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(12) Patent Application Publication (10) Pub. No.: US 2016/0082123 A1 RAU Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0082123 A1 RAU Et Al US 20160O821 23A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0082123 A1 RAU et al. (43) Pub. Date: Mar. 24, 2016 (54) HYDROGEL-LINKED PRODRUGS (30) Foreign Application Priority Data RELEASING TAGGED DRUGS Apr. 22, 2013 (EP) .................................. 13164669.7 (71) Applicant: ASCENDIS PHARMA A/S, Hellerup Oct. 8, 2013 (EP) .................................. 13187784.7 (DK) Publication Classification (72) Inventors: Harald RAU, Dossenheim (DE); Nora KALUZA, Heidelberg (DE); Ulrich (51) Int. Cl. HERSEL, Heidelberg (DE); Thomas A647/48 (2006.01) KNAPPE, Heidelberg (DE); Burkhardt (52) U.S. Cl. LAUFER, Dossenheim (DE) CPC. A61 K47/48784 (2013.01); A61K 47/48215 2013.O1 (73) Assignee: Ascendis Pharma A/S, Hellerup (DK) ( ) (21) Appl. No.: 14/786,481 (57) ABSTRACT 1-1. The present invention relates to a process for the preparation (22) PCT Filed: Apr. 16, 2014 of a hydrogel-linked prodrug releasing a tag moiety-biologi (86). PCT No.: PCT/EP2014/057753 releasingcally active a tag moiety moiety-biologically conjugate, to a hydrogel-linked active moiety conjugate prodrug S371 (c)(1), obtainable by Such process, to pharmaceutical compositions (2) Date: Oct. 22, 2015 comprising said prodrug and their use as a medicament. US 2016/00821 23 A1 Mar. 24, 2016 HYDROGEL-LINKED PRODRUGS boxyl (-COOH) or activated carboxyl ( COY, RELEASING TAGGED DRUGS wherein Y is selected from formulas (fi) to (f-vi): FIELD OF THE INVENTION 0001. The present invention relates to a process for the (f-i) preparation of a hydrogel-linked prodrug releasing a tag moi ety-biologically active moiety conjugate, to a hydrogel linked prodrug releasing a tag moiety-biologically active moiety conjugate obtainable by Such process, to pharmaceu tical compositions comprising said prodrug and their use as a medicament. (f-ii) BACKGROUND OF THE INVENTION 0002 Hydrogels are versatile carriers for carrier-linked prodrugs, see for example WO2006003.014A2 and WO2011 012715A1. As at least most of the drugs are con nected to the inside of the hydrogel, they are protected from modifying and/or degrading enzymes present in a patients body which extends the time period over which active drugs (f-iii) are released from Such prodrugs. 0003. However, once the drug is released from the hydro y O gel carrier, it is subject to renal clearance and exposed to modifying and/or degrading enzymes that reduce the half-life of the released drug. NO2, 0004) To avoid this Harris (WO199922770) has devised (f-iv) hydrogel prodrugs which release biologically active moiety Fb. poly(ethylene glycol) (PEG) conjugates. These prodrugs w O have two major disadvantages. On the one hand polymeriza tion of the Harris hydrogel occurs in the presence of drug S molecules which get coupled to the forming hydrogel during polymerization. This may cause drug molecules to be (f-v) entrapped in the hydrogel which may lead to a burst-type release of drug during hydrogel degradation. 0005. On the other hand drug molecules are released upon O F degradation of labile bonds present in the hydrogel matrix. As the degradation process leads to fragments of various sizes, and the exact nature of the PEG tag attached to the released F F biologically active moiety varies between different degrada tion products. The variable size of the PEG tags leads to F different residual activities of the conjugates which are (f-vi) undesired from a pharmacological view point. DETAILED DESCRIPTION OF THE INVENTION 0006. Accordingly, there is a need for hydrogel-linked prodrugs, which at least partially overcome the shortcomings 0011 wherein described before. 0012 the dashed lines indicate attachment to the rest 0007. It is therefore an object of the present invention to of the molecule, overcome at least some of the above-mentioned shortcomings and to provide a hydrogel, which releases drugs with 0013 b is 1, 2, 3 or 4 improved pharmacologic properties, like for example 0014 X is C1, Br, I, or F); extended half-lives. This is achieved by releasing drugs with 00.15 (a-ii) at least one crosslinker reagent, wherein a tag, i.e. tag moiety-biologically active moiety conjugates, the at least one crosslinker reagent has a molecular from the hydrogel-linked prodrugs of the present invention. weight ranging from 0.2 to 40 kDa and comprises at 0008. In one aspect, the present invention relates to a pro least two functional end groups selected from the cess for the preparation of a hydrogel-linked prodrug releas group consisting of activated ester groups, activated ing a tag moiety-biologically active moiety conjugate com carbamate groups, activated carbonate groups, acti prising the steps of: vated thiocarbonate groups and amine groups; 0009 (a) providing a mixture comprising 0016 in a weight ratio of the at least one backbone 0010 (a-i) at least one backbone reagent, wherein the reagent to the at least one crosslinker reagent ranging at least one backbone reagent has a molecular weight from 1:99 to 99:1 and wherein the molar ratio of A' ranging from 1 to 100 kDa, and comprises at least to functional end groups is >1; three functional groups A", wherein each A' is an 0017 (b) polymerizing the mixture of step (a) to a amine ( NH or —NH ), hydroxyl ( OH), car hydrogel; US 2016/00821 23 A1 Mar. 24, 2016 0018 (c) optionally covalently conjugating a spacer cally active moiety conjugate conjugated to the reagent of formula (VI) hydrogel of step (b) or (c); or 10030) (d-vi)areversible prodrug linker reagent to A' Axl-SP2-AX2 (VI), or A' of the hydrogel of step (b) or (c), respectively, 0019 wherein resulting in a reversible prodrug linker moiety conju 10020 SP is Clso alkyl, Clso alkenyl or Clso alky gated to the hydrogel of step (b) or (c), followed by nyl, which Clso alkyl, C-soalkenyland Clso alkynyl covalent conjugation of a tag moiety-biologically is optionally interrupted by one or more group(s) active moiety conjugate reagent to said reversible pro selected from the group consisting of —NH-, drug linker moiety through a functional group of the —N(C. alkyl)-, —O— —S, —C(O)— —C(O) tag moiety; NH, —C(O)N(C. alkyl)-, - O C(O) , 0031 (d-vii) a reversible prodrug linker moiety-tag —S(O)— —S(O) , 4- to 7-membered heterocy moiety conjugate reagent to A' or A' of the hydrogel clyl phenyl and naphthyl; of step (b) or (c), respectively, through a functional I0021 A' is a functional group for reaction with A' group of the reversible prodrug linker moiety, fol of the hydrogel; and lowed by covalent conjugation of a drug to said tag (0022 A' is a functional group; moiety; or 0032 (d-viii) a reversible prodrug linker moiety-tag 0023 to A' of the hydrogel from step (b); and moiety-biologically active moiety conjugate reagent 0024 (d) covalently conjugating to A' or A* of the hydrogel of step (b) or (c), respec I0025 (d-i) a reversible prodrug linker reagent to A' tively, through a functional group of the reversible or A* of the hydrogel of step (b) or (c), respectively, prodrug linker moiety; resulting in a reversible prodrug linker moiety conju wherein the linkage between the reversible prodrug linker gated to the hydrogel of step (b) or (c), followed by moiety and the biologically active moiety in the prodrug covalent conjugation of a drug to said reversible pro according to (d-i), (d-ii), (d-iii) and (d-iv) and the linkage drug linker moiety resulting in a reversible prodrug between the reversible prodrug linker moiety and the tag linker moiety-biologically active moiety conjugate moiety in the prodrug according to (d-V), (d-vi), (d-vii) and conjugated to the hydrogel of step (b) or (c), followed (d-viii) is reversible. by covalent conjugation of a tag reagent to the bio 0033. It was now surprisingly found that such hydrogel logically active moiety resulting in a reversible pro linked prodrugs have a release kinetic that is only governed by drug linker moiety-biologically active moiety-tag the release kinetic of the reversible prodrug linker and the moiety conjugate conjugated to the hydrogel of step released tag moiety-biologically active moiety conjugate has (b) or (c); or improved pharmacologic properties, like for example an (0026 (d-ii) a reversible prodrug linker reagent to A' extended half-life, compared to the corresponding drug with or A* of the hydrogel of step (b) or (c), respectively, out the tag moiety. In contrast to the various conjugates of resulting in a reversible prodrug linker moiety conju Harris (WO199922770) the released tag moiety-biologically gated to the hydrogel of step (b) or (c), followed by active moiety conjugates have a well-defined structure. covalent conjugation of a biologically active moiety 0034. Within the present invention the terms are used with tag moiety conjugate reagent to said reversible pro the meaning as follows. drug linker moiety through a functional group of the 0035. As used herein, the term “hydrogel' means a hydro biologically active moiety resulting in a reversible philic or amphiphilic polymeric network composed of prodrug linker moiety-biologically active moiety-tag homopolymers or copolymers, which is insoluble due to the moiety conjugate conjugated to the hydrogel of step presence of covalent chemical crosslinks. The crosslinks pro (b) or (c); or vide the network structure and physical integrity. Hydrogels 0027 (d-iii) a reversible prodrug linker moiety-bio exhibit a thermodynamic compatibility with water which logically active moiety conjugate reagent to A" or allows them to Swell in aqueous media. A° of the hydrogel of step (b) or (c), respectively, 0036. As used herein, the term “reagent’ means a chemi through a functional group of the reversible prodrug cal compound which comprises at least one functional group linker moiety, followed by covalent conjugation of a for reaction with the functional group of another reagent or tag reagent to said biologically active moiety; or moiety.
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