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(12) Patent Application Publication (10) Pub. N0.: US 2013/0053301 A1 Rau Et A] US 20130053301A1 (19) United States (12) Patent Application Publication (10) Pub. N0.: US 2013/0053301 A1 Rau et a]. (43) Pub. Date: Feb. 28, 2013 (54) DIPEPTIDE-BASED PRODRUG LINKERS A61P 25/00 (2006.01) FOR ALIPHATIC AMINE-CONTAINING A611) 31/00 (200601) DRUGS A61M 5/31 (2006.01) (75) Inventors: Harald Rau; Dossenheim (DE); Torben ‘461p 3 7/02 (200601) Lessmann; Neustadt an der Weinstrasse A611’ 3/04 (2006.01) (DE) A61P 7/02 (2006.01) (73)(21) Assignee:Appl. No.: Ascendis13/574,092 Pharma A/S; Hellerup (DK) C07D 413/140 (2006.01) _ A61P 37/08 (2006.01) (22) PCT Flled: Jan‘ 21’ 2011 (52) us. Cl. .......... .. 514/13; 530/308; 540/551; 604/82 (86) PCT No.: PCT/EP2011/050821 (57) ABSTRACT § 371 (0)0), (2); (4) Date: Oct. 15, 2012 The present invention relates to a prodrug or a pharmaceuti _ _ _ _ _ cally acceptable salt thereof; comprising a drug linker conju (30) Forelgn Apphcatlon Prmnty Data gate D-L; Wherein D being a biologically active moiety con Jan. 22, 2010 (EP) ................................ .. 10151465.1 raining an alliphmiC amine group is conjugated to one Or more polymeric carriers via dipeptide-containing linkers L. Such Publication Classi?cation carrier-linked prodrugs achieve drug releases With therapeu (51) Int CL tically useful half-lives. The invention also relates to pharma (‘0 7K 1 7/08 (200601) ceutical compositions comprising said prodrugs and their use A61K 38/05 (2006.01) as medicaments. US 2013/0053301A1 Feb. 28, 2013 DIPEPTIDE-BASED PRODRUG LINKERS dence of the release mechanism of the drug upon biodegra FOR ALIPHATIC AMINE-CONTAINING dation may cause interpatient variability. DRUGS [0007] Alternatively, the drugs may be conjugated to a car [0001] The present application claims priority from PCT rier through permanent covalent bonds. This approach is PatentApplication No. PCT/EP2011/050821 ?led on Jan. 21, applied to various classes of molecules, from so-called small 2011, Which claims priority from European Patent Applica molecules, through natural products up to larger proteins. tion No. EP 10 151 564.1 ?led on Jan. 22, 2010, the disclo [0008] Liraglutide is an example of a peptide drug that sures of Which are incorporated herein by reference in their achieves an extended half-life by permanent covalent modi entirety. ?cation With a palmitoyl moiety. The fatty acid alkyl chain serves to provide albumin binding in vivo and the palmitoy BACKGROUND OF THE INVENTION lated peptide forms an albumin complex that acts as a drug reservoir in the blood stream. 1. Field of the Invention [0009] Albuferon is an example of a protein drug that achieves an extended half-life by permanent covalent modi [0002] The present invention is directed to carrier-linked ?cation With another protein that in itself has a long half-life. prodrugs having temporary amide linkages betWeen substi The corresponding fusion protein of albumin and interferon tuted dipeptide moieties and aliphatic amine groups of bio alpha, Albuferon, exhibits a signi?cantly extended half-life as logically active entities such as peptides, proteins, natural compared to interferon alpha. products or synthetic chemical compounds. Such carrier linked prodrugs are characterized by sloW release of unmodi [0010] Many small molecule medicinal agents, like alka ?ed biologically active entity. loids and anti-tumor agents, shoW loW solubility in aqueous ?uids. One Way to solubiliZe these small molecule com [0003] It is noted that citation or identi?cation of any docu pounds is to conjugate the small molecule compounds to ment in this application is not an admission that such docu hydrophilic (Water-soluble) polymers. A variety of Water ment is available as prior art to the present invention. soluble polymers, such as human serum albumin, dextran, [0004] Typically, carriers employed for extended time-ac lectins, poly(ethylene glycol) (PEG), poly(styrene-co-maleic tion engineering in drug delivery are either used in a non anhydride), poly(N-hydroxypropylmethacrylamide), poly covalent fashion, With the drug physicochemically formu (divinyl ether-co-maleic anhydride), hyaluronic acid have lated into a solvent-carrier mixture, or by permanent covalent been described for this purpose (R. Duncan, Nature Rev. Drug attachment of a carrier reagent to one of the drug’s functional Disc., 2003, 2, 347-360). groups. [0011] Covalent modi?cation of biological molecules With [0005] Non-covalent drug encapsulation into polymeric poly(ethylene glycol) has been extensively studied since the carriers has been applied to depot formulations for long late 1970s. So-called PEGylated proteins have shoWn acting release pro?les. Typically, the drug is mixed With car improved therapeutic e?icacy by increasing solubility, reduc rier material and processed in such fashion, that the drug ing immunogenicity, and increasing circulation half-live in becomes distributed inside the bulk carrier. For instance poly vivo due to reduced renal clearance and proteolysis by mer-drug aggregates may be shaped as microparticles Which enZymes (see, for example, Caliceti P., Veronese F. M., Adv. are administered as an injectable suspension or the polymer Drug Deliv. Rev. 2003, 55, 1261-1277). drug aggregates are formulated as gels Which are adminis tered in a single bolus injection. Known in the art are also [0012] HoWever, many biological molecules such as IFN liposomal formulations, Where the carrier may be a polymeric alfa 2, saquinavir or somatostatin are inactive or shoW or non-polymeric entity capable of solubiliZing the drug. decreased biological activity When a carrier is covalently Drug release occurs When the carrier sWells or physically conjugated to the drug (T. Peleg-Shulman et al., J. Med. deteriorates or chemical degradation alloWs diffusion of the Chem., 2004, 47, 4897-4904). drug to the exterior and subsequently into the biological envi [0013] In order to avoid shortcomings imposed by either ronment. Such chemical degradation processes may be auto the non-covalent polymer mixtures or the permanent covalent hydrolytic or enZyme-catalyZed. An example for a marketed attachment, it may be preferable to employ a prodrug drug based on bolus administration of a drug-polymer gel is approach for chemical conjugation of the drug to the polymer Lupron Depot. An example for a marketed drug based on carrier. In such polymeric prodrugs, the biologically active suspended microparticles is Nutropin Depot. An example for moieties (drugs, therapeutic, biological molecule, etc.) are a marketed drug based on a liposomal formulation is Doxil. typically linked to the polymeric carrier moiety by a tempo [0006] A disadvantage of the non-covalent approach is that rary bond formed betWeen the carrier moiety and a hydroxy, in order to prevent uncontrolled, burst-type release of the amino or carboxy group of the drug molecule. drug, encapsulation of the drug has to be highly e?icient by [0014] Prodrugs are therapeutic agents that are almost inac creating a sterically highly croWded environment. Restrain tive per se but are predictably transformed into active molecu ing the diffusion of an unbound, Water soluble drug molecule lar entities (see B. Testa, J. M: Mayer in Hydrolysis in Drug requires strong van der Waals contacts, frequently mediated and Prodrug Metabolism, Wiley-VCH, 2003, page 4). The through hydrophobic moieties. Many conformationally sen carrier prodrug approach may be applied in such a fashion sitive drugs, such as proteins or peptides, are rendered dys that the drug is released in vivo from the polymer in order to functional during the encapsulation process and/or during regain its biological activity. The reduced biological activity subsequent storage of the encapsulated drug. In addition, of the prodrug as compared to the released drug is of advan such amino-containing drugs readily undergo side reactions tage if a sloW or controlled release of the drug is desired. In With carrier degradation products (see, for example, D. H. Lee this case, a relatively large amount of prodrug may be admin et al., J. Contr. Rel., 2003, 92, 291-299). Furthermore, depen istered Without concomitant side effects and the risk of over US 2013/0053301A1 Feb. 28, 2013 dosing. Release of the drug occurs over time, thereby reduc ration of the prodrug, the amino groups may be more ing the necessity of repeated and frequent administration of chemoselectively addressed and serve as a better handle for the drug. conjugating the carrier and the drug because of their greater [0015] Prodrug activation may occur by enzymatic or non nucleophilicity as compared to hydroxylic or phenolic enzymatic cleavage of the temporary bond betWeen the car groups. This is particularly true for proteins and peptides rier and the drug molecule, or a sequential combination of Which may contain a great variety of different reactive func both, i.e. an enzymatic step followed by a non-enzymatic tionalities, Where non-selective conjugation reactions lead to rearrangement. In an enzyme-free in-vitro environment such undesired product mixtures Which require extensive charac as an aqueous buffer solution, a temporary bond such as an terization or puri?cation and may decrease reaction yield and ester or amide may undergo hydrolysis, but the corresponding therapeutic e?iciency of the product. rate of hydrolysis may be much too sloW and thus outside the [0021] Amide bonds are usually much more stable against therapeutically useful range. In an in vivo environment, hydrolysis than ester bonds, and the rate of clevage of the esterases or amidases are typically present and the esterases amide bond Would be too sloW for therapeutic utility in a and amidases may cause signi?cant catalytic acceleration of carrier-linked prodrug. Therefore it is advantageous to add the kinetics of hydrolysis from tWofold up to several orders of structural chemical components such as neighbouring groups magnitude (see, for example, R. B. GreenWald et al. J. Med. in order to exert control over the cleavability of the prodrug Chem.
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