Dopexamine, Abacavir sulfate, Abarelix, Acarbose, Acebutolol hydrochlo Dopexamine hydrochloride, Doripenem, Dorzolamide ride, Aceclofenac, Acyline, Adaphostin, Adaprolol maleate, hydrochloride, d-Pseudoephedrine hydrochloride, Droxi Adaprolol oxalate, Adecypenol, Adirogolide hydrochloride, navir, Duloxetine hydrochloride, Duocarmycin A, Duocar Aglaiastatin C, Alchemix, Alinidine, Alkasar-18, Alminopro mycin B1, Duocarmycin B2, Duocarmycin C1, Duocarmycin fen, Alniditan, alpha-Methylepinephrine, Alprafenone C2, Dynemicin A. Dynemicin C. Ebanicline, Ecteinascidin hydrochloride, Alprenolol hydrochloride, Alprenoxime 1560, Ecteinascidin 722, Ecteinascidin 729, Ecteinascidin hydrochloride, Altromycin A, Altromycin C, Alvespimycin 736, Ecteinascidin 745, Ecteinascidin 770, Ecteinascidin hydrochloride, Ambroxol nitrate, Amfebutamone hydrochlo 875, Efaroxan, Efegatran sulfate hydrate, Efepristin, Efonid ride, Amibegron hydrochloride, Amifostine hydrate, ipine hydrochloride ethanol, Elagolix sodium, Elansolid C1, Amineptine, Aminocandin, Aminochinol, Amitivir, Amlo Elarofiban, Elbanizine, Elgodipine hydrochloride, Elinafide dipine, Amlodipine besylate. Amocarzine, Amodiaquine, mesilate, Elinogrel potassium, Elnadipine, Enalapril maleate, Amosulalol hydrochloride, Amoxapine, Amsacrine, Ana Enalapril nitrate, Enalaprilat, EnaZadrem, Enkastin (D), basine hydrochloride, Anisperimus, Antide-1, Aranidipine, Enkastin (D), Enkastin (D), Enkastin AD, Enkastin AE, Araprofen, Arbutamine hydrochloride, Ardeemin, Arformot Enkastin ID, Enkastin IE, Enkastin VD, Enkastin VE, Enoxa erol tartrate, Argatroban monohydrate, Argiopine, Arotinolol cin, Epibatidine, Epostatin, Eremomycin, Ersentilide, Ersen hydrochloride, Asperlicin E, Atenolol, Atevirdine mesylate, tilide hydrochloride, Ertapenem Sodium, Esculeogenin A, Azathioprine, AZelnidipine, AZepinostatin, Balamapimod, Esculeoside A, Esmolol hydrochloride, Esperamicin A1, Balhimycin, Balofloxacin, Balofloxacin dihydrate, Bam Etamsylate, Ethoxy-idazoxan, Eugenodilol, Ezlopitant, buterol, Bamirastine hydrate, Banoxantrone, Baogongteng A, Falnidamol, Farglitazar, Fasobegron hydrochloride, Fasudil Barixibat, Barnidipine hydrochloride, Batoprazine, Batzel hydrochloride, Felodipine, Fenoldopam mesilate, Fenoterol line A, Batzelline B. Batzelline C. Becampanel, Bederocin, hydrobromide, Fepradinol, Ferroquine, Ferulinolol, Fina Bedoradrine sulfate. Befunolol hydrochloride, Belactin B, floxacin hydrochloride, Flecainide acetate, Florbetaben, Belotecan hydrochloride, Benazepril hydrochloride, Ben Florbetapir F 18, Flufenoxine, Flumezapine, Fluodipine, Flu droflumethiazide, Benidipine hydrochloride, Berlafenone oxetine hydrochloride, Fluparoxan, Flupirtine maleate, Foe US 2014/02962.57 A1 Oct. 2, 2014 37 tidine 1, Foetidine 2, Folinic acid, Formoterol fumarate, Odanacatib, Olanzapine, Olanzapine pamoate, Olradipine Forodesine hydrochloride, Fosaprepitant dimeglumine, hydrochloride, Ontazolast, OPC-17083, Orbifloxacin, Orci Fosopamine, Frovatriptan, Furnidipine, Furosemide, prenaline sulphate. Orienticin A. Orienticin B. Orienticin C, Gaboxadol, Gadobenic acid dimeglumine salt, Gadopen Oritavancin, Osemozotan hydrochloride, Osutidine, Otena tetate dimeglumine, Gadoterate meglumine, Galactomycin I. bant hydrochloride, Ovothiol B, Oxprenolol hydrochloride, Galactomycin II, Garenoxacin mesilate, Gatifloxacin, Gefi Ozenoxacin, Pafenolol, Palau'amine, Palindore fumarate, tinib. Glucolanomycin, Glutapyrone, Gosogliptin hydrochlo Panobinostat, Parodilol hemifumarate, Parogrelil hydrochlo ride, Grepafloxacin hydrochloride, Gypsetin, Halofuginone ride, Paroxetine, Paroxetine ascorbate, Paroxetine camsilate, hydrobromide, Helvecardin A, Helvecardin B. Herquline B. Paroxetine hydrochloride, Paroxetine mesilate, Pazelliptine Hesperadin, Himastatin, Hispidospermidin, Homoepibati trihydrochloride, Pazelliptine trihydrochloride monohydrate, dine, Hydrochlorothiazide, Hydroflumethiazide, Hydroxy Pelitinib, Pelitrexol, Penbutolol sulfate, Pentostatin, Peplo chloroquine Sulfate, Ibopamine, IdaZoxan hydrochloride, mycin, Perindopril, Perzinfotel, Phendioxan, Pibutidine Iganidipine hydrochloride, Imidapril, Imidapril hydrochlo hydrochloride, Picumeterol fumarate, Pindolol, Pirbuterol ride, Imidazoacridinone, Imisopasem manganese, Immepip, hydrochloride, Pittsburgh Compound B, Pixantrone maleate, Immepyr, Incadronate, Indacaterol, Indantadol hydrochlo Plerixafor hydrochloride, Polyglutamate camptothecin, ride, Indeloxazine hydrochloride, Indolmycin, Inogatran, Pozanicline hydrochloride, Pradimicin A, Pradimicin B, Intoplicine, Iofetamine hydrochloride I-123. Iptakalim Pradimicin D, Pradimicin FA-1, Pradimicin FL, Pradimicin hydrochloride, Isavuconazonium chloride hydrochloride, FS, Pradimicin L. Pradimicin S. Pradofloxacin, Pramipexole Isepamicin Sulfate, Isofagomine tartrate, Isoquine, Isproni hydrochloride, Pranedipine tartrate, Pranidipine, Prefolic A. cline, Isradipine, Iturelix, Kaitocephalin, Ketamine hydro Premafloxacin, Premafloxacin hydrochloride, Premafloxacin chloride, Kopsinine, Korupensamine A, Korupensamine B. magnesium, Primaquine phosphate, Prisotinol, Procaterol Korupensamine C, Kosinostatin, Labedipinedilol A, Labe Hydrochloride Hemihydrate, Propafenone hydrochloride, dipinedilol B, Labetalol hydrochloride, Labradimil, Lacid Propranolol hydrochloride, Protriptyline hydrochloride, ipine, Ladasten, Ladostigil tartrate, Lagatide, Landiolol. Proxodolol, Pumaprazole, Pyrindamycin A. Pyrindamycin B, Lapatinib ditosylate, Lenapenem hydrochloride, Lenapenem Quinapril hydrochloride, Quinpramine, rac-Debromoflustra hydrochloride hydrate, Lerisetron, Leucovorin calcium, mine E. Radezolid, Rafabegron, Ralfinamide, Ramipril, Levobetaxolol hydrochloride, Levobunolol hydrochloride, Rasagiline mesilate, Razupenem, Reboxetine mesilate, Repi Levoleucovorin calcium, Levonebivolol, Liblomycin, notan, Repinotan hydrochloride, Reproterol hydrochloride, Linaprazan, Lisinopril, Litoxetine, Lobenzarit sodium, Retaspimycin hydrochloride, Retigabine hydrochloride, Lodamin, Lofexidine hydrochloride, Lomefloxacin hydro Rhodostreptomycin A. Rhodostreptomycin B. Rifabutin, Ril chloride, Lorcaserin, Lotrafiban, Loviride, Lubazodone menidine dihydrogen phosphate, Rimoterol hydrobromide, hydrochloride, Lumiracoxib, Mabuterol hydrochloride, Risotilide, Rivanicline, Robenacoxib, Rolapitant hydrochlo Makaluvamine D, Makaluvamine E. Makaluvamine F. ride, Safinamide mesilate, Sagandipine, Salbostatin, Salbuta Makaluvone, Manidipine hydrochloride, Manifaxine hydro mol nitrate, Salbutamol sulfate, Salmaterol, Salmeterol Xin chloride, Manzamine B. Manzamine D. Maprotiline hydro afoate, Sarizotan hydrochloride, Saussureamine C, chloride, Maropitant, Masnidipine hydrochloride, Mecamy Sazetidine-A, Selodenoson, Sertraline, Sertraline hydrochlo lamine hydrochloride, Meclofenamate sodium, Mefenamic ride, Setazindol, Sezolamide hydrochloride, Shishijimicin A, acid, Mefloquine hydrochloride, Melagatran, Melogliptin, Shishijimicin B, Shishijimicin C, Sibanomicin, Sibenadet Meluadrine, Meluadrine tartrate, Memoduin, Mepindolol hydrochloride, Silodosin, Sitamaquine hydrochloride, Sive sulfate, Mepindolol transdermal patch, Meropenem, Meth lestat sodium hydrate, Sofinicline, Solabegron hydrochlo amphetamine hydrochloride, Methoctramine, Methy ride, Solpecainol hydrochloride, Soraprazan, Sotalol hydro clothiazide, Methylhistaprodifen, Methylphenidate hydro chloride, Sparfloxacin, Spermine dialdehyde, Spirapril, chloride, Metipranolol, Metolazone, Metoprolol fumarate, Spiroquinazoline, Squalamine lactate, Streptomycin, Stress Metoprolol succinate, Metoprolol tartrate, Mezacopride, inl-A, Sumanirole maleate, Suprofenac 1, Suprofenac 2. Michellamine B, Microcin J25, Micronomicin sulfate, Suprofenac 3, Suronacrine maleate, Tafamidis meglumine, Midafotel, Milacemide-2H), Minaprine hydrochloride, Tafenoquine Succinate, Talarozole, Talibegron, Talibegron Mirabegron, Mitomycin, Mitoxantrone hydrochloride, hydrochloride, Talniflumate, Talotrexin, Taltobulin, Talu Mivobulin isethionate, Modipafant, Moexipril hydrochlo dipine hydrochloride, Tamsulosin hydrochloride, Tanespi ride, Moexiprilat, Montirelin tetrahydrate, Moranolin, Mote mycin, Tanogitran, Tauropyrone, Tazopsine, Tecalcet hydro sanib diphosphate, Moxifloxacin hydrochloride, Moxonidine chloride, Tecastemizole, Technetium (99mTc) apcitide, hydrochloride hydrate, Muraminomicin I, Mureidomycin E, Technetium (99mTc) bicisate, Telatinib, Telavancin hydro Mureidomycin F. Mureidomycins, N1,N8-Bisnorcymserine, chloride, Temacrazine mesilate, Temafloxacin hydrochlo Nadolol, Naproxen piperazine, Napsamycin A, Napsamycin ride, Temocapril hydrochloride, Terbutaline sulfate, B, Napsamycin C, Napsamycin D. Nardeterol, N-demethy Terodiline hydrochloride, Tertatolol hydrochloride, Tetra lated sildenafil. Nebivolol, Nemonapride, Neomycin-acri caine hydrochloride, Tetrahydrodercitin 1, Tetrindole, dine, Neratinib, Netilmicin sulfate, Nicardipine hydrochlo Tezampanel. Thiamet-G, Thiofedrine, Tiamdipine, Tiameni ride, Nifedipine, Nifekalant hydrochloride, Niguldipine dine, Tianeptine Sodium, Tiapafant, Tienoxolol hydrochlo hydrochloride, Nilvadipine, Nimodipine, Nipradilol, Nisol ride, Tigecycline, Tilisolol hydrochloride, Timolol hemihy dipine, Nitracrine dihydrochloride hydrate, Nitrendipine, drate, Timolol maleate, Tinazoline hydrohloride, Tirofiban Nitrofenac, Nitroso-nifedipine, Noberastine, Noberastine hydrochloride, Tizanidine hydrochloride, Toborinone, Tolfe citrate, NO-ciprofloxacin, N-Octyl-beta-valienamine, Nolo namic acid, Tomatine, Tomoxetine hydrochloride, Topix mirole hydrochloride, Norfloxacin, Norsegoline, Nortopix antrone hydrochloride, Torasemide, Trabectedin, Trandola antrone hydrochloride, Nortriptyline hydrochloride, N-tert pril, Trandolaprilat, Trantinterol hydrochloride, Treprostinil butyl isoquine, Oberadilol, Oberadilol monoethyl maleate, diethanolamine, Tresperimus triflutate, Triacetyl dynemicin US 2014/02962.57 A1 Oct. 2, 2014

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, mPEG5-Nalbuphine, 7,7a-Diepialexine, 7-Deoxytaxol. Utibapril, Utibaprilat, Vabicaserin hydrochloride, Vancomy 8(R)-Fluoroidarubicin hydrochloride, 9,11-Dehydrocortex cin hydrochloride, Vandetanib, Vanidipinedilol, Vaninolol, olone 17alpha-butyrate, 9.9-Dihydrotaxol. 9-18FFluoro Vapitadine hydrochloride, Varenicline tartrate, Varlitinib, propyl-(+)-dihydrotetrabenazine, 99mTc-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. 0505 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 (-)-Cicloprolol, (-)-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, Albitiazolium 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-Tyr1Arg(Me)9 MS-10, Alvespimycin hydrochloride, Alvocidib hydrochloride, D-Tyr1AzaGly7, Arg(Me)9 MS-10, D-Tyr1 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. pothilone D, 11-Keto-Beta-Boswellic Acid, 12-Methylthio Amphidinolide T1, Amphinidin A, Amphotericin B, vinblastine dihydrochloride, 13-Deoxyadriamycin hydro Amprenavir, Amrubicin Hydrochloride, Amycolamicin, chloride, 14alpha-Lipoyl andrographolide, 14beta Amycomycin, Anandamide, Andenallene, ANDREA-1, Hydroxydocetaxel-1,14-acetonide, 14beta Androstanolone, Androxolutamide, Anecortave acetate, Hydroxytaxotere, 14-C-Methyltriptolide, Anguinomycin C, Anguinomycin D. Anidulafungin, Ankino 14-Demethylmycoticin A, 14-Hydroxyclarithromycin, mycin, Annamycin, Annocherimolin, Antheliatin, Antide, 14-Isobutanoylandrographolide, 14-Pivaloylandrogra Antide-1, Antide-2, Antide-3, Antiflammin-1, Antiflammin pholide, 15-Methylepothilone B, 16-Methyloxazolomycin, 3. Apadenoson, Apaziquone, Aphidicolin, Aphidicolin Gly 17-Aminogeldanamycin, 17beta-Hydroxywortmannin, cinate, ApicularenA, Apicularen B, Aplaviroc hydrochloride, 18, 19-Dehydrobuprenorphine hydrochloride, 18-Hydroxy Apricitabine, Aragusterol A, Aragusterol C, Aranorosin, Ara coronaridine, 19-O-Demethylscytophycin C, 19-O-Meth norosinol A, Aranorosinol B, Aranose, Arbekacin, Arbekacin ylgeldanamycin, 1alpha,25-Dihydroxyvitamin D3-23.26 sulfate, Arborcandin A, Arborcandin B, Arborcandin C, lactone, 1alpha-Hydroxyvitamin D4, 1-Oxorapamycin, Arborcandin D, Arborcandin E, Arborcandin F, Arbutamine 21-Aminoepothilone B, 22-Ene-25-oxavitamin D, 22-OX hydrochloride, Archazolid A, Archazolid B, Arformoterol acalcitriol, 24(S)-Ocotillol, 24-Deoxyascomycin, 25-Anhy tartrate, Arimoclomol maleate, Arisostatin A, Arisugacin A, drocimigenol-3-O-beta-D-Xylopyranoside, 26-Fluoroe Arotinolol hydrochloride, Artelinate, Arteminolide A, pothilone, 2-Aminoaristeromycin, 2-Aminoneplanocin A, Arteminolide B, Arteminolide C, Arteminolide D, Artilide 2-Methoxyestradiol. 2'-Palmitoylpaclitaxel, 3,5-Dicaf fumarate, Arundifungin, Ascosteroside, Asiatic acid, Asiati feoylquinic acid, 3,7a-Diepialexine, 36-Dihydroisorollini coside, Asimadoline, Asperlicin B, Asperlicin E, Assamicin I. astatin 1, 3-Allyl farnesol, 3-Bromodiosmine, 3-Chlo Assamicin II, Astromicin Sulfate, Atazanavir Sulfate, rodiosmine, 3-Deazaadenosine, 3-Epimaxacalcitol. 4.6- Atenolol, Atigliflozin, Atorvastatin, Atorvastatin calcium, diene-Cer. 41-Demethylhomooligomycin B, Atorvastatin-Aliskiren, Atosiban, Atovaquone, Atrinositol, 44-Homooligomycin B, 4-Chlorophenylthio-DADMe-im Auristatin E. Aurothioglucose, Australifungin, Australine, mucillin-A, 4-Demethylepothilone B, 4-Ethynylstavudine, Avicenol A, Avicequinone A, Avicin D, Avicin G, AVorelin, 4"-Hydroxymevastatin lactone, 5(R)-Hydroxytriptolide, Axitirome, AZacitidine, AZaromycin SC, Azithromycin, 5,4'-Diepiarbekacin, 5,6-Dehydroascomycin, 5'-Epiequise Azithromycin Copper Complex, Bactobolin, Bafilomycin tin, 5-Ethylthioribose, 5-N-Acetyl-15balpha-hy A1, Bafilomycin C1, Baicalin, Balhimycin, Bambuterol, droxyardeemin, 5-Phenylthioacyclouridine, 5-Thiae Baogongteng A, Barixibat, Barusiban, Basifungin, Becate US 2014/02962.57 A1 Oct. 2, 2014 39 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, Deoxynoirimy 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 cin H, Carbovir, Caribaeolin, Caribaeoside, Carisbamate, clesonide, Deslorelin, Desmethyleleutherobin, Desmin-370, Carmoterol hydrochloride, Carpesterol, Carquinostatin A, Desogestrel, Desoxyepothilone B. Desoxyepothilone F. Des Carsatirin, Carteolol hydrochloride, Carteramine A, Carvas oxylaulimalide, Desvenlafaxine Succinate, Dexamethasone, tatin, Carvedilol, Caspofungin acetate, Castanospermine, Dexamethasone beloxil, Dexamethasone cipecilate, Dexam CefbuperaZone sodium, Cefcanel, Cefonicid sodium, Cefos ethasone Palmitate, Dexamethasone sodium phosphate, Dex elis sulfate, Celgosivir, Celikalim, Celiprolol hydrochloride, anabinol, Dexelvucitabine, Dexylosylbenanomycin A, DHA Cephalostatin 1, Cephalostatin 2, Cephalostatin 3, Cepha paclitaxel, Diadenosine tetraphosphate, Dictyostatin 1, lostatin 4, Cephalostatin 7, Cephalostatin 8, Cephalostatin 9. Didemnin X, DidemninY. Dideoxyinosine, Dienogest, Diep Ceramidastin, Cerebroside A, Cerebroside B, Cerebroside C, oxin-sigma, Diflomotecan, Digalactosyldiacylglycerol, Cerebroside D, Cerivastatin sodium, Ceruletide diethy Digoxin, Diheteropeptin, Dihydro-alpha-ergokryptine mesy lamine, Cethromycin, Cetrorelix Acetate, Chackol, Cha late, Dihydrocostatolide, Dihydroeponemycin, Dihydroer etoatrosin A, Chafuroside, Chenodeoxycholic acid, Cheto gotamine mesylate, Dihydrogranaticin B. Dihydroheptapre cin, Chinoin-169, Chloptosin, ChloraZicomycin, nol, Dihydroisosteviol, Dilevalol, Dilevalol hydrochloride, Chlorofusin, Chlorogentisylquinone, Chloroorienticin A, Dilimapimod, Dimelamol, Dimethandrolone, Dimethylcur Chloroorienticin B, Chlortalidone, Cholerae Autoinducer-1, cumin, di-mPEG5-Atazanavir, Dinaphine, Dioncoquinone Choline alfoscerate, Ciclesonide, Cidofovir, Cimaterol, A, Dioncoquinone B, Dioxolanethymine nucleoside, Dipera Cimetropium bromide, Cinatrin A, Cinatrin B, Cinatrin C1, mycin, Dipivefrine hydrochloride, Dipyridamole, Dipy Cinatrin C2, Cinatrin C3, Cinnabaramide A, Cinolazepam, ridamole beta-cyclodextrin complex, Dicquafosol tetraso Ciprokiren, Citicoline, Citreamicin-eta, Citropeptin, Citrulli dium, Dirithromycin, Discodermide, Discodermide acetate, mycine A, Cladribine, Clarithromycin, Clavaric acid, Cla Disermolide, Disodium cromproxate, Disodium lettusate, Varinone, Clavulanate potassium, ClaZosentan, Clevudine, Disorazol E1, Docetaxel, Docosanol, Docosyl cidofovir, Clidinium bromide, Clindamycin hydrochloride, Clitocine, Dofequidar fumarate, Dolastatin 13, Doramectin, Doranida Clobenoside, Clofarabine, Clopithepin, Cloranolol hydro Zole, Doretinel, Doripenem, Dorrigocin A, Dorrigocin B, chloride, Cocositol, Colabomycin A, Coleneuramide, Doxefazepam, Doxercalciferol, Doxifluridine, Doxorubicin Coleophomone B, Colestimide, Colforsin, Colforsin Hydrochloride, Doxorubicin, Morpholinyl, DoxoTam 12, daproate hydrochloride, Colletoic acid, Colupulon, Conage Doxycycline hyclate, Dridocainide, Droxidopa, Droximavir, nin, Coniferol Alcohol, Coniosetin, Conocurvone, Conophyl Drupangtonine, DTPA-adenosylcobalamin, Duramycin, line, Contignasterol, Contortumine hydrochloride, Contu Dutomycin, Ecdysterone, Ecomustine, Ecraprost, Ecteinas US 2014/02962.57 A1 Oct. 2, 2014 40 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, Iohexol, 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 P, Fingolimod hydrochloride, Finrozole, Flomoxef Sodium, chloride hydrochloride, Isepamicin sulfate, Isodoxorubicin, Flopristin, Floxuridine, Fluconazole, Fludarabine phosphate, Isoeleutherobin A, Isofagomine tartrate, Isofloxythepin, Iso Fludelone, Fludeoxyglucose (18F), Flumecinol, Flunisolide, homohalichondrin B, Isosorbide 5-mononitrate, IsoSpongia Flunoprost, Fluocinonide, Fluoroindolocarbazole A, Fluor diol, Isoxazoledehydelone, Isoxazolefludelone, Itavastatin oindolocarbazole B, Fluoroindolocarbazole C, Fluoronepl calcium, Itrocinonide, Ixabepilone, Jadomycin B, Janthino anocin A. Fluostatin B, Flupentixolhydrochloride, Fluphena mycin A, Janthinomycin B. Janthinomycin C, Jorumycin, zine hydrochloride, Flurithromycin, Fluticasone furoate, Kadsuphilin C, Kahalalide F, Kaitocephalin, Kanamycin, Fluticasone propionate, Flutropium Bromide, Fluvastatin Kanglemycin A, Kansuinin B, kappa-Conotoxin P VIIA, sodium, Fluvirucin B2, Foetidine 1, Foetidine 2, Fonda Karalicin, Katanosin A, Katanosin B. Khafrefungin, Kifun parinux sodium, Formamicin, Formestane, Formosyn A, For ensine, Kigamicin A, Kigamicin B. Kigamicin C, Kigamicin moterol fumarate. Forodesine hydrochloride, Fosteabine D. Kigamicin E. Kigamicinone, Kijimicin, Kinsenoside, sodium hydrate, Frederine, Fucoxanthin, Fudosteine, Fula Kobifuranone B, Kobin, Kodaistatin A, Kodaistatin B, dectin component A3, Fuladectin component A4, Fulves Kodaistatin C, Kodaistatin D. Kosinostatin, Kuehneromycin trant, Fumagalone, Furaquinocin A, Furaquinocin B, Fusa A. Kurasoin B. Kynostatin-227. Kynostatin-272, Labe candin A, Fusacandin B, Fuscoside B, Fusidate silver, dipinedilol A, Labedipinedilol B, Labetalol hydrochloride, Fusidienol, Gabusectin, Gabusectin methyl ester, Labradimil, Lactonamycin, Lactosylphenyl trolox, Ladirubi Gadobutrol, Gadocoletic acid trisodium salt, Gadomelitol, cin, Lagatide, Laherradurin, Lamivudine, Landiolol, Lan Gadoterate meglumine, Gadoteridol, Galactomycin I, Galac reotide acetate, Lanthiopeptin, Larotaxel dihydrate, Lasi tomycin II, Galactosyllactose, Galamustine hydrochloride, navir, LaSonolide A. Latanoprost, Latrunculin S. Galantamine hydrobromide, Galarubicin hydrochloride, Lavanduquinocin, Lecirelin, LedaZerol, Leinamycin, Galocitabine, Ganaxolone, Ganciclovir, Ganciclovir elaidic Lemuteporphin, Lenapenem hydrochloride, Lenapenem acid, Ganciclovir monophosphate, Ganciclovir Sodium, hydrochloride hydrate, Leptocillin, Leptofuranin.A, Leptofu Ganefromycin Alpha, Ganefromycin Beta, Ganglioside ranin B. Lersivirine, Lestaurtinib, Leuprolide acetate, Leuru GM1, Ganirelix, Ganirelix acetate, Ganoderic acid X, bicin, Leustroducsin A, Leustroducsin B. LeuStroducsin C, Garomefrine hydrochloride, Garveatin E, Garveatin F, Gem Leustroducsin H. Levalbuterol hydrochloride, Levobetaxolol citabine, Gemcitabine elaidate, Gemeprost, Genaconazole, hydrochloride, Levobunolol hydrochloride, Levodopa 3-O- Genipin, Gestrinone, Gilatide, Gimatecan, Girodazole, Glau glucoside, Levodopa 4-O-glucoside, Levodropropizine, cocalyxin A, Glemanserin, Glenvastatin, Glidobactin PF-1, Levonadifloxacin arginine salt, Levonebivolol, Levonorg US 2014/02962.57 A1 Oct. 2, 2014

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 A2, Microcolin A, Micronomicin sulfate, Midecamycin morphazole dihydrochloride, Oxymorphone hydrochloride, acetate, Mideplanin, Mifepristone, Miglitol, Miglustat, Oxymorphone-Val-carbamate, Oxynor, Oxyphencyclimine Milataxel, Milbemycin alpha-9, Milrinone Lactate, Miner hydrochloride, Ozarelix, Pachastrissamine, Pachymedusa val, Minocycline hydrochloride, Minodronate, Miporamicin, dacnicolor Tryptophyllin-1, Paciforgine, Paclitaxel, Pacli Mipragoside, Mirabegron, Mirodenafil hydrochloride, Mis taxel ceribate, Paecilaminol, Paeciloquinone D. Pafenolol, akinolide, Misoprostol, Mitemcinal fumarate, Mitoxantrone Palau'amine, Paldimycin B, Palinavir, Palmidrol, Palosuran hydrochloride, Mizoribine, Modecainide, Modithromycin, Sulfate, Pamapimod, Pamaqueside, Pamidronate Sodium Pan Moenomycin A chloride bismuth salt, Mometasone furoate, amesine hydrochloride, Pancratistatin disodium phosphate, Momordin Ic, Monamidocin, Monlicin A, Monogalactosyl Pancratistatin-3,4-cyclic phosphate sodium salt, Panipenem, diacylglycerol, Monohydroxyethylrutoside, Monophospho Pantethine, Papuamide A, Papuamide B, Papuamide C. Pap ryl lipid A. Montelukast sodium, Morphine Glucuronide, uamide D, Papyracillic acid, Paraherquamide G. Parasin I, Morphine hydrochloride, Morphine sulfate, Motexafin gado Paricalcitol, Parodilol Hemifumarate, Paromomycin, Parthe linium, Motexafin lutetium, Moxidectin, Mozenavir mesi nin, Parvisporin B, Patellazole A, Patellazole B, Patellazole late, Multiforisin A, Mumbaistatin, Mupirocin, Muramino C, Patupilone, Pauciflorine A, Pauciflorine B, Paulomycin, micin A, Muraminomicin B. Muraminomicin C, Paulomycin A2, Paulomycin B, Paulomycin C, Paulomycin MuraminomicinD, Muraminomicin E1, Muraminomicin E2, D, Paulomycin E, Paulomycin F. PEG40000-Paclitaxel, Muraminomicin F. Muraminomicin G, Muraminomicin H, PEG5000-Paclitaxel, PEG-conjugated camptothecin, PEG Muraminomicin I, Muraminomicin Z1, Muraminomicin Z2, Vancomycin, Peloruside A, Penasterol, Penbutolol sulfate, Muraminomicin Z3, Muraminomicin Z4, Muramyl dipeptide Penciclovir, Penicillide, Pentostatin, Peplomycin, Pepluanin C. Mureidomycin A, Mureidomycin B. Mureidomycin C, A. Peramivir, Percyduinnin, Periciazine, Perillyl alcohol, Mureidomycin D. Mureidomycin E, Mureidomycins, Myca Perphenazine, Persin, Petrosaspongiolide M. Phaseolinone, lamide A, Mycaperoxide A, Mycaperoxide B, Mycestericin Phenochalasin A, Phenochalasin B. Philinopside A, Phomac E. Mycolactone A, Mycolactone B. Myrciacitrin I, Myrci tin A, Phomactin B, Phomactin E, Phomactin F. Phomactin G, acitrin II, Myrciaphenone B. Myrocin C, Mytolbillinol, Phomoidride A, Phomopsichalasin, Phorboxazole A, Phor N4-Hexadecyl-dC-AZT, N-9-Oxadecyl-6-methyl-DGJ, boxazole B. Phospholine, Phosphostim, Picumeterol fuma N-Acetylsperamycin A1, N-Acetylsperamycin AlB, N-Ace rate, Pimecrolimus, Pimilprost, Pindolol, Pinitol, Pipalamy tylsperamycin A2, Nadifloxacin, Nadolol, Nafarelin acetate, cin, Pipenzolate bromide, Pipotiazine, Pirarubicin, Pirbuterol Naftopidil, Nafuredin, Nafuredin-gamma, Nagstatin, Nalbu hydrochloride, Pirmenol hydrochloride, Pironetin, Piroxi US 2014/02962.57 A1 Oct. 2, 2014 42 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 B1, Pneumocandin B0 2-phosphate, ascorbyl phosphate, Siwenmycin, Sizofiran, 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, Rhodostreptomycin B. Ribavirin, Ribavirin eicosenate cis, Temiverine hydrochloride hydrate, Tempol, Temsirolimus, Ribavirin eicosenate trans, Ribavirin elaidate, Ribavirinole Temurtide, Tenidap, Teniposide, Tenoxicam, Tenuifoliside A, ate, Rifabutin, Rifalazil, Rifamexil, Rifampicin, Rifapentine, Tenuifoliside B, Tenuifoliside C, Tenuifoliside D, Terbutaline Rifaximin, Rilmakalim hemihydrate, Rimexolone, Rimot sulfate, Terestigmine tartrate, Terfenadine, Teriflunomide, erol hydrobromide, Risedronate sodium, Ritipenem acoxil, Terlakiren, Ternatin, Terreulactone A, Terreulactone B, Ter Ritonavir, Rivastigmine tartrate, Rivenprost, Rocagloic acid, reulactone C, Terreulactone D, Tertatolol hydrochloride, Rocuronium bromide, Rofleponide, Rofleponide palmitate, Tesetaxel, Testosterone glucoside, Tetracosylcidofovir, Tet Rohitukine, Rokitamycin, Rolliniastatin 1, Romurtide, racycline hydrochloride, Tetrafibricin, Tetrahydrocortisol, Rosaprostol sodium, Roscovitine, Roselipin 1A, Roselipin Tetrahydroechinocandin B, Tetrahydroswertianolin, Tetrahy 1B, Roselipin2A, Roselipin2B, Rostafuroxine, Rosuvastatin droxyquinone, Tetromycin A, Tetromycin B, Tetronothiodin, calcium, Rosuvastatin Sodium, Rotigaptide, Roxatidine bis TeXenomycin A, Tezacitabine, TeZosentan, TeZosentan diso muth citrate, Roxithromycin, Rubiginone A1, Rubiginone dium, Thenorphine. Theopederin D. Theoperidin E, Theo A2, Rubiginone B1, Rubiginone C1, Rubitecan, Ruboxyl, phylline rutoside. Thermozymocidin, Thiamet-G, Thiam Rugatocenone B. Rumycin 1, Rumycin 2, Sabarubicin hydro phenicol. Thiarubrine E. Thiarubrine F. Thiarubrine G. chloride, Safingol, Saishin N. Sakyomicin A, Sakyomicin E, Thiarubrine H, Thiazinotrienomycin B. Thiazohalostatin, Salbostatin, Salbutamol nitrate, Salbutamol sulfate, Salicyli Thielocin, Thiofedrine. Thiomarinol, Thiomarinol B, Thiom halamide A, Salicylihalamide B, Salinamide A, Salinospora arinol C, Thiomarinol D, Thiomarinol E. Thiomarinol F. mide A, Saliphenylhalamide, Salmaterol, Salmeterol xin Thioviridamide. Thioxamycin, Thrazarine, Thymallene, afoate, Samaderine X, Sanfetrinem, Sanfetrinem cilexetil, Thymectacin, Tibolone, Tidembersat, Tienoxolol hydrochlo Sanfetrinem sodium, Sanglifehrin A, Sanglifehrin B, San ride, Tigecycline, Tilisolol hydrochloride, Timolol hemihy glifehrin C, Sanglifehrin D. Sapacitabine, Saquinavir, drate, Timolol maleate, Tiotropium bromide, Tipranavir, Saquinavir mesilate, Sarcophytol A, Sarcophytol B, Sarican Tiqueside, Tisocalcitate, Tixocortol buryrate propionate, din, Saussureamine D. Saussureamine E. Saxagliptin, Saze Toborinone, Tobramycin, Toloxatone, Tolvaptan, Tolytoxin, tidine-A, Schizandrin, Scopinast fumarate, Scopolamine, Tomatine, Tomeglovir, Tonabersat, Topixantrone hydrochlo Scyphostatin, Secalciferol, Secobatzelline A, Secobatzelline ride, Topotecan Acetate, Topotecane Hydrochloride, Torcit B, Secoisolariciresinol diglucoside, Securioside A, Securio abine, Torezolid, Toripristone, Tosagestin, Tosedostat, Tra side B, Selamectin, Selank, Selodenoson, Semagacestat, bectedin, Tradecamide, Tramadol hydrochloride, Tramadol Semduramicin, Semorphone hydrochloride, Seocalcitol, N-oxide, Trantinterol hydrochloride, Travoprost, Traxo US 2014/02962.57 A1 Oct. 2, 2014

prodil, Traxoprodil mesylate, Trecadrine, Trecetilide fuma Amamistatin B, Amarogentin, Amelubant, Amidox, Ami rate, Treprostinil diethanolamine, Treprostinil Sodium, nocandin, Amodiaquine, Amoxicillin trihydrate, Amrubicin Trewiasine, Triamcinolone acetonide, Triamcinolone hexac Hydrochloride, Amurensin H. Anguillosporal, Anidulafun etonide, Trichodimerol, Trichomycin A, Trichostatin D, Tric gin, Ankinomycin, Annamycin, Annulin C, Antimycin A11, iferol, Triciribine, Triciribine phosphate, Trifluridine, Trihex Antimycin A12, Antimycin A13, Antimycin A14, Antimycin yphenidyl hydrochloride, Trilostane, TrimaZosin A15, Antimycin A16, Apicularen A, Apicularen B, Apigenin, hydrochloride, Trimegestone, Trimoprostil, Tripterifordin, Apomine, Apomorphine hydrochloride, Arbidol, Arbutamine Tripterin, Tripterinin, Triptolide, Troxacitabine, Tsukubamy hydrochloride, Arformoterol tartrate, Artepillin C, Arzox cin A, Tubelactomicin A, Tuberactomycin B, Tuberactomy ifene hydrochloride, Aspoxicillin, Atalaphillidine, Atal cin D, Tuberactomycin E. Tubingensin B, Tuftsin, Tulathro aphillinine, Atraric acid, AVorelin, AXitirome, AZaresveratrol, mycin A, Tulathromycin B, Tulobuterol hydrochloride, AZatoxin, AZepinostatin, Baicalein, Baicalin, Balhimycin, Turbostatin 1, Turbostatin 2, Turbostatin 3, Turbostatin 4, 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, Vaninolol. 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, Cefpiramide 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 0506 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 (+)-Etorphine, (+)-Indocarbazostatin, (+)-SCH-351448, (R)- tin B-3, Combretastatin B-4, Combretastatin D-1, Combret Gossypol, (S)-(+)-Curcuphenol, (S)-Methylnaltrexone bro astatin D-2, Complestatin, Coniferol Alcohol, Conophylline, mide, 8-Gingerol, Arg(Me)9 MS-10, D-Tyr1Arg(Me)9] Corynecandin, Cosalane, Crisamicin C, Crobenetine, Crobe MS-10, D-Tyr1AZaGly7, Arg(Me)9 MS-10, D-Tyr1 netine hydrochloride, Curtisian A. Curtisian B, Curtisian D, MS-10, psiCH2NHITpg4Vancomycin aglycon, Trp 19 Cyanidin Chloride Monohydrate, Cyclocommunol, Cyclo MS-10, 13-Deoxyadriamycin hydrochloride, 14-Meth proparadicicol, Cyclotheonamide A, Cyclothialidine, Cyr oxymetopon, 14-Phenylpropoxymetopon, 18, 19-Dehy tominetin, Cytogenin, Cytosporone B, Cytotrienin I, Cytot drobuprenorphine hydrochloride, 2,12-Dimethyleurotinone, rienin II, Dactylocycline A, Dactylocycline B. Dalargin, 2'-Hydroxymatteucinol, 2-Methoxyestradiol, 2-Methyleuro Dalbavancin, Damunacantal, Daphnodorin A, Daphnodorin tinone, 3.5-Dicaffeoylquinic acid, 3-Bromodiosmetime, B. Daphnodorin C ((-)-enantiomer), Darbufelone, Dar 3-Bromodiosmine, 3-Chlorodiosmetine, 3-Chlorodiosmine, bufelone mesilate, Daunorubicin, Daurichromenic acid, 4,7,8-Trihydroxyisoflavone, 4-Aminosalicylic acid, 4-Hy Davidigenin, Deacetyl moxisylyte hydrochloride, Decapla droxyatomoxetine, 4-Iodopropofol. 5-Iodofredericamycin A, nin, Decyl gallate, Deferasirox, Dehydrozingerone, Del 5Z-7-Oxozeaenol, 6-Carboxygenistein, 6-O-mPEG4-Nal phinidin, Denopamine, Deoxymulundocandin, Dersalazine, bupine, 6-O-mPEG5-Nalbuphine, 7-Methylcapillarisin, Desacetylravidomycin N-oxide, Desglugastrin 8(R)-Fluoroidarubicin hydrochloride, 8.9-Dehydroasco tromethamine, Deslorelin, Desmopressin acetate, DeSven chlorin, 8-Carboxy-iso-iantheran A, 8-Paradol, 8-Prenylapi lafaxine Succinate, Dexanabinol, Dextrorphan, Dexylosyl genin, 8-Prenylmaringenin, 9-HydroxycrisamicinA, A-42867 benanomycin A, D-Fluviabactin, Diazaphilonic acid, Diaz pseudoaglycone, Abarelix, Acacetin, Aclarubicin, Acolb epinomicin, Dieckol, Diflunisal, Dihydrexidine, ifene hydrochloride, Acotiamide hydrochloride hydrate, Dihydroavenanthramide D, Dihydrogranaticin B, Dihydro Acrovestone, Actinoplanone A, Actinoplanone B. Aculeacin honokiol B, Dihydroraloxifene, Dilevalol, Dilevalol hydro Agamma, Adaphostin, Adarotene, AdXanthromycin A, Aero chloride, Dinapsoline, Dinoxyline, Dioncoquinone A, Dion thricin 1, Aerothricin 16, Aerothricin 41, Aerothricin 45, coquinone B, Dipotassium gossypolate, Dobutamine Aerothricin 50, Aerothricin 55, Ajulemic acid, Alchemix, hydrochloride, Dobutamine Phosphate, Dopexamine, Aldifen, alpha-Mangostin, alpha-Methylepinephrine, alpha Dopexamine hydrochloride, Dosmalfate, Doxorubicin Methylnorepinephrine, Alpha-Peltatin, Altromycin A. Altro Hydrochloride, Doxorubicin, Morpholinyl, DoxoTam 12, mycin B. Altromycin C. Altromycin D. Altromycins, Alvi Doxycycline hyclate, Dronabinol, Droxidopa, Duocarmycin mopan hydrate, Alvocidib hydrochloride, Amamistatin A, B1, Duocarmycin B2, Duocarmycin C1, Duocarmycin C2, US 2014/02962.57 A1 Oct. 2, 2014 44

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, Modecainide, 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-Demethylmurrayafoline A, Oenothein B, Hericenal A, Hericenal B, Hericenal C, Hidrosmin, His B, Okicenone, Olanzapine pamoate, Olcegepant, Olsalazine trelin, Histrelin acetate, Hongoquercin A, Hongoquercin B, Sodium, Onjixanthone I. Onjixanthone II, Oolonghomobis Honokiol diepoxide, Honokiol diepoxide, Human angio flavan A, Oolonghomobisflavan C, Orciprenaline sulphate, tensin II, Hydromorphone methiodide, Hymenistatin 1, Orienticin A, Orienticin B, Orienticin C, Orienticin D, Orita Hypeptin, Hypericin, Hyperoside, Icariin, Idarubicin hydro vancin, Orniplabin, Orthosomycin A, Orthosomycin B, chloride, Idronoxil, Ifenprodil, Imidazoacridinone, Incyclin Orthosomycin C, Orthosomycin D, Orthosomycin E, Ortho ide, Indacaterol, Indanocine, IntegracinA, Integracin B, Inte somycin F. Orthosomycin G, Orthosomycin H, Osutidine, gracin C, Integramycin, Integrastatin A, Integrastatin B, Oximidine III, Oxymetazoline hydrochloride, Oxymorp Intoplicine, Iodochlorhydroxyquin, Iododiflunisal, Iodoru hazole dihydrochloride, Oxymorphone hydrochloride, bidazone (p), Iolopride (123I), Ioxipride, Iralukast, Iralukast Oxyphenarsine, Ozarelix, Paeciloquinine A, Paeciloquinine Sodium, Irciniastatin A, Irciniastatin B, Isalmadol, Isoba D. Paeciloquinone B, Paeciloquinone D. Pancratistatin-3,4- Vachalcone, Isodoxorubicin, Iso-iantheran A, Isoliquiritige cyclic phosphate Sodium salt, Pannorin, Papuamide A, Pap nin, Isomolpan Hydrochloride, Isoquine, Isovanihuperzine uamide B, Papuamide C. Papuamide D, Paracetamol, A, Jadomycin B, Jasplakinolide, Kadsuphilin C, Kaitocepha Parvisporin B. PEG-Vancomycin, Penicillide, Pentazocine lin, Kampanol A, Kampanol B, Kanglemycin A, Kapurimy hydrochloride, Pepticinnamin E, Phaffiaol, Phakellistatin 7. cin A1, Kapurimycin A3, Kapurimycin A3. Kehokorin D, Phakellistatin 8, Phakellistatin 9, Phenochalasin A, Phento Kehokorin E. Kigamicin A, Kigamicin B. Kigamicin C, lamine mesilate, Phlorofucofuroeckol, Phomopsichalasin, Kigamicin D. Kigamicin E. Kigamicinone, Kistamicin A, Phthalascidin, Physostigmine salicylate, Piceatannol, Pido Klainetin A, Klainetin B, Kodaistatin A, Kodaistatin B, benzone, Pinocembrin, Pipendoxifene, Pirarubicin, Pitts Kodaistatin C, Kodaistatin D. Korupensamine A, Korupen burgh Compound B, Platencin, Platensimycin, Pluraflavin A, samine B. Korupensamine C, Korupensamine D. Kosinosta Pluraflavin B, Pluraflavin E, Pneumocandin A0, Pneumocan tin, Labetalol hydrochloride, Laccaridione A, Lactonamycin, din B0, Pneumocandin B0 2-phosphate, Pneumocandin D0, Lactosylphenyltrolox, Ladirubicin, Lamellarin alpha 20-sul Polyestradiol phosphate, Polyketomycin, Popolohuanone E. fate sodium salt, Lamifiban, Lanreotide acetate, LaSofox Pradimicin A, Pradimicin B, Pradimicin D, Pradimicin E, ifene, Lasofoxifene tartrate, Latamoxef sodium, L-Chicoric Pradimicin FA-1, Pradimicin FA-2, Pradimicin FL, Pradimi acid, L-Dopamide, Lecirelin, LedaZerol, Leuprolide acetate, cin FS ((+)-enantiomer), Pradimicin L. Pradimicin Q. Leurubicin, Levalbuterol hydrochloride, Levodopa, Pradimicin S, Pradimicin T1, Pradimicin T2, Prinaberel, Levodopa 3-O-glucoside, Levodopa 4-O-glucoside, Levor Probucol, Procaterol Hydrochloride Hemihydrate, Propofol, phanol tartrate, L-Fluviabactin, Lipiarmycin B3, Lipiarmy Propyl gallate, Protocatechuic acid, Protocatechuicaldehyde, cin B4, Liquiritin apioside, Lithospermic acid B magnesium Pseudohypericin, Purpuromycin, Pyrindamycin A. Pyrinda salt, Lobatamide C, Lobatamide F, Loloatin B, Luminacin D, mycin B, Quercetin-3-O-methyl ether, Quinagolide hydro Luteolin, Macrocarpin A, Macrocarpin B. Makaluvamine D. chloride, Quinobene, rac-Apogossypolone, Rac-Tolterodine, Makaluvamine E. Malonoben, Maltolyl p-coumarate, Man Raloxifene hydrochloride, Ramoplanin A1, Ramoplanin A2, nopeptimycin beta, Manzamine F, Marinopyrrole A, Marme Ramoplanin A3. Ramorelix, Ravidomycin N-oxide, Raw US 2014/02962.57 A1 Oct. 2, 2014

sonol, Reblastatin, Reproterol hydrochloride, Resobene, palene, Adarotene, Ademetionine tosylate Sulfate, AdXan Resorthiomycin, Retaspimycin hydrochloride, Rhodiocy thromycin A, Ajulemic acid, Alacepril, Aladapcin, anoside B, Rhododaurichromanic acid A, Rifabutin, Rifala Aleglitazar, Alitretinoin, Alminoprofen, Alogliptin benzoate, zil, Rifamexil, Rifampicin, Rifapentine, Rifaximin, Rimot alpha-Linolenic acid, alpha-Lipoic acid, alpha-Methyltryp erol hydrobromide, Riodoxol, Rohitukine, Rotigaptide, tophan, Alprostadil. Altemicidin, Alutacenoic acid B, Alvi Rotigotine, Roxindole Mesilate, Ruboxyl, Rufigallol, Rumy mopan hydrate, Amiglumide, Amineptine, Aminocaproic cin 1, Rumycin 2, Russuphelin A, Sabarubicin hydrochloride, acid, Aminolevulinic acid hydrochloride, Amlexanox, Saintopin, Saintopin E. Sakyomicin A, Sakyomicin E. Sala Amoxicillin trihydrate, Amphotericin B, Amsilarotene, Zopyridazin, Salbutamol nitrate, Salbutamol sulfate, Salca Anakinra, Antiflammin-1, Antiflammin-2, Antiflammin-3, prozic acid sodium salt, SalicylaZobenzoic acid, Salicylihala Apalcillin Sodium, Aplaviroc hydrochloride, Argatroban mide A, Salicylihalamide B, Saliphenylhalamide, monohydrate, Argimesna, Artelinate, Artepillin C, Artesu Salmaterol, Salmeterol Xinafoate, Saloxin, Salvianolic acid L. Sampatrilat, Sanglifehrin A, Sanglifehrin B, Sanglifehrin nate, Arundifungin, Ascosteroside, Asiatic acid, Aspirin, C, Sanglifehrin D. Saptomycin D. Sapurimycin, Saricandin, Aspoxicillin, Assamicin I. Assamicin II, Ataluren, Atorvasta Secoisolariciresinol diglucoside, Seglitide, Semorphone tin, Atorvastatin calcium, Atrasentan, AZaromycin SC, AZe hydrochloride, Shishijimicin A, Shishijimicin B, Shishijimi laic Acid, AZepinostatin, AZilsartan, AZOxybacilin, AZtre cin C, Sibenadet hydrochloride, Silychristin, Sinomenine, onam, Aztreonam L-lysine, AZumamide E. Baclofen, Sivifene, Siwenmycin, Sootepenseone, Spinorphin, Spino Bafilomycin C1, Baicalin, Balhimycin, Balofloxacin, Balof sulfate A, Spinosulfate B, Spiroximicin, Stachybocin A, loxacin dihydrate, Balsalazide disodium, Bamirastine Stachybocin B, Stachybocin C, Stachybotrin C, Stachybotry hydrate, Belactosin A, Belactosin C, Benanomicin A, Bena dial, Staplabin, Sterenin A, Sterenin C, Sterenin D. Strepto nomicin B, Benastatin A, Benastatin B, Benazepril hydro pyrrole. Succinobucol, Sulfasalazine, Sulphazocine, Susali chloride, Benthocyanin A, Bepotastine besilate, Beraprost mod, Symbioimine, Syriacusin A, Syriacusin B, Syriacusin sodium, Besifloxacin hydrochloride, Beta-Boswellic Acid, C, Tageflar, Taiwanhomoflavone A, TAP-doxorubicin, Tap beta-Hydroxy beta-methylbutyrate, Betamipron, Beta-Sialo entadol hydrochloride, Taramanon A, Tazofelone, Tazopsine, sylcholesterol Sodium Salt, Bevirimat, Bexarotene, Bezafi Tebufelone, Technetium Tc 99m depreotide, Teicoplanin brate, Biapenem, Bilastine, Bimosiamose, Bindarit, Bin A2-1, Teicoplanin-A2-2, Teicoplanin-A2-3, Teicoplanin-A2 floxacin, Biphenyl-indanone A, Boc-Belactosin A, 3, Teicoplanin-A2-5, Telavancin hydrochloride, Temoporfin, Borrellidin, Brasilicardin A, Brasilinolide A, Bremelanotide, Teniposide, Tenuifoliside A, Tenuifoliside B, Tenuifoliside Brevifolin carboxylic acid, Bucillamine, Bumetanide, Bun C, Terbutaline sulfate, Terprenin, Tetracycline hydrochloride, geolic acid, Buprenorphine hemiadipate, Buprenorphine Tetragalloylquinic acid, Tetrahydrocurcumin, Tetrahydro Val-carbamate, Butibufen, Butoctamide hemisuccinate, echinocandin B, Tetrahydroswertianolin, Thenorphine, ButyZamide, Cabin 1, Cadrofloxacin hydrochloride, Calbis Theophylline rutoside. Thiazinotrienomycin B. Thiazinot trin A, Calbistrin B, Calbistrin C, Calbistrin D, Calcium-like rienomycin F. Thiazinotrienomycin G. Thielavin G. Thielo peptide 1, Calcium-like peptide 2, Caloporoside B, Caloporo cin B3, Thymopentin, Tigecycline, Tipelukast, Tocotrienol, side C, Caloporoside D, Caloporoside E. Caloporoside F. Tokaramide A, Tolcapone, Tolterodine Tartrate, Topotecan Calpinactam, Calteridol calcium, Camprofen, Candesartan, Acetate, Topotecane Hydrochloride, Topsentine B1, Trabect Candoxatril, Candoxatrilat, Canfosfamide hydrochloride, edin, trans-Resveratrol, Traxoprodil, Traxoprodil mesylate, Canrenoate potassium, CapraZamycin A, CapraZamycin B, Trimidox, Triphendiol, Troglitazone, Tubastrine, Tubulysin CapraZamycin C, CapraZamycin E. CapraZamycin F. Capto A, Tubulysin B, Tubulysin C, Tucaresol, Tyropeptin A10. pril, Carbidopa, Carmoxirole hydrochloride, Carprofen, Tyropeptin A6, Tyropeptin A9, Tyroservatide, Tyrphostin 47. Cefaclor, Cefalexin monohydrate, Cefbuperazone sodium, Uncarinic acid A, Uncarinic acid B, Uncialamycin, Valrubi Cefcanel, Cefdaloxime, Cefdinir, Cefetecol, Cefixime, Cef cin, Vancomycin hydrochloride, Veinamitol, Venorphin, Ver matilenhydrochloride hydrate, Cefnmenoxime hydrochloride, ticillatine, Vexibinol, Vialinin B, Vinaxanthone, W Peptide, Cefninox sodium, Cefodizime, Cefonicid sodium, Cefopera Wiedendiol A, Wiedendiol B, Woodorien, Xamoterol Fuma Zone sodium, Cefoselis sulfate, Cefotiam hydrochloride, rate, Xanthoangelol E., Xanthofulvin, Xanthomegnin, Xipa Cefoxitin, Ce?pimizole sodium, Ce?piramide sodium, Cef mide, Yatakemycin, Zelandopam hydrochloride, Zorubicin prozil, Cefprozil monohydrate, Ceftaroline fosamil acetate, hydrochloride. Ceftazidime, Ceftibuten, Ceftobiprole, Cefuroxime, Cer anapril, Cerivastatin sodium, Ceruletide diethylamine, Cet 0507 Suitable drugs with a carboxyl group may be be efloxacin, Cetirizine hydrochloride, Chenodeoxycholic acid, selected from the list containing (-)-Subersic acid, (+)- Chinoin-169, Chlorambucil, Chloroorienticin A, Chloroori Deoxoartelinic acid, (+)-Hemipalmitoylcarnitinium, (+)-In enticin B, Choline fenofibrate, Choline thioctate, Chrolacto dobufen, (+)-SCH-351448, (E)-p-Coumaroylquinic acid, mycin, Cilastatin Sodium, CilaZapril, Cilengitide, Cilomilast, (Z)-Indenaprost, 111 In-DTPA-Prol,Tyr4 bombesin, 90Y Ciluprevir, Cinaciguat, Cinalukast, Cinatrin A, Cinatrin B, DOTAGA-substance P. psiCH2NHITpg4Vancomycin Cinatrin C1, Cinatrin C2, Cinatrin C3, Cinnatriacetin A, Cin aglycon, 111 In-Pentetreotide, 11-Keto-Beta-Boswellic Acid, natriacetin B, Ciprofibrate, Ciprofloxacin hydrochloride, Cir 15-Methoxypinusolidic acid, 1-Methyl-D-tryptophan, 3.5- cinamide, Cispentacin, Citrullimycine A, Clavaric acid, Cla Dicaffeoylquinic acid, 3-MATIDA, 3-O-Acetyloleanolic Vulanate potassium, Clinofibrate, Clopidogrel Sulfate, acid, 4-Aminosalicylic acid, 6alpha-FluorourSodeoxycholic Colletoic acid, Complestatin, Conagenin, Cosalane, Creatine acid, 6-Carboxygenistein, 7-Chlorokynurenic acid, 8-Car phosphate, Cyclocreatine, Cycloplatam, Cyclothialidine, boxy-iso-iantheran A, 99mTc-c(RGDfK*)2HYNIC, Cytomodulin, Cytosporic acid, Dabigatran, Daglutril, Dalar A-42867 pseudoaglycone, Aceclofenac, Acemetacin, Ace gin, Dalbavancin, Danegaptide hydrochloride, Danofloxacin, neuramic acid sodium salt, Acetyl-11-Keto-Beta-Boswellic Darinaparsin, Darusentan, Daurichromenic acid, Davu Acid, Acetyl-Beta-Boswellic Acid, Acetylcysteine, Achimil netide, Decahydromoenomycin A, Decaplanin, Decatromi lic Acids, Acipimox, AcitaZanolast, Acrivastine, Actarit, Ada cin A, Decatromicin B. Deferasirox, Delafloxacin, Delapril US 2014/02962.57 A1 Oct. 2, 2014 46

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, Ketorolac, Ketorolac tromethamine, Khafrefungin, Kijimi Desglugastrin tromethamine, Desmin-370, Dexibuprofen, cin, Kistamicin A, L-4-Oxalysine, Labradimil, Lamectacin, Dexibuprofen lysine, Dexketoprofen, Dexketoprofen cho Lamifiban, Lanthiopeptin, Lapaquistat acetate, LaraZotide line, Dexketoprofen D.L-lysine, Dexketoprofen lysine, acetate, Laropiprant, Latamoxef sodium, L-Chicoric acid, Dexketoprofen meglumine, Dexketoprofen trometamol. Lenapenem hydrochloride, Lenapenem hydrochloride Dexloxiglumide, Dexpemedolac, dextro-Ciprofibrate, Dexy hydrate, Levocabastine hydrochloride, Levocetirizine dihy losylbenanomycin A, Diacerein, Diazaphilonic acid, Di-Cal drochloride, levo-Ciprofibrate, Levodopa, Levodopa 3-O- ciphor, Difenoxin, Diflunisal, Dihydroavenanthramide D, glucoside, Levodopa 4-O-glucoside, Levofloxacin, Dihydrogranaticin B, Dihydroisosteviol, Dihydrolipoic acid, Levonadifloxacin arginine salt, L-Homothiocitrulline, Disalazine, Disila-bexarotene, Disodium cromproxate, Diso Licofelone, Licorice-Saponin C2, Lidorestat, Limaprostalfa dium lettusate, Doqualast, Doripenem, Dormitroban, Dorri dex, Limazocic, Linoleic acid 18:2W6-cis, 9-cis, Linotroban, gocin A, Dorrigocin B, Droxidopa, DTPA-adenosylcobal Lintitript, Lipohexin, Lisinopril, Lithium Succinate, Lithos amin, Duramycin, Dynemicin A, Ecabet Sodium, permic acid B magnesium salt, Loloatin B, Lomefloxacin Ecenofloxacin hydrochloride, Econazole Sulfosalicylate, hydrochloride, Lometrexol, Longestin, Lonidamine, Lora Edetic acid, Edotreotide yttrium, Efletirizine, Eflornithine carbef hydrate, Lorglumide, Lotrafiban, Loxiglumide, hydrochloride, Eglumetadhydrate, Elansolid C1, Elarofiban, L-Simexonyl homocysteine, L-Thiocitrulline, Lubiprostone, Elastatinal B, Elastatinal C, Elsibucol, Eltrombopagolamine, Lumiracoxib, Lu-TeX bis(gluconate), Lysinated-betulonic Elvitegravir, Emricasan, Enalapril maleate, Enalapril nitrate, acid, Lysine acetylsalicylate, Macrocarpin B. Madecassic Enalaprilat, Enfumafungin, Enkastin (D), Enkastin AD, acid, Maracenin A1, Maracenin A2, Maracenin B1, Marace Enkastin AE, Enkastin ID, Enkastin IE, Enkastin VD, Enkas nin B2, Maracenin C1, Maracenin C2, Maracenin D1, tin VE, Enoloxone, Enoxacin, Enrasentan, Enrofloxacin, Maracenin D2, Marbofloxacin, Maslinic acid, Matristatin Epalrestat, Epidioxymanadic acid A, Epidioxymanadic acid A1, Matristatin A2, Matteuorienate A, Matteuorienate B, B, Epithalon, Epofolate, Epoprostenol sodium, Epostatin, 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, Faro troban, Mispyric acid, Mixanpril, Moenomycin A chloride penem Sodium, Fasobegron hydrochloride, FebuXostat, Feg bismuth salt, Moexipril hydrochloride, Moexiprilat, Mof lymycin, Felbinac, Felbinac Lysine Salt, Fenbufen, Fex eZolac, Momordin Ic, Monamidocin, Monoethanolamine ofenadine hydrochloride, Fidexaban, Finafloxacin oleate, Montelukast sodium, Morphine Glucuronide, Moxi hydrochloride, Fleroxacin, Flobufen, Flomoxef Sodium, floxacin hydrochloride, Mumbaistatin, Mupirocin, Muragli Flunoprost, Flunoxaprofen, Flurbiprofen, Fluvastatin tazar, Muraminomicin A, Muraminomicin B. Muraminomi Sodium, Folinic acid, Fondaparinux sodium, Fosfosal, cin C, Muraminomicin D, Muraminomicin E1, Fradafiban, Frusemide, Fudosteine, Furprofen, G1 peptide, Muraminomicin E2, Muraminomicin F. Muraminomicin G, Gabadur, Gabapentin, Gabapentin enacarbil, Gabusectin, Muraminomicin H, Muraminomicin I, Muraminomicin Z1, Gadobenic acid dimeglumine salt, Gadobutrol, Gadocoletic Muraminomicin Z2, Muraminomicin Z3, Muraminomicin acid trisodium salt, Gadodenterate, Gadomelitol, Gadopen Z4, Mureidomycin A, Mureidomycin B. Mureidomycin C, tetate dimeglumine, Gadoterate meglumine, Gadoteridol. Mureidomycin D, Mureidomycin E, Mureidomycin F. Mure Gambogic acid, Gamendazole, Gamma-Linolenic Acid, idomycins, Mycaperoxide A, Mycaperoxide B, Mycestericin Ganefromycin Alpha, Ganefromycin Beta, Ganglioside E. Mycophenolic acid sodium salt, Myriceric acid A. Mytol GM1, Ganoderic acid X, Garenoxacin mesilate, Gastrazole, bilin acid, Nadifloxacin, Nafagrel hydrochloride, Nafagrel Gatifloxacin, Gemfibrozil, Gemifloxacin mesilate, Gemopat hydrochloride hemihydrate, Nagstatin, Napirimus, Napsa rilat, Gilatide, Gimatecan, Giripladib, Glaspimod, Glucaro gatran, Napsamycin A, Napsamycin B, Napsamycin C, Nap lactam potassium, Gludopa, Glutathione Monoethyl Ester, samycin D. Nateglinide, Naveglitazar, Nebostinel, Nemon Glutathione Monoisopropyl Ester, Glycine-proline-Mel oxacin, Neu5Ac2en, Niacin, Niglizin, Nileprost beta phalan, Glycopin, Glycyrrhizinic acid, Golotimod, Goody cyclodextrin clathrate, Nooglutil, Norfloxacin, Norfloxacin eroside B. Goralatide, Grepafloxacin hydrochloride, GS-143, Succinil, Obeticholic acid, Octacosamicin A, Octacosamicin Haterumadioxin A, Haterumadioxin B, Helvecardin A, B, O-Demethylchlorothricin, Ofloxacin, Olamufloxacin, Helvecardin B, Heptelidic acid chlorohydrin, Hericenal A. Olamufloxacin mesilate, Olanzapine pamoate, Oleanolic Hericenal B. Hericenal C. Homoindanomycin, Hongoquer acid, Olmesartan, Olopatadine Hydrochloride, Olsalazine cin A, Hongoquercin B. Human angiotensin II, Hyaluronate sodium, Omapatrilat, Onnamide A, OPC-17083, Opiorphin, Sodium, Hydrostatin A, Ibuprofen, Icatibant acetate, Icofun Orbifloxacin, Oreganic acid, Orienticin A. Orienticin B, Ori gipen, Idrapril, Ifetroban, Ilepatril, Iloprost, Imidapril, Imi enticin C, Orienticin D. Oritavancin, Orniplabin, Oseltamivir dapril hydrochloride, Imiglitazar, Imipenem, Indianaprost carboxylate. Ovothiol A, Ovothiol B, Ovothiol C, Oxaprozin, (S), Indanomycin, Indeglitazar, Indobufen, Indole-3-propi Oxeglitazar, Oxiglutatione sodium, Oxymorphone-Val-car onic acid, Indometacin, Indomethacintrometamol, Indoxam, bamate, Oxynor, OZagrel hydrochloride, Ozenoxacin, Pac Indynaprost, Inogatran, Inosiplex, Iododiflunisal, Iodofiltic timibe, Padoporfin, Paeciloquinone B, Paeciloquinone D. acid-123.I. IodoStearic Acid, Iralukast, Iralukast Sodium, Paldimycin B, Palovarotene, Panipenem, Parasin I, Parinaric Isalsteine, Isobongkrekic acid, Isotretinoin, Itavastatin cal acid, Paulomycin, Paulomycin A2, Paulomycin B, Paulomy US 2014/02962.57 A1 Oct. 2, 2014 47 cin C, Paulomycin D. Paulomycin E, Paulomycin F. PaZu Thermozymocidin, Thiazohalostatin, Thielavin G. Thielocin, floxacin, PaZufloxacin mesilate, Pefloxacin, PEG-vancomy Thielocin B3. Thiofoscarnet, Thioxamycin, Thrazarine, Thy cin, Pelagiomicin C, Peliglitazar, Pelitrexol, Pelretin, mic humoral factor gamma-2, Thymopentin, Tiagabine Penasterol, Penicillamine, Peramivir, Perindopril, PG-camp hydrochloride, Tibenelast, Ticolubant, Tilarginine hydro tothecin, Phomallenic acid C, Phomoidride A, Phomoidride chloride, Tiliquinatine, Timodepressin, Tipelukast, Tiplasi B. Phosphinic cyclocreatine, Phosphosalsalate, Physostig nin, Tirofiban hydrochloride, Tisartan, Tolfenamic acid, Tol mine salicylate, Pibaxizine, Pidotimod, Piraxostat, Piret metin, Tolrestatin, Tomopenem, ToSufloxacin, ToSufloxacin anide, Pirfenoxone, Pirprofen, Pivagabine, Pixantrone male Tosilate, Trandolapril, Trandolaprilat, Tranexamic acid, Tra 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 Tubulysin C, Tucaresol, Tuftsin, Turbinaric acid, Tyroser FL, Pradimicin FS ((+)-enantiomer), Pradimicin L. Pradimi Vatide, Ubenimex, Ulifloxacin, Uncarinic acid A, Uncarinic cin Q, Pradimicin S. Pradimicin T1, Pradimicin T2, Pradof acid B, Unoprostone, Ursodeoxycholic acid, Ursolic acid loxacin, Pralatrexate, Pranoprofen, Prefolic A. Pregabalin, phosphate, Utibapril, Utibaprilat, Vadimezan, Valonomycin Premafloxacin, Premafloxacin hydrochloride, Prezatide cop A. Valproate Semisodium, Valproic acid, Valsartan, Vanco per acetate, Proamipide, Probenecid, Probestin, Procysteine, mycin hydrochloride, Varespladib, Vebufloxacin, Vedapro Proglumide, Propagermanium, Propofol hemisuccinate, fen, Veliflapon, Verlukast, Vinaxanthone, Vicquidacin, Virana Prostatin, Prostratin succinate, Protocatechuic acid, Proto porphyrin IX gallium(III) complex, Prulifloxacin, Prulifloxa mycin-A, Viscosin, Vitilevuamide, Voreloxin, W Peptide, cin Hydrochloride, Prulifloxacin Mesylate, Pseudomycin A', Xanthofulvin, Zabicipril Hydrochloride, Zabiciprilat Hydro Pseudomycin B". Pycnanthuquinone A. Pycnanthuquinone B. chloride, Zabofloxacin hydrochloride, Zaltoprofen, Zan Pyloricidin B, Pyridazomycin, Pyrrolosporin A, Quiflapon amivir, Zaragozic acid D3, Zenarestat, Zofenoprilat, Zofeno Sodium, Quinapril hydrochloride, Quinlukast, Rafabegron, prilat arginine, Zolasartan, Zonampanel. Ragaglitazar, Raltitrexed, Ramatroban, Ramipril, Raxofelast, 0508 Suitable drugs with a phosphate group may be RaZupenem, Rebamipide bismuth citrate tetramethyl selected fromt the group consisting of Adenophostin A, edamine, Rebamipide bismuth L-tartrate tetramethyl Adenophostin B, Atrinositol, Buflomedil pyridoxalphos edamine, Repaglinide, Resobene, Reveromycin A, phate, Cytostatin, Fludarabine phosphate, Fosfluconazole, Rhododaurichromanic acid A. Ridogrel, Robenacoxib, Roca Fosfonochlorin, Fosfosal, Fosopamine, Fosquidone, Fos gloic acid, Rolafagrel, Romazarit, Romurtide, Rosaprostol tamatinib, Ganciclovir monophosphate, Genistein-7-phos Sodium, Rosuvastatin calcium, Rosuvastatin Sodium, phate, Hydroxyphoslactomycin B. Leustroducsin A, Leustro Rufloxacin Gluconate, Rufloxacin hydrochloride, Rumycin ducsin B. Leustroducsin C. LeuStroducsin H. Mangafodipir 1. Rumycin 2, Salazopyridazin, Salcaprozic acid sodium salt, trisodium, Menadiol sodium diphosphate, Miproxifene phos Salicylazobenzoic acid, S-Allylmercaptocaptopril, Salm phate, Monophosphoryl lipid A. Phospholine, Phosphosal isteine, Salvianolic acid L. Samixogrel, Sampatrilat, San salate, Pneumocandin B02-phosphate, Tafluposide, Tricirib fetrinem, Sanfetrinem sodium, Sapurimycin, Sarpogrelate ine phosphate, Ursolic acid phosphate. hydrochloride, Saussureamine A, Saussureamine B, Saus 0509 Suitable drugs with a thiol group may be selected Sureamine C. Saussureamine D. Saussureamine E. Scabro fromt the group consisting of Acetylcysteine, Antileukinate, nine G. Scopadulcic acid B, Securioside A, Securioside B, Argimesna, Bucillamine, Butixocort, Captopril, Dihydroli Selank, Semduramicin, Seocalcitol, Seratrodast, Serofendic poic acid, Gemopatrilat, Glutathione monoethyl ester, Glu acid, Sessiloside. Shepherdin, Sialosylcholesterol-Alpha tathione monoisopropyl ester, Midoriamin, Omapatrilat, Sodium Salt, Sitafloxacin hydrate, S-Nitrosocaptopril, S-Ni Ovothiol A, Ovothiol B, Ovothiol C, Penicillamine, Rebim trosoglutathione, Sodelglitazar, Sodium cromoglycate, astat, Shepherdin, Zofenoprilat, Zofenoprilat arginine. Sodium oxybate, Sofalcone, Solabegron hydrochloride, Sor 0510. In the following sections preferred embodiments of bicillactone A, Sparfloxacin, Sphingofungin F. Spinorphin, the present invention are described. Spirapril, Spiriprostil, Spiroglumide, Spiroximicin, Squal 0511. In a preferred embodiment, the carrier of formula (I) estatin I, Stachybocin A, Stachybocin B, Stachybocin C, Sta comprises a quaternary carbon, in particular a quaternary plabin, Starrhizin, Sterenin D. Subtilopentadecanoic acid, carbon of a branching core moiety B, wherein B is pentaryth Succinobucol, Sufotidine bismuth citrate, Sugammadex ritol in bound form. Preferably, each A is independently a Sodium, SulfaSalazine, Sulindac, Sulopenem, Sulukast, Sun PEG-based polymeric chain terminally attached to the qua flower trypsin inhibitor-1, Susalimod, Tafamidis meglumine, ternary carbon of pentaerythritol via the —CH O— moi Tageflar, Talaglumetad hydrochloride, Talibegron, Tali eties of pentaerythritol by a permanent covalent linkage, and begron hydrochloride, Talopterin, Taltobulin, Tamibarotene, the distal end of each moiety A is covalently bound to a Tanogitran, Tanomastat, TAP-doxorubicin, Tarenflurbil, moiety Hyp, each moiety Hyp is conjugated to m moieties L. Targinine, Tazarotenic Acid, Tebipenem, Teicoplanin-A2-1, either directly or indirectly through a moiety SP and which Teicoplanin-A2-2, Teicoplanin-A2-3, Teicoplanin-A2-5. moieties L are each connected to a biologically active moiety Telavancin hydrochloride, Telmesteine, Telmisartan, Tema D floxacin hydrochloride, Temocapril hydrochloride, 0512. In one preferred embodiment, a moiety Hyp of for Temurtide, Tenosal, Terbogrel, Terestigmine tartrate, Terikal mula (I) comprises, preferably consists of branched ant fumarate, Tesaglitazar, Tetomilast, Tetradecylselenoace polyamines comprising at least 2 amine groups. Preferably, tic acid, Tetrafibricin, Tetragalloylquinic acid, Tetrahydro Such branched polyamine comprises one or more lysine resi echinocandin B, Tetronothiodin, TeZampanel, dues in bound form. Preferably, each Hyp of formula (I) has US 2014/02962.57 A1 Oct. 2, 2014 48 a molecular weight of from 0.1 kDa to 4 kDa, in particular of 3, 7 or 15 lysines in bound form, more preferably of 1, 3 or 7 from 0.2 to 2 kDa. In a preferred embodiment, n is 4 and each lysines in bound form. Most preferably, Hyp comprises, in of the 4 moieties Hyp may independently consist of the same particular consists of heptalysinyl. or different moieties Hyp. In a preferred embodiment, the 4 0514 Preferably, the carrier of formula (I) with n=4 has a molecular weight of from 1 kDa to 80 kDa, more preferably moieties Hyp are the same. of from 1 kDa to 40 kDa and even more preferably of from 10 0513. In a preferred embodiment, a moiety Hyp com kDa to 40 kDa. prises, in particular consists of between 1 and 32 lysines in 0515 Preferred carrier moieties of formula (I) are selected bound form, preferably comprises, in particular consists of 1. from structures (i) to (iii):

(i)

H C 'N-1shO1, g

(ii)

H C N-nO1, hg US 2014/02962.57 A1 Oct. 2, 2014 49

-continued (iii)

NH a.

O NH

HN C H

0516 wherein form the carrier. It is understood that the lysines can be 0517 dashed lines indicate attachment to sub-struc partially or fully protected by protective groups during the tures —(SP)-L-D of formula (I), coupling steps and that also the final carrier may contain 0518 p is an integer from 5 to 2000, preferably from 10 protective groups. A preferred building block is bis-boc to 1000, more preferably from 10 to 500, and even more lysine. preferably from 100 to 500, 0523 Alternatively, instead of sequential additions of 0519 q is 1 or 2. lysine residues, a branched polylysine moiety may be 0520. In a preferred embodiment, B is pentaerythritol. assembled first and subsequently coupled to the 4-arm-PEG 0521. Another subject of the present invention is a method amine reagent. Such polylysine may be obtained by batch for the synthesis of the water-soluble carrier-linked prodrug condensation or by means of sequential assembly using pro of formula (I) or a pharmaceutically acceptable salt thereof. tected lysine building blocks. Water-soluble carrier-linked prodrugs of formula (I) or pre 0524 For example it may be desirable to obtain such car cursors thereof invention may be prepared by known methods rier carrying 32 amino groups, consequently seven lysines or in accordance with the reaction sequences described would be attached to each arm of a 4-arm-PEGamine. below. The starting materials used in the preparation (synthe 0525. In another embodiment, the PEG reagent may be a sis) of water-soluble carrier-linked prodrugs of formula (I) or 4-arm-PEG-carboxylate. In this case the dendritic moieties precursors thereof are known or commercially available, or may be generated from glutamic or aspartic acid, and the can be prepared by known methods or as described below. resulting carrier would carry a number of terminal carboxy 0522. A preferred starting material is a 4-arm-PEGamine groups. reagent with the 4-arm-PEGamine reagent having a molecu 0526 Alternatively, instead of sequential additions of lar weight ranging from 0.2 to 160 kDa. To such 4-arm-PEG glutamic or aspartic acid residues, a branched poly-glutamate amine reagent, lysine residues are coupled sequentially to or poly-aspartate moiety may be assembled first and Subse US 2014/02962.57 A1 Oct. 2, 2014 50 quently coupled to the 4-arm-PEG-carboxylate reagent. Such 0536 (i) Buffering agents: physiologically tolerated buff polyglutamate or -aspartate may be obtained by batch con ers to maintain pH in a desired range, such as Sodium densation or by means of sequential assembly using corre phosphate, bicarbonate. Succinate, histidine, citrate and sponding protected amino acid building blocks. acetate, Sulphate, nitrate, chloride, pyruvate. Antacids such 0527. In yet another embodiment, an oligo- or polyglyc as Mg(OH) or ZnCO may be also used. Buffering capac erol may be converted into a corresponding poly-amine com ity may be adjusted to match the conditions most sensitive prising a glycerol condensation product core. Such polyglyc to pH stability erol-derived poly-amine may be coupled to a 4-arm-PEG 0537 (ii) Isotonicity modifiers: to minimize pain that can carboxylate reagent to yield a suitable carrier. It is understood result from cell damage due to osmotic pressure differ that carboxy groups may be activated to enhance their reac ences at the injection depot. Glycerin and sodium chloride tivity. For instance, the carboxy group may be converted into are examples. Effective concentrations can be determined a chloride or an active ester. by osmometry using an assumed osmolality of 285-315 0528. It is also understood that all or a fraction of the mOsmol/kg for serum carrier's reactive functional groups may be present in a free 0538 (iii) Preservatives and/or antimicrobials: multidose form, as salts or conjugated to protecting or activating groups. parenteral preparations require the addition of preserva Due to practical reasons, the carrier reagent's number of tives at a Sufficient concentration to minimize risk of branches per arm of the multi-arm, such as a 4-arm PEG patients becoming infected upon injection and correspond reagent will be in a range of, for example 1 to 15, more ing regulatory requirements have been established. Typical preferably 1 to 7. preservatives include m-cresol, phenol, methylparaben, 0529 Functional groups of the carrier are then used for ethylparaben, propylparaben, butylparaben, chlorobu coupling linker reagents comprising Suitable complementary tanol, benzyl alcohol, phenylmercuric nitrate, thimerosol, functional groups to yield carrier-linker conjugate reagents. Sorbic acid, potassium Sorbate, benzoic acid, chlorocresol, To such carrier-linker conjugate reagents are Subsequently and benzalkonium chloride drugs coupled. Alternatively, a drug moiety may first be 0539 (iv) Stabilizers: Stabilization is achieved by coupled to a linker reagent and Subsequently, the biologically strengthening of the protein-Stabilizing forces, by destabi active moiety-linker reagent is coupled to the carrier. lization of the denatured state, or by direct binding of 0530 Another aspect of the present invention is a pharma excipients to the protein. Stabilizers may be amino acids ceutical composition comprising the water-soluble carrier Such as alanine, arginine, aspartic acid, glycine, histidine, linked prodrugs of formula (I) or a pharmaceutical salt lysine, proline, Sugars such as glucose, Sucrose, trehalose, thereof, and optionally one or more pharmaceutically accept polyols such as glycerol, mannitol, Sorbitol, salts such as able excipients. potassium phosphate, Sodium Sulphate, chelating agents 0531. The pharmaceutical composition is further Such as EDTA, hexaphosphate, ligands Such as divalent described in the following paragraphs. metal ions (Zinc, calcium, etc.), other salts or organic mol 0532. The pharmaceutical composition comprising the ecules Such as phenolic derivatives. In addition, oligomers water-soluble carrier-linked prodrug of formula (I) may be or polymers such as cyclodextrins, dextran, dendrimers, provided as a liquid composition or as a dry composition. PEG or PVP or protamine or HSA may be used Suitable methods of drying are, for example, spray-drying 0540 (v) Anti-adsorption agents: Mainly ionic or non and lyophilization (freeze-drying). A preferred method of ionic Surfactants or other proteins or soluble polymers are drying is lyophilization. used to coat or adsorb competitively to the inner surface of 0533 Preferably, the water-soluble carrier-linked prodrug the composition’s or composition's container. Suitable of formula (I) is sufficiently dosed in the composition to Surfactants are e.g., alkylsulfates, such as ammonium lau provide a therapeutically and/or diagnostically effective ryl sulfate and sodium lauryl sulfate, alkyl ether sulfates, amount of the biologically active moiety, in particular for at Such as Sodium laureth Sulfate and sodium myreth Sulfate, least one day in one application. More preferably, one appli Sulfonates Such as dioctyl Sodium sulfoSuccinates, perfluo cation of the pharmaceutical composition comprising the rooctanesulfonates, perfluorobutanesulfonates, alkylben water-soluble carrier-linked prodrug is sufficient for at least Zene Sulfonates, phosphates, such as alkyl aryl ether phos two days, such as three days, four days, five days, six days, or phates and alkyl ether phosphates, carboxylates. Such as is sufficiently dosed for at least one week, such as for one fatty acid salts (soaps) or sodium Stearate, sodium lauroyl week, two weeks, three weeks, four weeks, five weeks, six sarcosinate, perfluorononanoate, perfluorooctanoate, weeks, seven weeks, eight weeks, three months, four months, octenidine dihydrochloride, quaternary ammonium cat five months or six months. ions such as cetyl trimethylammonium bromide, cetyl tri 0534. A pharmaceutical composition comprising a water methylammonium chloride, cetylpyridinium chloride, soluble carrier-linked prodrug or a pharmaceutically accept polyethoxylated tallow amine, benzalkonium chloride, able salt thereof of formula (I) preferably comprises one or benzethonium chloride, 5-bromo-5-nitor-1,3-dioxane, more excipients. dimethyldioctadecylammonium chloride, dioctade 0535 Excipients may be categorized as buffering agents, cyldimethylammonium bromide, Zwitterionics, such as isotonicity modifiers, preservatives, stabilizers, anti-adsorp 3-(3-cholamidopropyl)dimethylammonio-1-propane tion agents, oxidation protection agents, viscosifiers/viscos Sulfonate, cocamidopropyl hydroxysultaine, amino acids, ity enhancing agents, or otherauxiliary agents. In some cases, imino acids, cocamidopropyl betaine, lecithin, fatty alco these ingredients may have dual or triple functions. The phar hols, such as cetyl alcohol, Stearyl alcohol, cetostearyl maceutical compositions of water-soluble carrier-linked pro alcohol, oleyl alcohol, polyoxyethylene glycol alkyl drugs according to the present invention preferably comprise ethers, such as octaethylene glycol monododecyl ether, one or more excipients, selected from the groups consisting pentaethylene glycol monododecyl ether, polyoxypropy of: lene glycol alkyl ethers, glucoside alkyl ethers, such as US 2014/02962.57 A1 Oct. 2, 2014 51

decyl glucoside, lauryl glucoside, octyl glucoside, poly ing that the container in which it is Supplied contains more oxyethylene glycol octylphenol ethers such as Triton than one therapeutic dose, i.e., a multiple dose composition X-100, polyoxyethylene glycol alkylphenol ethers such as contains at least 2 doses in case of therapeutically active nonoxynol-9, glycerol alkyl esters such as glyceryl laurate, drugs. Such multiple dose composition of water-soluble car polyoxyethylene glycol Sorbitan alkyl esters such as rier-linked prodrug can either be used for different patients in polysorbates, sorbitan alkyl esters, cocamide MEA and need thereof or can be used for one patient, wherein the cocamide DEA, dodecyl dimethylamine oxide, block remaining doses are stored after the application of the first copolymers of polyethylene glycol and polypropylene gly dose until needed. col, such as poloxamers (Pluronic F-68), PEG dodecyl 0548. In another aspect of the present invention the phar ether (Brij 35), polysorbate 20 and 80, other anti-absorp maceutical composition is in a container. Suitable containers tion agents are dextran, polyethylene glycol, PEG-polyhis for liquid or dry compositions are, for example, Syringes, tidine, BSA and HSA and gelatines. Chosen concentration vials, vials with stopper and seal, ampouls, and cartridges. In and type of excipient depends on the effect to be avoided particular, the liquid or dry composition comprising the but typically a monolayer of surfactant is formed at the water-soluble carrier-linked prodrug of formula (I) is pro interface just above the CMC value vided in a syringe. If the pharmaceutical composition com 0541 (vi) Lyo- and/or cryoprotectants: During freeze- or prising the water-soluble carrier-linked prodrug is a dry phar spray drying, excipients may counteract the destabilizing maceutical composition the container preferably is a dual effects caused by hydrogen bond breaking and water chamber Syringe. In such embodiment, said dry removal. For this purpose Sugars and polyols may be used pharmaceutical composition is provided in a first chamber of but corresponding positive effects have also been observed the dual-chamber Syringe and reconstitution Solution is pro for Surfactants, amino acids, non-aqueous solvents, and vided in the second chamber of the dual-chamber syringe. other peptides. Trehalose is particulary efficient at reduc 0549. Prior to applying the dry composition of water ing moisture-induced aggregation and also improves ther soluble carrier-linked prodrug to a patient in need thereof, the mal stability potentially caused by exposure of protein dry composition is reconstituted. Reconstitution can take hydrophobic groups to water. Mannitol and Sucrose may place in the container in which the dry composition of water also be used, either as solely of cryoprotectant or in com soluble carrier-linked prodrug is provided. Such as in a vial, bination with each other where higher ratios of mannitol: Syringe, dual-chamber Syringe, ampoule, and cartridge. Sucrose are known to enhance physical stability of a lyo Reconstitution is done by adding a predefined amount of philized cake. Mannitol may also be combined with reconstitution solution to the dry composition. Reconstitution trehalose. Trehalose may also be combined with sorbitol or solutions are sterile liquids, such as water or buffer, which sorbitol used as the sole protectant. Starch or starch deriva may contain further additives, such as preservatives and/or tives may also be used antimicrobials, such as, for example, benzylalcohol and 0542 (vii) Oxidation protection agents: antioxidants such cresol. Preferably, the reconstitution solution is sterile water. as ascorbic acid, ectoine, methionine, glutathione, mono When a dry composition is reconstituted, it is referred to as a thioglycerol, morin, polyethylenimine (PEI), propyl gal “reconstituted pharmaceutical composition” or “reconsti late, vitamin E, chelating agents such aus citric acid, tuted composition'. EDTA, hexaphosphate, thioglycolic acid 0550 An additional aspect of the present invention relates 0543 (viii) Spreading or diffusing agent: modifies the per to the method of administration of a reconstituted or liquid meability of connective tissue through the hydrolysis of pharmaceutical composition comprising the water-soluble components of the extracellular matrix in the intrastitial carrier-linked prodrug of formula (I). The pharmaceutical space Such as but not limited to hyaluronic acid, a polysac composition comprising water-soluble carrier-linked pro charide found in the intercellular space of connective tis drug may be administered by methods of inhalation, injection Sue. A spreading agent such as but not limited to hyalu or infusion, including intradermal, Subcutaneous, intramus ronidase temporarily decreases the Viscosity of the cular, intravenous, intraosseous, and intraperitoneal. Prefer extracellular matrix and promotes diffusion of injected ably, the pharmaceutical composition comprising water drugs. soluble carrier-linked prodrug is administered 0544 (ix) Other auxiliary agents: Such as wetting agents, Subcutaneously. viscosity modifiers, antibiotics, hyaluronidase. Acids and 0551. The preferred method of administration for dry bases such as hydrochloric acid and Sodium hydroxide are pharmaceutical compositions comprising the water-soluble auxiliary agents necessary for pH adjustment during manu carrier-linked prodrugs of the present invention is via inhala facture. tion. 0545. In a general embodiment the pharmaceutical com 0552. Therefore, in a preferred embodiment, the present position comprising the water-soluble carrier-linked pro invention relates to a water-soluble carrier-linked prodrug or drugs of formula (I) in either dry or liquid form may be a pharmaceutically acceptable salt thereof of formula (I) or a provided as a single or multiple dose composition. pharmaceutical composition of the present invention, for use 0546. In one embodiment of the present invention, the as medicament for topical, enteral administration, parenteral liquid or dry pharmaceutical composition comprising the administration, inhalation, injection, or infusion, intraarticu water-soluble carrier-linked prodrug is provided as a single lar, intradermal, Subcutaneous, intramuscular, intravenous, dose, meaning that the container in which it is Supplied con intraosseous, and intraperitoneal, intrathecal, intracapsular, tains one pharmaceutical dose in case of therapeutically intraorbital, intracardiac, transtracheal, Subcuticular, intraar active drugs. ticular, Subcapsular, Subarachnoid, intraspinal, intraventricu 0547 Alternatively, in one embodiment, the liquid or dry lar or intrasternal administration. pharmaceutical composition comprising the water-soluble 0553. Therefore, in another preferred embodiment, the carrier-linked prodrug is a multiple dose composition, mean present invention relates to a water-soluble carrier-linked pro US 2014/02962.57 A1 Oct. 2, 2014 52 drug or a pharmaceutically acceptable salt thereof of formula 0567 A preferred kit of parts comprises a needle and a (I) or a pharmaceutical composition of the present invention, container containing the composition according to the present wherein such water-soluble carrier-linked prodrug or phar invention and optionally further containing a reconstitution maceutically acceptable salt thereof or pharmaceutical com Solution, the container being adapted for use with the needle. position is suitable to be administered to a patient via topical, Preferably, the container is a dual-chamber syringe. enteral or parenteral administration and by methods of exter 0568. In another aspect, the invention provides a cartridge nal application, inhalation, injection or infusion, including comprising a pharmaceutical composition of water-soluble intraarticular, intradermal, Subcutaneous, intramuscular, carrier-linked prodrug as hereinbefore described for use with intravenous, intraosseous, and intraperitoneal, intrathecal, a pen injector device. The cartridge may contain a single dose intracapsular, intraorbital, intracardiac, transtracheal, Subcu or multiplicity of doses of the water-soluble carrier-linked ticular, intraarticular, Subcapsular, Subarachnoid, intraspinal, prodrug. intraventricular and intrasternal application. 0569. Yet another aspect of the present invention is a 0554. A further aspect is a method of preparing a recon water-soluble carrier-linked prodrug or a pharmaceutically stituted composition comprising a diagnostically and/or acceptable salt thereof of formula (I) or a pharmaceutical therapeutically effective amount of water-soluble carrier composition of the present invention, for use as a medicament linked prodrug of formula (I), and optionally one or more and/or diagnostic. pharmaceutically acceptable excipients, the method compris 0570. In another embodiment, the present invention ing the step of relates to the use of a water-soluble carrier-linked prodrug of 0555 contacting the pharmaceutical composition com formula (I) or a pharmaceutically acceptable salt thereof, or a prising water-soluble carrier-linked prodrug of formula pharmaceutical composition of the present invention for the (I) with a reconstitution solution. preparation of a medicament and/or diagnostic, in particular 0556. Another aspect is a reconstituted pharmaceutical for the treatment and/or diagnosis of diseases. composition comprising a diagnostically and/or therapeuti 0571. It is understood, that the disease that can be treated cally effective amount of the water-soluble carrier-linked pro and/or diagnosed a water-soluble carrier-linked prodrug of drug of formula (I), and optionally one or more pharmaceu the present invention or a pharmaceutically acceptable salt tically acceptable excipients. thereof, or a pharmaceutical composition of the present 0557. Another aspect of the present invention is the invention depends on the active agent. A water-soluble car method of manufacturing a dry composition of water-soluble rier-linked prodrug with an active agent moiety which has carrier-linked prodrug. In one embodiment, such dry compo anti-cancer activity, like Doxorubicin, is typically adminis sition is obtainable by tered to a cancer patient. Analogously, a water-soluble car 0558 (i) admixing the water-soluble carrier-linked pro rier-linked prodrug with an active agent moiety which has drug with one or more excipients, anti-inflammatory activity, like aminosalicylic acid, is typi 0559 (ii) transfering amounts equivalent to single or cally administered to a patient who suffers from an inflam multiple doses into a suitable container, matory disease, like rheumatoid arthritis, IBD or Morbus 0560 (iii) drying the composition in said container, and Crohn. Analogously, a water-soluble carrier-linked prodrug 0561 (iv) sealing the container. with an active agent moiety which has neurological activity is 0562 Suitable containers are vials, syringes, dual-cham typically administered to a patient Suffering from a neurologi ber Syringes, ampoules, and cartridges. cal disease like Alzheimer's disease or Parkinson's disease. 0563 Another aspect of the present invention is a kit of Analogously, a water-soluble carrier-linked prodrug with an parts. active agent moiety which has anti-infective activity, like 0564) If the administration device is simply a hypodermic Gancyclovir, is typically administered to a patient Suffering Syringe then the kit may comprise the Syringe, a needle and a from a infectious disease like bacterial, viral, protozoal or container comprising the dry pharmaceutical composition of fungal infection. water-soluble carrier-linked prodrug suitable for use with the 0572. In case the water-soluble carrier-linked prodrugs Syringe and a second container comprising the reconstitution according to the invention contain one or more acidic or basic Solution. groups, the invention also comprises their corresponding 0565. If the pharmaceutical composition is a liquid com pharmaceutically or toxicologically acceptable salts, in par position then the kit may comprise the Syringe, a needle and ticular their pharmaceutically utilizable salts. Thus, the a container comprising the liquid composition of water water-soluble carrier-linked prodrugs according to the inven soluble carrier-linked prodrug suitable for use with the tion which contain acidic groups can be used according to the Syringe. invention, for example, as alkali metal salts, alkaline earth 0566 In more preferred embodiments, the injection metal salts or as ammonium salts. More precise examples of device is other than a simple hypodermic syringe and so the Such salts include Sodium salts, potassium salts, calcium salts, separate container with reconstituted or liquid water-soluble magnesium salts or salts with ammonia or organic amines carrier-linked prodrug is adapted to engage with the injection Such as, for example, ethylamine, ethanolamine, triethanola device such that in use the liquid composition in the container mine or amino acids. Water-soluble carrier-linked prodrugs is in fluid connection with the outlet of the injection device. according to the invention which contain one or more basic Examples of administration devices include but are not lim groups, i.e. groups which can be protonated, can be present ited to hypodermic syringes and pen injector devices. Particu and can be used according to the invention in the form of their larly preferred injection devices are the pen injectors in which addition salts with inorganic or organic acids. Examples for case the container is a cartridge, preferably a disposable car Suitable acids include hydrogen chloride, hydrogen bromide, tridge. Optionally, the kit of parts comprises a safety device phosphoric acid, Sulfuric acid, nitric acid, methanesulfonic for the needle which can be used to cap or cover the needle acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, after use to prevent injury. oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic US 2014/02962.57 A1 Oct. 2, 2014

acid, benzoic acid, formic acid, propionic acid, pivalic acid, LTQ Orbitrap Discovery instrument and spectra were, if nec diethylacetic acid, malonic acid. Succinic acid, pimelic acid, essary, interpreted by Thermo scientific software xcalibur. fumaric acid, maleic acid, malic acid, Sulfaminic acid, phe M/Z signals corresponding to the most abundant isotope are nylpropionic acid, gluconic acid, ascorbic acid, isonicotinic given. acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the water-soluble carrier-linked Example 1 prodrugs according to the invention simultaneously contain acidic and basic groups in the molecule, the invention also Synthesis of Pramipexole Linker Building Block includes, in addition to the salt forms mentioned, inner salts or betaines (Zwitterions). The respective salts can be obtained by Synthesis of pramipexole(boc) 1 a customary methods which are known to the person skilled in 0579 the art like, for example by contacting these with an organic or la inorganic acid or base in a solvent or dispersant, or by anion boc exchange or cation exchange with other salts. The present invention also includes all salts of the prodrugs which, owing S N-1N to low physiological compatibility, are not directly suitable HN-K for use in pharmaceuticals but which can be used, for N example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. 0573 Yet another aspect of the present invention is a 0580 Pramipexole dihydrochloride (MW 284 g/mol, 400 method of treating, controlling, delaying or preventing in a mg, 1.41 mmol) and Di-tert-butyl dicarbonate (MW 218 mammalian patient, preferably in a human, in need of the g/mol, 307 mg, 1.41 mmol) were dissolved in DMSO (5 mL). treatment of one or more conditions comprising administer DIEA (735 uL, 4.22 mmol) was added and solution was ing to said patient a diagnostically and/or therapeutically stirred for 3 hat RT. 1a was purified by RP-HPLC. effective amount of a water-soluble carrier-linked prodrug of 0581. Yield: 422 mg (0.99 mmol, TFA salt). the present invention or a pharmaceutical composition com 0582 MS: m/z. 312.2=M+H" (MW calculated=311.5 prising the water-soluble carrier-linked prodrug of the present g/mol). invention or a pharmaceutically acceptable salt thereof. Synthesis of Fmoc-Gly-pramipexole(boc) 1b OPERATIVE EXAMPLES 0583 0574. The subject matter of the present invention is eluci 1b dated in more detail below, using examples, without any boc intention that the subject matter of the invention should be O confined to these exemplary embodiments. N Materials and Methods fmoc1 Rul N-(| \ S11 N1). N (0575 Pramipexole dihydrochloride was obtained from Carbone Scientific Co., Ltd., Wuhan, China. Amino 4-arm PEGs were obtained from Jenkem Technology, Beijing, P. R. 0584) Pramipexole(boc) 1a (MW 311, 5 g/mol, 50 mg, China. 2-Chlorotrityl chloride resin was obtained from 0.118 mmol), Fmoc-Gly-OH (MW 297 g/mol, 52 mg, 0.176 Merck Biosciences GmbH. Schwalbach/Ts. Germany. Pali mmol) and PyBOP (104 mg., 0.200 mmol) were dissolved in peridone was purchased from Carbon Scientific Co., Ltd, DMSO (200 uL). DIEA (90 uL, 0.517 mmol) was added and London, UK. All other chemicals were purchased from the solution was agitated for 15 h. Fmoc-protected interme Sigma-ALDRICH Chemie GmbH. Taufkirchen, Germany. diate 1b was purified by RP-HPLC. 0576 Solid phase synthesis was performed in syringes 0585. Yield: 72 mg (0.12 mmol). 0586 MS: m/z 591.3-M+H" (MW calculated=590.8 equipped with polyethylene frits as reaction vessels. g/mol). RP-HPLC Purification: Synthesis of H-Gly-pramipexole(boc) 1c 0577 RP-HPLC was done on a 100x20 or a 100x40 mm C18 ReproSil-Pur 300 ODS-3 5 pm column (Dr. Maisch, 0587 1c Ammerbuch, Germany) connected to a Waters 600 HPLC boc System and Waters 2487 Absorbance detector. Linear gradi O ents of solution A (0.1% TFA in HO) and solution B (0.1% N TFA in acetonitrile or 0.1% TFA in 2/1 (v/v) methanol/iso IN- S n1N propanol) were used. HPLC fractions containing product N ( were lyophilized. Alternatively, if the HCl salt of the purified N product was desired, TFA was replaced by 0.01% HCl (v/v, 37% HCl) in solution A and solution B. 0588 Compound 1b was dissolved in piperidine/DBU/ DMF (2/2/96) and stirred for 30 min at RT. LC-MS Analytics: 0589 Product 1c was purified by RP-HPLC. 0578 Liquid chromatography-electronspray ionization 0590. Yield: 30.6 mg (0.06 mmol, TFA salt). mass spectrometry was performed on a Waters Acquity Ultra 0591 MS: m/z 369.2=M+H" (MW calculated=368.5 Performance LC instrument connected to a Thermo scientific g/mol). US 2014/02962.57 A1 Oct. 2, 2014 54

Synthesis of Pramipexole Linker Building Block 1d 0592

C 1. Fmoc-Ava-OH loading 1. bis(pentafluorophenyl) carbonate 2. Fmoc deprotection 2. H-Gly-pramipexole(boc)3 Her

resin cleavage and deprotection

0593 2-Chlorotrityl chloride resin (1.0 mmol/g, 420 mg. 0599 4-Arm-PEG5000 tetraamine (MW ca. 5200 g/mol, 0.42 mmol) was loaded with Fmoc-4-aminovaleric acid 5.20 g, 1.00 mmol, HCl salt) was dissolved in 20 mL of according to manufacturers instruction. For Fmoc removal, DMSO (anhydrous). Boc-Lys(Boc)-OH (2.17 g. 6.25 mmol) the resin was agitated with 2/2/96 (v/v/v) piperidine/DBU/ in 5 mL of DMSO (anhydrous), EDC HCl (1.15 g. 6.00 DMF (two times, 10 min each) at RT and washed with DMF mmol), HOBt.HO (0.96 g. 6.25 mmol), and collidine (5.20 (ten times). mL, 40 mmol) were added. The reaction mixture was stirred 0594 Synthesis of urea: Resin was washed with DCM (10 for 30 min at RT. The reaction mixture was diluted with 1200 times) and reacted with bis(pentafluorophenyl) carbonate mL of dichloromethane and washed with 600 mL of 0.1 N (MW 394 g/mol, 414 mg, 1.05 mmol) and DIEA (365 uL.2.1 mmol) in DCM at RT for 45 min. Resin was washed with HSO (2x), brine (1x), 0.1 M NaOH (2x), and 1/1 (v/v) DCM (5 times) and DMF (10 times) and reacted with 1c (MW brine/water (4x). Aqueous layers were reextracted with 500 482.5 g/mol. 203 mg 0.42 mmol) and 2.5 eq DIEA (183 uL. mL of DCM. Organic phases were dried over NaSO, fil 1.05 mmol) in DMF for 75 minat RT. Resin was washed with tered and evaporated to give 6.3 g of crude product 2a as DMF (10 times). colorless oil. Compound 2a was purified by RP-HPLC. 0595 Cleavage from resin and boc deprotection: Resin 0600 Yield 3.85 g (59%) colorless glassy product 2a. was washed with DCM (10 times) and treated three times for 0601 MS: m/z 1294.4=M+5H (m/z of M+5H* cal 30 minutes with 7/3 (v/v) DCM/HFIP. Eluates were com culated for a 4-Arm-PEG containing a total of 107 ethylene bined and volatiles were removed under reduced pressure. glycol units=1294.6). Residue was incubated in TFA for 10 min at RT. TFA was removed under a stream of nitrogen and 1d was purified by Synthesis of 4-Arm PEG Lysine 2b RP-HPLC. 0596) Yield: 160 mg (0.258 mmol, HCl salt). 0602 0597 MS: m/z 412.2=M+H" (MW calculated=411.5 g/mol). Example 2 NH Synthesis of 4-Arm PEG Trilysine Carrier H C O N Synthesis of 4-arm PEG lysine(boc) 2a N-1-on 0598 O 2a

boc HN1 NH2 H 4 C O N-1-on N O 0603 Compound 2b was obtained by stirring 3.40 g of boc compound 2a (0.521 mmol) in 5 mL of methanol and 9 mL of N1 4N HCl in dioxane at RT for 15 min. Volatiles were removed H 4 in vacuo. The product was used in the next step without further purification. 0604 MS: m/z. 1151.9-M+5H" (m/z calculated=1152. 0). US 2014/02962.57 A1 Oct. 2, 2014 55

Synthesis of 4-arm PEG trilysine(boc) 2c 0605

H N-boc

O

HN N-boc N-1-on O O

N H

N-boc H n^28

0606 For synthesis of compound 2c, 3.26 g of compound Synthesis of 4-arm PEG trilysine 2d 2b (0.54 mmol) were dissolved in 15 mL of DMSO (anhy 0611 drous). 2.99 g, Boc-Lys(Boc)-OH (8.64 mmol) in 15 mL DMSO (anhydrous), 1.55 g EDC HCl (8.1 mmol), 1.24 g 2d HOBt. HO (8.1 mmol), and 5.62 mL of collidine (43 mmol) NH2 were added. The reaction mixture was stirred for 30 min at RT.

O 0607 Reaction mixture was diluted with 800 mL DCM and washed with 400 mL of 0.1 NHSO (2x), brine (1x), 0.1 HN NH2 MNaOH (2x), and 1/1 (v/v) brine/water (4x). Aqueous layers O N-1-on were reextracted with 800 mL of DCM. Organic phases were O dried with NaSO4, filtered and evaporated to give a glassy O NH N 2 crude product. H

0608 Product was dissolved in DCM and precipitated with cooled (-18° C.) diethyl ether. This procedure was repeated twice and the precipitate was dried in vacuo. NH2 , n^28

0609 Yield: 4.01 g (89%) colorless glassy product 2c, 0612 Compound 2d was obtained by stirring a solution of which was used in the next step without further purification. compound 2c (3.96 g., 0.47 mmol) in 7 mL of methanol and 20 mL of 4 NHCl in dioxane at RT for 15 min. Volatiles were removed in vacuo. The product was used in the next step 0610 MS: m/z 1405.4=M+6H" (m/z calculated=1405. without further purification. 4). 0613 MS: m/z 969.6=M+7H7 (m/z calculated=969.7). US 2014/02962.57 A1 Oct. 2, 2014 56

Example 3 Synthesis of carrier linked prodrug 4-arm PEG trilysine tetrapramipexole 3 0614

O O S

HN NH N1)H MN O

O O N

C O NH HN fir-Si-kCV n-1N N-1-on- O O N O O O O N

N H--~~~-N-g H N1) S O 'N 1-1 H O H

O "~ H N-H - O O O S v-n-

0615. 2d (MW approx 6500 g/mol. 20 mg, 3.1 umol) in DMF (1 mL) is reacted with compound 1d (MW 448 g/mol, 90 mg 0.2 mmol), PyBOP (MW 520 g/mol, 105 mg, 0.2 mmol) and collidine (132 uL. 1.0 mmol) for 3 hat RT. 3 is purified by means of RP-HPLC. Example 4 Synthesis of Branched Paliperidone Building Block Synthesis of Intermediate 4a 0616 4a O F N -u Co-Ob- r S

0617 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. 4a was purified by RP-HPLC. 0618. Yield: 1.60 g (2.77 mmol, 60%, HCl salt). 0619 MS: m/z 541.2=M+H" (MW calculated=540.7) US 2014/02962.57 A1 Oct. 2, 2014 57

Synthesis of Intermediate 4b 0620

4b -----O O O

0621 4a (1.50 g, 2.77 mmol) was dissolved in 40 mL DCM (dry, mol. sieve). DCC (1.72g, 8.32 mmol), N-hydroxy succinimide (1.60 g, 13.87 mmol) and a catalytic amount of DMAP was added and mixture was stirred for 3 h at RT. Precipitate was filtered off and the solvent was removed under reduced pressure. Residue was dissolved with ACN/water 1/1 and acidified with acetic acid until pH reached about 4.4b was purified by RP-HPLC. 0622 Yield: 1.25 g (TFA salt, 1.66 mmol, 60%). 0623 MS: m/z 638.25-M+H" (MW calculated=637.67) Synthesis of Intermediate 4c 0624 4c O OH

l

0625. A solution of lysine (19 mg 0.13 mmol) in 2.5 mL acetic acid to a pH of approx. 4 and diluted with water and 0.5M sodium borate buffer pH 8.5 was given to a solution of acetonitrile. 4c was purified by RP-HPLC. 0626. Yield: 125 mg (HCl salt, 0.10 mmol, 74%). 4b (TFA salt, 3OO ng, O40 mmol) in 5 mL DMSO. Mixture 0627 MS: m/Z 1.191 .55=M+H" (MW calculated=1191. was stirred for 60 min at RT. Solution was acidified with 35) US 2014/02962.57 A1 Oct. 2, 2014 58

Synthesis of Intermediate 4d 0628

O) O HN

O-N s

F N -CCO l

0629 4c (bis HCl salt, 196 mg, 0.155 mmol) was dis solved in 12 mL DCM (anhydrous, mol. sieve). Bis(pen tafluorophenyl) carbonate (MW 394 g/mol. 122 mg, 0.310 mmol) and sym-collidine (205 uL. 1.55 mmol) were added and mixture was stirred for 16 hat RT. Product was precipi tated from reaction mixture by adding 30 mL MTBE (puriss., p.a. D99.5%) and separated by centrifugation. Precipitate was redissolved in DCM and precipitation procedure was repeated. Precipitate was redissolved in DCM and volatiles were removed in vacuo (waterbath at 20°C.). Product 4d was dried by means of lyophilizer. 0630. Yield: 185 mg (88%) 0631 MS: m/z 1357.52=M+H" (MW calculated=1357. 40) 0632 Pfp ester of 4d is partially hydrolyzed under LCMS conditions. A purity of 95% (LCMS, 215 nm) was confirmed after derivatization of 1d with 1-dodecylamine. For derivati Zation purpose 0.1 mg 4d is reacted with 0.3 mg 1-dodecy lamine for 5 min at RT in DCM and analyzed by means of LCMS. US 2014/02962.57 A1 Oct. 2, 2014 59

Example 5 Synthesis of carrier linked prodrug 4-arm PEG 20 kDa-octapaliperidone 0633

5 N-O | O N F N

H N O

O O O o-ha- O -> --~.NH O

NNO n-115

0634) Amino 4-Arm PEG 20 kDa (MW 21 kDa, 60 mg, was plotted against time. Drug release was found to follow 2.9 umol) was reacted with intermediate 4d (32 mg, 23 umol) first order kinetics. Curve fitting software was used to deter in ACN (1.5 mL, anhydrous, mol. sieve) and DIEA (8 uL, 47 mine half life time of drug release from the respective conju umol) under stirring for 16 hat RT. Mixture was quenched by gate. A paliperidone release half life time of 5.5 d was addition of 1-dodecylamine (2.5 mg), acidified with acetic obtained. acid and diluted with water, followed by purification of com pound 5 by RP-HPLC (main peak, 215 nm). Combined ABBREVIATIONS HPLC fractions (40 mL) were mixed with water (30 mL) and 0.5 M sodium phosphate pH 7.4 (4 mL). The mixture was 0637 ACN acetonitrile extracted with DCM (25 mL, 3x) and combined organic 0638 Boc t-butyloxycarbonyl phases were dried over NaSO and evaporated under 0639 DCC N,N'-dicyclohexylcarbodiimide reduced pressure. Yield: 54 mg 0640 DCM dichloromethane 0635 Compound 5 proved to be a uniform material 0641 DIEA diisopropylethylamine according to UPLC analytics (Waters BEH300 C18 column, 0642 DMAP dimethylamino-pyridine 2.1 x50 mm, 1.7 pm particle size, flow 0.25 mL/min, linear 0643 DMF N,N-dimethylformamide gradient 0-70% B in 4 min, mobile phase A: 0.05% TFA in 0644 DMSO dimethylsulfoxide water, mobile phase B: 0.04% TFA in acetonitrile), eluting at 0645 EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodi 3.60 min. imide 0646 eq Stoichiometric equivalent Example 6 (0647 HOBt hydroxybenzotriazole 0648 LCMS mass spectrometry-coupled liquid chroma Drug Release Kinetics from PEG Conjugate 5 tography 0636 Conjugate 5 (1.8 mg) was dissolved in acetonitrile 0649) MS mass spectrum (100 ul) and diluted with pH 7.4 buffer (60 mM sodium 0650 MTBE methyl-tert-butylether phosphate, 3 mM EDTA, 0.01% Tween-20, 1.4 mL). Sample 0651) MW molecular mass was incubated at 37°C. At various time points aliquots were 0652 NMP N-methyl-2-pyrrolidone analyzed by UPLC and the amount of released paliperidone 0653 PEG poly(ethylene glycol) US 2014/02962.57 A1 Oct. 2, 2014 60

0654 PyBOP benzotriazol-1-yl-oxytripyrrolidinophos 21. The water-soluble carrier-linked prodrug, or a pharma phonium hexafluorophosphate ceutically acceptable salt thereof, as claimed in claim 19, 0655 RP-HPLC reversed-phase high performance liquid wherein p is an integer from 100 to 1000. chromatography 22. The water-soluble carrier-linked prodrug, or a pharma 0656 RT room temperature ceutically acceptable salt thereof, as claimed in claim 14. 0657 TFA trifluoroacetic acid wherein each Hyp independently comprises a moiety selected 0658 While this invention has been described in conjunc from the group consisting of tion with the specific embodiments outlined above, it is evi a polyalcohol in bound form comprising at least 2 hydroxyl dent that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, the pre groups: ferred embodiments of the invention as set forth above are a polyamine in bound form comprising at least 2 amine intended to be illustrative, not limiting. Various changes may groups; and be made without departing from the spirit and scope of the a polycarboxylate in bound form comprising at least 2 inventions as defined in the following claims. carboxylate groups. 1-13. (canceled) 23. The water-soluble carrier-linked prodrug, or a pharma 14. A water-soluble carrier-linked prodrug of formula (I), ceutically acceptable salt thereof, as claimed in claim 22, or a pharmaceutically acceptable salt thereof, wherein the polyalcohol is selected from the group consisting of:

I glycerol, pentaerythritol, dipentaerythritol, tripentaeryth B-E-A-Hyp--SP---L-D)) (I) ritol, hexaglycerine, Sucrose, Sorbitol, fructose, manni tol, glucose, cellulose, amyloses, starches, hydroxyalkyl starches, polyvinylalcohols, dextranes, and hyualuro wherein aS. B, A and Hyp form a carrier moiety, and wherein 24. The water-soluble carrier-linked prodrug, or a pharma B is a branching core, ceutically acceptable salt thereof, as claimed in claim 22, each A is independently a poly(ethylene glycol)-based wherein the polyamine is selected from the group consisting polymeric chain, of: each Hyp is independently a branched moiety, ornithine, diornithine, triornithine, tetraornithine, pentaor each SP is independently a spacer moiety, nithine, hexaornithine, heptaornithine, octaornithine, each L is independently a reversible prodrug linker moi nonaornithine, decaornithine, undecaornithine, dodeca ety, ornithine, tridecaornithine, tetradecaornithine, pentade each D is independently a biologically active moiety, caornithine, hexadecaornithine, heptadecaornithine, octadecaornithine, nonadecaornithine, diaminobutyric each x is independently 0 or 1, acid, di(diaminobutyric acid), tri(diaminobutyric acid), each m is independently an integer of from 2 to 64, and tetra(diaminobutyric acid), penta(diaminobutyric acid), n is an integer from 3 to 32. hexadiaminobutyric acid), hepta(diaminobutyric acid), 15. The water-soluble carrier-linked prodrug, or a pharma octa(diaminobutyric acid), nona (diaminobutyric acid), ceutically acceptable salt thereof, as claimed in claim 14. decadiaminobutyric acid), undecacdiaminobutyric wherein m is an integer from 2 to 32. acid), dodecadiaminobutyric acid), tridecadiaminobu 16. The water-soluble carrier-linked prodrug, or a pharma tyric acid), tetradecadiaminobutyric acid), pentadeca ceutically acceptable salt thereof, as claimed in claim 15, (diaminobutyric acid), hexadecadiaminobutyric acid), wherein m is 2, 3, 4, 5, 6, 7, or 8. heptadecadiaminobutyric acid), octadecadiaminobu 17. The water-soluble carrier-linked prodrug, or a pharma tyric acid), nonadecadiaminobutyric acid), lysine, dil ceutically acceptable salt thereof, as claimed in claim 14. ysine, trilysine, tetralysine, pentalysine, hexalysine, wherein n is an integer from 3 to 16. heptalysine, octalysine, nonalysine, decalysine, unde 18. The water-soluble carrier-linked prodrug, or a pharma calysine, dodecalysine, tridecalysine, tetradecalysine, ceutically acceptable salt thereof, as claimed in claim 17, pentadecalysine, hexadecalysine, heptadecalysine, wherein n is 4. octadecalysine, nonadecalysine, oligolysines, triorni 19. The water-soluble carrier-linked prodrug, or a pharma thine, tetraornithine, pentaornithine, hexaornithine, ceutically acceptable salt thereof, as claimed in claim 14. heptaornithine, octaornithine, nonaornithine, decaorni wherein each A independently comprises the formula thine, undecaornithine, dodecaornithine, tridecaorni thine, tetradecaornithine, pentadecaornithine, hexade caornithine, heptadecaornithine, octadecaornithine, wherein nonadecaornithine, tridiaminobutyric acid, tetradiami n1 and n2 are independently 1, 2, 3, or 4: nobutyric acid, pentadiaminobutyric acid, hexadiami p is an integer from 5 to 2000; nobutyric acid, heptadiaminobutyric acid, octadiami X3 is a chemical bond or linkage group covalently linked to nobutyric acid, nonadiaminobutyric acid, B; and decadiaminobutyric acid, undecadiaminobutyric acid, X2 is a chemical bond or linkage group covalently linked to dodecadiaminobutyric acid, tridecadiaminobutyric Hyp. acid, tetradecadiaminobutyric acid, pentadecadiami 20. The water-soluble carrier-linked prodrug, or a pharma nobutyric acid, hexadecadiaminobutyric acid, hepta ceutically acceptable salt thereof, as claimed in claim 19, decadiaminobutyric acid, octadecadiaminobutyric acid, wherein n1 and n2 are independently 2 or 3. nonadecadiaminobutyric acid. US 2014/02962.57 A1 Oct. 2, 2014 61

25. The water-soluble carrier-linked prodrug, or a pharma glycerol, pentaerythritol, dipentaerythritol, tripentaeryth ceutically acceptable salt thereof, as claimed in claim 22, ritol, hexaglycerine, Sucrose, Sorbitol, fructose, manni wherein the polycarboxylate is selected from the group con tol, glucose, cellulose, amyloses, starches, hydroxyalkyl sisting of: starches, polyvinylalcohols, dextranes, and hyualuro di(glutamic acid), tri(glutamic acid), tetra(glutamic acid), aS. penta(glutamic acid), hexacglutamic acid), hepta 30. The water-soluable carrier-linked prodrug as claimed in claim 28, wherein the polyamine is selected from the group (glutamic acid), octa(glutamic acid), nona (glutamic consisting of: acid), decac glutamic acid), undecac glutamic acid), ornithine, diornithine, triornithine, tetraornithine, pentaor dodecacglutamic acid), tridecac glutamic acid), tetradeca nithine, hexaornithine, heptaornithine, octaornithine, (glutamic acid), pentadecac glutamic acid), hexadeca nonaornithine, decaornithine, undecaornithine, dodeca (glutamic acid), heptadecac glutamic acid), octadeca ornithine, tridecaornithine, tetradecaornithine, pentade (glutamic acid), nonadecaglutamic acid), di(aspartic caornithine, hexadecaornithine, heptadecaornithine, acid), tri(aspartic acid), tetra(aspartic acid), penta(aspar octadecaornithine, nonadecaornithine, diaminobutyric tic acid), hexa(aspartic acid), hepta(aspartic acid), octa acid, di(diaminobutyric acid), tri(diaminobutyric acid), (aspartic acid), nona (aspartic acid), decacaspartic acid), tetra(diaminobutyric acid), penta(diaminobutyric acid), undecacaspartic acid), dodecacaspartic acid), tridecacas hexadiaminobutyric acid), hepta(diaminobutyric acid), partic acid), tetradecacaspartic acid), pentadecacaspartic octa(diaminobutyric acid), nona (diaminobutyric acid), acid), hexadecacaspartic acid), heptadecacaspartic acid), decadiaminobutyric acid), undecacdiaminobutyric octadecacaspartic acid), nonadecacaspartic acid), poly acid), dodecadiaminobutyric acid), tridecadiaminobu ethyleneimines, and polyvinylamines. tyric acid), tetradecadiaminobutyric acid), pentadeca 26. The water-soluble carrier-linked prodrug, or a pharma (diaminobutyric acid), hexadecadiaminobutyric acid), ceutically acceptable salt thereof, as claimed in claim 14. heptadecadiaminobutyric acid), octadecadiaminobu wherein Hyp has a molecular weight of from 0.1 to 4 kDa. tyric acid), nonadecadiaminobutyric acid), lysine, dil 27. The water-soluble carrier-linked prodrug, or a pharma ysine, trilysine, tetralysine, pentalysine, hexalysine, ceutically acceptable salt thereof, as claimed in claim 14. heptalysine, octalysine, nonalysine, decalysine, unde wherein Hyp has a molecular weight of from 0.2 to 2 kDa. calysine, dodecalysine, tridecalysine, tetradecalysine, 28. The water-soluble carrier-linked prodrug as claimed in pentadecalysine, hexadecalysine, heptadecalysine, claim 14, wherein B comprises a moiety selected from the octadecalysine, nonadecalysine, oligolysines, polyeth group consisting of yleneimines, and polyvinylamines. a polyalcohol in bound form comprising at least 2 hydroxyl 31. The water-soluble carrier-linked prodrug or a pharma groups; and ceutically acceptable salt thereof, as claimed in claim 14. a polyamine in bound form comprising at least 2 amine wherein B comprises pentaerythritol. groups. 32. The water-soluble carrier-linked prodrug, or a pharma 29. The water-soluable carrier-linked prodrug as claimed ceutically acceptable salt thereof, as claimed in claim 14. in claim 28, wherein the polyalcohol is selected from the wherein the carrier moiety is selected from one of structures group consisting of (i) to (iii):

(i)

H C N-1shO1, g US 2014/02962.57 A1 Oct. 2, 2014 62

-continued (ii)

NH

(iii)

NH US 2014/02962.57 A1 Oct. 2, 2014 63

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 1 or 2. ticular, Subcapsular, Subarachnoid, intraspinal, intraventricu 33. The water-soluable carrier-linked prodrug, or a phar lar and intrasternal administration. maceutically acceptable salt thereof, as claimed in claim 32, 37. A method of treating, controlling, delaying or prevent wherein p is an integer from 100 to 500. ing in a mammalian patient in need of the treatment of one or 34. A pharmaceutical composition comprising the water more conditions comprising administering to the patient a soluble carrier-linked prodrug, or a pharmaceutically accept diagnostically and/or therapeutically effective amount of the able salt thereof, as claimed in claim 14, further comprising pharmaceutical composition of claim 34. one or more pharmaceutically acceptable excipients. 38. The method of claim 37, wherein administration of the 35. A method of treating, controlling, delaying or prevent pharmaceutical composition is selected from the group con ing in a mammalian patient in need of the treatment of one or sisting of topical, enteral, parenteral, inhalation, injection, more conditions comprising administering to the 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 14. ticular, intraarticular, Subcapsular, Subarachnoid, intraspinal, 36. The method of claim 35, wherein the administration of intraventricular and intrasternal administration. the prodrug is selected from the group consisting of topical, k k k k k