Sustained-release CNP-acting agent having increased NEP stability

Abstract

To provide more efficacious and safer C-type natriuretic peptide (CNP) agonists.SOLUTION: The present invention provides: controlled-release CNP agonists having an at least 5 times longer degradation half-life in an in vitro NEP degradation assay than the corresponding released CNP agonist; pharmaceutical compositions comprising the controlled-release CNP agonist; use of them; and methods of treatment.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a sustained-release CNP agonist having a degradation half-life at least 5-fold longer than the corresponding released CNP agonist in an in vitro NEP degradation assay, a pharmaceutical composition comprising said sustained-release CNP agonist, their use and a method of treatment.

Background Art

[0002] Achondroplasia (ACH) is caused by a gain-of-function mutation of FGFR3. Binding of CNP to its receptor, natriuretic peptide receptor B (NPR-B), inhibits signal transduction downstream of FGFR3 and thus causes endochondral growth and skeletal overgrowth as observed in both mice and humans overexpressing CNP. Overproduction of CNP in cartilage, or continuous administration of CNP by intravenous (iv) injection normalizes the dwarfism of achondroplasia mice, suggesting that administration of supra-physiological levels of CNP is a strategy for treating ACH.

[0003] However, considering the short half-life of CNP-22 (2 minutes after iv administration), CNP as a therapeutic agent requires continuous infusion and is thus difficult in the pediatric population. Moreover, since CNP is completely inactivated in subcutaneous tissue, intravenous injection is required.

[0004] Potter (FEBS Journal 278 (2011) 1808-1817) describes the clearance of CNP resulting from two degradation pathways, namely receptor-mediated degradation and degradation by extracellular proteases. CNP is degraded by the action of neutral endopeptidase 24.11 (NEP) and is also removed from the systemic circulation by the natriuretic peptide clearance receptor NPR-C, which binds CNP and accumulates it within lysosomes where CNP is degraded.

[0005] Reducing the degradation by these two clearance pathways, or by one of them, seems to help extend the half-life of CNP.

[0006] Due to the limited size of the cavity in its active site, NEP selects and recognizes substrates smaller than about 3 kDa. U.S. Patent No. 8,377,884 B2 describes a variant of CNP optionally and permanently conjugated with a PEG polymer to enhance resistance to NEP cleavage. However, the addition of PEG to wild-type CNP decreases CNP activity, even for PEG as small as about 0.6 kDa, and the addition of PEG greater than about 2 or 3 kDa to CNP or its variant has been found to decrease the functional activity of CNP in a size-dependent manner. Therefore, adding PEG molecules greater than 2 - 3 kDa to reduce NEP degradation is accompanied by a loss of activity, which may reduce the therapeutic potential of such molecules.

[0007] In addition to adversely affecting the activity of the peptide, the attachment of PEG or other polymers to CNP may also prevent effective distribution to the growth plate. Farnum et al. (Anat Rec A Discov Mol Cell Evol Biol. 2006 January; 288(1): 91 - 103) demonstrated that the distribution of molecules from the systemic vasculature to the growth plate is size-dependent, and that small molecules (less than 10 kDa) can be distributed to the growth plate, while molecular sizes greater than 40 kDa prevent migration to the growth plate.

[0008] Different approaches to creating NEP-resistant CNP molecules to enable subcutaneous administration are described in The American Journal of Human Genetics 91, 1108-1114. BMN-111 is a modified recombinant human C-type natriuretic peptide (CNP) with 17 amino acids added to form a 39-amino acid CNP pharmacological analog. BMN-111 mimics the pharmacological activity of CNP in the growth plate and has a longer half-life as a result of being resistant to neutral endopeptidase (NEP), which enables once-daily subcutaneous (SC) administration. Since BMN-111 is a non-natural peptide, the risk of inducing an immune response is higher compared to natural peptides, and an immune response to BMN-111 was observed in animal experiments as described by Martz in "sFGFR for achondroplasia" (SciBx, Biocentury October 2013), but the presence of antibodies did not affect the pharmacological activity of this drug. However, since the half-life of BMN-111 is only 20 minutes, even with daily administration, the duration of exposure to an effective level of the drug is short.

[0009] To increase exposure to an effective level of the drug, the dosage of the drug with CNP activity can be increased. Since natriuretic peptides are a family of hormones that can affect blood volume and blood pressure, an increase in dosage may be associated with cardiovascular side effects. Studies of BMN-111 in animals and humans have demonstrated that as the dosage increases, arterial pressure decreases and heart rate increases. In healthy individuals, administration of BMN-111 at a dosage of 15 μg / kg or less resulted in mild hypotension. Therefore, increasing the dosage of the drug with CNP activity to increase drug exposure can result in unacceptable cardiovascular side effects.

[0010] Therefore, increasing the dosage of the drug with CNP activity to increase drug exposure can result in unacceptable cardiovascular side effects such as hypotension.

[0011] In summary, there is a need for a more effective and safe CNP therapy.

Prior Art Documents

Patent Documents

[0012]

Patent Document 1

Non-Patent Documents

[0013]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0014] Accordingly, an object of the present invention is to overcome at least in part the above-mentioned drawbacks.

Means for Solving the Problems

[0015] This object is achieved by a sustained-release CNP agonist that releases one or more CNP agonists and has a degradation half-life that is at least 5 times longer than the corresponding released CNP agonist in an in vitro NEP degradation assay.

Brief Description of the Drawings

[0016] [FIG. 1] Structure of CNP according to Sequence No. 1

Mode for Carrying Out the Invention

[0017] Surprisingly, it has been found that the use of a sustained-release CNP agonist provides efficient protection against NEP degradation that increases the half-life of the CNP agonist. The sustained-release CNP agonist of the present invention also releases the CNP agonist, which can exert its full activity and its access to the growth plate is not restricted.

[0018] In the present invention, the terms having the following meanings are used.

[0019] As used herein, the term "CNP agonist" activates the natriuretic peptide receptor B (NPR-B) and has an EC that is up to 50-fold higher than the NPR-B activity of CNP-22 (Sequence No. 1). 50 refers to any compound having.

[0020] As used herein with respect to the sustained-release CNP agonist and the CNP agonist, "EC 50 " refers to the concentration of the sustained-release CNP agonist and the CNP agonist at which maximum half-maximal cGMP production is induced. The EC of the released CNP agonist of the sustained-release CNP agonist and that of CNP-22 50 The NPR-B activity in the form of is measured by culturing NIH-3T3 (mouse embryonic fibroblast cell line) cells expressing NPR-B on the cell surface and incubating the cells with the sustained-release CNP agonist, the corresponding released CNP agonist or CNP-22, respectively, and determining the intracellular production of the second messenger cGMP using a standard cGMP assay. In particular, the assay is performed as follows: (1) Mouse NIH-3T3 cells expressing endogenous NPR-B are cultured in DMEM F-12 medium with 5% FBS and 5 mM glutamine at 37 °C and 5% CO2; (2) For each assay, resuspend 50,000 cells in Dulbecco's PBS with IBMX and incubate at different concentrations with either a sustained-release CNP agonist, the corresponding released CNP agonist, or CNP-22; (3) After incubating at 37 °C and 5% CO2 for 30 minutes, lyse the cells and determine the cGMP level; and (4) Generate an EC 50 value from the determined cGMP level.

[0021] Preferably, the IBMX concentration in step (2) is 0.5 mM.

[0022] Step (3) can be performed using any assay for measuring cGMP, which is a standard procedure well-known to those skilled in the art. Preferably, step (3) is performed using a cGMP TR-FRET assay, more preferably using a cGMP TR-FRET assay from Cisbio, catalog number 62GM2PEB.

[0023] During such experiments, since the sustained-release CNP agonist releases a certain amount of CNP agonist and the released CNP agonist distorts the results, the measurement of the NPR-B activity of the sustained-release CNP agonist is preferably performed in the form of a stable analog that does not release CNP agonist.

[0024] As used herein, the term "sustained-release CNP agonist" refers to any compound, conjugate, crystal, or mixture that contains at least one CNP agonist and the at least one CNP agonist is released with a release half-life of at least 6 hours.

[0025] As used herein, the term "CNP agonist equivalent" refers to the molar content of the CNP agonist contained in the sustained-release CNP agonist.

[0026] As used herein, the term "degradation half-life" refers to the time required for half of all CNP-agonist molecules to be degraded in an in vitro NEP degradation assay.

[0027] As used herein, the term "release half-life" refers to the time required for half of all CNP-agonist molecules to be released from a sustained-release CNP-agonist under physiological conditions.

[0028] A preferred in vitro NEP degradation assay for monitoring the decrease over time of non-digestible CNP-agonist (normalized using the internal standard pentafluorophenol (PFP)) with respect to time t0 is as follows: (1) Recombinant human NEP and the internal standard PFP are added to the sustained-release CNP-agonist and to the released CNP-agonist, respectively, in a digestion buffer; (2) The solution is incubated at 37 °C, samples are taken at different time intervals, and the reaction is stopped by combined reduction and heat denaturation; (3) The resulting reaction products are analyzed using HPLC-MS; and (4) The half-lives of both the sustained-release CNP-agonist and the released CNP-agonist are calculated by the change in the ratio of the HPLC-UV peak areas of the CNP variants and PFP over time.

[0029] Preferably, the digestion buffer is 50 mM Tris-HCl, pH 7.4, 10 mM NaCl.

[0030] It is understood that the degradation time in the NEP degradation assay is affected by a) the NEP concentration used in the digestion assay, and b) the proteolytic activity of the NEP quality and lot used. One skilled in the art can adjust the concentration of NEP used in the assay to obtain an appropriate degradation half-life.

[0031] Preferably, NEP (order number BML-SE532-0010) is obtained from Enzo Life Sciences GmbH (Loerrach, Germany).

[0032] Preferably, in the digestion assay, a final NEP concentration of 2.5 μg / mL is used.

[0033] As used herein, the term "CNP" preferably refers to all CNP polypeptides derived from mammalian species, more preferably human and mammalian species, even more preferably human and murine species, as well as variants, analogs, orthologs, homologs and derivatives thereof, and fragments thereof, which are characterized by the control of growth, proliferation and differentiation of chondrocyte growth plate chondrocytes. Preferably, the term "CNP" refers to the CNP polypeptide of SEQ ID NO: 24, as well as variants, homologs and derivatives thereof that exhibit substantially the same biological activity, namely the control of growth, proliferation and differentiation of chondrocyte growth plate chondrocytes. More preferably, the term "CNP" refers to the polypeptide of SEQ ID NO: 24.

[0034] In another preferred embodiment, the term "CNP" refers to the polypeptide of SEQ ID NO: 20.

[0035] In another preferred embodiment, the term "CNP" refers to the polypeptide of SEQ ID NO: 21.

[0036] In another preferred embodiment, the term "CNP" refers to the polypeptide of SEQ ID NO: 22.

[0037] In another preferred embodiment, the term "CNP" refers to the polypeptide of SEQ ID NO: 23.

[0038] In another preferred embodiment, the term "CNP" refers to the polypeptide of SEQ ID NO: 30.

[0039] Naturally occurring CNP-22 (SEQ ID NO: 1) has the following sequence: GLSKGCFGLKLDRIGSMSGLGC has, and the cysteines at positions 6 and 22 are linked by a disulfide bridge as shown in Figure 1.

[0040] SEQ ID NO: 24 is the following sequence: LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC has, and the cysteines at positions 22 and 38 are linked by a disulfide bridge.

[0041] The term "CNP" also includes all CNP variants, analogs, orthologs, homologs and derivatives, and fragments thereof, described in WO 2009 / 067639 A2 and WO 2010 / 135541 A2, which are incorporated herein by reference.

[0042] Accordingly, the term "CNP" preferably also represents the following peptide sequences: SEQ ID NO: 2 (CNP-53): DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 3 (G-CNP-53): GDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 4 (M-CNP-53): MDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 5 (P-CNP-53): PDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 6 (CNP-53 M48N): DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; Accession number 7 (CNP-53 Δ15-31): DLRVDTKSRAAWARGLSKGCFGLKLDRIGSMSGLGC; Accession number 8 (CNP-52): LRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession number 9 (CNP-51): RVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession number 10 (CNP-50): VDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession number 11 (CNP-49): DTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession number 12 (CNP-48): TKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession number 13 (CNP-47): KSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession number 14 (CNP-46): SRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession number 15 (CNP-45): RAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession number 16 (CNP-44): AAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession number 17 (CNP-44 Δ14-22): AAWARLLQEHPNAGLSKGCFGLKLDRIGSMSGLGC; Accession No. 18 (CNP-44 Δ15-22): AAWARLLQEHPNARGLSKGCFGLKLDRIGSMSGLGC; Accession No. 19 (CNP-43): AWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 20 (CNP-42): WARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 21 (CNP-41): ARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 22 (CNP-40): RLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 23 (CNP-39): LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 24 (CNP-38): LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 25 (CNP-37): QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 26 (CNP-37 Q1pQ, where pQ = pyroglutamic acid in the sequence): pQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 27 (G-CNP-37): GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 28 (P-CNP-37): PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 29 (M-CNP-37): MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 30 (PG-CNP-37): PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 31 (MG-CNP-37): MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 32 (CNP-37 M32N): QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; SEQ ID NO: 33 (G-CNP-37 M32N): GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; SEQ ID NO: 34 (G-CNP-37 K14Q): GQEHPNARKYKGANQKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 35 (G-CNP-37 K14P): GQEHPNARKYKGANPKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 36 (G-CNP-37 K14Q, Δ15): GQEHPNARKYKGANQGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 37 (G-CNP-37 K14Q, K15Q): GQEHPNARKYKGANQQGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 38 (CNP-36): EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 39 (CNP-35): HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 40 (CNP-34): PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 41 (CNP-33): NARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 42 (CNP-32): ARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 43 (CNP-31): RKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 44 (CNP-30): KYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 45 (CNP-29): YKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 46 (CNP-28): KGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 47 (GHKSEVAHRF-CNP-28): GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 48 (CNP-27): GANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 49 (CNP-27 K4Q, K5Q): GANQQGLSKGCFGLKLDRIGSMSGLGC; Accession No. 50 (CNP-27 K4R, K5R): GANRRGLSKGCFGLKLDRIGSMSGLGC; Accession No. 51 (CNP-27 K4P, K5R): GANPRGLSKGCFGLKLDRIGSMSGLGC; Accession No. 52 (CNP-27 K4S, K5S): GANSSGLSKGCFGLKLDRIGSMSGLGC; Accession No. 53 (CNP-27 K4P, K5R): GANGANPRGLSRGCFGLKLDRIGSMSGLGC; Accession No. 54 (CNP-27 K4R, K5R, K9R): GANRRGLSRGCFGLKLDRIGSMSGLGC; Accession No. 55 (CNP-27 K4R, K5R, K9R, M22N): GANRRGLSRGCFGLKLDRIGSNSGLGC; Accession No. 56 (P-CNP-27 K4R, K5R, K9R): PGANRRGLSRGCFGLKLDRIGSMSGLGC; Accession No. 57 (M-CNP-27 K4R, K5R, K9R): MGANRRGLSRGCFGLKLDRIGSMSGLGC; Accession No. 58 (HSA fragment-CNP-27): GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLG; Accession No. 59 (HSA fragment-CNP-27 M22N): GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSNSGLGC; Accession No. 60 (M-HSA fragment-CNP-27): MGHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 61 (P-HSA fragment-CNP-27): PGHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 62 (CNP-26): ANKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 63 (CNP-25): NKKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 64 (CNP-24): KKGLSKGCFGLKLDRIGSMSGLGC; Accession No. 65 (CNP-23): KGLSKGCFGLKLDRIGSMSGLGC; Accession No. 66 (R-CNP-22): RGLSKGCFGLKLDRIGSMSGLGC; Sequence number 67 (ER-CNP-22): ERGLSKGCFGLKLDRIGSMSGLGC; Sequence number 68 (R-CNP-22 K4R): RGLSRGCFGLKLDRIGSMSGLGC; Sequence number 69 (ER-CNP-22 4KR): ERGLSRGCFGLKLDRIGSMSGLGC; Sequence number 70 (RR-CNP-22): RRGLSRGCFGLKLDRIGSMSGLGC; Sequence number 71 (HRGP fragment-CNP-22): GHHSHEQHPHGANQQGLSKGCFGLKLDRIGSMSGLGC; Sequence number 72 (HRGP fragment-CNP-22): GAHHPHEHDTHGANQQGLSKGCFGLKLDRIGSMSGLGC; Sequence number 73 (HRGP fragment-CNP-22): GHHSHEQHPHGANPRGLSKGCFGLKLDRIGSMSGLGC; Sequence number 74 (IgG1(F c ) fragment-CNP-22): GQPREPQVYTLPPSGLSKGCFGLKLDRIGSMSGLGC; Sequence number 75 (HSA fragment-CNP-22): GQHKDDNPNLPRGANPRGLSKGCFGLKLDRIGSMSGLGC; Sequence number 76 (HSA fragment-CNP-22): GERAFKAWAVARLSQGLSKGCFGLKLDRIGSMSGLGC; Sequence number 77 (Osteocrin NPR C inhibitor fragment-CNP22): FGIPMDRIGRNPRGLSKGCFGLKLDRIGSMSGLGC; Sequence number 78 (FGF2 heparin-binding domain fragment-CNP22): GKRTGQYKLGSKTGPGPKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 79 (IgG1(F c ) fragment - CNP - 22 K4R): GQPREPQVYTGANQQGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO: 80 (HSA fragment - CNP - 22 K4R): GVPQVSTSTGANQQGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO: 81 (fibronectin fragment - CNP - 22 K4R): GQPSSSSQSTGANQQGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO: 82 (fibronectin fragment - CNP - 22 K4R): GQTHSSGTQSGANQQGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO: 83 (fibronectin fragment - CNP - 22 K4R): GSTGQWHSESGANQQGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO: 84 (Zn finger fragment - CNP - 22 K4R): GSSSSSSSSSGANQQGLSRGCFGLKLDRIGSMSGLGC; SEQ ID NO: 85 (CNP - 21): LSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 86 (CNP - 20): SKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 87 (CNP - 19): KGCFGLKLDRIGSMSGLGC; SEQ ID NO: 88 (CNP - 18): GCFGLKLDRIGSMSGLGC; SEQ ID NO: 89 (CNP - 17): CFGLKLDRIGSMSGLGC; SEQ ID NO: 90 (BNP fragment - CNP - 17 - BNP fragment): SPKMVQGSGCFGLKLDRIGSMSGLGCKVLRRH; SEQ ID NO: 91 (CNP-38 L1G): GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; SEQ ID NO: 92 (Ac-CNP-37; Ac = acetyl in the sequence): Ac-QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC.

[0043] It is understood that in SEQ ID NOs: 2 to 92 as well, those corresponding to the 22nd and 38th cysteines of SEQ ID NO: 24 are linked by a disulfide bridge.

[0044] More preferably, the term "CNP" refers to the sequences of SEQ ID NOs: 2, 19, 20, 21, 22, 23, 24, 25, 26, 30, 32, 38, 39, 40, 41, 42, 43, 91, and 92. Even more preferably, the term "CNP" refers to the sequences of SEQ ID NOs: 23, 24, 25, 26, 38, 39, 91, and 92. In a particularly preferred embodiment, the term "CNP" refers to the sequence of SEQ ID NO: 24. In an equally preferred embodiment, the term "CNP" refers to the sequence of SEQ ID NO: 30. In an equally preferred embodiment, the term "CNP" refers to the sequence of SEQ ID NO: 20. In an equally preferred embodiment, the term "CNP" refers to the sequence of SEQ ID NO: 21. In an equally preferred embodiment, the term "CNP" refers to the sequence of SEQ ID NO: 22. In an equally preferred embodiment, the term "CNP" refers to the sequence of SEQ ID NO: 23.

[0045] In another preferred embodiment, the term "CNP" refers to the sequence of SEQ ID NO: 93 QEHPNARX1YX2GANX3X4GLSX5GCFGLX6LDRIGSMSGLGC refers to, in this sequence, X1, X2, X3, X4, X5 and X6 are independently selected from the group consisting of K, R, P, S and Q, provided that at least one of X1, X2, X3, X4, X5 and X6 is selected from the group consisting of R, P, S and Q; preferably, X1, X2, X3, X4, X5 and X6 are selected from the group consisting of K and R, provided that at least one of X1, X2, X3, X4, X5 and X6 is R; Even more preferably, the term "CNP" refers to the sequence of SEQ ID NO: 94 QEHPNARKYKGANX1X2GLSX3GCFGLX4LDRIGSMSGLGC refers to, in this sequence, X1, X2, X3 and X4 are independently selected from the group consisting of K, R, P, S and Q, provided that at least one of X1, X2, X3 and X4 is selected from the group consisting of R, P, S and Q; preferably, X1, X2, X3 and X4 are selected from K and R, provided that at least one of X1, X2, X3 and X4 is R; Most preferably, the term "CNP" refers to the sequence of SEQ ID NO: 95 QEHPNARKYKGANX1X2GLSKGCFGLKLDRIGSMSGLGC refers to, in this sequence, X1X2 is selected from the group consisting of KR, RK, KP, PK, SS, RS, SR, QK, QR, KQ, RQ, RR and QQ.

[0046] It is understood that in SEQ ID NOs: 2 to 95, those corresponding to the cysteines at positions 22 and 38 of SEQ ID NO: 24 are linked by a disulfide bridge.

[0047] The present invention is also understood to include CNP variants, in which any one or more, up to all, of the residues that are susceptible to amide hydrolysis or amide hydrolysis-like reactions (such as isomerization), regardless of the extent up to a maximum of 100% conversion for each converted residue, can be converted to other residues by amide hydrolysis or amide hydrolysis-like reactions. In certain embodiments, this specification includes CNP variants, in which: (1) Any one or some, up to all, of the asparagine (Asn / N) residues can be converted to aspartic acid or aspartate, and / or isoaspartic acid or isoaspartate, by amide hydrolysis, up to about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% conversion for each converted residue; or (2) Any one or some, up to all, of the glutamine (Gln / Q) residues can be converted to glutamic acid or glutamate, and / or isoglutamic acid or isoglutamate, by amide hydrolysis, up to about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% conversion for each converted residue; or (3) Any one or some, up to all, of the aspartic acid or aspartate (Asp / D) residues can be converted to isoaspartic acid or isoaspartate by an amide hydrolysis-like reaction (also referred to as isomerization), up to about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% conversion for each converted residue; or (4) Any one or some, up to all, of the glutamic acid or glutamate (Glu / E) residues can be converted to isoglutamic acid or isoglutamate by an amide hydrolysis-like reaction (also referred to as isomerization), up to about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% conversion for each converted residue; or (5) If present, the N-terminal glutamine may be converted to pyroglutamate until reaching about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% conversion; or (6) The above combination.

[0048] As used herein, the term "CNP polypeptide variant" refers to a polypeptide derived from the same species that is different from the reference CNP polypeptide. Preferably, such a reference CNP polypeptide sequence is the sequence of SEQ ID NO: 24. Generally, since the differences are limited, the amino acid sequences of the reference and the variant are very similar overall and identical in many regions. Preferably, the CNP polypeptide variant is at least 70%, 80%, 90% or 95% identical to the reference CNP polypeptide, preferably the CNP polypeptide of SEQ ID NO: 24. A polypeptide having, for example, at least 95% "identical" amino acid sequence to the query amino acid sequence means that the amino acid sequence of the subject polypeptide may contain no more than 5 amino acid changes per 100 amino acids of the query amino acid sequence and is otherwise identical to the query sequence. Such changes in the reference sequence may occur at the amino-terminal (N-terminal) or carboxy-terminal (C-terminal) positions of the reference amino acid sequence, but may also occur individually between residues within the reference sequence anywhere between such terminal positions, or as one or more adjacent groups within the reference sequence. The query sequence may be the complete amino acid sequence of the reference sequence or any of the designated fragments described herein. Preferably, the query sequence is the sequence of SEQ ID NO: 24.

[0049] Such CNP polypeptide variants can be naturally occurring variants, such as naturally occurring allelic variants encoded by one of several alternative forms of CNP that occupy a certain locus of a chromosome or an organism, or isoforms encoded by naturally occurring splice variants derived from a single primary transcript. Alternatively, the CNP polypeptide variant can be a naturally occurring unknown variant that can be produced by mutagenesis techniques known in the art.

[0050] It is known in the art that one or more amino acids can be deleted from the N-terminus and / or C-terminus of a bioactive peptide or protein without substantially losing its biological function. Such N-terminal and / or C-terminal deletions are also included in the term CNP polypeptide variant.

[0051] It is also recognized by those skilled in the art that a part of the amino acid sequence of a CNP polypeptide can be altered without significantly affecting the structure or function of the peptide. Such variants contain deletions, insertions, inversions, repeats, and substitutions selected according to principles known in the art so as to have little effect on activity. For example, guidelines for methods of making phenotypically silent amino acid substitutions are provided in Bowie et al. (1990), Science 247:1306-1310, which is hereby incorporated by reference in its entirety, where the authors show that there are two main approaches for considering the tolerance of amino acid sequence change.

[0052] The term "CNP polypeptide" also includes all CNP polypeptides encoded by CNP analogs, orthologs, and / or species homologs. As used herein, the term "CNP analog" refers to CNP from another unrelated organism that performs the same function in each organism but does not originate from the ancestral structure commonly possessed by the ancestors of those organisms. Instead, the analog CNP arose separately and then evolved to perform the same or similar functions. In other words, an analog CNP polypeptide is a polypeptide that has a considerably different amino acid sequence but achieves the same biological activity, namely, the control of the growth, proliferation, and differentiation of chondrocytes in the cartilage growth plate.

[0053] As used herein, the term "CNP ortholog" refers to CNP present in two different species, the sequences of which are related to each other through a common homologous CNP in the ancestral species but have evolved to be different from each other.

[0054] As used herein, the term "CNP homolog" refers to CNP of different organisms that performs the same function in each organism and originates from the ancestral structure commonly possessed by the ancestors of those organisms. In other words, a homolog CNP polypeptide is a polypeptide that has a very similar amino acid sequence and achieves the same biological activity, namely, the control of the growth, proliferation, and differentiation of chondrocytes in the cartilage growth plate. Preferably, a CNP polypeptide homolog can be defined as a polypeptide that exhibits at least 40%, 50%, 60%, 70%, 80%, 90%, or 95% identity to a reference CNP polypeptide, preferably the CNP polypeptide of SEQ ID NO: 24.

[0055] Thus, the CNP polypeptide of the present invention can be, for example, (i) a CNP polypeptide in which at least one of the amino acid residues is substituted by a conservative or non-conservative amino acid residue, preferably by a conservative amino acid residue, and such substituted amino acid residues may or may not be encoded by the genetic code; and / or (ii) a CNP polypeptide in which at least one of the amino acid residues contains a substituent; and / or (iii) a CNP polypeptide in which the CNP polypeptide is fused to another compound, and the compound is, for example, a compound that lengthens the half-life of the polypeptide (such as polyethylene glycol); and / or (iv) an additional amino acid is fused to the CNP polypeptide, and it is, for example, an IgG Fc fusion region peptide, or a leader sequence, or a secretion sequence, or a sequence used for purification of the polypeptide in the above form, or a preprotein sequence.

[0056] As used herein, the term "CNP polypeptide fragment" refers to any peptide that includes a continuous range of a portion of the amino acid sequence of a CNP polypeptide, preferably the polypeptide of SEQ ID NO: 24.

[0057] More specifically, the CNP polypeptide fragment comprises at least 6 consecutive amino acids of the CNP polypeptide, more preferably the polypeptide of SEQ ID NO: 24, for example, at least 8, at least 10, or at least 17 consecutive amino acids. The CNP polypeptide fragment can further be described as a subclass of the CNP polypeptide containing at least 6 amino acids, where "at least 6" is defined as any integer between 6 and the integer representing the C-terminal amino acid of the CNP polypeptide, and this CNP polypeptide is preferably the polypeptide of SEQ ID NO: 24. Further, the molecular species described above, which are CNP polypeptide fragments with a length of at least 6 amino acids as described above and further specified for the N-terminal and C-terminal positions, are included. Also, the term "CNP polypeptide fragment" includes all CNP polypeptide fragments with a length of at least 6 amino acids as described above that can be specifically identified by the N-terminal and C-terminal positions as individual molecular species. That is, fragments with a length of at least 6 consecutive amino acid residues that can occupy any combination of N-terminal and C-terminal positions on any given amino acid sequence of the CNP polypeptide, preferably the CNP polypeptide of SEQ ID NO: 24, are included in the present invention.

[0058] The term "CNP" also includes poly(amino acid) conjugates having the above-described sequence but having a backbone containing both amide bonds and non-amide bonds such as ester bonds, for example, depsipeptides. A depsipeptide is a chain of amino acid residues whose backbone contains both amide (peptide) bonds and ester bonds. Thus, the term "side chain" as used herein, when the amino acid moiety is linked by an amine bond as in a polypeptide, refers to the portion attached to the α-carbon of the amino acid moiety, or, for example, in the case of a depsipeptide, refers to any carbon atom-containing portion attached to the backbone of the poly(amino acid) conjugate. Preferably, the term "CNP" refers to a polypeptide having a backbone formed by amide (peptide) bonds.

[0059] Since the term "CNP" includes the above-mentioned variants, analogs, orthologs, homologs, derivatives and fragments of CNP, any reference to a specific position within the reference sequence includes the equivalent positions in the variants, analogs, orthologs, homologs, derivatives and fragments of the CNP moiety, even if not specifically mentioned.

[0060] As used herein, the term "loop portion" refers to a continuous series of contiguous amino acid residues of a CNP drug or CNP moiety that are located between two cysteine residues that form an intramolecular disulfide bridge or between homologous amino acid residues that are linked via a chemical cross-linking agent. Preferably, the loop portion is between two cysteine residues that form an intramolecular disulfide bridge. These two cysteines correspond to the cysteines at positions 22 and 38 in the sequence of CNP-38 (SEQ ID NO: 24). Thus, when a CNP drug or CNP moiety has the sequence of CNP-38, amino acids 23 to 37 are located in the aforementioned loop portion.

[0061] Regardless of the length of the CNP moiety, the sequence of the loop portion of wild-type CNP is FGLKLDRIGSMSGLG (SEQ ID NO: 96).

[0062] As noted above, the term "CNP" relates to CNP drugs or CNP moieties having different numbers of amino acids. One of ordinary skill in the art will recognize that the positions of corresponding amino acids vary in CNP drugs or CNP moieties of different lengths, and there will be no difficulty in identifying the two cysteines that form the disulfide bridge or the two homologous amino acid residues that are linked to each other via a chemical linker in the longer version, shorter version, and / or otherwise modified version of CNP.

[0063] The term CNP includes the above-mentioned variants, analogs, orthologs, homologs, derivatives and fragments of CNP, so the term "ring portion" also includes the corresponding variants, analogs, orthologs, homologs, derivatives and fragments of the sequence of SEQ ID NO: 96. Accordingly, any reference to a specific position within the reference sequence also includes the equivalent position in the variants, analogs, orthologs, homologs, derivatives and fragments of the CNP portion, even if not explicitly mentioned.

[0064] As used herein, the term "random coil" refers to a peptide or protein that assumes / has / forms a three-dimensional structure that is substantially devoid of a defined secondary and tertiary structure, as determined by circular dichroism spectroscopy performed in an aqueous buffer at pH 7.4 at room temperature. Preferably, room temperature (ambient temperature) is about 20 °C, i.e., 18 °C to 22 °C, and most preferably, room temperature is 20 °C.

[0065] As used herein, the term "micelle" means an aggregate of amphiphilic molecules dispersed in a liquid colloid. In an aqueous solution, a typical micelle forms an aggregate in which the hydrophilic portions of the surfactant molecules face the surrounding solvent and the hydrophobic portions of the surfactant molecules face inward, and is also called a "normal-phase micelle". In a "reverse micelle", the hydrophilic portions face inward and the hydrophobic portions face the surrounding solvent.

[0066] As used herein, the term "liposome" refers to a vesicle having at least one lipid bilayer, preferably a spherical vesicle. Preferably, the liposome contains phospholipids, and even more preferably contains phosphatidylcholine. The term "liposome" refers to vesicles of various structures and sizes, such as multilamellar liposome vesicles (MLV) having two or more concentric lipid bilayers and an average diameter ranging from 100 to 1000 nm, small unilamellar liposome vesicles (SUV) having one lipid bilayer and an average diameter ranging from 25 to 100 nm, large unilamellar liposome vesicles (LUV) having one lipid bilayer and an average diameter of about 1000 μm, and giant unilamellar vesicles (GUV) having one lipid bilayer and an average diameter ranging from 1 to 100 μm. The term "liposome" also includes deformable vesicles such as transferosomes and exosomes.

[0067] As used herein, the term "aquasome" refers to spherical nanoparticles having at least three layers of self-assembled structures, with diameters ranging from 60 to 300 nm, which are solid-phase nanocrystal cores coated with oligomeric films that adsorb drug molecules, either by modifying the drug or without modification.

[0068] As used herein, the term "ethosome" refers to a lipid vesicle containing phospholipids, ethanol and / or isopropanol at relatively high concentrations, and water, and having a size ranging from several tens of nanometers to micrometers.

[0069] As used herein, the term "LeciPlex" refers to a vesicle system based on positively charged phospholipids, which contains soybean PC, a cationic substance, and a biocompatible solvent such as PEG 300, PEG 400, diethylene glycol monoethyl ether, tetrahydrofurfuryl alcohol polyethylene glycol ether, or 2-pyrrolidone or N-methyl-2-pyrrolidone.

[0070] As used herein, the term "niosome" refers to a unilamellar or multilamellar vesicle containing a nonionic surfactant.

[0071] As used herein, the term "pharmacosome" refers to an ultrafine, micellar or hexagonal aggregate composed of lipids covalently bonded to a bioactive moiety.

[0072] As used herein, the term "proniosome" refers to a dry preparation of a surfactant-coated carrier that, upon rehydration and gentle agitation, gives rise to niosomes.

[0073] As used herein, the term "polymersome" refers to an artificial spherical vesicle containing a membrane formed from an amphiphilic synthetic block copolymer and, optionally, an aqueous solution in its core. Polymersomes have diameters in the range of 50 nm to 5 μm or more. This term includes syntosomes, which are polymersomes made to contain channels that allow specific chemicals to pass through the membrane and enter and exit the vesicle.

[0074] As used herein, the term "sphingosome" refers to a concentric bilayer vesicle in which an aqueous solution is completely enclosed by a lipid bilayer mainly composed of natural or synthetic sphingolipids.

[0075] As used herein, the term "transferosome" refers to a highly deformable lipid vesicle containing an aqueous core, formed from a mixture of common polar, appropriately end-activated lipids, which mixture facilitates the formation of highly curved bilayers that make the transferosome very deformable.

[0076] As used herein, the term "ufasome" represents a vesicle containing unsaturated fatty acids.

[0077] As used herein, the term "aptamer" refers to an oligonucleotide or peptide molecule that binds to a specific molecule. The term "aptamer" includes DNA, RNA, XNA, and peptide aptamers.

[0078] As used herein, the term "oligonucleotide" refers to a short nucleic acid polymer of up to 100 bases.

[0079] As used herein, the term "polypeptide" refers to a peptide containing up to and including 50 amino acid monomers. For CNP drugs and CNP moieties only, sequences having more than 50 amino acids are also referred to as "polypeptides" for simplicity.

[0080] As used herein, the term "protein" refers to a peptide of more than 50 amino acid residues. Preferably, the protein contains up to 20,000 amino acid residues, such as up to 15,000 amino acid residues, such as up to 10,000 amino acid residues, such as up to 5,000 amino acid residues, such as up to 4,000 amino acid residues, such as up to 3,000 amino acid residues, such as up to 2,000 amino acid residues, such as up to 1,000 amino acid residues.

[0081] As used herein, the terms "small molecule drug" and "small molecule bioactive moiety" refer to drugs and biologically active moieties that are organic compounds having a molecular weight of 1 kDa or less, such as up to 900 Da.

[0082] As used herein, the term "natural product" refers to a purified organic compound isolated from a natural source and produced by a primary or secondary metabolic pathway.

[0083] As used herein, the term "physiological conditions" refers to an aqueous buffer at pH 7.4 and 37°C.

[0084] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more active ingredients, such as the sustained-release CNP agonist of the present invention, and one or more additives, and in addition, any product directly or indirectly obtained as a result of the blending, complex formation, or aggregation of any two or more of the components of the composition, or as a result of the dissociation of one or more components, or as a result of other types of reactions or interactions of one or more components. Thus, the pharmaceutical composition of the present invention encompasses any composition prepared by mixing one or more of the sustained-release CNP agonists of the present invention and pharmaceutically acceptable additives.

[0085] As used herein, the term "liquid composition" refers to a mixture containing a water-soluble sustained-release CNP agonist and one or more solvents, such as water.

[0086] The term "suspension composition" relates to a mixture containing a water-insoluble sustained-release CNP agonist and one or more solvents, such as water.

[0087] As used herein, the term "dry composition" means that the pharmaceutical composition is provided in a dried state. Suitable drying methods are spray drying and freeze drying, i.e., lyophilization. Such a dry composition of the sustained-release CNP agonist of the present invention has a residual moisture content of at most 10%, preferably less than 5%, more preferably less than 2% as measured by Karl Fischer. The pharmaceutical composition of the present invention is preferably dried by freeze drying.

[0088] As used herein, the term "drug" refers to a substance used for the treatment, cure, prevention, or diagnosis of a disease, or a substance used to enhance physical or mental health. When a drug is conjugated to another moiety, the moiety of the resulting product originating from the drug is called the "bioactive moiety".

[0089] As used herein, the term "prodrug" refers to a bioactive moiety reversibly and covalently linked to a specific protecting group via a reversible prodrug linker moiety, where the reversible prodrug linker is a linker moiety that includes a reversible bond with the bioactive moiety, whereby the specific protecting group modifies or removes an undesirable property of the parent molecule. This includes enhancing the desirable properties of the drug and suppressing undesirable properties. A non-toxic specific protecting group is referred to as a "carrier". A prodrug releases the reversibly and covalently bound bioactive moiety in the form of the corresponding drug. In other words, a prodrug is a conjugate containing a bioactive moiety, where the bioactive moiety is covalently and reversibly conjugated to a carrier moiety via a reversible prodrug linker moiety, and the covalent and reversible bond between the carrier and the reversible prodrug linker moiety is either direct or through a spacer. Such a conjugate releases the originally conjugated bioactive moiety in the form of a free drug.

[0090] A "biodegradable bond" or "reversible bond" is a bond that is decomposable, i.e., cleavable, by hydrolysis without an enzyme under physiological conditions (aqueous buffer at pH 7.4, 37 °C), and the half-life is from 1 hour to 6 months, preferably from 1 hour to 4 months, more preferably from 1 hour to 3 months, even more preferably from 1 hour to 2 months, and even more preferably from 1 hour to 1 month. Thus, a "stable bond" is a bond having a half-life exceeding 6 months under physiological conditions (aqueous buffer at pH 7.4, 37 °C).

[0091] Thus, a "reversible prodrug linker moiety" is a moiety that is covalently conjugated to a bioactive moiety, such as a CNP agonist moiety, by a reversible bond and is also covalently conjugated to a carrier moiety, such as -Z or -Z', where the covalent bond with the carrier moiety is either direct or through a spacer moiety such as -L 2 -. The bond between -Z or -Z' and -L 2 - is preferably a stable bond.

[0092] As used herein, the term "non - leaving prodrug linker" means a reversible prodrug linker that releases the drug in its free form upon cleavage. The "free form" of a drug as used herein means the unmodified pharmacologically active form of the drug.

[0093] As used herein, the term "additive (excipient)" refers to a diluent, adjuvant, or vehicle that is used together to administer a therapeutic agent such as a drug or prodrug. Such pharmaceutical additives can be sterile liquids, such as water and oils, and the oils include those of petroleum, animal, plant, or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered orally, water is a preferred additive. When the pharmaceutical composition is administered intravenously, physiological saline and glucose aqueous solution are preferred additives. As liquid additives for injections, it is preferred to use physiological saline, glucose aqueous solution, and glycerol solution. Suitable pharmaceutical additives include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, cereal flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The pharmaceutical composition may optionally contain a small amount of wetting agent or emulsifier, pH buffer, such as acetate, succinate, tris, carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), etc., and may also contain surfactants, such as Tween, poloxamer, poloxamine, CHAPS, Igepal, etc., or amino acids, such as glycine, lysine, or histidine, etc. Such pharmaceutical compositions can take forms such as solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. The pharmaceutical composition may also be formulated as a suppository using conventional binders and additives, such as triglycerides. Oral formulations can contain standard additives, such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such compositions will contain a therapeutically effective amount of a drug or bioactive moiety together with a suitable amount of additives to provide a form for proper administration to a patient. The formulation should be suitable for the method of administration.

[0094] As used herein, the term "reagent" means a compound containing at least one functional group for reacting with a functional group of another compound or drug. Drugs containing functional groups (such as primary or secondary amines or hydroxyl functional groups) are also understood to be reagents.

[0095] As used herein, the term "moiety (substructure)" means a part of a molecule that has one or more fewer atoms compared to the corresponding reagent. For example, when a reagent of the formula "H-X-H" reacts with another reagent and becomes part of the reaction product, the corresponding moiety of the reaction product has the structure "H-X-" or "-X-", where each "-" represents a bond to another moiety. Thus, a biologically active moiety is released from a prodrug as a drug.

[0096] When an atomic group is provided with an array or chemical structure of an atomic group that is bonded to two moieties or has inserted into one moiety, unless otherwise clearly stated, it is understood that the said array or chemical structure may be bonded to the two moieties in any orientation. For example, the moiety "-C(O)N(R 1 )-" may be bonded to two moieties as "-C(O)N(R 1 )-" or as "-N(R 1 )C(O)-", or may have inserted into one moiety. Similarly, the moiety

[0097]

Chem.

[0098]

Chem.

[0099]

Chem.

[0100] As used herein, the term "functional group" means an atomic group capable of reacting with other atomic groups. Functional groups include, but are not limited to, the following groups: carboxylic acid (-(C=O)OH), primary or secondary amine (-NH2, -NH-), maleimide, thiol (-SH), sulfonic acid (-(O=S=O)OH), carbonate, carbamate (-O(C=O)N<), hydroxyl (-OH), aldehyde (-(C=O)H), ketone (-(C=O)-), hydrazine (>N-N<), isocyanate, isothiocyanate, phosphoric acid (-O(P=O)OHOH), phosphonic acid (-O(P=O)OHH), haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, disulfide, sulfonamide, sulfonic acid, vinyl sulfone, vinyl ketone, diazoalkane, oxirane and aziridine.

[0101] When the sustained-release CNP agonist of the present invention contains one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, particularly their pharmaceutically available salts. Thus, the sustained-release CNP agonist of the present invention containing an acidic group can be used according to the present invention, for example, as an alkali metal salt, an alkaline earth metal salt, or an ammonium salt. More detailed examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine, etc.) or amino acids. There may also be a sustained-release CNP agonist of the present invention containing one or more basic groups, i.e., groups that can be protonated, which can be used according to the present invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenolpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. Further methods for converting basic groups to cations, such as alkylation of amine groups to provide appropriate counterions for positively charged ammonium groups and their salts, are known to those skilled in the art. When the sustained-release CNP agonist of the present invention contains both acidic and basic groups simultaneously, the present invention also includes inner salts or betaines (zwitterions) in addition to the salt forms mentioned. Each salt can be obtained by conventional methods known to those skilled in the art, for example, by contacting these prodrugs with organic or inorganic acids or bases in a solvent or dispersion, or by anion exchange or cation exchange with other salts. The present invention includes all salts of the prodrugs of the present invention, which, although not directly suitable for use in pharmaceuticals due to low physiological compatibility, can be used, for example, as intermediates in chemical reactions or in the preparation of pharmaceutically acceptable salts.

[0102] The term "pharmaceutically acceptable" means a substance that does not cause harm when administered to a patient, and preferably means that it is approved for use in animals, preferably for use in humans, by a regulatory agency, such as the EMA (Europe) and / or the FDA (USA) and / or any other national regulatory agency.

[0103] The term "about" as used in combination with a numerical value herein means, in addition to the numerical value itself, a range of plus / minus up to 10% of the numerical value, more preferably up to 8% of the numerical value, even more preferably up to 5% of the numerical value, and most preferably up to 2% of the numerical value. For example, the phrase "about 200" means a range of 200+ / -10%, i.e., a range of 180 to 220, preferably a range of 200+ / -8%, i.e., a range of 184 to 216, even more preferably a range of 200+ / -5%, i.e., a range of 190 to 210, and most preferably a range of 200+ / -2%, i.e., a range of 196 to 204. It is understood that the percentage indicated as "about 20%" does not mean a range of "20%+ / -10%", i.e., 10 to 30%, but rather that "about 20%" means a range of plus / minus 10% of the numerical value of 20, i.e., 18 to 22.

[0104] As used herein, the term "polymer" means a molecule containing repeating structural units, i.e., monomers, linked by chemical bonds in a linear, cyclic, branched, cross-linked, or dendrimeric form, or a combination thereof, which may be of synthetic origin, biological origin, or a combination of both. It is understood that polymers may also contain one or more other chemical groups and / or moieties, such as, for example, one or more functional groups. Preferably, soluble polymers have a molecular weight of at least 0.5 kDa, for example, at least 1 kDa, at least 2 kDa, at least 3 kDa, or at least 5 kDa. When the polymer is soluble, it preferably has a molecular weight of up to 1000 kDa, for example, up to 750 kDa, for example, up to 500 kDa, for example, up to 300 kDa, for example, up to 200 kDa, for example, up to 100 kDa. In the case of insoluble polymers such as hydrogels, it is understood that no meaningful molecular weight range can be provided. Proteins are also understood to be polymers (macromolecules) in which the amino acids are the repeating structural units, although the side chains of each amino acid may vary.

[0105] As used herein, the term "polymeric" means a reagent or moiety containing one or more polymers or polymer moieties. The polymeric reagent or moiety may optionally also contain one or more other moieties, and such other moieties are preferably selected from the group consisting of: · C 1-50 alkyl, C 2-50 alkenyl, C 2-50 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, phenyl, naphthyl, indenyl, indanyl, and tetralinyl, and · bonds selected from the group consisting of:

Chemical formula

[0106] Those skilled in the art will understand that the polymerization products obtained from the polymerization reaction do not necessarily all have the same molecular weight, but rather exhibit a molecular weight distribution. Therefore, the molecular weight ranges, molecular weights, monomer number ranges in the polymer, and monomer numbers used herein refer to the number average molecular weight and the average number of monomers, that is, the arithmetic mean of the molecular weights of the polymer or polymer portion, and the arithmetic mean of the number of monomers in the polymer or polymer portion.

[0107] Thus, in the case of a polymer portion containing "x" monomer units, any integer applied to "x" corresponds to the arithmetic mean of the monomers. Any range of integers applied to "x" provides a range of integers in which the arithmetic mean of the monomers exists. The integer "x" indicated as "about x" means that the arithmetic mean of the monomers exists within the integer range of x + / - 10%, preferably x + / - 8%, more preferably x + / - 5%, and most preferably x + / - 2%.

[0108] The term "number average molecular weight" used herein means the ordinary arithmetic mean of the molecular weights of the individual polymers.

[0109] The term "water-soluble" used herein with respect to the carrier means that when such a carrier is part of the sustained-release CNP agonist of the present invention, at least 1 g of the sustained-release CNP agonist containing such a water-soluble carrier can be dissolved in 1 liter of water at 20 °C to form a homogeneous solution. Therefore, the term "water-insoluble" with respect to the carrier means that when such a carrier is part of the sustained-release CNP agonist of the present invention, less than 1 g of the sustained-release CNP agonist containing such a water-insoluble carrier can be dissolved in 1 liter of water at 20 °C to form a homogeneous solution.

[0110] As used herein, the term "hydrogel" refers to a hydrophilic or amphiphilic polymer network composed of a homopolymer or copolymer, which is insoluble due to the presence of covalent chemical cross-links. The cross-links provide network structure and physical integrity.

[0111] As used herein, the term "thermogelation" refers to a liquid or low-viscosity solution having a viscosity of less than 500 cps at 25°C at a shear rate of about 0.1 / sec at a low temperature (this low temperature is from about 0°C to about 10°C), but a compound having a higher viscosity of less than 10,000 cps at 25°C at a shear rate of about 0.1 / sec at a higher temperature (this higher temperature is from about 30°C to about 40°C, for example about 37°C).

[0112] As used herein, the term "PEG-based" with respect to a moiety or reagent means that the moiety or reagent contains PEG. Preferably, the PEG-based moiety or reagent contains at least 10% (w / w) PEG, such as at least 20% (w / w) PEG, such as at least 30% (w / w) PEG, such as at least 40% (w / w) PEG, such as at least 50% (w / w), such as at least 60 (w / w) PEG, such as at least 70% (w / w) PEG, such as at least 80% (w / w) PEG, such as at least 90% (w / w), such as at least 95% (w / w) PEG. The remaining weight percentage of the PEG-based moiety or reagent is preferably other moieties selected from the following moieties and linkages: ·C 1-50 alkyl, C 2-50 alkenyl, C 2-50 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and ·linkages selected from the group consisting of:

Chemical formula

[0113] As used herein, the term "PEG-based containing at least X% PEG" with respect to a moiety or reagent means that the moiety or reagent contains at least X% (w / w) ethylene glycol units (-CH2CH2O-), and the ethylene glycol units may be arranged in an alternating block pattern or randomly distributed within the moiety or reagent. Preferably, all the ethylene glycol units of the moiety or reagent are present within one block, and the remaining weight percentage of the PEG-based moiety or reagent is preferably another moiety selected from the following moieties and bonds: · C 1-50 alkyl, C 2-50 alkenyl, C 2-50 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, phenyl, naphthyl, indenyl, indanyl, and tetralinyl, and · bonds selected from the group consisting of the following:

Chemical formula

[0114] The term "hyaluronic acid-based containing at least X% hyaluronic acid" is used as appropriate.

[0115] As used herein, the term "substituted" means that one or more -H atoms of a molecule or moiety are replaced by another atom or atomic group, and the other atom or atomic group is referred to as a "substituent".

[0116] Preferably, one or more additional optional substituents are, independently of each other, halogen, -CN, -COOR x1 , -OR x1 , -C(O)R x1 , -C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 , -S(O)R x1 , -N(R x1 ), S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 ), C(O)R x1a , -N(R x1 ), S(O)2R x1a , -N(R x1 ), S(O)R x1a , -N(R x1 ), C(O)OR x1a , -N(R x1 ), C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 , C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl selected from the group consisting of, where -T 0 , C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl are optionally substituted with one or more of the same or different -R x2 , and C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl contain -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 ), -S(O)2N(R x3)-, -S(O)N(R x3 )-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-, -N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )- from the group consisting of one or more groups optionally inserted, -R x1 , -R x1a , -R x1b are, independently of each other, -H, -T 0 , C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl selected from the group consisting of, said -T 0 , C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl may be optionally substituted with one or more -R x2 and said C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl include -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )(-, -S(O)2N(R x3 )(-, -S(O)N(R x3 )-; -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-, -N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )- from the group consisting of one or more groups optionally inserted, each T 0 is, independently, phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10Selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic, each T 0 is independently optionally substituted with one or more identical or different -R x2 and each R x2 is independently halogen, -CN, oxo(=O), -COOR x4 , -OR x4 , -C(O)R x4 , -C(O)N(R x4 R x4a ), -S(O)2N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O)2R x4 , -S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO2, -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O)2R x4a , -N(R x4 )S(O)R x4a , -N(R x4 )C(O)OR x4a , -N(R x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ), and C 1-6 alkyl selected from the group consisting of, said C 1-6 alkyl is optionally substituted with one or more identical or different halogens, each -R x3 , -R x3a , -R x4 , -R x4a , -R x4b is independently selected from the group consisting of -H and C 1-6 alkyl, said C 1-6The alkyl is optionally substituted with one or more of the same or different halogens.

[0117] More preferably, one or more further optional substituents are, independently of one another, halogen, -CN, -COOR x1 , -OR x1 , -C(O)R x1 , -C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 , -S(O)R x1 , -N(R x1 )(S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )(C(O)R x1a , -N(R x1 )(S(O)2R x1a , -N(R x1 )(S(O)R x1a , -N(R x1 )(C(O)OR x1a , -N(R x1 )(C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 , C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, where -T 0 , C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl are optionally substituted with one or more of the same or different -R x2 , and C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl have -T 0-, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-, -S(O)2N(R x3 )-, -S(O)N(R x3 )-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-, -N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )- may optionally be interrupted by one or more groups selected from the group consisting of, each -R x1 , -R x1a , -R x1b , -R x3 , -R x3a is independently selected from the group consisting of -H, halogen, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each T 0 is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic, and each said T 0 is independently optionally substituted with one or more of the same or different -R x2 . each R x2 is independently halogen, -CN, oxo (=O), -COOR x4 , -OR x4 , -C(O)R x4 , -C(O)N(R x4 R x4a ), -S(O)2N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O)2R x4 , -S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SRx4 , -N(R x4 R x4a ), -NO2, -OC(O)R x4 , -N(R x4 )(O)C(R x4a , -N(R x4 )(O)2S(R x4a , -N(R x4 )(O)S(R x4a , -N(R x4 )(O)OC(R x4a , -N(R x4 )(O)CN(R x4a R x4b ), -OC(O)N(R x4 R x4a ), and C 1-6 alkyl selected from the group consisting of, said C 1-6 alkyl is optionally substituted with one or more same or different halogens, each -R x4 , -R x4a , -R x4b is independently selected from the group consisting of -H, halogen, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl.

[0118] Even more preferably, one or more additional optional substituents are, independently of each other, halogen, -CN, -COOR x1 , -OR x1 , -C(O)R x1 , -C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 , -S(O)R x1 , -N(R x1 )(O)2SN(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )(O)CN(Rx1a 、 -N(R x1 )S(O)2R x1a 、 -N(R x1 )S(O)R x1a 、 -N(R x1 )C(O)OR x1a 、 -N(R x1 )C(O)N(R x1a R x1b )、 -OC(O)N(R x1 R x1a )、 -T 0 、 C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl selected from the group consisting of, where -T 0 、 C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl may be optionally substituted with one or more -R x2 , and said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl may optionally contain one or more groups selected from the group consisting of -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-, -S(O)2N(R x3 )-, -S(O)N(R x3 )-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-, -N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )- interrupting, each -R x1 , -R x1a , -R x1b , -R x2 , -R x3 , -R x3a is independently -H, halogen, C 1-6 alkyl, C 2-6 alkenyl and C2-6 selected from the group consisting of alkynyl, each T 0 is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic, and each said T 0 is independently optionally substituted with one or more -R x2 groups.

[0119] Preferably, up to 6 of the -H atoms of the optionally substituted molecule are independently replaced by substituents, for example, 5 -H atoms are independently replaced by substituents, 4 -H atoms are independently replaced by substituents, 3 -H atoms are independently replaced by substituents, 2 -H atoms are independently replaced by substituents, or 1 -H atom is replaced by a substituent.

[0120] The term "interrupted" means that the moiety is inserted between two carbon atoms or, if the insertion is at the end of the moiety, the moiety is inserted between a carbon or heteroatom and a hydrogen atom, preferably between a carbon and a hydrogen atom.

[0121] The term "C 1-4 alkyl" as used herein alone or in combination means a straight or branched alkyl moiety having 1 to 4 carbon atoms. When present at the end of a molecule, examples of straight or branched C 1-4 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. When two moieties of a molecule are joined by C 1-4 alkyl, examples of such C 1-4 alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. C 1-4Each hydrogen of the alkyl carbon may optionally be replaced by a substituent as defined above. Optionally, one or more moieties as defined below may be inserted into the C 1-4 alkyl.

[0122] The term "C 1-6 alkyl" as used herein alone or in combination means a straight-chain or branched alkyl moiety having 1 to 6 carbon atoms. When present at the end of a molecule, examples of straight-chain and branched C 1-6 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. When two moieties of a molecule are linked by a C 1-6 alkyl group, examples of such C 1-6 alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. Each hydrogen atom of the C 1-6 carbon may optionally be replaced by a substituent as defined above. Optionally, one or more moieties as defined below may be inserted into the C 1-6 alkyl.

[0123] Thus, "C 1-10 alkyl", "C 1-20 alkyl", or "C 1-50 alkyl" means an alkyl chain having 1 to 10, 1 to 20, or 1 to 50 carbon atoms, respectively, and each hydrogen atom of C 1-10 , C 1-20 or C 1-50 carbon may optionally be replaced by a substituent as defined above. Optionally, one or more moieties as defined below may be inserted into C 1-10 or C 1-50 alkyl.

[0124] The term "C 2-6 alkenyl", used alone or in combination herein, means a straight-chain or branched hydrocarbon moiety having from 2 to 6 carbon atoms and containing at least one carbon-carbon double bond. When present at the end of a molecule, examples are -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3, and -CH=CH-CH=CH2. When two portions of a molecule are joined by C 2-6 alkenyl, an example of such C 2-6 alkenyl is -CH=CH-. Each hydrogen atom of the C 2-6 alkenyl moiety may optionally be replaced by a substituent as defined above. Optionally, one or more moieties as defined below may be interposed in the C 2-6 alkenyl.

[0125] Accordingly, the term "C 2-10 alkenyl", "C 2-20 alkenyl", or "C 2-50 alkenyl", used alone or in combination, means a straight-chain or branched hydrocarbon moiety having from 2 to 10, from 2 to 20, or from 2 to 50 carbon atoms and containing at least one carbon-carbon double bond. Each hydrogen atom of the C 2-10 alkenyl, C 2-20 alkenyl, or C 2-50 alkenyl group may optionally be replaced by a substituent as defined above. Optionally, one or more moieties as defined below may be interposed in the C 2-10 alkenyl, C 2-20 alkenyl, or C 2-50 alkenyl.

[0126] The term "C 2-6"Alkynyl" means a straight-chain or branched hydrocarbon moiety having from 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. When present at the end of a molecule, examples are -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, and CH2-C≡C-CH3. When two moieties of a molecule are joined by an alkynyl group, an example is -C≡C-. C 2-6 Each hydrogen atom of the alkynyl group may optionally be replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-6 One or more moieties as defined below may be interposed in the alkynyl.

[0127] Accordingly, the term "C 2-10 alkynyl", "C 2-20 alkynyl", or "C 2-50 alkynyl" as used herein alone or in combination each means a straight-chain or branched hydrocarbon moiety having from 2 to 10, 2 to 20, or 2 to 50 carbon atoms and containing at least one carbon-carbon triple bond. C 2-10 alkynyl, C 2-20 alkynyl, or C 2-50 alkynyl group may each hydrogen atom optionally be replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-10 alkynyl, C 2-20 alkynyl, or C 2-50 alkynyl may one or more moieties as defined below be interposed.

[0128] As described above, C 1-4 alkyl, C 1-6 alkyl, C 1-10 alkyl, C 1-20 alkyl, C 1-50 alkyl, C 2-6 alkenyl, C 2-10 alkenyl, C 2-20 alkenyl, C 2-50 alkenyl, C 2-6 alkynyl, C 2-10 alkynyl, C2-20 Alkenyl or C 2-50 In alkynyl, one or more moieties may optionally intervene, and the one or more moieties are preferably

Chemical formula

[0129] As used herein, the term "C 3-10 cycloalkyl" means a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl. Each hydrogen atom of C 3-10 cycloalkyl carbon may be replaced by a substituent as defined above. The term "C 3-10 cycloalkyl" also includes bridged bicyclics such as norbornane or norbornene.

[0130] The term "8- to 30-membered carbopolysicyclic" or "8- to 30-membered carbon polycycle" means a polycyclic moiety having 8 to 30 ring atoms, in which two adjacent rings share at least one ring atom, and which can contain up to the maximum number of double bonds (fully saturated, partially saturated or unsaturated, aromatic or non-aromatic rings). Preferably, 8- to 30-membered carbopolysicyclic means a cyclic moiety of 2, 3, 4 or 5 rings, more preferably 2, 3 or 4 rings.

[0131] As used herein, the term "3- to 10-membered heterocyclyl" or "3- to 10-membered heterocyclic ring" means a ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, wherein at least 1 and up to a maximum of 4 ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and which can contain up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings), and is a ring bonded to the remainder of the molecule by a carbon or nitrogen atom. Examples of 3- to 10-membered heterocyclic rings include, but are not limited to, aziridine, oxirane, thiirane, azirine, oxirene, thiirene, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine, and homopiperazine. Each hydrogen atom of a 3- to 10-membered heterocyclyl or 3- to 10-membered heterocyclic group may optionally be replaced by a substituent as defined below.

[0132] As used herein, the term "8- to 11-membered heterobicyclic" or "8- to 11-membered heterocyclic bicyclic" means a bicyclic heterocyclic moiety having 8 to 11 ring atoms and containing up to the maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings), wherein at least one ring atom is shared by both rings, and at least one ring atom, up to a maximum of 6 ring atoms, is replaced by a heteroatom selected from the group consisting of sulfur (-S(O)-, -S(O)2-), oxygen, and nitrogen (=N(O)-), and said ring is attached to the remainder of the molecule by a carbon or nitrogen atom. Examples of 8- to 11-membered heterocyclic bicyclics are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, and pteridine. The term 8- to 11-membered heterocyclic bicyclic also includes bicyclic spiro structures such as 1,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles such as 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom of an 8- to 11-membered heterobicyclic or 8- to 11-membered heterocyclic bicyclic carbon may optionally be replaced by a substituent as defined below.

[0133] Similarly, the term "8- to 30-membered hetero polycyclic" or "8- to 30-membered hetero polycycle" means a heterocyclic moiety having 8 to 30 ring atoms and capable of containing up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings), of two or more rings, preferably 3, 4 or 5 rings, wherein two adjacent rings share at least one ring atom, and at least one ring atom, up to a maximum of 10 ring atoms, is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and wherein said ring is attached to the remainder of the molecule by a carbon or nitrogen atom.

[0134] Structure:

Chem.

Chem.

[0135] Structure:

Chem.

Chem.

[0136] As used herein, "halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that the halogen be fluoro or chloro.

[0137] Generally, the term "comprising" or "comprises" also encompasses "consisting of" or "consists of".

[0138] The sustained-release CNP agonist of the present invention has a degradation half-life that is at least 5 times longer than that of the corresponding released CNP agonist in an in vitro NEP degradation assay. Preferably, the sustained-release CNP agonist of the present invention has a degradation half-life that is at least 10 times longer than that of the corresponding released CNP agonist in an in vitro NEP degradation assay. Even more preferably, the sustained-release CNP agonist of the present invention has a degradation half-life that is at least 15 times longer than that of the corresponding released CNP agonist in an in vitro NEP degradation assay. Even more preferably, the sustained-release CNP agonist of the present invention has a degradation half-life that is at least 20 times longer than that of the corresponding released CNP agonist in an in vitro NEP degradation assay. Even more preferably, the sustained-release CNP agonist of the present invention has a degradation half-life that is at least 25 times longer than that of the corresponding released CNP agonist in an in vitro NEP degradation assay. Even more preferably, the sustained-release CNP agonist of the present invention has a degradation half-life that is at least 30 times longer than that of the corresponding released CNP agonist in an in vitro NEP degradation assay.

[0139] The sustained-release CNP agonist of the present invention releases at least one CNP agonist with a release half-life of at least 6 hours under physiological conditions. Preferably, the sustained-release CNP agonist of the present invention releases at least one CNP agonist with a release half-life of at least 12 hours under physiological conditions. Even more preferably, the sustained-release CNP agonist of the present invention releases at least one CNP agonist with a release half-life of at least 24 hours under physiological conditions. Even more preferably, the sustained-release CNP agonist of the present invention releases at least one CNP agonist with a release half-life of at least 48 hours under physiological conditions. Even more preferably, the sustained-release CNP agonist of the present invention releases at least one CNP agonist with a release half-life of at least 72 hours under physiological conditions. Even more preferably, the sustained-release CNP agonist of the present invention releases at least one CNP agonist with a release half-life of at least 96 hours under physiological conditions. Even more preferably, the sustained-release CNP agonist of the present invention releases at least one CNP agonist with a release half-life of at least 120 hours under physiological conditions. Even more preferably, the sustained-release CNP agonist of the present invention releases at least one CNP agonist with a release half-life of at least 144 hours under physiological conditions. Even more preferably, the sustained-release CNP agonist of the present invention releases at least one CNP agonist with a release half-life of at least 168 hours under physiological conditions. Even more preferably, the sustained-release CNP agonist of the present invention releases at least one CNP agonist with a release half-life of at least 192 hours under physiological conditions.

[0140] The sustained-release CNP agonist preferably contains a CNP agonist selected from the group consisting of small molecules, natural products, oligonucleotides, polypeptides, and proteins.

[0141] In one embodiment, the CNP agonist contains a small molecule. Preferably, the CNP agonist is a small molecule.

[0142] In another embodiment, the CNP agonist contains a natural product. Preferably, the CNP agonist is a natural product.

[0143] In another embodiment, the CNP agonist comprises an oligonucleotide. Preferably, such oligonucleotides are selected from the group consisting of antisense oligonucleotides, aptamers, RNAi, and siRNA. Preferably, the CNP agonist is an oligonucleotide, more preferably selected from the group consisting of antisense oligonucleotides, aptamers, RNAi, and siRNA.

[0144] In another embodiment, the CNP agonist comprises a protein. Preferably, the CNP agonist is a protein.

[0145] In a preferred embodiment, the CNP agonist comprises a polypeptide. More preferably, the CNP agonist is a polypeptide. Preferably, the CNP agonist comprises a CNP molecule or moiety. More preferably, the CNP agonist is CNP. Even more preferably, the CNP agonist comprises a CNP molecule or moiety having the sequence of SEQ ID NO: 24, SEQ ID NO: 25, or SEQ ID NO: 30. Even more preferably, the CNP agonist is CNP having the sequence of SEQ ID NO: 24, SEQ ID NO: 25, or SEQ ID NO: 30. In one embodiment, the CNP agonist is CNP having the sequence of SEQ ID NO: 24. In another embodiment, the CNP agonist is CNP having the sequence of SEQ ID NO: 25. In another embodiment, the CNP agonist is CNP having the sequence of SEQ ID NO: 30.

[0146] In one embodiment, the sustained release CNP agonist is water-insoluble.

[0147] Preferably, the sustained release CNP agonist is selected from the group consisting of crystals, nanoparticles, microparticles, nanospheres, and microspheres.

[0148] In one embodiment, the sustained release CNP agonist is a crystal comprising at least one CNP agonist.

[0149] In another embodiment, the sustained release CNP agonist is a nanoparticle comprising at least one CNP agonist.

[0150] In another embodiment, the sustained-release CNP agonist is microparticles comprising at least one CNP agonist.

[0151] In another embodiment, the sustained-release CNP agonist is nanospheres comprising at least one CNP agonist.

[0152] In another embodiment, the sustained-release CNP agonist is microspheres comprising at least one CNP agonist.

[0153] In one embodiment, the sustained-release CNP agonist is a vesicle comprising at least one CNP agonist. Preferably, such a vesicle comprising at least one CNP agonist is a micelle, liposome or polymersome.

[0154] In one embodiment, the sustained-release CNP agonist is a micelle comprising at least one CNP agonist.

[0155] In another embodiment, the sustained-release CNP agonist is a liposome comprising at least one CNP agonist. Preferably, such liposomes are selected from the group consisting of aquasomes; non-ionic surfactant vesicles such as niosomes and proniosomes; cationic liposomes such as LeciPlex; transferosomes; esosomes; ufasomes; sphingosomes; and pharmacosomes.

[0156] In another embodiment, the sustained-release CNP agonist is a polymersome comprising at least one CNP agonist.

[0157] In another embodiment, the sustained-release CNP agonist comprises at least one CNP agonist non-covalently embedded in a water-insoluble polymer. Preferably, such a water-insoluble polymer is selected from the group consisting of 2-methacryloyl-oxyethyl phosphorylcholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amide amines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyl oxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxy methacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyl oxazolines), poly(organic phosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinyl methyl ethers), poly(vinyl pyrrolidones), silicones, celluloses, carboxymethyl celluloses, hydroxypropyl methyl celluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon-based polymers, xylans, and copolymers thereof.

[0158] In a preferred embodiment, the sustained release CNP comprises at least one CNP agonist non-covalently embedded in poly(lactic-co-glycolic acid) (PLGA).

[0159] In another embodiment, the sustained-release CNP agonist comprises at least one CNP agonist covalently and reversibly bound to a water-insoluble polymer. Preferably, such a water-insoluble polymer is selected from the group consisting of 2-methacryloyl-oxyethyl phosphorylcholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amide amines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxymethacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organic phosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinyl methyl ethers), poly(vinyl pyrrolidones), silicones, celluloses, carboxymethyl celluloses, hydroxypropyl methyl celluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon-based polymers, xylans, and copolymers thereof.

[0160] Preferably, such a sustained-release CNP agonist comprising at least one CNP agonist covalently and reversibly bound to a water-insoluble polymer is a CNP agonist prodrug comprising conjugate D-L, - D is a CNP agonist moiety; - L is a reversible prodrug linker moiety -L 1 - comprising; - L 1 - is, -L 2 - substituted with -Z’ and optionally further substituted, - L 2 - is a single chemical bond or a spacer moiety; - Z’ is a water-insoluble carrier moiety.

[0161] Moiety -L 2 - L 1 - It is understood that a plurality of Ds are linked to the water-insoluble carrier -Z’.

[0162] The water-insoluble carrier-Z' is preferably a hydrogel. Preferably, such a hydrogel is selected from the group consisting of 2-methacryloyl-oxyethyl phosphoryl cholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amide amines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxy methacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organic phosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinyl methyl ethers), poly(vinyl pyrrolidones), silicones, celluloses, carboxymethyl celluloses, hydroxypropyl methyl celluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon-based polymers, xylans, and copolymers thereof.

[0163] When the carrier-Z' is a hydrogel, a hydrogel containing PEG or hyaluronic acid is preferred. Most preferably, such a hydrogel contains PEG. In a similarly preferred embodiment, such a hydrogel contains hyaluronic acid.

[0164] Even more preferably, the carrier-Z' is a hydrogel as described in WO 2006 / 003014 A2, WO 2011 / 012715 A1 or WO 2014 / 056926 A1 (which are hereby incorporated herein by reference in their entireties).

[0165] In another embodiment, Z' is a polymer network formed by physical aggregation of polymer chains, and the physical aggregation is preferably caused by hydrogen bonding, crystallization, helix formation, or complex formation. In one embodiment, such a polymer network is a thermogel polymer.

[0166] In another embodiment, the sustained-release CNP agonist is water-soluble.

[0167] In one embodiment, the CNP agonist is a polypeptide or a protein, and the sustained-release CNP agonist is a fusion protein comprising such a polypeptide or protein CNP agonist moiety fused to one or more additional polypeptide or protein moieties. Preferably, the CNP agonist is released from the fusion protein by enzymatic cleavage. Preferably, such at least one or a plurality of additional polypeptide or protein moieties are the carboxyl terminal peptide of chorionic gonadotropin described in US2012 / 0035101A1 (incorporated herein by reference); albumin; the XTEN sequence described in WO2011123813A2 (incorporated herein by reference); the proline / alanine random coil sequence described in WO2011 / 144756A1 (incorporated herein by reference); the proline / alanine / serine random coil sequences described in WO2008 / 155134A1 and WO2013 / 024049A1 (incorporated herein by reference); and Fc fusion proteins, selected from the group consisting of.

[0168] In a preferred embodiment, the sustained-release CNP agonist is a CNP agonist prodrug of formula (Ia) or (Ib).

Chemical formula

[0169] Preferably, x in formula (Ia) is an integer selected from the group consisting of 1, 2, 3, 4, 6, and 8. More preferably, x in formula (Ia) is an integer selected from the group consisting of 1, 2, 4, and 6. Even more preferably, x in formula (Ia) is an integer selected from the group consisting of 1, 4, and 6, and most preferably, x in formula (Ia) is 1.

[0170] Preferably, y in formula (Ib) is an integer selected from the group consisting of 2, 3, 4, and 5, even more preferably, an integer selected from the group consisting of 2, 3, or 4, and most preferably, an integer selected from the group consisting of 2 or 3.

[0171] In another preferred embodiment, y in formula (Ib) is an integer selected from the group consisting of 1, 2, or 3. In one preferred embodiment, y in formula (Ib) is 1. In a similarly preferred embodiment, y in formula (Ib) is 2.

[0172] Preferably, the sustained-release CNP-acting agent is a CNP-acting agent prodrug of formula (Ia) where x = 1.

[0173] Sub-L 1 - is a reversible prodrug linker from which the drug, i.e., the CNP-acting agent, is released in its free form, i.e., -L 1 - is a prodrug linker that leaves no trace. Suitable prodrug linkers, for example, the reversible prodrug linker moieties disclosed in WO 2005 / 099768 A2, WO 2006 / 136586 A2, WO 2011 / 089216 A1, and WO 2013 / 024053 A1, which are incorporated herein by reference, are known in the art.

[0174] In another embodiment, -L 1- is a reversible prodrug linker as described in WO 2011 / 012722 A1, WO 2011 / 089214 A1, WO 2011 / 089215 A1, WO 2013 / 024052 A1 and WO 2013 / 160340 A1, which are incorporated herein by reference.

[0175] Sub - L 1 - can be linked to - D via any kind of linker, provided that it is reversible. Preferably, - L 1 - is linked to - D via a linker selected from the group consisting of amide, ester, carbamate, acetal, aminals, imine, oxime, hydrazone, disulfide and acylguanidine. Even more preferably, - L 1 - is linked to - D via a linker selected from the group consisting of amide, ester, carbamate and acylguanidine. These linkers themselves may not be reversible, and it is understood that the adjacent groups contained in - L 1 - may be such that they make the linker reversible.

[0176] In a preferred embodiment, sub - L 1 - is linked to - D via an amide linker.

[0177] Particularly preferred sub - L 1 - is disclosed in WO 2009 / 095479 A2. Thus, in one preferred embodiment, sub - L 1 - has the formula (II):

[0178]

Chemical formula

[0179] Preferably, -L 1 - in formula (II) is substituted by one moiety -L 2 -Z or -L 2 -Z'.

[0180] In one embodiment, -L 1 - in formula (II) is not further substituted.

[0181] When -R 3 / -R 3a in formula (II) forms, together with the nitrogen atom to which they are attached, a 3- to 10-membered heterocyclic ring, it is understood that only such 3- to 10-membered heterocyclic rings in which the atom directly bonded to nitrogen is an SP 3 hybridized carbon atom can be formed. In other words, -R 3 / -R 3aSuch 3- to 10-membered heterocycles formed by them and the nitrogen atoms to which they are attached have the following structure:

Chemical formula

[0182] It is also understood that the 3- to 10-membered heterocycle may be further substituted.

[0183] -R in formula (II) 3 / -R 3a Exemplary embodiments of suitable 3- to 10-membered heterocycles formed by them and the nitrogen atoms to which they are attached are as follows:

Chemical formula

[0184] Optionally, -L in formula (II) 1 - may be further substituted. Generally, any substituent may be used as long as it does not affect the principle of cleavage, that is, the hydrogen marked with an asterisk in formula (II) is not replaced, and the nitrogen in the moiety

Chemical formula

[0185] In one embodiment, -R of formula (II) 1 or -R 1a is replaced with -L 2 -Z or -L 2 -Z'. In another embodiment, -R of formula (II) 2 or -R 2a is replaced with -L 2 -Z or -L 2 -Z'. In another embodiment, -R of formula (II) 3 or -R 3a is replaced with -L 2 -Z or -L 2 -Z'. In another embodiment, -R of formula (II) 4 is replaced with -L 2 -Z or -L 2 -Z'. In another embodiment, -R of formula (II) 5 or -R 5a is replaced with -L 2 -Z or -L 2 -Z'. In another embodiment, -R of formula (II) 6 is replaced with -L 2 -Z or -L 2 -Z'. In another embodiment, -R of formula (II) 7 or -R 7a is replaced with -L 2 -Z or -L 2 -Z'. In another embodiment, -R of formula (II) 8 or -R 8a is replaced with -L 2 -Z or -L 2 -Z'. In another embodiment, -R of formula (II) 9 or -R 9a is replaced with -L 2 -Z or -L 2 -Z'.

[0186] Most preferably, -R of formula (II) 4 is replaced with -L 2 -Z or -L 2 -Z'.

[0187] Preferably, -X- in formula (II) is -C(R 4 R 4a )- or -N(R 4 )-. Most preferably, -X- in formula (II) is -C(R 4 R 4a ).

[0188] Preferably, X 1 in formula (II) is C.

[0189] Preferably, =X 3 in formula (II) is =O.

[0190] Preferably, -X 2 - in formula (II) is -C(R 8 R 8a ).

[0191] Preferably, -R 8 and -R 8a in formula (II) are independently selected from the group consisting of -H, methyl, and ethyl. More preferably, at least one of -R 8 and -R 8a in formula (II) is -H. Even more preferably, both -R 8 and -R 8a in formula (II) are -H.

[0192] Preferably, -R 1 and -R 1a in formula (II) are independently selected from the group consisting of -H, methyl, and ethyl. More preferably, at least one of -R 1 and -R 1a in formula (II) is -H. Even more preferably, both -R 1 and -R 1a in formula (II) are -H.

[0193] Preferably, -R 2 and -R 2ais independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R of formula (II) 2 and -R 2a at least one of is -H. Even more preferably, -R of formula (II) 2 and -R 2a both are H.

[0194] Preferably, -R of formula (II) 3 and -R 3a are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Even more preferably, at least one of -R of formula (II) 3 and -R 3a is methyl. In a similarly preferred embodiment, -R of formula (II) 3 and -R 3a are both -H. In another similarly preferred embodiment, -R of formula (II) 3 and -R 3a are both methyl.

[0195] Preferably, -R of formula (II) 3 is -H and -R of formula (II) 3a is methyl.

[0196] Preferably, -R of formula (II) 4 and -R 4a are independently selected from the group consisting of -H, methyl and ethyl. More preferably, at least one of -R of formula (II) 4 and -R 4a is -H. Even more preferably, -R of formula (II) 4 and -R 4a both are -H.

[0197] Preferably, moiety -L 1 - is of formula (IIa):

Chemical formula

[0198] Preferably, the -L 1 - in formula (IIa) is substituted with one moiety -L 2 -Z or -L 2 -Z’.

[0199] Preferably, the moiety -L 1 - in formula (IIa) is not further substituted.

[0200] Preferably, -R 1 and -R 1a in formula (IIa) are independently selected from the group consisting of -H, methyl, and ethyl. More preferably, at least one of -R 1 and -R 1a in formula (IIa) is -H. Even more preferably, both -R 1 and -R 1a in formula (IIa) are -H.

[0201] Preferably, -R 4 and -R 4ais independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R of formula (IIa) 4 and -R 4a at least one of is -H. Even more preferably, -R of formula (IIa) 4 and -R 4a both are -H.

[0202] Preferably, -X of formula (IIa) 2 - is -C(R 8 R 8a ).

[0203] Preferably, -R of formula (IIa) 8 and -R 8a are independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R of formula (IIa) 8 and -R 8a at least one of is -H. Even more preferably, -R of formula (IIa) 8 and -R 8a both are -H.

[0204] Preferably, -R of formula (IIa) 2 and -R 2a are independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R of formula (IIa) 2 and -R 2a at least one of is -H. Even more preferably, -R of formula (IIa) 2 and -R 2a both are H.

[0205] Preferably, -R of formula (IIa) 3 and -R 3a are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Even more preferably, -R of formula (IIa) 3 and -R 3a at least one of is methyl. In a similarly preferred embodiment, -R of formula (IIa) 3 and -R 3aBoth are -H. In another equally preferred embodiment, -R of formula (IIa) 3 and -R 3a are both methyl.

[0206] Preferably, -R of formula (IIa) 3 is -H, and -R of formula (IIa) 3a is methyl.

[0207] Preferably, the moiety -L 1 - is of formula (IIb):

Chemical formula

[0208] Preferably, -L of formula (IIb) 1 - is replaced by one moiety -L 2 -Z or -L 2 -Z'.

[0209] Preferably, the moiety -L of formula (IIb) 1 - is not further substituted.

[0210] Preferably, -X of formula (IIb) 2 - is -C(R8 R 8a ) - is.

[0211] Preferably, -R of formula (IIb) 8 and -R 8a are independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R of formula (IIb) 8 and -R 8a at least one of them is -H. Even more preferably, -R of formula (IIb) 8 and -R 8a both are -H.

[0212] Preferably, -R of formula (IIb) 2 and -R 2a are independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R of formula (IIb) 2 and -R 2a at least one of them is -H. Even more preferably, -R of formula (IIb) 2 and -R 2a both are H.

[0213] Preferably, -R of formula (IIb) 3 and -R 3a are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Even more preferably, -R of formula (IIb) 3 and -R 3a at least one of them is methyl. In a similarly preferred embodiment, -R of formula (IIb) 3 and -R 3a both are -H. In another similarly preferred embodiment, -R of formula (IIb) 3 and -R 3a both are methyl.

[0214] Most preferably, -R of formula (IIb) 3 is -H, and -R of formula (IIb) 3a is methyl.

[0215] Even more preferably, moiety -L 1- is of the formula (IIb'): [Chemical formula] (wherein, The dashed line indicates the bond to the nitrogen of D, which is the CNP agonist moiety, by forming an amide bond, The dashed line with an asterisk represents the bond to -L 2 -, -R 2 , -R 2a , -R 3 , -R 3a , and -X 2 - are used as defined for formula (II)) has, Optionally, said -L 1 - is further substituted, provided that the hydrogen with an asterisk in formula (IIb') is not replaced by a substituent.

[0216] Preferably, the moiety -L 1 - of formula (IIb') is not further substituted.

[0217] Preferably, -X 2 - of formula (IIb') is -C(R 8 R 8a )-.

[0218] Preferably, -R 8 and -R 8a of formula (IIb') are independently selected from the group consisting of -H, methyl, and ethyl. More preferably, at least one of -R 8 and -R 8a of formula (IIb') is -H. Even more preferably, both -R 8 and -R 8a of formula (IIb') are -H.

[0219] Preferably, -R 2 and -R 2a of formula (IIb') are independently selected from the group consisting of -H, methyl, and ethyl. More preferably, -R 2and -R 2a at least one of which is -H. Even more preferably, -R of formula (IIb') 2 and -R 2a are both H.

[0220] Preferably, -R of formula (IIb') 3 and -R 3a are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Even more preferably, -R of formula (IIb') 3 and -R 3a at least one of which is methyl. In a similarly preferred embodiment, -R of formula (IIb') 3 and -R 3a are both -H. In another similarly preferred embodiment, -R of formula (IIb') 3 and -R 3a are both methyl.

[0221] Most preferably, -R of formula (IIb') 3 is -H and -R of formula (IIb') 3a is methyl.

[0222] Preferably, the moiety -L 1 - has the formula (IIc):

Chemical formula

[0223] Preferably, -L of formula (IIc)1 - is one moiety -L 2 -Z or -L 2 - is replaced by -Z'.

[0224] Preferably, the moiety -L of formula (IIc) 1 - is further unsubstituted.

[0225] In another preferred embodiment, the moiety -L 1 - has the formula (IIc-a): [Chemical formula] (wherein the dashed line indicates the bond to the nitrogen of -D which is the CNP agonist moiety by forming an amide bond) and said -L 1 - is -L 2 -Z or -L 2 - is replaced by -Z', said -L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIc-a) is not replaced by -L 2 -Z or -L 2 -Z' or a substituent.

[0226] Preferably, the -L of formula (IIc-a) 1 - is one moiety -L 2 -Z or -L 2 - is replaced by -Z'.

[0227] Preferably, the moiety -L of formula (IIc-a) 1 - is further unsubstituted.

[0228] In another preferred embodiment, the moiety -L 1 - has the formula (IIc-b): [Chemical formula] (wherein the dashed line indicates the bond to the nitrogen of -D which is the CNP agonist moiety by forming an amide bond) and The aforesaid -L 1 - is, -L 2 -Z or -L 2 -Z' and is substituted, Optionally, the aforesaid -L 1 - is further substituted, provided that the hydrogen with an asterisk in formula (IIc-b) cannot be replaced by -L 2 -Z or -L 2 -Z' or a substituent.

[0229] Preferably, the -L in formula (IIc-b) 1 - is one part -L 2 -Z or -L 2 -Z' and is substituted.

[0230] Preferably, the part -L in formula (IIc-b) 1 - is not further substituted.

[0231] Even more preferably, the part -L 1 - is of formula (IIc-i), (IIc-ii), (IIc-iii), (IIc-iv) and (IIc-v):

Chemical formula

[0232] Preferably, the partial-L of formula (IIc-i), (IIc-ii), (IIc-iii), (IIc-iv) and (IIc-v) 1 - is further unsubstituted.

[0233] In a particularly preferred embodiment, the partial-L 1 - is of formula (IIc-ii).

[0234] [Chemical formula] (wherein The unmarked dashed line indicates the bond to the nitrogen of -D, which is the CNP agonist moiety, by forming an amide bond, The dashed line with an asterisk is -L 2 -Z or -L 2 - indicates the bond to Z')

[0235] Preferably, -L of formula (IIc-ii) 1 - is one partial-L 2 -Z or -L 2 - is substituted with Z').

[0236] In a similarly preferred embodiment, the partial-L 1 - is of formula (IIc-i'), (IIc-ii'), (IIc-iii'), (IIc-iv') and (IIc-v'): [Chemical formula] (wherein The unmarked dashed line indicates the bond to the nitrogen of -D, which is the CNP agonist moiety, by forming an amide bond, The dashed line with an asterisk is -L 2 -Z or -L 2 - indicates the bond to Z') is selected from the group consisting of Optionally, the -L 1- is further substituted, provided that the hydrogen marked with an asterisk in formulas (IIc-i'), (IIc-ii'), (IIc-iii'), (IIc-iv') and (IIc-v') is not substituted by a substituent.

[0237] Preferably, the moiety -L of formulas (IIc-i'), (IIc-ii'), (IIc-iii'), (IIc-iv') and (IIc-v') 1 - is not further substituted.

[0238] In another particularly preferred embodiment, the moiety -L 1 - is of formula (IIc-ii’):

Chemical formula

[0239] Preferably, the -L of formula (IIc-ii') 1 - is substituted with one moiety -L 2 -Z or -L 2 -Z’.

[0240] In a similarly preferred embodiment, the moiety -L 1 - is of formulas (IIc-i''), (IIc-ii''), (IIc-iii'') and (IIc-iv''):

Chemical formula

[0241] Preferably, the -L moiety in formulas (IIc-i''), (IIc-ii''), (IIc-iii''), and (IIc-iv'') 1 - is not further substituted.

[0242] In another particularly preferred embodiment, the -L moiety 1 - is of formula (IIc-ii''):

Chemical formula

[0243] Preferably, the -L in formula (IIc-ii'') 1 - is substituted by one -L moiety 2 -Z or -L 2 -Z'.

[0244] The optional further substituents of -L in formulas (II), (IIa), (IIb), (IIb'), (IIc), (IIc-a), (IIc-b), (IIc-i), (IIc-ii), (IIc-iii), (IIc-iv), (IIc-v), (IIc-i'), (IIc-ii'), (IIc-iii'), (IIc-iv'), (IIc-v'), (IIc-i''), (IIc-ii''), (IIc-iii''), (IIc-iv'') 1 - are preferably as described above.

[0245] Another particularly preferred moiety - L 1 - is disclosed in WO 2016 / 020373 pamphlet A1. Accordingly, in another preferred embodiment, moiety - L 1 - is of formula (III): [Chemical formula] (wherein the dashed lines each represent a bond formed by forming a primary or secondary amine or amide or ester bond to - D which is a CNP moiety, - R 1 , - R 1a , - R 2 , - R 2a , - R 3 and - R 3a are each independently selected from the group consisting of - H, - C(R 8 R 8a R 8b ), - C(=O)R 8 , - C≡N, - C(=NR 8 )R 8a , - CR 8 (=CR 8a R 8b ), - C≡CR 8 and - T, - R 4 , - R 5 and - R 5a are each independently selected from the group consisting of - H, - C(R 9 R 9a R 9b ) and - T, a1 and a2 are each independently 0 or 1, each - R 6 , - R 6a , - R 7 , - R 7a , - R 8 , - R 8a , - R 8b , - R 9 , - R 9a , - R 9b is each independently selected from the group consisting of - H, halogen, - CN, - COOR 10 , - OR10 , -C(O)R 10 , -C(O)N(R 10 R 10a ), -S(O)2N(R 10 R 10a ), -S(O)N(R 10 R 10a ), -S(O)2R 10 , -S(O)R 10 , -N(R 10 ), S(O)2N(R 10a R 10b ), -SR 10 , -N(R 10 R 10a ), -NO2, -OC(O)R 10 , -N(R 10 ), C(O)R 10a , -N(R 10 ), S(O)2R 10a , -N(R 10 ), S(O)R 10a , -N(R 10 ), C(O)OR 10a , -N(R 10 ), C(O)N(R 10a R 10b ), -OC(O)N(R 10 R 10a ), -T, C 1-20 alkyl, C 2-20 alkenyl, and C 2-20 alkynyl selected from the group consisting of, wherein said -T, C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl is optionally substituted with one or more -R 11 and C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl may contain -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 12 ), -S(O)2N(R 12 ), -S(O)N(R 12 ), -S(O)2-, -S(O)-, -N(R 12 ), S(O)2N(R 12a ), -S-, -N(R 12 ), -OC(OR 12)(R 12a )-, -N(R 12 )C(O)N(R 12a )-, and -OC(O)N(R 12 )- may be interrupted by one or more groups selected from the group consisting of, each -R 10 , -R 10a , -R 10b is independently selected from the group consisting of -H, -T, C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl, and said -T, C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl may be optionally substituted with one or more of the same or different -R 11 , and said C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl may be interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 12 )-, -S(O)2N(R 12 )-, -S(O)N(R 12 )-, -S(O)2-, -S(O)-, -N(R 12 )S(O)2N(R 12a )-, -S-, -N(R 12 )-, -OC(OR 12 )(R 12a )-, -N(R 12 )C(O)N(R 12a )-, and -OC(O)N(R 12 )- may be interrupted by one or more groups selected from the group consisting of, each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic, and each said T is independently optionally substituted with one or more of the same or different -R 11 , each -R 11 is independently selected from the group consisting of halogen, -CN, oxo (=O), -COOR 13 , -OR13 , -C(O)R 13 , -C(O)N(R 13 R 13a ), -S(O)2N(R 13 R 13a ), -S(O)N(R 13 R 13a ), -S(O)2R 13 , -S(O)R 13 , -N(R 13 )S(O)2N(R 13a R 13b ), -SR 13 , -N(R 13 R 13a ), -NO2, -OC(O)R 13 , -N(R 13 )C(O)R 13a , -N(R 13 )S(O)2R 13a , -N(R 13 )S(O)R 13a , -N(R 13 )C(O)OR 13a , -N(R 13 )C(O)N(R 13a R 13b ), -OC(O)N(R 13 R 13a ), and C 1-6 alkyl selected, wherein said C 1-6 alkyl is optionally substituted with one or more of the same or different halogens, each -R 12 , -R 12a , -R 13 , -R 13a , -R 13b is independently selected from the group consisting of -H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more of the same or different halogens, optionally, the pair -R 1 / -R 1a , -R 2 / -R 2a , -R 3 / -R 3a , -R 6 / -R 6a , -R 7 / -R 7aOne or more of them, together with the atoms to which they are attached, form a C 3-10 cycloalkyl or 3- to 10-membered heterocyclyl, optionally, pair-R 1 / -R 2 ,-R 1 / -R 3 ,-R 1 / -R 4 ,-R 1 / -R 5 ,-R 1 / -R 6 ,-R 1 / -R 7 ,-R 2 / -R 3 ,-R 2 / -R 4 ,-R 2 / -R 5 ,-R 2 / -R 6 ,-R 2 / -R 7 ,-R 3 / -R 4 ,-R 3 / -R 5 ,-R 3 / -R 6 ,-R 3 / -R 7 ,-R 4 / -R 5 ,-R 4 / -R 6 ,-R 4 / -R 7 ,-R 5 / -R 6 ,-R 5 / -R 7 ,-R 6 / -R 7 One or more of them, together with the atoms to which they are attached, form ring A, A is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic) having, said -L 1 - is -L 2 -Z or -L 2-is replaced by -Z’, and optionally, said -L 1 -is further replaced, -L 2 -is a single chemical bond or a spacer, -Z is a water-soluble carrier, -Z’ is a water-insoluble carrier.

[0246] -L of formula (III) 1 Any optional further substituents of - are preferably as described above.

[0247] Preferably, -L of formula (III) 1 -is one moiety -L 2 -Z or -L 2 -is substituted with -Z’.

[0248] In one embodiment, -L of formula (III) 1 -is not further substituted.

[0249] -L 1 Further preferred embodiments for -L are disclosed in European Patent No. 1536334 B1, WO2009 / 009712 A1, WO2008 / 034122 A1, WO2009 / 143412 A2, WO2011 / 082368 A2, and US Patent No. 8,618,124 B2, which patent documents are hereby incorporated by reference in their entirety.

[0250] -L 1 Further preferred embodiments for -L are disclosed in US Patent No. 8,946,405 B2 and US Patent No. 8,754,190 B2, which patent documents are hereby incorporated by reference in their entirety. Accordingly, the preferred moiety -L 1 -is of formula (IV):

Chemical formula

[0251] Any optional further substituents of -L 1 - in formula (IV) are preferably as described above.

[0252] Preferably, -L 1 - in formula (IV) is substituted with one moiety -L 2 -Z or -L 2 -Z'.

[0253] In one embodiment, -L 1 - in formula (IV) is not further substituted.

[0254] The terms used exclusively in connection with formula (IV) have the following meanings:

[0255] As used herein, the term "alkyl" includes straight-chain, branched or cyclic saturated hydrocarbon groups having 1 to 8 carbon atoms, or in some embodiments 1 to 6 or 1 to 4 carbon atoms.

[0256] The term "alkoxy" includes alkyl groups bonded to oxygen, such as methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy and the like.

[0257] The term "alkenyl" includes non-aromatic unsaturated hydrocarbons having a carbon-carbon double bond.

[0258] The term "alkynyl" includes non-aromatic unsaturated hydrocarbons having a carbon-carbon triple bond.

[0259] The term "aryl" includes aromatic hydrocarbon groups having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, such as phenyl, naphthyl and anthracenyl. The term "heteroaryl" includes groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl and the like, containing 3 to 15 carbon atoms and at least one N, O or S atom, preferably containing 3 to 7 carbon atoms and at least one N, O or S atom, and including an aromatic ring.

[0260] In some cases, the alkenyl, alkynyl, aryl or heteroaryl moiety may be coupled to the remainder of the molecule by an alkylene bond. Substituents in these situations are referred to as alkenylalkyl, alkynylalkyl, arylalkyl or heteroarylalkyl, which indicate that the alkylene moiety is between the alkenyl, alkynyl, aryl or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl or heteroaryl is coupled.

[0261] The term "halogen" includes bromo, fluoro, chloro and iodo.

[0262] The term "heterocyclic ring" refers to a 4- to 8-membered aromatic or non-aromatic ring containing 3 to 7 carbon atoms and at least 1 N, O or S atom. Examples are piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine and tetrahydrofuranyl, and are based on the preferred examples provided above for the term "heteroaryl".

[0263] When the ring system is optionally substituted, suitable substituents are selected from the group consisting of alkyl, alkenyl, alkynyl or a further ring, each of which is optionally further substituted. Optional substituents for any of the groups including the above are halo, nitro, cyano, -OR, -SR, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -SO2R, -SONR2, -SO2NR2, where each R is independently alkyl, alkenyl, alkynyl, aryl or heteroaryl, or two R groups cooperate with the atoms to which they are attached to form a ring.

[0264] -L 1 Further preferred embodiments for - are disclosed in WO2013 / 036857A1, which patent document is incorporated herein by reference in its entirety. Thus, the preferred moiety -L 1 - is of formula (V):

Chemical formula

[0265] The optional further substituent of -L in formula (V) 1 is preferably as described above.

[0266] Preferably, -L in formula (V) 1 - is substituted with one moiety -L 2 -Z or -L 2 -Z’.

[0267] In one embodiment, -L in formula (V) 1- is further unsubstituted.

[0268] Terms used exclusively in connection with formula (V) have the following meanings:

[0269] "Alkyl", "alkenyl" and "alkynyl" include straight-chain, branched or cyclic hydrocarbon groups having 1 to 8, or 1 to 6, or 1 to 4 carbon atoms, where alkyl is a saturated hydrocarbon, alkenyl contains one or more carbon-carbon double bonds, and alkynyl contains one or more carbon-carbon triple bonds. Unless otherwise specified, these contain 1 to 6 C.

[0270] "Aryl" includes aromatic hydrocarbon groups having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, such as phenyl, naphthyl and anthracene. "Heteroaryl" includes groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl and the like, containing 3 to 15 carbon atoms and at least one N, O or S atom, preferably containing 3 to 7 carbon atoms and at least one N, O or S atom, and including an aromatic ring.

[0271] The term "substituted" means an alkyl, alkenyl, alkynyl, aryl or heteroaryl group containing one or more substituents in place of one or more hydrogen atoms. Substituents generally include halogen (including F, Cl, Br and I), lower alkyl (including straight-chain, branched and cyclic), lower haloalkyl (including fluoroalkyl, chloroalkyl, bromoalkyl and iodoalkyl), OH, lower alkoxy (including straight-chain, branched and cyclic), SH, lower alkylthio (including straight-chain, branched and cyclic), amino, alkylamino, dialkylamino, silyl (including alkylsilyl, alkoxysilyl and arylsilyl), nitro, cyano, carbonyl, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aminocarbonyl, aminoacyl, carbamate, urea, thiocarbamate, thiourea, ketene, sulfone, sulfonamide, aryl (including phenyl, naphthyl and anthracenyl), heteroaryl (including 5-membered heteroaryl such as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole and tetrazole, 6-membered heteroaryl such as pyridine, pyrimidine and pyrazine, and fused heteroaryl such as benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzisoxazole and benzisothiazole) and can be selected from.

[0272] -L 1 - Further preferred embodiments for are disclosed in U.S. Patent No. 7,585,837 B2, which patent document is incorporated herein by reference in its entirety. Thus, the preferred moiety -L 1 - is of formula (VI):

Chemical formula

[0273] Preferred substituents of formula (VI) are alkyl (e.g., C 1-6 alkyl), alkenyl (e.g., C 2-6 alkenyl), alkynyl (e.g., C 2-6 alkynyl), aryl (e.g., phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (e.g., aromatic 4-7 membered heterocycle) or halogen moieties.

[0274] Preferably, -L 1 - of formula (VI) is substituted with one moiety -L 2 -Z or -L 2 -Z'.

[0275] Any optional further substituents of -L 1 - of formula (VI) are preferably as described above.

[0276] In one embodiment, -L 1 - of formula (VI) is not further substituted.

[0277] The terms used exclusively in connection with formula (VI) have the following meanings:

[0278] The terms "alkyl", "alkoxy", "alkoxyalkyl", "aryl", "alkaryl" and "aralkyl" mean alkyl radicals having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl, and aryl radicals having 6 to 10 carbon atoms, such as phenyl and naphthyl. The term "halogen" includes bromo, fluoro, chloro and iodo.

[0279] -L 1 Further preferred embodiments for - are disclosed in WO2002 / 089789A1, which patent document is hereby incorporated by reference in its entirety. Accordingly, the preferred moiety -L 1 - is of formula (VII):

Chemical formula

[0280] Preferably, the -L in formula (VII) 1 - is substituted with one moiety -L 2 -Z or -L 2 -Z’.

[0281] The optional further substituent of the -L in formula (VII) 1 - is preferably as described above.

[0282] In one embodiment, the -L in formula (VII) 1 - is not further substituted.

[0283] The terms used exclusively in connection with formula (VII) have the following meanings:

[0284] The term "alkyl" is understood to include, for example, linear, branched, substituted C 3-8 alkyl such as alkoxy, C 1-12 cycloalkyl or substituted cycloalkyl.

[0285] The term "substituted" is to be understood to include adding one or more atoms contained in a functional group or compound and replacing with one or more different atoms.

[0286] Substituted alkyl includes carboxyalkyl, aminoalkyl, dialkylamino, hydroxyalkyl and mercaptoalkyl, substituted cycloalkyl includes moieties such as 4-chlorocyclohexyl, aryl includes moieties such as naphthyl, substituted aryl includes moieties such as 3-bromo-phenyl, aralkyl includes moieties such as toluyl, heteroalkyl includes moieties such as ethylthiophene, substituted heteroalkyl includes moieties such as 3-methoxythiophene, alkoxy includes moieties such as methoxy, and phenoxy includes moieties such as 3-nitrophenoxy. Halo- is to be understood to include fluoro, chloro, iodo and bromo.

[0287] In another preferred embodiment, -L 1 - is a substructure of formula (VIII)

Chemical formula

[0288] Preferably, -L of formula (VIII) 1- is one moiety -L 2 -Z or -L 2 - is replaced by -Z'.

[0289] -L of formula (VIII) 1 Any optional further substituents of - are preferably as described above.

[0290] In one embodiment, -L of formula (VIII) 1 - is further unsubstituted.

[0291] In another preferred embodiment, -L 1 - is a substructure of formula (IX)

Chemical formula

[0292] -L of formula (IX) 1 Any optional further substituents of - are preferably as described above.

[0293] Preferably, -L of formula (IX) 1 - is one moiety -L 2 -Z or -L 2 -Z' and is replaced.[[]]

[0294] In one embodiment, -L of formula (IX) 1 - is further unsubstituted.

[0295] Preferably, -D of formula (Ia), (Ib), (II), (IIa), (IIb), (IIb’), (IIc), (IIc-a), (IIc-b), (IIc-i), (IIc-ii), (IIc-iii), (IIc-iv), (IIc-v), (IIc-i'), (IIc-ii'), (IIc-iii'), (IIc-iv'), (IIc-v'), (IIc-i''), (IIc-ii''), (IIc-iii''), (IIc-iv''), (III), (IV), (V), (VI), (VII), (VIII) and (IX) is a CNP moiety. Sub-part -D may be linked to -L 1 - via any functional group of D-H, preferably via an amine functional group of D-H 1 - is linked. This may be an amine functional group provided by the N-terminal amine functional group or a lysine side chain, i.e., when CNP has the sequence of SEQ ID NO: 24, by lysines at positions 9, 11, 15, 16, 20 and 26.

[0296] Surprisingly, it has been found that the attachment of -L 1 - to the ring of the CNP moiety significantly reduces the affinity of the CNP prodrug for NPR-B compared to attachment at the N-terminus of CNP or to the acyclic moiety. This reduced affinity for NPR-B then reduces the risk of cardiovascular side effects such as hypotension.

[0297] Accordingly, -L 1 - is preferably attached to the side chain of an amino acid residue of the ring portion of -D or to the backbone of the ring portion of -D. Even more preferably, -L 1 - is covalently and reversibly attached to the side chain of an amino acid residue of the ring portion of -D. When -D is a CNP moiety having the sequence of SEQ ID NO: 24, -L 1 - is preferably attached to the amine functional group provided by the lysine at position 26 of the corresponding drug D-H.

[0298] Part - L 2 - is a chemical bond or a spacer moiety.

[0299] In one embodiment, - L 2 - is a chemical bond.

[0300] In another embodiment, - L 2 - is a spacer moiety.

[0301] Part - L 2 - can be bonded to - L by replacing any existing - H, unless specifically excluded. 1 - that is present.

[0302] - L 2 When - L is other than a single chemical bond, - L 2 is preferably selected from - T -, - C(O)O -, - O -, - C(O) -, - C(O)N(R y1 ), -, - S(O)2N(R y1 ), -, - S(O)N(R y1 ), -, - S(O)2 -, - S(O) -, - N(R y1 ),S(O)2N(R y1a ), -, - S -, - N(R y1 ), -, - OC(OR y1 )(R y1a ), -, - N(R y1 ),C(O)N(R y1a ), -, - OC(O)N(R y1 ),C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; - T -, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl may be substituted with one or more identical or different - R y2 s, and C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl are - T -, - C(O)O -, - O -, - C(O) -, - C(O)N(R y3 ), -, - S(O)2N(Ry3 )-, -S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-, -N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- from the group consisting of may optionally be interrupted; -R y1 and -R y1a are each independently, -H, -T, C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl selected from the group consisting of; -T, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl may be substituted with one or more identical or different -R y2 and C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl is, -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y4 )-, -S(O)2N(R y4 )-, -S(O)N(R y4 )-, -S(O)2-, -S(O)-, -N(R y4 )S(O)2N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-, -N(R y4 )C(O)N(R y4a )-, and -OC(O)N(R y4 )- from the group consisting of may optionally be interrupted; Each T is independently, phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10Selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, 8- to 30-membered carbocyclic, and 8- to 30-membered heterocyclic; each T is independently one or more identical or different -R y2 and may be substituted with; each -R y2 is independently halogen, -CN, oxo(=O), -COOR y5 , -OR y5 , -C(O)R y5 , -C(O)N(R y5 R y5a ), -S(O)2N(R y5 R y5a ), -S(O)N(R y5 R y5a ), -S(O)2R y5 , -S(O)R y5 , -N(R y5 ), S(O)2N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO2, -OC(O)R y5 , -N(R y5 ), C(O)R y5a , -N(R y5 ), S(O)2R y5a , -N(R y5 ), S(O)R y5a , -N(R y5 ), C(O)OR y5a , -N(R y5 ), C(O)N(R y5a R y5b ), -OC(O)N(R y5 R y5a , and C 1-6 alkyl selected from the group consisting of; C 1-6 alkyl may be substituted with one or more identical or different halogens; each -R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b is independently -H, and C 1-6selected from the group consisting of alkyl; C 1-6 The alkyl may be substituted with one or more identical or different halogen atoms.

[0303] -L 2 When -L- is other than a single chemical bond, -L 2 - is more preferably -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 ), -S(O)2N(R y1 ), -S(O)N(R y1 ), -S(O)2-, -S(O)-, -N(R y1 )S(O)2N(R y1a ), -S-, -N(R y1 ), -OC(OR y1 )(R y1a ), -N(R y1 )C(O)N(R y1a ), -OC(O)N(R y1 ), C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl selected from the group consisting of; -T-, C 1-20 alkyl, C 2-20 alkenyl, and C 2-20 alkynyl may be substituted with one or more identical or different -R y2 , and C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 ), -S(O)2N(R y3 ), -S(O)N(R y3 ), -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a ), -S-, -N(R y3 ), -OC(OR y3 )(R y3a ), -N(R y3 )C(O)N(R y3a ), and -OC(O)N(R y3)- may optionally be interrupted by one or more groups selected from the group consisting of; -R y1 and -R y1a are each independently, -H, -T, C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl selected from the group consisting of; -T, C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl may be substituted with one or more identical or different -R y2 ; C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl is, -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y4 )-, -S(O)2N(R y4 )-, -S(O)N(R y4 )-, -S(O)2-, -S(O)-, -N(R y4 )S(O)2N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-, -N(R y4 )C(O)N(R y4a )-, and -OC(O)N(R y4 )- may optionally be interrupted by one or more groups selected from the group consisting of; each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3 - to 10 - membered heterocyclyl, 8 - to 11 - membered heterobicyclic, 8 - to 30 - membered carbocyclic polycycle, and 8 - to 30 - membered heterocyclic polycycle; each T is independently optionally substituted with one or more identical or different -R y2 ; -R y2 is halogen, -CN, oxo(=O), -COOR y5 , -OR y5 , -C(O)R y5 , -C(O)N(R y5 R y5a ), -S(O)2N(R y5 Ry5a ), -S(O)N(R y5 R y5a ), -S(O)R y5 , -S(O)R y5 , -N(R y5 )S(O)2N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO2, -OC(O)R y5 , -N(R y5 )C(O)R y5a , -N(R y5 )S(O)2R y5a , -N(R y5 )S(O)R y5a , -N(R y5 )C(O)OR y5a , -N(R y5 )C(O)N(R y5a R y5b ), -OC(O)N(R y5 R y5a ), and C 1-6 alkyl; 1-6 The alkyl may be optionally substituted with one or more identical or different halogens; Each-R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b are each independently -H and C 1-6 alkyl; C 1-6 The alkyl may be optionally substituted with one or more halogens which may be the same or different.

[0304] -L 2 If - is other than a single chemical bond, -L 2 - is even more preferably -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-, -S(O)2N(R y1 )-, -S(O)N(R y1 )-, -S(O)2-, -S(O)-, -N(R y1)S(O)2N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-, -N(R y1 )C(O)N(R y1a )-, -OC(O)N(R y1 )-, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl selected from the group consisting of; -T-, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl may be substituted with one or more identical or different -R y2 and C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-, -S(O)2N(R y3 )-, -S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-, -N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- selected from the group consisting of may optionally intervene; -R y1 and -R y1a are independently selected from the group consisting of -H, -T, C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl; Each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, 8- to 30-membered carbocyclic polycycle, and 8- to 30-membered heterocyclic polycycle; Each -R y2is selected from the group consisting of halogen and C 1-6 alkyl; each -R y3 、-R y3a 、-R y4 、-R y4a 、-R y5 、-R y5a and -R y5b is independently selected from the group consisting of -H and C 1-6 alkyl; C 1-6 alkyl may be substituted with one or more identical or different halogens.

[0305] Even more preferably, -L 2 - is a C 1-20 alkyl chain, which may optionally be interrupted by one or more groups independently selected from -O-, -T- and -C(O)N(R y1 ); C 1-20 alkyl chain may optionally be substituted with one or more groups independently selected from -OH, -T and -C(O)N(R y6 R y6a ); -R y1 、-R y6 、-R y6a is independently selected from the group consisting of H and C 1-4 alkyl, and T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, 8- to 30-membered carbocyclic polycycle, and 8- to 30-membered heterocyclic polycycle.

[0306] Preferably, -L 2 - has a molecular weight in the range of 14 g / mol to 750 g / mol.

[0307] Preferably, -L 2 - is

Chemical formula

[0308] In a preferred embodiment, -L 2 - has a chain length of 1 to 20 atoms.

[0309] As used herein, the term "chain length" with respect to moiety -L 2 - refers to the number of atoms in -L 1 - that is present in the shortest connection between -L 2 - and -Z.

[0310] Preferably, -L 2 - is of the following formula (i).

Chemical formula

[0311] Preferably, -R of formula (i) 1 is selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. Even more preferably, -R of formula (i) 1 is selected from the group consisting of -H, methyl, ethyl, and propyl. Even more preferably, -R of formula (i) 1is selected from the group consisting of -H and methyl. Most preferably, -R of formula (i) 1 is methyl.

[0312] Preferably, n in formula (i) is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. Even more preferably, n in formula (i) is selected from the group consisting of 0, 1, 2, 3, 4 and 5. Even more preferably, n in formula (i) is selected from the group consisting of 0, 1, 2 and 3. Even more preferably, n in formula (i) is selected from the group consisting of 0 and 1. Most preferably, n in formula (i) is 0.

[0313] In a preferred embodiment, -L 2 - is

Chemical formula

[0314] In a preferred embodiment, -L 2 - is

Chemical formula

[0315] Even more preferred -L 2 - is [Chemical formula] selected from the group consisting of The dashed line marked with an asterisk is a bond to -L 1 - indicates a bond to; The unmarked dashed line indicates a bond to -Z or -Z'.

[0316] Even more preferably, -L 2 - is of the following formula (xvi). [Chemical formula] In the formula, The dashed line marked with an asterisk is a bond to -L 1 - indicates a bond to; The unmarked dashed line indicates a bond to -Z or -Z'.

[0317] In a preferred embodiment, the moiety -L 1 -L 2 - is [Chemical formula] selected from the group consisting of; In the formula, The unmarked dashed line indicates a bond to the nitrogen of -D, which is a CNP agonist moiety, by forming an amide bond; The dashed line marked with an asterisk indicates a bond to -Z or -Z'.

[0318] In an even more preferred embodiment, the moiety -L 1 -L 2 - is of the following formula (IId-ii). [Chemical formula] In the formula, The unmarked dashed line indicates a bond to the nitrogen of -D, which is a CNP agonist moiety, by forming an amide bond; The dashed line marked with an asterisk indicates a bond to -Z or -Z'.

[0319] In the most preferred embodiment, sub-L 1 -L 2 - is of the following formula (IId-ii′). [Chemical formula] In the formula, The unmarked dashed line indicates the bond to the nitrogen of -D, which is the CNP agonist moiety, by forming an amide bond; The dashed line marked with an asterisk indicates the bond to -Z or -Z′.

[0320] In another preferred embodiment, sub-L 1 -L 2 - is [Chemical formula] selected from the group consisting of The unmarked dashed line indicates the bond to the nitrogen of -D, which is the CNP agonist moiety, by forming an amide bond; The dashed line marked with an asterisk indicates the bond to -Z or -Z′.

[0321] In an even more preferred embodiment, sub-L 1 -L 2 - is of the following formula (IId-iia). [Chemical formula] In the formula, The unmarked dashed line indicates the bond to the nitrogen of -D, which is the CNP agonist moiety, by forming an amide bond; The dashed line marked with an asterisk indicates the bond to -Z or -Z′.

[0322] In the most preferred embodiment, sub-L 1 -L 2 - is of the following formula (IId-iia′). [Chemical formula] In the formula, The dashed line without a mark indicates the bond to the nitrogen of -D, which is the CNP agonist moiety, by forming an amide bond; The dashed line marked with an asterisk indicates the bond to -Z or -Z'.

[0323] In another preferred embodiment, the moiety -L 1 -L 2 - is

Chemical formula

[0324] In an even more preferred embodiment, the moiety -L 1 -L 2 - is of the following formula (IId-iib).

Chemical formula

[0325] In the most preferred embodiment, the moiety -L 1 -L 2 - is of the following formula (IId-iib').

Chemical formula

[0326] Preferably, -Z of formula (Ia) or (Ib) has a molecular weight in the range of 5 to 200 kDa. Even more preferably, -Z of formula (Ia) or (Ib) has a molecular weight in the range of 8 to 100 kDa, even more preferably 10 to 80 kDa, even more preferably 12 to 60 kDa, even more preferably 15 to 40 kDa, and most preferably -Z of formula (Ia) or (Ib) has a molecular weight of about 20 kDa. In another equally preferred embodiment, -Z of formula (Ia) or (Ib) has a molecular weight of about 40 kDa.

[0327] The carrier -Z of formula (Ia) or (Ib) is C 8-24It contains an alkyl moiety or a polymer. Preferably, -Z in formula (Ia) or (Ib) is a polymer, preferably 2-methacryloyloxyethyl phosphorylcholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amide amines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxy methacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organic phosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinyl methyl ethers), poly(vinyl pyrrolidones), silicones, celluloses, carboxymethyl celluloses, hydroxypropyl methyl celluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon-based polymers, xylans, and copolymers thereof.

[0328] In another preferred embodiment, -Z of formula (Ia) or (Ib) comprises a fatty acid derivative. Preferred fatty acid derivatives are those disclosed in WO 2005 / 027978 A2 and WO 2014 / 060512 A1 (incorporated herein by reference).

[0329] In one embodiment, -Z of formula (Ia) or (Ib) comprises a protein. Preferred proteins are the carboxyl-terminal peptide of chorionic gonadotropin as described in US2012 / 0035101A1 (incorporated herein by reference); albumin; the XTEN sequence as described in WO2011123813A2 (incorporated herein by reference); the proline / alanine random coil sequence as described in WO2011 / 144756A1 (incorporated herein by reference); the proline / alanine / serine random coil sequence as described in WO2008 / 155134A1 and WO2013 / 024049A1 (incorporated herein by reference); and Fc fusion proteins.

[0330] In one embodiment, -Z of formula (Ia) or (Ib) is polysarcosine.

[0331] In another preferred embodiment, -Z of formula (Ia) or (Ib) comprises poly(N-methylglycine).

[0332] In a particularly preferred embodiment, -Z of formula (Ia) or (Ib) comprises a random coil protein moiety.

[0333] In a preferred embodiment, -Z of formula (Ia) or (Ib) comprises one random coil protein moiety.

[0334] In another preferred embodiment, -Z of formula (Ia) or (Ib) comprises two random coil protein moieties.

[0335] In another preferred embodiment, -Z of formula (Ia) or (Ib) comprises three random coil protein moieties.

[0336] In another preferred embodiment, -Z in formula (Ia) or (Ib) comprises four random coil protein moieties.

[0337] In another preferred embodiment, -Z in formula (Ia) or (Ib) comprises five random coil protein moieties.

[0338] In another preferred embodiment, -Z in formula (Ia) or (Ib) comprises six random coil protein moieties.

[0339] In another preferred embodiment, -Z in formula (Ia) or (Ib) comprises seven random coil protein moieties.

[0340] In another preferred embodiment, -Z in formula (Ia) or (Ib) comprises eight random coil protein moieties.

[0341] Preferably, such random coil protein moieties contain at least 25 amino acid residues and at most 2000 amino acids. Even more preferably, such random coil protein moieties contain at least 30 amino acid residues and at most 1500 amino acid residues. Even more preferably, such random coil protein moieties contain at least 50 amino acid residues and at most 500 amino acid residues.

[0342] In a preferred embodiment, -Z in formula (Ia) or (Ib) comprises a random coil protein moiety in which at least 80%, preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, even more preferably at least 98% and most preferably at least 99% of the total number of amino acids forming the random coil protein moiety are selected from alanine and proline. Even more preferably, at least 10% but less than 75%, preferably less than 65% of the total number of amino acid residues of such a random coil protein moiety are proline residues. Preferably, such a random coil protein moiety is as described in WO2011 / 144756A1 (the entire content of which is incorporated herein by reference). Even more preferably, -Z comprises at least one moiety selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 51 and SEQ ID NO: 61 disclosed in WO2011 / 144756 (incorporated herein by reference). A moiety containing such a random coil protein containing alanine and proline is referred to as "PA" or "PA moiety".

[0343] Accordingly, -Z in formula (Ia) or (Ib) comprises a PA moiety.

[0344] In a similarly preferred embodiment, -Z in formula (Ia) or (Ib) comprises a random coil protein moiety in which at least 80%, preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, even more preferably at least 98% and most preferably at least 99% of the total number of amino acids forming the random coil protein moiety are selected from alanine, serine and proline. Even more preferably, at least 4% but less than 40% of the total number of amino acid residues of such a random coil protein moiety are proline residues. Preferably, such a random coil protein moiety is as described in WO2008 / 155134A1 (incorporated herein by reference in its entirety). Even more preferably, -Z in formula (Ia) or (Ib) comprises at least one moiety selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54 and SEQ ID NO:56 as disclosed in WO2008 / 155134A1 (incorporated herein by reference). A moiety comprising such a random coil protein moiety containing alanine, serine and proline is referred to as a "PAS" or "PAS moiety".

[0345] Accordingly, -Z in formula (Ia) or (Ib) comprises a PAS moiety.

[0346] In a similarly preferred embodiment, -Z in formula (Ia) or (Ib) comprises a random coil protein moiety in which at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, even more preferably at least 98% and most preferably at least 99% of the total number of amino acids forming the random coil protein moiety are selected from alanine, glycine and proline. A moiety comprising such a random coil protein moiety containing alanine, glycine and proline is referred to as a "PAG" or "PAG moiety".

[0347] Therefore, -Z in formula (Ia) or (Ib) comprises a PAG moiety.

[0348] In a similarly preferred embodiment, -Z in formula (Ia) or (Ib) comprises a random coil protein moiety in which at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, even more preferably at least 98% and most preferably at least 99% of the total number of amino acids forming the random coil protein moiety are selected from proline and glycine. A moiety comprising such a random coil protein containing proline and glycine is referred to as a "PG" or "PG moiety".

[0349] Preferably, such a PG moiety comprises a moiety of the following formula (a-0). [(Gly) p -Pro-(Gly) q r (a-0); Wherein p is selected from the group consisting of 0, 1, 2, 3, 4 and 5; q is selected from the group consisting of 0, 1, 2, 3, 4 and 5; r is an integer in the range of 10 to 1000 (including both ends); provided that at least one of p and q is at least 1.

[0350] ​Preferably, p in formula (a-0) is selected from the group consisting of 1, 2, and 3.

[0351] Preferably, q in formula (a-0) is selected from 0, 1, and 2.

[0352] Even more preferably, the PG moiety comprises the sequence of SEQ ID NO: 97: GGPGGPGPGGPGGPGPGGPG.

[0353] Even more preferably, the PG moiety comprises the sequence of the following formula (a-0-a). (GGPGGPGPGGPGGPGPGGPG) v (a-0-a) [wherein, v is an integer in the range of 1 to 50 (including both ends)].

[0354] It is understood that the sequence of formula (a-0-a) contains v repetitions of the sequence of SEQ ID NO: 97.

[0355] Therefore, -Z in formula (Ia) or (Ib) comprises a PG moiety.

[0356] In a similarly preferred embodiment, -Z in formula (Ia) or (Ib) comprises a random coil protein moiety in which at least 80%, preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, even more preferably at least 98% and most preferably at least 99% of the total number of amino acids forming the random coil protein moiety are selected from alanine, glycine, serine, threonine, glutamic acid and proline. Preferably, such a random coil protein moiety is as described in WO2010 / 091122A1 (incorporated herein by reference). Even more preferably, -Z in formula (Ia) or (Ib) comprises at least one moiety selected from the group consisting of SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184; SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, SEQ ID NO: 193, SEQ ID NO: 194, SEQ ID NO: 195, SEQ ID NO: 196, SEQ ID NO: 197, SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 200, SEQ ID NO: 201, SEQ ID NO: 202, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 205, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 210, SEQ ID NO: 211, SEQ ID NO: 212, SEQ ID NO: 213, SEQ ID NO: 214, SEQ ID NO: 215, SEQ ID NO: 216, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 220, SEQ ID NO: 221, SEQ ID NO: 759, SEQ ID NO: 760, SEQ ID NO: 761, SEQ ID NO: 762, SEQ ID NO: 763, SEQ ID NO: 764, SEQ ID NO: 765, SEQ ID NO: 766, SEQ ID NO: 767, SEQ ID NO: 768, SEQ ID NO: 769, SEQ ID NO: 770, SEQ ID NO: 771, SEQ ID NO: 772, SEQ ID NO: 773, SEQ ID NO: 774, SEQ ID NO: 775, SEQ ID NO: 776, SEQ ID NO: 777, SEQ ID NO: 778, SEQ ID NO: 779, SEQ ID NO: 1715, SEQ ID NO: 1716, SEQ ID NO: 1718, SEQ ID NO: 1719, SEQ ID NO: 1720, SEQ ID NO: 1721 and SEQ ID NO: 1722 as disclosed in WO2010 / 091122A1 (incorporated herein by reference).Such a portion containing a random coil protein portion containing alanine, glycine, serine, threonine, glutamic acid and proline is referred to as "XTEN" or "XTEN portion" in accordance with the designation in WO2010 / 091122A1.

[0357] Accordingly, -Z of formula (Ia) or (Ib) contains an XTEN portion.

[0358] In another preferred embodiment, -Z of formula (Ia) or (Ib) is a hyaluronic acid-based polymer.

[0359] In one embodiment, -Z of formula (Ia) or (Ib) is a carrier disclosed in WO2013 / 024047A1 (incorporated herein by reference).

[0360] In another embodiment, -Z of formula (Ia) or (Ib) is a carrier disclosed in WO2013 / 024048A1 (incorporated herein by reference).

[0361] In another preferred embodiment, -Z of formula (Ia) or (Ib) is a PEG-based polymer. Even more preferably, -Z is a branched or multi-branched PEG-based polymer.

[0362] In a preferred embodiment, -Z of formula (Ia) or (Ib) is a branched polymer. In one embodiment, -Z of formula (Ia) or (Ib) is a branched polymer having 1, 2, 3, 4, 5 or 6 branch points. Preferably, -Z of formula (Ia) or (Ib) is a branched polymer having 1, 2 or 3 branch points. In one embodiment, -Z of formula (Ia) or (Ib) is a branched polymer having 1 branch point. In another embodiment, -Z of formula (Ia) or (Ib) is a branched polymer having 2 branch points. In another embodiment, -Z of formula (Ia) or (Ib) is a branched polymer having 3 branch points.

[0363] The branch point is preferably selected from the group consisting of -N<, -CH<, and C<.

[0364] Preferably, such a branched moiety -Z of formula (Ia) or (Ib) is PEG-based.

[0365] In one embodiment, such a branched moiety -Z of formula (Ia) or (Ib) has a molecular weight in the range of 5 kDa to 500 kDa (including both ends), more preferably in the range of 10 kDa to 250 kDa (including both ends), even more preferably in the range of 10 kDa to 150 kDa (including both ends), even more preferably in the range of 12 kDa to 100 kDa (including both ends), and most preferably in the range of 15 kDa to 80 kDa (including both ends).

[0366] Preferably, such a branched moiety -Z of formula (Ia) or (Ib) has a molecular weight in the range of 10 kDa to 80 kDa (including both ends). In one embodiment, the molecular weight is about 10 kDa. In another embodiment, the molecular weight of such a branched moiety -Z of formula (Ia) or (Ib) is about 20 kDa. In another embodiment, the molecular weight of such a branched moiety -Z of formula (Ia) or (Ib) is about 30 kDa. In another embodiment, the molecular weight of such a branched moiety -Z of formula (Ia) or (Ib) is about 40 kDa. In another embodiment, the molecular weight of such a branched moiety -Z of formula (Ia) or (Ib) is about 50 kDa. In another embodiment, the molecular weight of such a branched moiety -Z of formula (Ia) or (Ib) is about 60 kDa. In another embodiment, the molecular weight of such a branched moiety -Z of formula (Ia) or (Ib) is about 70 kDa. In another embodiment, the molecular weight of such a branched moiety -Z of formula (Ia) or (Ib) is about 80 kDa. Most preferably, such a branched moiety -Z of formula (Ia) or (Ib) has a molecular weight of about 40 kDa.

[0367] The applicant 1 -L 2-The N-terminal binding of -Z was found to be significantly more effective with respect to NEP stability compared to the binding at internal sites, and the binding site that is least effective with respect to NEP stability is the loop portion of the CNP moiety. However, the Applicants have surprisingly found that this drawback of the binding to the loop with respect to NEP stability can be compensated for by using a branched moiety-Z having a molecular weight of at least 10 kDa, such as at least 12 kDa, such as at least 15 kDa, such as at least 18 kDa, such as at least 20 kDa, such as at least 24 kDa, such as at least 25 kDa, such as at least 27 kDa, such as at least 30 kDa. Preferably, such a branched moiety-Z has a molecular weight of 500 kDa or less, preferably 250 kDa or less, preferably 200 Da or less, preferably 150 kDa or less, most preferably 100 kDa or less. Most preferably, such a branched moiety-Z has a molecular weight of about 40 kDa. As a result, the use of such a branched moiety-Z at the loop portion of the CNP moiety not only results in an increase in NEP stability, but also combines the increase in NEP stability with a decrease in NPR-B binding related to binding to the loop.

[0368] Surprisingly, it was found that the binding of a 5 kDa carrier to the loop portion has no significant effect on NPR-C affinity, even if the loop portion is involved in NPR-C binding. Furthermore, surprisingly, even when the total molecular weight is the same, a branched carrier having a 4×10 kDa carrier bound to the loop portion, i.e., a branched carrier having four 10 kDa arms, is more effective in reducing NPR-C affinity than a 2×20 kDa carrier, i.e., a branched carrier having two 20 kDa arms. Therefore, it is not only the total molecular weight of the carrier bound to the loop portion but also the specific branching pattern of the carrier that affects the NPR-C binding affinity.

[0369] This finding is also supported by the NPR-C affinity measured with a 4-arm 40 kDa carrier having different branching patterns that also showed high NPR-C affinity.

[0370] In summary, surprisingly, it has been found that NPR-C affinity can be effectively reduced by a multi-branched carrier bound to a ring moiety having a first branch point close to the CNP moiety of less than 300 atoms, preferably less than 200 atoms, more preferably less than 100 atoms, even more preferably less than 50 atoms, even more preferably less than 25 atoms, and most preferably less than 10 atoms from the CNP moiety, for example.

[0371] Even more preferably, one or more additional branch points are located within less than 500 atoms, even more preferably less than 300 atoms, even more preferably less than 200 atoms, even more preferably less than 100 atoms, even more preferably less than 75 atoms, even more preferably less than 50 atoms, even more preferably less than 40 atoms, and most preferably less than 35 atoms from the CNP moiety.

[0372] Furthermore, it has also been found that such a branching pattern is useful for the in vivo stability of the CNP moiety, i.e., protection against proteolysis. Surprisingly, it has been found that N-terminal degradation is stronger when using a 2×20 kDa carrier compared to a 4×10 kDa carrier. Similarly, even stronger N-terminal degradation was shown by using a 4-arm 40 kDa carrier with different branching patterns.

[0373] Preferably, -Z or -Z' comprises the following moiety.

Chemical formula

[0374] Similarly, in a preferred embodiment, -Z or -Z' comprises an amide bond.

[0375] In one embodiment, -Z of formula (Ia) or (Ib) comprises a moiety of the following formula (a). [Chemical formula] In the formula, The dashed line represents the bond to the remainder of -L 2 - or -Z; BP a is a branch point selected from the group consisting of -N<, -CR<, and C<; -R is selected from the group consisting of -H and C 1-6 alkyl; a is 0 when BP a is -N< or -CR<, and a is 1 when BP a is >C<; -S a -, -S a′ -, -S a″ - and -S a″′ - are each independently a chemical bond or C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl may be substituted with one or more identical or different -R 1 and C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl may optionally be interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 2 ), -S(O)2N(R 2 ), -S(O)N(R 2 ), -S(O)2-, -S(O)-, -N(R 2 )S(O)2N(R 2a ), -S-, -N(R 2 ), -OC(OR 2 )(R 2a ), -N(R 2 )C(O)N(R 2a ), and -OC(O)N(R 2 ); Each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, 8- to 30-membered carbocyclic polycycle, and 8- to 30-membered heterocyclic polycycle; each -T- may independently be substituted with one or more identical or different -R 1 ; Each -R 1 is independently selected from the group consisting of halogen, -CN, oxo(=O), -COOR 3 , -OR 3 , -C(O)R 3 , -C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R 3 , -S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R 3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ) and C 1-6 alkyl; C 1-6 alkyl may optionally be substituted with one or more identical or different halogens; Each -R 2 , -R 2a , -R 3 , -R 3a and -R 3b is independently -H and C1-6 selected from the group consisting of alkyl, C 1-6 alkyl may be substituted with one or more identical or different halogen atoms; -P a′ 、-P a″ and -P a″′ are each independently a polymer moiety.

[0376] Optionally, the moiety of formula (a) is substituted with one or more substituents.

[0377] In one embodiment, BP in formula (a) a is -N<.

[0378] In another embodiment, BP in formula (a) a is -CR<. Preferably, -R is -H. Accordingly, a in formula (a) is preferably 0.

[0379] In another embodiment, BP in formula (a) a is >C<.

[0380] In one embodiment, -S a - in formula (a) is a chemical bond.

[0381] In another embodiment, -S a - in formula (a) is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl, and C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl is -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 ), -, -S(O)2N(R 4 ), -, -S(O)N(R 4 ), -, -S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a ), -, -S-, -N(R 4 ), -, -OC(OR 4 )(R 4a ), -, -N(R 4)C(O)N(R 4a )-, and -OC(O)N(R 4 )- from the group consisting of may optionally be interrupted by one or more chemical groups selected from the group consisting of; -R 4 and -R 4a are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Preferably, the -S a - of formula (a) is selected from the group consisting of methyl, ethyl, propyl, butyl, and they are -O-, -C(O)- and -C(O)N(R 4 )- from the group consisting of may optionally be interrupted by one or more chemical groups selected from the group consisting of.

[0382] In one embodiment, the -S a′ - of formula (a) is a chemical bond.

[0383] In another embodiment, the -S a′ - of formula (a) is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl, and C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl are -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O)2N(R 4 )-, -S(O)N(R 4 )-, -S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-, -N(R 4 )C(O)N(R 4a )-, and -OC(O)N(R 4 )- from the group consisting of may optionally be interrupted by one or more chemical groups selected from the group consisting of; -R 4 and -R 4a are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Preferably, the -S a′- is selected from the group consisting of methyl, ethyl, propyl, and butyl, and one or more chemical groups selected from the group consisting of -O-, -C(O)-, and -C(O)N(R 4 )- may optionally be interrupted.

[0384] In one embodiment, the -S a″ - in formula (a) is a chemical bond.

[0385] In another embodiment, the -S a″ - in formula (a) is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, and C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl are -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O)2N(R 4 )-, -S(O)N(R 4 )-,-S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-,-S-,-N(R 4 )-,-OC(OR 4 )(R 4a )-,-N(R 4 )C(O)N(R 4a )- and -OC(O)N(R 4 )- may optionally be interrupted by one or more chemical groups selected from the group consisting of; -R 4 and -R 4a are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. Preferably, the -S a″ - in formula (a) is selected from the group consisting of methyl, ethyl, propyl, and butyl, and one or more chemical groups selected from the group consisting of -O-, -C(O)-, and -C(O)N(R 4 )- may optionally be interrupted.

[0386] In one embodiment, the -S a″′ - in formula (a) is a chemical bond.

[0387] In another embodiment, the -S of formula (a) a″′ - is C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl, selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl is -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O)2N(R 4 )-, -S(O)N(R 4 )-,-S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-, -N(R 4 )C(O)N(R 4a )-, and -OC(O)N(R 4 )-; optionally interrupted by one or more chemical groups selected from the group consisting of -R 4 and -R 4a are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Preferably, the -S of formula (a) a″′ - is selected from the group consisting of methyl, ethyl, propyl, butyl, which may optionally be interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)- and -C(O)N(R 4 ).

[0388] Preferably, the -P of formula (a) a′ , -P a″ and -P a″′independently includes polymers selected from the group consisting of 2-methacryloyloxyethyl phosphorylcholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amideamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxy methacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organic phosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinyl methyl ethers), poly(vinyl pyrrolidones), silicones, celluloses, carboxymethyl celluloses, hydroxypropyl methyl celluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon-based polymers, xylans, and copolymers thereof.

[0389] Preferably, -P of formula (a) a′ , -P a″ and -P a″′independently has a molecular weight in the range of 5 kDa to 50 kDa (including both ends), more preferably in the range of 5 kDa to 40 kDa (including both ends), even more preferably in the range of 7.5 kDa to 35 kDa (including both ends), even more preferably in the range of 7.5 to 30 kDa, and even more preferably in the range of 10 to 30 kDa (including both ends).

[0390] In one embodiment, -P of formula (a) a′ , -P a″ and -P a″′ has a molecular weight of about 5 kDa.

[0391] In another embodiment, -P of formula (a) a′ , -P a″ and -P a″′ has a molecular weight of about 7.5 kDa.

[0392] In another embodiment, -P of formula (a) a′ , -P a″ and -P a″′ has a molecular weight of about 10 kDa.

[0393] In another embodiment, -P of formula (a) a′ , -P a″ and -P a″′ has a molecular weight of about 12.5 kDa.

[0394] In another embodiment, -P of formula (a) a′ , -P a″ and -P a″′ has a molecular weight of about 15 kDa.

[0395] In another embodiment, -P of formula (a) a′ , -P a″ and -P a″′ has a molecular weight of about 20 kDa.

[0396] More preferably, -P of formula (a) a′ , -P a″ and -P a″′independently contains a PEG moiety. Even more preferably, the -P of formula (a) a′ and -P a″ and -P a″′ each independently contain a PEG moiety that contains at least 20% PEG, even more preferably at least 30%, even more preferably at least 40% PEG, even more preferably at least 50% PEG, even more preferably at least 60% PEG, even more preferably at least 70% PEG, even more preferably at least 80% PEG, and most preferably at least 90% PEG.

[0397] In a similarly preferred embodiment, the -P of formula (a) a′ and -P a″ and -P a″′ each independently contain a random coil protein moiety selected from the group consisting of protein moieties, more preferably random coil protein moieties, and most preferably PA, PAS, PAG, PG, and XTEN moieties.

[0398] In one embodiment, the -P of formula (a) a′ and -P a″ and -P a″′ are PA moieties.

[0399] In another embodiment, the -P of formula (a) a′ and -P a″ and -P a″′ are PAS moieties.

[0400] In another embodiment, the -P of formula (a) a′ and -P a″ and -P a″′ are PAG moieties.

[0401] In another embodiment, the -P of formula (a) a′ and -P a″ and -P a″′ are PG moieties.

[0402] In another embodiment, the -P of formula (a) a′ and -P a″and -P a″′ is the XTEN part.

[0403] In one embodiment, -Z includes one part of formula (a).

[0404] In another embodiment, -Z includes two parts of formula (a).

[0405] In another embodiment, -Z includes three parts of formula (a).

[0406] In another embodiment, -Z includes four parts of formula (a).

[0407] In another embodiment, -Z includes five parts of formula (a).

[0408] In another embodiment, -Z includes six parts of formula (a).

[0409] In a preferred embodiment, -Z includes two parts of formula (a).

[0410] In a preferred embodiment, -Z includes a part of the following formula (b).

Chemical formula

[0411] In some cases, the moiety of formula (b) is substituted with one or more substituents.

[0412] Preferably, b3 and b4 in formula (b) are the same integer.

[0413] In a preferred embodiment, both b3 and b4 are integers in the range of 200 to 250, and most preferably b3 and b4 in formula (b) are about 225.

[0414] In another preferred embodiment, both b3 and b4 are integers in the range of 400 to 500, and most preferably b3 and b4 in formula (b) are about 450.

[0415] Preferably, b1 in formula (b) is selected from the group consisting of 0, 1, 2, 3, and 4. More preferably, b1 in formula (b) is selected from the group consisting of 1, 2, and 3. Most preferably, b1 in formula (b) is 2.

[0416] Preferably, b2 in formula (b) is selected from the group consisting of 1, 2, 3, 4, and 5. More preferably, b2 in formula (b) is selected from the group consisting of 2, 3, and 4. Most preferably, b2 in formula (b) is 3.

[0417] In a particularly preferred embodiment, b1 in formula (b) is 2, b2 in formula (b) is 3, and both b3 and b4 are about 450.

[0418] In another particularly preferred embodiment, b1 in formula (b) is 2, b2 in formula (b) is 3, and both b3 and b4 are about 225.

[0419] In one embodiment, -Z contains one moiety of formula (b).

[0420] In another embodiment, -Z contains two moieties of formula (b).

[0421] In another embodiment, -Z contains three moieties of formula (b).

[0422] In another embodiment, -Z contains four moieties of formula (b).

[0423] In another embodiment, -Z contains five moieties of formula (b).

[0424] In another embodiment, -Z contains six moieties of formula (b).

[0425] In a preferred embodiment, -Z contains two moieties of formula (b).

[0426] In an even more preferred embodiment, -Z contains a moiety of formula (c).

Chemical Formula

[0427] Optionally, the moiety of formula (c) is substituted with one or more substituents.

[0428] Preferably, both c1 and c2 of formula (c) are the same integer.

[0429] In a certain preferred embodiment, c1 and c2 of formula (c) are in the range of 200 to 250 (including both ends), and most preferably about 225. In another preferred embodiment, c1 and c2 of formula (c) are in the range of 400 to 500 (including both ends), and most preferably about 450.

[0430] In a preferred embodiment, Sub-Z is a branched PEG-based polymer containing at least 10% PEG, has one branching point and two PEG-based polymer arms, and has a molecular weight of about 40 kDa. Accordingly, each of the two PEG-based polymer arms has a molecular weight of about 20 kDa. Preferably, the branching point is -CH<.

[0431] In one embodiment, -Z contains one moiety of formula (c).

[0432] In another embodiment, -Z contains two moieties of formula (c).

[0433] In another embodiment, -Z contains three moieties of formula (c).

[0434] In another embodiment, -Z contains four moieties of formula (c).

[0435] In another embodiment, -Z contains five moieties of formula (c).

[0436] In another embodiment, -Z contains six moieties of formula (c).

[0437] In a preferred embodiment, -Z contains two moieties of formula (c).

[0438] In a certain preferred embodiment, Sub-Z is of the following formula (d).

Chemical formula

[0439] Optionally, the moiety of formula (d) is substituted with one or more substituents.

[0440] The BP of formula (d) a , -S a , -S a′ , -S a″ , -S a″′ , -P a′ , -Pa″ -P a″′ The preferred embodiment of -P is as defined above for formula (a).

[0441] Preferably, -Z of formula (d) a is the same as that of formula (b). The preferred embodiments of b1, b2, b3 and b4 are as described for formula (b).

[0442] In an even more preferred embodiment, the moiety -Z of formula (Ia) or (Ib) is of the following formula (e).

Chemical formula

Chemical formula

[0443] Optionally, the moiety of formula (e) is substituted with one or more substituents.

[0444] The preferred embodiments for b1, b2, b3 and b4 of formula (e) are as defined above for formula (b).

[0445] In one embodiment, e in formula (e) is 1. In another embodiment, e in formula (e) is 2. In another embodiment, e in formula (e) is 3. In another embodiment, e in formula (e) is 4. In another embodiment, e in formula (e) is 5. In another embodiment, e in formula (e) is 6. In another embodiment, e in formula (e) is 7. In another embodiment, e in formula (e) is 8. In another embodiment, e in formula (e) is 9. In another embodiment, e in formula (e) is 10. In another embodiment, e in formula (e) is 11. In another embodiment, e in formula (e) is 12. In another embodiment, e in formula (e) is 13. In another embodiment, e in formula (e) is 14. In another embodiment, e in formula (e) is 15.

[0446] Preferably, e in formula (e) is selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, and 9. Even more preferably, e in formula (e) is selected from 3, 4, 5, and 6. Most preferably, e in formula (e) is 5.

[0447] Preferably, e in formula (e) is 5, b1 in formula (e) is 2, b2 in formula (e) is 3, and both b3 and b4 in formula (e) are about 450.

[0448] In a similarly preferred embodiment, sub-Z in formula (Ia) or (Ib) is of the following formula (e-i) or (e-i′).

Chemical formula

Chemical formula

[0449] Preferred embodiments for b1, b2, b3 and b4 of formulas (e-i) and (e-i') are as defined above for formula (b).

[0450] Preferred embodiments for e of formulas (e-i) and (e-i') are as described for formula (e).

[0451] Preferably, b1 of formulas (e-i) and (e-i') is 2, b2 of formulas (e-i) and (e-i') is 3, and both b3 and b4 of formulas (e-i) and (e-i') are about 450.

[0452] In a preferred embodiment, -Z of formula (Ia) or (Ib) is that of formula (e-i).

[0453] In another preferred embodiment, moiety -Z is a branched PEG-based polymer containing at least 10% PEG, has 3 branch points and 4 PEG-based polymer arms, and has a molecular weight of about 40 kDa. Accordingly, each of the 4 PEG-based polymer arms has a molecular weight of about 10 kDa. Preferably, each of the 3 branch points is -CH<.

[0454] In a preferred embodiment, moiety -Z is that of the following formula (f).

Chemical formula

Chemical Formula

[0455] Optionally, the moiety of formula (f) is substituted with one or more substituents.

[0456] BP of formula (f) a , -S a -, -S a′ -, -S a″ -, -S a″′ -, -P a′ , -P a″ and -P a″′ The preferred embodiments of are as defined above for formula (a).

[0457] Preferably, BP of formula (f) f is -CR<, and r is 0. Preferably, -R is -H. Preferably, -S of formula (f) f - is a chemical bond.

[0458] Preferably, -Z of formula (f) a′ , -Z a″ and -Z a″′ have the same structure. Preferably, -Z of formula (f) a′ , -Z a″ and -Z a″′ is of formula (b).

[0459] The preferred embodiments of b1, b2, b3 and b4 are as described for formula (b).

[0460] Preferably, -S of formula (f) f - is a chemical bond, and BP of formula (f) a is -CR<, and -R is -H. Even more preferably, -S of formula (f) f - is a chemical bond, and BP of formula (f) a is -CR<, and -R is -H, and -Z of formula (f) a′ , -Z a″ and -Za″′ is of formula (b).

[0461] Even more preferably, -Z is of the following formula (g).

Chemical formula

Chemical formula

[0462] Optionally, the moiety of formula (g) is substituted with one or more substituents.

[0463] The BP of formula (g) a , -S a , -S a′ , -S a″ , -S a″′ , -P a′ , -P a″ and -P a″′ preferred embodiments are as defined above for formula (a).

[0464] Preferably, the -S g - of formula (g) is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, which may be substituted with one or more identical or different -R 1 and -R 1 is halogen, oxo (=O), -COOR 3 , -OR 3 , -C(O)R 3 , -C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R 3 , -S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3, -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R 3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ), and C 1-6 selected from the group consisting of alkyl; C 1-6 alkyl may be substituted with one or more identical or different halogens; -R 3 , -R 3a and -R 3b are independently selected from -H, methyl, ethyl, propyl, and butyl.

[0465] Even more preferably, the -S g - of formula (g) is selected from C 1-6 alkyl.

[0466] Preferably, the -S g′ - of formula (g) is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, which may be substituted with one or more identical or different -R 1 ; -R 1 is halogen, oxo (=O), -COOR 3 , -OR 3 , -C(O)R 3 , -C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R 3、 -S(O)R 3 、 -N(R 3 )S(O)2N(R 3a R 3b )、 -SR 3 、 -N(R 3 R 3a )、 -NO2、 -OC(O)R 3 、 -N(R 3 )C(O)R 3a 、 -N(R 3 )S(O)2R 3a 、 -N(R 3 )S(O)R 3a 、 -N(R 3 )C(O)OR 3a 、 -N(R 3 )C(O)N(R 3a R 3b )、 -OC(O)N(R 3 R 3a )、 and C 1-6 selected from the group consisting of alkyl; C 1-6 alkyl may be substituted with one or more identical or different halogens; -R 3 、 -R 3a and -R 3b are independently selected from -H, methyl, ethyl, propyl, and butyl.

[0467] Even more preferably, the -S g′ - of formula (g) is selected from C 1-6 alkyl.

[0468] Preferably, the -S g″ - of formula (g) is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, which may be substituted with one or more identical or different -R 1 ; -R 1 is halogen, oxo (=O), -COOR 3 、 -OR 3 、 -C(O)R 3 、 -C(O)N(R 3 R 3a )、 -S(O)2N(R3 R 3a )、-S(O)N(R 3 R 3a )、-S(O)2R 3 、-S(O)R 3 、-N(R 3 )S(O)2N(R 3a R 3b )、-SR 3 、-N(R 3 R 3a )、-NO2、-OC(O)R 3 、-N(R 3 )C(O)R 3a 、-N(R 3 )S(O)2R 3a 、-N(R 3 )S(O)R 3a 、-N(R 3 )C(O)OR 3a 、-N(R 3 )C(O)N(R 3a R 3b )、-OC(O)N(R 3 R 3a )、and C 1-6 selected from the group consisting of alkyl; C 1-6 alkyl may be substituted with one or more identical or different halogens; -R 3 、-R 3a and -R 3b are independently selected from -H, methyl, ethyl, propyl and butyl.

[0469] Even more preferably, the -S g″ - in formula (g) is selected from C 1-6 alkyl.

[0470] Preferably, the -Z a and -Z a′ in formula (g) have the same structure. Preferably, the -Z a and -Z a′ in formula (g) are those of formula (b).

[0471] In another even more preferred embodiment, the -Z in formula (Ia) or (Ib) is that of the following formula (g-i). [Chemical formula] In the formula, The dashed line represents the bond to -L 2 -; -S g -, -S g′ - and -S g″ - are each independently selected from the group consisting of C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl may be substituted with one or more identical or different -R 1 and may be interrupted by one or more groups independently selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl may be interrupted by one or more groups independently selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 2 ), -S(O)2N(R 2 ), -S(O)N(R 2 ), -S(O)2-, -S(O)-, -N(R 2 )S(O)2N(R 2a )-, -S-, -N(R 2 ), -OC(OR 2 )(R 2a ), -N(R 2 )C(O)N(R 2a ), and -OC(O)N(R 2 ); Each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, 8- to 30-membered carbocyclic polycycle, and 8- to 30-membered heterocyclic polycycle; each -T- may be substituted with one or more identical or different -R 1 ; Each R 1 is independently halogen, -CN, oxo (=O), -COOR 3 , -OR3 , -C(O)R 3 , -C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R 3 , -S(O)R 3 , -N(R 3 ), S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R 3 ), C(O)R 3a , -N(R 3 ), S(O)2R 3a , -N(R 3 ), S(O)R 3a , -N(R 3 ), C(O)OR 3a , -N(R 3 ), C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ), and C 1-6 alkyl selected from the group consisting of; C 1-6 alkyl may be substituted with one or more identical or different halogens; each -R 2 , -R 2a , -R 3 , -R 3a and -R 3b are independently selected from the group consisting of -H and C 1-6 alkyl, and C 1-6 alkyl may be substituted with one or more identical or different halogens; -Y a1 - and -Y a1′ - are

Chemical formula

[0472] Optionally, the moiety of formula (g-i) is substituted with one or more substituents.

[0473] Preferably, -Y a1 - and -Y a1′ - are both [Chemical formula] and is wherein The dashed lines marked with asterisks are each bonded to -Z a or -Z a′ .

[0474] For BP in formula (g-i) a , -S a , -S a′ , -S a″ , -S a″′ , -P a′ , -P a″ and -P a″′ the preferred embodiments are as defined above for formula (a).

[0475] For -S in formula (g-i) g , -S g′ - and -S g″ the preferred embodiments are as defined for formula (g).

[0476] Preferably, -Z in formula (g-i) a and -Z a′have the same structure. Preferably, -Z of formula (g-i) a and -Z a′ are those of formula (b). Preferred embodiments for b1, b2, b3 and b4 are as described for formula (b).

[0477] Even more preferably, -Z is of the following formula (h).

Chemical formula

Chemical formula

[0478] Optionally, the moiety of formula (h) is substituted with one or more substituents.

[0479] Preferably, both c1s of formula (h) are the same.

[0480] Preferably, both c1s of formula (h) are about 225.

[0481] Even more preferably, -Z of formula (Ia) or (Ib) is the following formula (h-a):

Chemical formula

Chemical formula

[0482] Optionally, the part of formula (h - a) is substituted with one or more substituents.

[0483] Preferably, each k of formula (h - a) is independently selected from the group consisting of 2, 3, 4, 5, 6 and 7. Preferably, both k of formula (h - a) are the same.

[0484] Preferably, both c1 of formula (h - a) are the same.

[0485] Preferably, both c1 of formula (h - a) are about 225.

[0486] Preferably, -Y a1 - and -Y a1′ - are both [Chemical formula] and wherein the dashed line marked with an asterisk is bonded to -Z c is bonded to.

[0487] In an even more preferred embodiment, the part -Z is of the following formula (h - i). [Chemical formula] wherein the dashed line indicates the bond to -L 2 -; each -Z c is the following part: [Chemical formula] and each c1 is independently an integer in the range of 200 to 250.

[0488] In some cases, the part of formula (h - i) is substituted with one or more substituents.

[0489] Preferably, both c1s in formula (h - i) are the same.

[0490] Preferably, both c1s in formula (h - i) are about 225.

[0491] In another even more preferred embodiment, the -Z part of formula (Ia) or (Ib) is the one of the following formula (h - ia). [Chemical formula] In the formula, the dashed line represents a bond to -L 2 ; each k is independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; -Y a1 - and -Y a1′ - are [Chemical formula] and each -Z c is the following part: [Chemical formula] and each c1 is independently an integer in the range of 200 to 250.

[0492] Preferably, each k in formula (h - ia) is independently selected from the group consisting of 2, 3, 4, 5, 6, and 7. Preferably, both ks in formula (h - ia) are the same.

[0493] Preferably, both c1s in formula (h - ia) are the same.

[0494] Preferably, C1 in both of the formula (h-ia) is about 225.

[0495] Preferably, -Y in the formula (h-ia) a1 - and -Y a1′ - are both

Chemical formula

[0496] In equally preferred embodiments, -Z in the formula (Ia) or (Ib) includes a moiety selected from the group consisting of the following.

Chemical formula

Chemical formula

[0497] In certain preferred embodiments, the -Y d1 -and -Y d2 -and the -Y d1 -、-Y d2 -、-Y d3 -and -Y d4 -of formulas (j-iv), (j-v) and (j-vi) and the -Y

Chemical formula

[0498] In another preferred embodiment, -Y in formulas (j-iv), (j-v) and (j-vi) d1 - and -Y d2 - and -Y in formula (j-vii) d1 -, -Y d2 -, -Y d3 -, -Y and -Y d4 - are

Chemical formula

[0499] Preferably, -X in formula (j-i) f1 , -X f2 , -X f3 , -X f4 , -X f5 , -X f6 , -X f7 , -X f8 and -X are -H; -X in formula (j-i) d1 and -X are -OH; -X in formula (j-i) d2 and -X are selected from the group consisting of -H and methyl; s1, s2, s3 and s4 in formula (j-i) are selected from the group consisting of 2, 3, 4, 5 and 6. Even more preferably, -X in formula (j-i) e1 , -X e2 , -X f1 , -X f2 , -X f3 , -X f4 , -X f5 , -X f6 , -X f7 and -X are -H; -X in formula (j-i) f8 , -X d1 and -X are -OH; -X in formula (j-i) d2 and -X are e1and -X e2 is -H; s1, s2, s3, and s4 of formula (j-i) are 4.

[0500] Preferably, -X of formula (j-ii) f1 , -X f2 , -X f3 and -X f4 is -H; -X of formula (j-ii) d1 , -X d2 , -X d3 and -X d2 is -OH; -X of formula (j-ii) e1 , -X e2 , -X e3 and -X e4 is selected from the group consisting of -H and methyl; s1, s2, s3, s4, and s5 of formula (j-ii) are selected from the group consisting of 1, 2, 3, 4, 5, and 6. Even more preferably, -X of formula (j-ii) f1 , -X f2 , -X f3 and -X f4 is -H; -X of formula (j-ii) d1 , -X d2 , -X d3 and -X d2 is -OH; -X of formula (j-ii) e1 , -X e2 , -X e3 and -X e4 is -H; s1 is 4 of formula (j-ii), and s2, s3, s4, and s5 of formula (j-ii) are 1.

[0501] Preferably, -X of formula (j-iii) f1 , -X f2 , -X f3 , -X f4 , -X f5 , -X f6 , -X f7 , -X f8 , -X f9 and -X f10 is -H; -X of formula (j-iii) d1 , -X d2 , -X d3 and -X d4 is -OH; -X of formula (j-iii)e1 、 -X e2 、 -X e3 and -X e4 is selected from the group consisting of -H and methyl; s1, s2 and s3 of formula (j-iii) are selected from the group consisting of 2, 3, 4, 5 and 6. Even more preferably, -X of formula (j-iii) f1 、 -X f2 、 -X f3 、 -X f4 、 -X f5 、 -X f6 、 -X f7 、 -X f8 、 -X f9 and -X f10 is -H; -X of formula (j-iii) d1 、 -X d2 、 -X d3 and -X d4 is -OH; -X of formula (j-iii) e1 、 -X e2 、 -X e3 and -X e4 is -H; s1, s2 and s3 of formula (j-iii) are 4.

[0502] Preferably, -X of formula (j-iv) f1 、 -X f2 、 -X f3 、 -X f4 、 -X f5 and -X f6 is -H; s1, s2, s3, s4, s5, s6 and s7 of formula (j-iv) are selected from the group consisting of 1, 2, 3, 4, 5, 6 and 7; -Y d1 - and -Y d2 - is [Chemical formula] is selected from the group consisting of.

[0503] In an even more preferred embodiment, -X of formula (j-iv) f1 、 -X f2 、 -X f3 、 -X f4 、 -X f5 and -X f6is -H; s1 in formula (j-iv) is 3, s2 in formula (j-iv) is 5, s3 in formula (j-iv) is 2, s4 in formula (j-iv) is 4, s5 in formula (j-iv) is 5, s6 in formula (j-iv) is 2, s7 in formula (j-iv) is 4; -Y in formula (j-iv) d1 - and -Y d2 - is

Chemical formula

[0504] Similarly, in a preferred embodiment, -X in formula (j-iv) f1 , -X f2 , -X f3 , -X f4 , -X f5 and -X f6 is -H; s1 in formula (j-iv) is 3, s2 in formula (j-iv) is 5, s3 in formula (j-iv) is 2, s4 in formula (j-iv) is 4, s5 in formula (j-iv) is 5, s6 in formula (j-iv) is 2, s7 in formula (j-iv) is 4; -Y in formula (j-iv) d1 - and -Y d2 - is

Chemical formula

[0505] The dashed lines marked with asterisks are respectively directed towards -Z d1 , -Z d2 , -Z d3 and -Z d4 respectively, and the unmarked dashed line is directed towards -L 2 -.

[0506] Preferably, -X in formula (j-v) f1 , -X f2 , -X f3 and -X f4 is -H; s1, s2, s3, s4 and s5 in formula (j-v) are selected from the group consisting of 1, 2, 3, 4, 5, 6 and 7; -Y in formula (j-v)d1 - and -Y d2 - is [Chemical formula] selected from the group consisting of.

[0507] In an even more preferred embodiment, -X in formula (j-v) f1 , -X f2 , -X f3 and -X f4 are -H; s1 in formula (j-v) is 3, s2 in formula (j-v) is 2, s3 in formula (j-v) is 1, s4 in formula (j-v) is 2, s5 in formula (j-v) is 1; -Y in formula (j-v) d1 - and -Y d2 - is [Chemical formula] as follows.

[0508] In a similarly preferred embodiment, -X in formula (j-v) f1 , -X f2 , -X f3 and -X f4 are -H; s1 in formula (j-v) is 3, s2 in formula (j-v) is 2, s3 in formula (j-v) is 1, s4 in formula (j-v) is 2, s5 in formula (j-v) is 1; -Y in formula (j-v) d1 - and -Y d2 - is [Chemical formula] as follows; wherein

[0509] the dashed lines marked with asterisks are each directed towards -Z d1 , -Z d2 , -Z d3 and -Z d4 , and the unmarked dashed line is directed towards -L 2 .

[0510] Preferably, -X in formula (j-vi)f1 、 -X f2 、 -X f3 、 -X f4 、 -X f5 、 -X f6 、 -X f7 、 -X f8 、 -X f9 and -X f10 is -H; s1, s2, s3, s4, s5, s6, s7, s8 and s9 of formula (j-vi) are selected from the group consisting of 1, 2, 3, 4, 5, 6 and 7; -Y of formula (j-vi) d1 - and -Y d2 - is

Chemical formula

[0511] In a further more preferred embodiment, -X of formula (j-vi) f1 、 -X f2 、 -X f3 、 -X f4 、 -X f5 、 -X f6 、 -X f7 、 -X f8 、 -X f9 and -X f10 is -H; s1 of formula (j-vi) is 4, s2 of formula (j-vi) is 5, s3 of formula (j-vi) is 2, s4 of formula (j-vi) is 4, s5 of formula (j-vi) is 4, s6 of formula (j-vi) is 5, s7 of formula (j-vi) is 2, s8 of formula (j-vi) is 4, s9 of formula (j-vi) is 4; -Y of formula (j-v) d1 - and -Y d2 - is

Chemical formula

[0512] In a similarly preferred embodiment, -X of formula (j-vi) f1 、 -X f2 、 -X f3 、 -X f4 、 -X f5 、 -X f6, -X f7 , -X f8 , -X f9 and -X f10 is -H; s1 in formula (j-vi) is 4, s2 in formula (j-vi) is 5, s3 in formula (j-vi) is 2, s4 in formula (j-vi) is 4, s5 in formula (j-vi) is 4, s6 in formula (j-vi) is 5, s7 in formula (j-vi) is 2, s8 in formula (j-vi) is 4, s9 in formula (j-vi) is 4; -Y in formula (j-v) d1 - and -Y d2 - are

Chemical formula

[0513] Preferably, -X in formula (j-vii) f1 , -X f2 , -X f3 , -X f4 , -X f5 , -X f6 , -X f7 , -X f8 , -X f9 , -X f10 , -X f11 , -X f12 , -X f13 and -X f14 is -H; s1, s2, s3, s4, s5, s6, s7, s8, s9, s10, s11, s12, s13, s14 and s15 in formula (j-vii) are selected from the group consisting of 1, 2, 3, 4, 5, 6 and 7; -Y in formula (j-vii) d1 -, -Y d2 -, -Y d3 - and -Y d4 - are

Chemical formula

[0514] In an even more preferred embodiment, -X of formula (j-vii) f1 , -X f2 , -X f3 , -X f4 , -X f5 , -X f6 , -X f7 , -X f8 , -X f9 , -X f10 , -X f11 , -X f12 , -X f13 and -X f14 is -H; is -H; s1 of formula (j-vii) is 4, s2 of formula (j-vii) is 4, s3 of formula (j-vii) is 5, s4 of formula (j-vii) is 2, s5 of formula (j-vii) is 4, s6 of formula (j-vii) is 5, s7 of formula (j-vii) is 2, s8 of formula (j-vii) is 4, s9 of formula (j-vii) is 4, s10 of formula (j-vii) is 5, s11 of formula (j-vii) is 2, s12 of formula (j-vii) is 4, s13 of formula (j-vii) is 5, s14 of formula (j-vii) is 2, s15 of formula (j-vii) is 4; -Y of formula (j-vii) d1 -, -Y d2 -, -Y d3 - and -Y d4 - are

Chemical Formula

[0515] In a similarly preferred embodiment, -X of formula (j-vii) f1 , -X f2 , -X f3 , -X f4 , -X f5 , -X f6 , -X f7 , -X f8 , -X f9 , -X f10 , -X f11 , -X f12 , -Xf13 and -X f14 is -H; is -H; s1 in formula (j-vii) is 4, s2 in formula (j-vii) is 4, s3 in formula (j-vii) is 5, s4 in formula (j-vii) is 2, s5 in formula (j-vii) is 4, s6 in formula (j-vii) is 5, s7 in formula (j-vii) is 2, s8 in formula (j-vii) is 4, s9 in formula (j-vii) is 4, s10 in formula (j-vii) is 5, s11 in formula (j-vii) is 2, s12 in formula (j-vii) is 4, s13 in formula (j-vii) is 5, s14 in formula (j-vii) is 2, s15 in formula (j-vii) is 4; -Y in formula (j-vii) d1 -, -Y d2 -, -Y d3 - and -Y d4 - is

Chemical formula

[0516] Preferably, -Z in formulas (j-i), (j-ii), (j-iii), (j-iv), (j-v), (j-vi) and (j-vii) d1 , -Z d2 , -Z d3 and -Z d4 have the same structure.

[0517] In one embodiment, -Z in formulas (j-i), (j-ii), (j-iii), (j-iv), (j-v), (j-vi) and (j-vii) d1 , -Z d2 , -Z d3 and -Z d4 is the PA part.

[0518] In another embodiment, -Z of formulas (j-i), (j-ii), (j-iii), (j-iv), (j-v), (j-vi) and (j-vii) d1 , -Z d2 , -Z d3 and -Z d4 is the PAS moiety.

[0519] In another embodiment, -Z of formulas (j-i), (j-ii), (j-iii), (j-iv), (j-v), (j-vi) and (j-vii) d1 , -Z d2 , -Z d3 and -Z d4 is the PAG moiety.

[0520] In another embodiment, -Z of formulas (j-i), (j-ii), (j-iii), (j-iv), (j-v), (j-vi) and (j-vii) d1 , -Z d2 , -Z d3 and -Z d4 is the PG moiety.

[0521] In another embodiment, -Z of formulas (j-i), (j-ii), (j-iii), (j-iv), (j-v), (j-vi) and (j-vii) d1 , -Z d2 , -Z d3 and -Z d4 is the XTEN moiety.

[0522] In a preferred embodiment, the CNP-activating agent prodrug of the present invention has formula (IIe): [Chemical formula] (wherein The unmarked dashed line indicates the bond to the nitrogen of -D, which is the CNP-activating agent moiety, by forming an amide bond, The dashed line with an asterisk is the moiety: [Chemical formula] indicates the bond to, wherein Each c1 is independently an integer in the range of 400 to 500).

[0523] Preferably, c1 of formula (IIe) is about 450.

[0524] In a similarly preferred embodiment, the CNP-acting agent prodrug of the present invention has formula (IIe-i):

Chemical formula

Chemical formula

[0525] Preferably, c1 of formula (IIe-i) is about 450.

[0526] In another similarly preferred embodiment, the CNP-acting agent prodrug of the present invention has formula (IIe-ii):

Chemical formula

Chemical formula

[0527] Preferably, c1 of formula (IIe-ii) is about 450.

[0528] Preferably, -D in formula (IIe), (IIe-i) and (IIe-ii) is a CNP moiety, that is, the prodrugs of formula (IIe), (IIe-i) and (IIe-ii) are CNP prodrugs. Even more preferably, -D in formula (IIe), (IIe-i) and (IIe-ii) is a CNP moiety having the sequence of SEQ ID NO: 24, SEQ ID NO: 25 or SEQ ID NO: 30. Most preferably, -D in formula (IIe), (IIe-i) and (IIe-ii) is a CNP moiety having the sequence of SEQ ID NO: 24. It is also preferred that -D in formula (IIe), (IIe-i) and (IIe-ii) is a CNP moiety having the sequence of SEQ ID NO: 20. It is also preferred that -D in formula (IIe), (IIe-i) and (IIe-ii) is a CNP moiety having the sequence of SEQ ID NO: 21. It is also preferred that -D in formula (IIe), (IIe-i) and (IIe-ii) is a CNP moiety having the sequence of SEQ ID NO: 22. It is also preferred that -D in formula (IIe), (IIe-i) and (IIe-ii) is a CNP moiety having the sequence of SEQ ID NO: 23. It is also preferred that -D in formula (IIe), (IIe-i) and (IIe-ii) is a CNP moiety having the sequence of SEQ ID NO: 30.

[0529] In one embodiment, -D in formula (IIe), (IIe-i) and (IIe-ii) is a CNP moiety that is attached to -L 1 via the nitrogen of the N-terminal amine functionality of CNP.

[0530] In a preferred embodiment, -D in formula (IIe), (IIe-i) and (IIe-ii) is a CNP moiety that is attached to -L 1 via the nitrogen provided by the amine functionality of the lysine side chain of the CNP moiety.

[0531] In one embodiment, when the CNP moiety is that of SEQ ID NO: 24, the lysine side chain is not part of a ring formed by a disulfide bridge between cysteine residues at positions 22 and 38.

[0532] Thus, in one embodiment, when the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formula (IIe), (IIe-i) and (IIe-ii) via the amine functional group provided by the side chain of lysine at position 9 1 -.

[0533] In another embodiment, when the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formula (IIe), (IIe-i) and (IIe-ii) via the amine functional group provided by the side chain of lysine at position 11 1 -.

[0534] In another embodiment, when the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formula (IIe), (IIe-i) and (IIe-ii) via the amine functional group provided by the side chain of lysine at position 15 1 -.

[0535] In another embodiment, when the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formula (IIe), (IIe-i) and (IIe-ii) via the amine functional group provided by the side chain of lysine at position 16 1 -.

[0536] In another embodiment, when the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formula (IIe), (IIe-i) and (IIe-ii) via the amine functional group provided by the side chain of lysine at position 20 1 -.

[0537] In a preferred embodiment, when the CNP moiety is that of SEQ ID NO: 24, the lysine side chain is part of a ring formed by a disulfide bridge between cysteine residues at positions 22 and 38

[0538] Thus, in one embodiment, when the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formula (IIe), (IIe-i) and (IIe-ii) via the amine functional group provided by the side chain of lysine at position 26. 1 - is linked.

[0539] The positions of the above cysteine and lysine vary depending on the length of the CNP moiety, and those skilled in the art will have no difficulty in identifying the corresponding cysteine and lysine in longer or shorter versions of the CNP moiety. For example, it is also understood that some lysines may not be present in shorter CNP moieties. For example, as a result of site-directed mutagenesis, it is further understood that more lysine residues may be present in the acyclic and / or cyclic portions of the CNP moiety.

[0540] In a preferred embodiment, the CNP prodrug of the present invention has formula (IIe) wherein c1 is about 450, the -D is a CNP moiety having the sequence of SEQ ID NO: 24, and is linked to -L by the amine functional group provided by the side chain of lysine at position 26. 1 - is bonded, and has formula (IIe).

[0541] In another preferred embodiment, the CNP prodrug of the present invention has formula (IIe-i) wherein c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 24, and is linked to -L by the amine functional group provided by the side chain of lysine at position 26. 1 - is bonded, and has formula (IIe-i).

[0542] In another preferred embodiment, the CNP prodrug of the present invention has formula (IIe-ii) wherein c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 24, and is linked to -L by the amine functional group provided by the side chain of lysine at position 26. 1 - is bonded, and has formula (IIe-ii).

[0543] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIe), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 20, and is linked to -L via an amine functional group provided by the side chain of lysine at position 30 1 -.

[0544] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIe-i), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 20, and is linked to -L via an amine functional group provided by the side chain of lysine at position 30 1 -.

[0545] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIe-ii), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 20, and is linked to -L via an amine functional group provided by the side chain of lysine at position 30 1 -.

[0546] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIe), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 21, and is linked to -L via an amine functional group provided by the side chain of lysine at position 29 1 -.

[0547] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIe-i), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 21, and is linked to -L via an amine functional group provided by the side chain of lysine at position 29 1 -.

[0548] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIe-ii), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 21, and is linked to -L via an amine functional group provided by the side chain of lysine at position 29 1 -.

[0549] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIe), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 22, and is attached to -L via an amine functional group provided by the side chain of lysine at position 28 1 - is attached.

[0550] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIe-i), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 22, and is attached to -L via an amine functional group provided by the side chain of lysine at position 28 1 - is attached.

[0551] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIe-ii), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 22, and is attached to -L via an amine functional group provided by the side chain of lysine at position 28 1 - is attached.

[0552] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIe), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 23, and is attached to -L via an amine functional group provided by the side chain of lysine at position 27 1 - is attached.

[0553] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIe-i), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 23, and is attached to -L via an amine functional group provided by the side chain of lysine at position 27 1 - is attached.

[0554] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIe-ii), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 23, and is attached to -L via an amine functional group provided by the side chain of lysine at position 27 1 - is attached.

[0555] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIe), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 30, and is attached to -L via the amine functional group provided by the side chain of lysine at position 27. 1 - is attached.

[0556] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIe-i), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 30, and is attached to -L via the amine functional group provided by the side chain of lysine at position 27. 1 - is attached.

[0557] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIe-ii), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 30, and is attached to -L via the amine functional group provided by the side chain of lysine at position 27. 1 - is attached.

[0558] In another preferred embodiment, the CNP active agent prodrug of the present invention has the formula (IIf):

Chemical formula

Chemical formula

Chemical formula

[0559] Preferably, each c1 of the formula (IIf) is about 225.

[0560] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-i):

Chemical formula

Chemical formula

Chemical formula

[0561] Preferably, each c1 of the formula (IIf-i) is about 225.

[0562] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-ii):

Chemical formula

Chemical formula

Chemical formula

[0563] Preferably, each c1 of formula (IIf-ii) is about 225.

[0564] Preferably, -D in formulas (IIf), (IIf-i) and (IIf-ii) is a CNP moiety, that is, the prodrugs of formulas (IIf), (IIf-i) and (IIf-ii) are CNP prodrugs. Even more preferably, -D in formulas (IIf), (IIf-i) and (IIf-ii) is a CNP moiety having the sequence of SEQ ID NO: 24, SEQ ID NO: 25 or SEQ ID NO: 30. Most preferably, -D in formulas (IIf), (IIf-i) and (IIf-ii) is a CNP moiety having the sequence of SEQ ID NO: 24.

[0565] In another embodiment, the CNP moiety of the CNP prodrugs of formulas (IIf), (IIf-i) and (IIf-ii) has the sequence of SEQ ID NO: 30.

[0566] In another embodiment, the CNP moiety of the CNP prodrugs of formulas (IIf), (IIf-i) and (IIf-ii) has the sequence of SEQ ID NO: 20.

[0567] In another embodiment, the CNP moiety of the CNP prodrugs of formulas (IIf), (IIf-i) and (IIf-ii) has the sequence of SEQ ID NO: 21.

[0568] In another embodiment, the CNP moiety of the CNP prodrugs of formulas (IIf), (IIf-i) and (IIf-ii) has the sequence of SEQ ID NO: 22.

[0569] In another embodiment, the CNP moiety of the CNP prodrugs of formulas (IIf), (IIf-i) and (IIf-ii) has the sequence of SEQ ID NO: 23.

[0570] In one embodiment, -D in formulas (IIf), (IIf-i), and (IIf-ii) is a CNP moiety that is linked to -L via the nitrogen of the N-terminal amine functionality of CNP. 1 It is a CNP moiety that is bonded to -L.

[0571] In a preferred embodiment, -D in formulas (IIf), (IIf-i), and (IIf-ii) is a CNP moiety that is linked to -L via the nitrogen provided by the amine functionality of the lysine side chain of the CNP moiety. 1 It is a CNP moiety that is bonded to -L.

[0572] In one embodiment, when the CNP moiety is that of SEQ ID NO: 24, the lysine side chain is not part of a ring formed by a disulfide bridge between cysteine residues at positions 22 and 38.

[0573] Thus, in one embodiment, when CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formulas (IIf), (IIf-i), and (IIf-ii) via the amine functionality provided by the side chain of lysine at position 9. 1 It is linked to -L.

[0574] In another embodiment, when CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formulas (IIf), (IIf-i), and (IIf-ii) via the amine functionality provided by the side chain of lysine at position 11. 1 It is linked to -L.

[0575] In another embodiment, when CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formulas (IIf), (IIf-i), and (IIf-ii) via the amine functionality provided by the side chain of lysine at position 15. 1 It is linked to -L.

[0576] In another embodiment, when the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formula (IIf), (IIf-i) and (IIf-ii) via an amine functional group provided by the side chain of lysine at position 16. 1 - is linked.

[0577] In another embodiment, when the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formula (IIf), (IIf-i) and (IIf-ii) via an amine functional group provided by the side chain of lysine at position 20. 1 - is linked.

[0578] In a preferred embodiment, when the CNP moiety is the one of SEQ ID NO: 24, the lysine side chain is part of a ring formed by a disulfide bridge between cysteine residues at positions 22 and 38.

[0579] Thus, in one embodiment, when the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formula (IIf), (IIf-i) and (IIf-ii) via an amine functional group provided by the side chain of lysine at position 26. 1 - is linked.

[0580] The above positions of cysteine and lysine vary depending on the length of the CNP moiety, and those skilled in the art will have no difficulty in identifying the corresponding cysteine and lysine in longer or shorter versions of the CNP moiety. It is also understood that, for example, some lysines may not be present in shorter CNP moieties. It is further understood that, as a result of site-directed mutagenesis, more lysine residues may be present in the acyclic and / or cyclic portions of the CNP moiety.

[0581] In a preferred embodiment, the CNP prodrug of the present invention has formula (IIf), where c1 is about 225, -D is a CNP moiety having the sequence of SEQ ID NO: 24, and is linked to -L via an amine functional group provided by the side chain of lysine at position 26. 1- is attached to.

[0582] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-i), where c1 is about 225, the CNP moiety has the sequence of SEQ ID NO: 24, and is attached to -L via the amine functional group provided by the side chain of lysine at position 26 1 - is attached to.

[0583] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-ii), where c1 is about 225, the CNP moiety has the sequence of SEQ ID NO: 24, and is attached to -L via the amine functional group provided by the side chain of lysine at position 26 1 - is attached to.

[0584] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIf), where c1 is about 225, -D is a CNP moiety having the sequence of SEQ ID NO: 20, and is attached to -L via the amine functional group provided by the side chain of lysine at position 30 1 - is attached to.

[0585] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-i), where c1 is about 225, the CNP moiety has the sequence of SEQ ID NO: 20, and is attached to -L via the amine functional group provided by the side chain of lysine at position 30 1 - is attached to.

[0586] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-ii), where c1 is about 225, the CNP moiety has the sequence of SEQ ID NO: 20, and is attached to -L via the amine functional group provided by the side chain of lysine at position 30 1 - is attached to.

[0587] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIf), where c1 is about 225, -D is a CNP moiety having the sequence of SEQ ID NO: 21, and is attached to -L via the amine functional group provided by the side chain of lysine at position 291 - is attached to.

[0588] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-i), where c1 is about 225, the CNP moiety has the sequence of SEQ ID NO: 21, and via the amine functional group provided by the side chain of lysine at position 29 -L 1 - is attached to.

[0589] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-ii), where c1 is about 225, the CNP moiety has the sequence of SEQ ID NO: 21, and via the amine functional group provided by the side chain of lysine at position 29 -L 1 - is attached to.

[0590] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIf), where c1 is about 225, -D is a CNP moiety having the sequence of SEQ ID NO: 22, and via the amine functional group provided by the side chain of lysine at position 28 -L 1 - is attached to.

[0591] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-i), where c1 is about 225, the CNP moiety has the sequence of SEQ ID NO: 22, and via the amine functional group provided by the side chain of lysine at position 28 -L 1 - is attached to.

[0592] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-ii), where c1 is about 225, the CNP moiety has the sequence of SEQ ID NO: 22, and via the amine functional group provided by the side chain of lysine at position 28 -L 1 - is attached to.

[0593] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIf), where c1 is about 225, -D is the CNP moiety having the sequence of SEQ ID NO: 23, and is linked to -L via an amine functional group provided by the side chain of the lysine at position 27 1 -.

[0594] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-i), where c1 is about 225, the CNP moiety has the sequence of SEQ ID NO: 23, and is linked to -L via an amine functional group provided by the side chain of the lysine at position 27 1 -.

[0595] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-ii), where c1 is about 225, the CNP moiety has the sequence of SEQ ID NO: 23, and is linked to -L via an amine functional group provided by the side chain of the lysine at position 27 1 -.

[0596] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIf), where c1 is about 225, -D is the CNP moiety having the sequence of SEQ ID NO: 30, and is linked to -L via an amine functional group provided by the side chain of the lysine at position 27 1 -.

[0597] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-i), where c1 is about 225, the CNP moiety has the sequence of SEQ ID NO: 30, and is linked to -L via an amine functional group provided by the side chain of the lysine at position 27 1 -.

[0598] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-ii), where c1 is about 225, the CNP moiety has the sequence of SEQ ID NO: 30, and is linked to -L via an amine functional group provided by the side chain of the lysine at position 27 1 -.

[0599] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf'):

Chemical formula

Chemical formula

Chemical formula

[0600] Preferably, each c1 of the formula (IIf') is about 225.

[0601] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIf-i'):

Chemical formula

Chemical formula

Chemical formula

[0602] Preferably, each c1 of formula (IIf-i') is about 225.

[0603] In another preferred embodiment, the CNP prodrug of the present invention has formula (IIf-ii'): [Chemical formula] (wherein The unmarked dashed line indicates a bond to the nitrogen provided by the side chain of lysine at position 26 of the CNP moiety of SEQ ID NO: 24 by forming an amide bond, The dashed line marked with an asterisk is the structure: [Chemical formula] represents a bond to -Z having the formula, wherein each Z a is [Chemical formula] and each c1 in this formula is independently an integer in the range of 200 to 250).

[0604] Preferably, each c1 of formula (IIf-ii') is about 225.

[0605] In a similarly preferred embodiment, the CNP-acting drug prodrug of the present invention is of the following formula (IIea). [Chemical formula] wherein The unmarked dashed line indicates a bond to the nitrogen of -D which is the CNP-acting drug moiety by forming an amide bond; k is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12; The dashed line marked with an asterisk is the following moiety: [Chemistry] indicates the bond to, each c1 is independently an integer in the range of 400 to 500.

[0606] Preferably, c1 of formula (IIea) is about 450.

[0607] Preferably, k of formula (IIea) is selected from the group consisting of 2, 3, 4, 5, 6, and 7. In a similarly preferred embodiment, the CNP-acting drug prodrug of the present invention is of the following formula (IIea-i). [Chemistry] In the formula, the unmarked dotted line indicates the bond to the nitrogen of -D, which is the CNP-acting drug moiety, by forming an amide bond; k is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; the dotted line marked with an asterisk represents the following moiety: [Chemistry] indicates the bond to, each c1 is independently an integer in the range of 400 to 500.

[0608] Preferably, k of formula (IIea-i) is selected from the group consisting of 2, 3, 4, 5, 6, and 7.

[0609] Preferably, c1 of formula (IIea-i) is about 450.

[0610] In another similarly preferred embodiment, the CNP-acting drug prodrug of the present invention is of the following formula (IIea-ii). [Chemistry] In the formula, The dashed line without a mark indicates the bond to the nitrogen of -D, which is the CNP-activating agent moiety, by forming an amide bond; k is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; The dashed line marked with an asterisk indicates the bond to the following moiety:

Chemical formula

[0611] Preferably, k in formula (IIea-ii) is selected from the group consisting of 2, 3, 4, 5, 6, and 7.

[0612] Preferably, c1 in formula (IIea-ii) is about 450.

[0613] Preferably, -D in formulas (IIea), (IIea-i), and (IIea-ii) is a CNP moiety, that is, the prodrugs of formulas (IIea), (IIea-i), and (IIea-ii) are CNP prodrugs. Even more preferably, -D in formulas (IIea), (IIea-i), and (IIea-ii) is a CNP moiety having the sequence of SEQ ID NO: 24, SEQ ID NO: 25, or SEQ ID NO: 30. Most preferably, -D in formulas (IIea), (IIea-i), and (IIea-ii) is a CNP moiety having the sequence of SEQ ID NO: 24.

[0614] It is also preferred that -D in formulas (IIea), (IIea-i), and (IIea-ii) is a CNP moiety having the sequence of SEQ ID NO: 20.

[0615] It is also preferred that -D in formulas (IIea), (IIea-i), and (IIea-ii) is a CNP moiety having the sequence of SEQ ID NO: 21.

[0616] It is also preferred that -D in formulas (IIea), (IIea-i), and (IIea-ii) is a CNP moiety having the sequence of SEQ ID NO: 22.

[0617] For -D in formulas (IIea), (IIea-i) and (IIea-ii), it is also preferable that it is a CNP moiety having the sequence of SEQ ID NO: 23.

[0618] For -D in formulas (IIea), (IIea-i) and (IIea-ii), it is also preferable that it is a CNP moiety having the sequence of SEQ ID NO: 30.

[0619] In one embodiment, -D in formulas (IIea), (IIea-i) and (IIea-ii) is a CNP moiety bonded to -L 1 through the nitrogen of the N-terminal amine functional group of CNP.

[0620] In a preferred embodiment, -D in formulas (IIea), (IIea-i) and (IIea-ii) is a CNP moiety bonded to -L 1 through the nitrogen provided by the amine functional group of the lysine side chain of the CNP moiety.

[0621] In one embodiment, when the CNP moiety is the one of SEQ ID NO: 24, the lysine side chain is not part of a ring formed by a disulfide bridge between the cysteine residues at positions 22 and 38.

[0622] Therefore, in one embodiment, when CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formulas (IIea), (IIea-i) and (IIea-ii) through the amine functional group provided by the side chain of lysine at position 9. 1

[0623] In another embodiment, when CNP has the sequence of SEQ ID NO: 24, the CNP moiety is linked to -L in the CNP prodrugs of formulas (IIea), (IIea-i) and (IIea-ii) through the amine functional group provided by the side chain of lysine at position 11. 1

[0624] ​​In another embodiment, when the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is attached to -L in the CNP prodrugs of formula (IIea), (IIea-i) and (IIea-ii) via an amine functional group provided by the side chain of lysine at position 15 1 - is linked.

[0625] In another embodiment, when the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is attached to -L in the CNP prodrugs of formula (IIea), (IIea-i) and (IIea-ii) via an amine functional group provided by the side chain of lysine at position 16 1 - is linked.

[0626] In another embodiment, when the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is attached to -L in the CNP prodrugs of formula (IIea), (IIea-i) and (IIea-ii) via an amine functional group provided by the side chain of lysine at position 20 1 - is linked.

[0627] In a preferred embodiment, when the CNP moiety is that of SEQ ID NO: 24, the lysine side chain is part of a ring formed by a disulfide bridge between cysteine residues at positions 22 and 38.

[0628] Thus, in one embodiment, when the CNP has the sequence of SEQ ID NO: 24, the CNP moiety is attached to -L in the CNP prodrugs of formula (IIea), (IIea-i) and (IIea-ii) via an amine functional group provided by the side chain of lysine at position 26 1 - is linked.

[0629] The positions of the above cysteine and lysine vary according to the length of the CNP moiety, and there is no difficulty for those skilled in the art to identify the corresponding cysteine and lysine in longer or shorter versions of the CNP moiety. For example, it is understood that some lysines may not exist in shorter CNP moieties. It is further understood that, as a result of site-directed mutagenesis, more lysine residues may be present in the acyclic and / or cyclic forming portions of the CNP moiety.

[0630] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIea), where c1 is about 450, -D is a CNP moiety having the sequence of SEQ ID NO: 24, and is linked to -L via an amine functional group provided by the side chain of the lysine at position 26 1 -.

[0631] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIea-i), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 24, and is linked to -L via an amine functional group provided by the side chain of the lysine at position 26 1 -.

[0632] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIea-ii), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 24, and is linked to -L via an amine functional group provided by the side chain of the lysine at position 26 1 -.

[0633] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIea), where c1 is about 450, -D is a CNP moiety having the sequence of SEQ ID NO: 20, and is linked to -L via an amine functional group provided by the side chain of the lysine at position 30 1 -.

[0634] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIea-i), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 20, and is linked to -L via an amine functional group provided by the side chain of lysine at position 30. 1 - is attached.

[0635] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIea-ii), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 20, and is linked to -L via an amine functional group provided by the side chain of lysine at position 30. 1 - is attached.

[0636] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIea), where c1 is about 450, -D is a CNP moiety having the sequence of SEQ ID NO: 21, and is linked to -L via an amine functional group provided by the side chain of lysine at position 29. 1 - is attached.

[0637] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIea-i), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 21, and is linked to -L via an amine functional group provided by the side chain of lysine at position 29. 1 - is attached.

[0638] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIea-ii), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 21, and is linked to -L via an amine functional group provided by the side chain of lysine at position 29. 1 - is attached.

[0639] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIea), where c1 is about 450, -D is a CNP moiety having the sequence of SEQ ID NO: 22, and is linked to -L via an amine functional group provided by the side chain of lysine at position 28. 1 - is attached.

[0640] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIea-i), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 22, and is linked to -L via the amine functional group provided by the side chain of lysine at position 28 1 -.

[0641] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIea-ii), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 22, and is linked to -L via the amine functional group provided by the side chain of lysine at position 28 1 -.

[0642] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIea), where c1 is about 450, -D is a CNP moiety having the sequence of SEQ ID NO: 23, and is linked to -L via the amine functional group provided by the side chain of lysine at position 27 1 -.

[0643] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIea-i), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 23, and is linked to -L via the amine functional group provided by the side chain of lysine at position 27 1 -.

[0644] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIea-ii), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 23, and is linked to -L via the amine functional group provided by the side chain of lysine at position 27 1 -.

[0645] In a preferred embodiment, the CNP prodrug of the present invention has the formula (IIea), where c1 is about 450, -D is a CNP moiety having the sequence of SEQ ID NO: 30, and is linked to -L via the amine functional group provided by the side chain of lysine at position 27 1 -.

[0646] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIea-i), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 30, and is attached to -L via the amine functional group provided by the side chain of lysine at position 27. 1 - is attached.

[0647] In another preferred embodiment, the CNP prodrug of the present invention has the formula (IIea-ii), where c1 is about 450, the CNP moiety has the sequence of SEQ ID NO: 30, and is attached to -L via the amine functional group provided by the side chain of lysine at position 27. 1 - is attached.

[0648] Therefore, in a preferred embodiment, the CNP prodrug of the present invention has the following formula (IIea').

Chemical formula

Chemical formula

[0649] Preferably, k in the formula (IIea') is selected from the group consisting of 2, 3, 4, 5, 6, and 7.

[0650] Preferably, each c1 in the formula (IIea') is about 450.

[0651] In another preferred embodiment, the CNP prodrug of the present invention is of the following formula (IIea-i′).

Chemical formula

Chemical formula

[0652] Preferably, k in formula (IIea-i′) is selected from the group consisting of 2, 3, 4, 5, 6 and 7.

[0653] Preferably, each c1 in formula (IIea-i′) is about 450.

[0654] In another preferred embodiment, the CNP prodrug of the present invention is of the following formula (IIea-ii′).

Chemical formula

Chemical formula

[0655] Preferably, k in formula (IIea-ii′) is selected from the group consisting of 2, 3, 4, 5, 6, and 7.

[0656] Preferably, each c1 in formula (IIea-ii′) is about 450.

[0657] In another preferred embodiment, the CNP prodrug of the present invention is of the following formula (IIfa).

Chemical formula

Chemical formula

Chemical formula

[0658] Preferably, k in formula (IIfa) is selected from the group consisting of 2, 3, 4, 5, 6, and 7.

[0659] Preferably, each c1 in formula (IIfa) is about 225.

[0660] In another preferred embodiment, the CNP prodrug of the present invention is of the following formula (IIfa-i).

Chemical formula

[0661] Preferably, k in formula (IIfa-i) is selected from the group consisting of 2, 3, 4, 5, 6 and 7.

[0662] Preferably, each c1 in formula (IIfa-i) is about 225.

[0663] In another preferred embodiment, the CNP prodrug of the present invention has the following formula (IIfa-ii). [Chemical formula] In the formula, The dashed line without a mark indicates the bond to the nitrogen of -D, which is the CNP moiety, by forming an amide bond; The dashed line marked with an asterisk indicates the following structure:: [Chemical formula] represents the bond to -Z having k is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12; each -Z a is [Chemical formula] and each c1 is independently an integer in the range of 200 to 250.

[0664] Preferably, each c1 of formula (IIfa-ii) is about 225.

[0665] In one embodiment, the CNP moiety of the CNP prodrugs of formulas (IIfa), (IIfa-i) and (IIfa-ii) has the sequence of SEQ ID NO: 25.

[0666] In another embodiment, the CNP moiety of the CNP prodrugs of formulas (IIfa), (IIfa-i) and (IIfa-ii) has the sequence of SEQ ID NO: 30.

[0667] In another embodiment, the CNP moiety of the CNP prodrugs of formulas (IIfa), (IIfa-i) and (IIfa-ii) has the sequence of SEQ ID NO: 20.

[0668] In another embodiment, the CNP moiety of the CNP prodrugs of formulas (IIfa), (IIfa-i) and (IIfa-ii) has the sequence of SEQ ID NO: 21.

[0669] In another embodiment, the CNP moiety of the CNP prodrugs of formulas (IIfa), (IIfa-i) and (IIfa-ii) has the sequence of SEQ ID NO: 22.

[0670] In another embodiment, the CNP moiety of the CNP prodrugs of formulas (IIfa), (IIfa-i) and (IIfa-ii) has the sequence of SEQ ID NO: 23.

[0671] In a preferred embodiment, the CNP moiety of the CNP prodrugs of formulas (IIfa), (IIfa-i) and (IIfa-ii) has the sequence of SEQ ID NO: 24.

[0672] In one embodiment, the CNP moiety is attached to -L in the CNP prodrugs of formulas (IIfa), (IIfa-i) and (IIfa-ii) via the nitrogen of the N-terminal amine functionality of the CNP. 1 - is attached.

[0673] In another preferred embodiment, the CNP prodrug of the present invention is of the following formula (IIfa′).

Chemical formula

Chemical formula

Chemical formula

[0674] Preferably, k in formula (IIfa′) is selected from the group consisting of 2, 3, 4, 5, 6 and 7.

[0675] Preferably, each c1 in formula (IIfa′) is about 225.

[0676] In another preferred embodiment, the CNP prodrug of the present invention is of the following formula (IIfa-i′).

Chemical formula

Chemical formula

Chemical formula

[0677] Preferably, k of formula (IIfa-i') is selected from the group consisting of 2, 3, 4, 5, 6 and 7.

[0678] Preferably, each c1 of formula (IIfa-i') is about 225.

[0679] In another preferred embodiment, the CNP prodrug of the present invention is of the following formula (IIfa-ii').

Chemical formula

Chemical formula

[0680] Preferably, k of formula (IIfa-ii′) is selected from the group consisting of 2, 3, 4, 5, 6 and 7.

[0681] Preferably, each c1 of formula (IIfa-ii′) is about 225.

[0682] Another aspect of the present invention is a pharmaceutical composition comprising at least one sustained-release CNP-acting agent of the present invention and at least one excipient.

[0683] In one embodiment, the pharmaceutical composition comprising at least one sustained-release CNP-acting agent of the present invention and at least one excipient is a liquid formulation or a suspension formulation (suspension agent formulation). When at least one sustained-release CNP-acting agent is water-insoluble, it is understood that the pharmaceutical composition is a suspension formulation.

[0684] In another embodiment, the pharmaceutical composition comprising at least one sustained-release CNP-acting agent of the present invention and at least one excipient is a dry formulation.

[0685] Such liquid, suspension or dry pharmaceutical compositions contain at least one excipient. Excipients used in parenteral formulations can be classified, for example, as buffers, isotonicity regulators, preservatives, stabilizers, adsorption inhibitors, antioxidants, thickeners / viscosity increasing agents, or other auxiliaries. However, in some cases, one excipient may have dual or triple functions. Preferably, at least one excipient contained in the pharmaceutical composition of the present invention is selected from the group consisting of:

[0686] (i) Buffer: Physiologically acceptable buffers for maintaining the pH within the desired range, such as sodium phosphate, bicarbonate, succinate, histidine, citrate, and acetate, sulfate, nitrate, chloride, pyruvate. Antacids such as Mg(OH)2 or ZnCO3 may also be used;

[0687] (ii) Isotonicity regulator: To minimize the pain that may result from cell damage caused by osmotic pressure differences in injection depots. Glycerol and sodium chloride are examples. The effective concentration can be determined by osmotic pressure measurement using an assumed molar osmotic concentration of 285 - 315 mOsmol / kg for serum;

[0688] (iii) Preservative and / or antibacterial agent: For multi - dose parenteral formulations, the addition of a sufficient concentration of preservative is required to minimize the risk of infection in patients by injection, and the corresponding regulatory requirements are established. Typical preservatives include m - cresol, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenylmercuric nitrate, thimerosal, sorbic acid, potassium sorbate, benzoic acid, chlorocresol, and benzalkonium chloride;

[0689] (iv) Stabilizer: Stabilization can be achieved by enhancing the protein - stabilizing force, destabilizing the denatured state, or directly binding the excipient to the protein. Stabilizers can be amino acids such as alanine, arginine, aspartic acid, glycine, histidine, lysine, proline; sugars such as glucose, sucrose, trehalose; polyols such as glycerol, mannitol, sorbitol; salts such as potassium phosphate, sodium sulfate; chelating agents such as EDTA, hexaphosphate; ligands such as divalent metal ions (zinc, calcium, etc.); other salts or organic molecules such as phenolic derivatives. In addition, oligomers or polymers such as cyclodextrin, dextran, dendrimer, PEG or PVP, or protamine or HSA may also be used;

[0690] (v) Adsorption inhibitors: Mainly ionic or non-ionic surfactants or other proteins or soluble polymers, such as poloxamer (Pluronic F-68), PEG dodecyl ether (Brij 35), polysorbates 20 and 80, dextran, polyethylene glycol, PEG-polyhistidine, BSA and HSA, and gelatin, are used for coating the inner surface of the formulation container or for competitive adsorption to the inner surface. The excipient concentration and type selected depend on the effect to be avoided, but typically a monolayer of surfactant is formed at the interface just above the CMC value;

[0691] (vi) Oxidation protectants: Antioxidants such as ascorbic acid, ectoine, methionine, glutathione, monothioglycerol, morin, polyethyleneimine (PEI), propyl gallate, and vitamin E. Chelating agents such as citric acid, EDTA, hexaphosphate, and thioglycolic acid may also be used;

[0692] (vii) Thickening agent or viscosity increasing agent: It delays the sedimentation of particles in vials and syringes, promotes the mixing and resuspension of particles, and is used to make the suspension easier to inject (i.e., with a small force on the syringe plunger). Suitable thickening agents or viscosity increasing agents include, for example, carbomer thickening agents such as Carbopol 940, Carbopol Ultrez 10; cellulose derivatives such as hydroxypropyl methylcellulose (hypromellose, HPMC) or diethylaminoethyl cellulose (DEAE or DEAE-C); colloidal magnesium silicate (Veegum) or sodium silicate; hydroxyapatite gel; tricalcium phosphate gel; xanthan; carrageenan such as Satia gum UTC 30; aliphatic poly(hydroxy acids) such as poly(D,L- or L-lactic acid) (PLA) and poly(glycolic acid) (PGA) and their copolymers (PLGA), a terpolymer of D,L-lactide, glycolide, and caprolactone; poloxamer; hydrophilic poly(oxyethylene) blocks and hydrophobic poly(oxypropylene) blocks for forming a triblock of poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) (e.g., Pluronic®); polyether ester copolymers such as polyethylene glycol terephthalate / polybutylene terephthalate copolymer; sucrose acetate isobutyrate (SAIB); dextran or its derivatives; a combination of dextran and PEG; polydimethylsiloxane; collagen; chitosan; vinyl alcohol (PVA) and derivatives; polyalkylimide; poly(acrylamide-co-diallyldimethylammonium (DADMA)); polyvinylpyrrolidone (PVP); glycosaminoglycans (GAG) such as dermatan sulfate, chondroitin sulfate, keratan sulfate, heparin, heparan sulfate, hyaluronan; ABA triblock or AB block copolymers composed of a hydrophobic A block such as polylactide (PLA) or poly(lactide-co-glycolide) (PLGA) and a hydrophilic B block such as polyethylene glycol (PEG) or polyvinylpyrrolidone.Such block copolymers and the above-mentioned poloxamers can exhibit inverse thermogelation behavior (flowing at room temperature to facilitate administration and gelling at a temperature higher than the sol-gel transition temperature at body temperature after injection);

[0693] (viii) Spreading or diffusing agents: Regulate the permeability of connective tissue by hydrolyzing components of the extracellular matrix in the interstitial cavity (e.g., hyaluronic acid, a polysaccharide found in the intercellular spaces of connective tissue, although not limited thereto). Spreading agents, such as, but not limited to, hyaluronidase, reduce the viscosity of the extracellular matrix and promote the diffusion of the injected drug; and

[0694] (ix) Other adjuvants: Wetting agents, viscosity modifiers, antibiotics, hyaluronidase, etc. Acids and bases such as hyaluronic acid and sodium hydroxide are adjuvants necessary for pH adjustment during production.

[0695] Another aspect of the present invention is the use of the sustained-release CNP agonist of the present invention or a pharmaceutical composition containing at least one sustained-release CNP agonist as a medicine.

[0696] Preferably, the medicament is used for the treatment of diseases selected from the group consisting of achondroplasia (achondrogenesis), hypochondroplasia (chondrodysplasia), short stature, dwarfism, osteochondrodysplasia (chondro-osseous dysplasia), lethal dysplasia (thanatophoric dysplasia), osteogenesis imperfecta, achondrogenesis, stippled chondrodysplasia, homozygous achondroplasia, bent limb dysplasia, congenital lethal hypophosphatasia, perinatal lethal osteogenesis imperfecta, short rib polydactyly syndrome, proximal stippled chondrodysplasia (proximal limb shortening type stippled chondrodysplasia), Jansen type metaphyseal dysplasia, congenital spinal and epiphyseal dysplasia, osteogenesis imperfecta, torsional osteodysplasia, congenital femoral shortening, Langer type intermediate limb dysplasia, Nievergelt type intermediate limb dysplasia, Robinow syndrome, Reinhardt syndrome, acro-osteogenesis imperfecta, peripheral osteogenesis imperfecta, Kniest osteochondrodysplasia, fibrochondrogenesis, Roberts syndrome, distal intermediate limb dysplasia, micromelia, Morquio syndrome, Kniest syndrome, dysplastic osteodysplasia, spinal epiphyseal metaphyseal dysplasia, neurofibromatosis, Legius syndrome, Leopard syndrome, Noonan syndrome, hereditary gingival fibromatosis, neurofibromatosis type 1, Legius syndrome, heart-face-skin syndrome, Costello syndrome, SHOX deficiency, idiopathic short stature, growth hormone deficiency, osteoarthritis, cleidocranial dysplasia, craniosynostosis (e.g., Muenke syndrome, Crouzon syndrome, Apert syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome, or Crouzonodermoskeletal syndrome), dactyly, brachydactyly, camptodactyly, polydactyly, syndactyly, segmental dysplasia dysplasia, enchondroma, fibrous osteodysplasia, hereditary multiple exostoses, hypophosphatemic rickets, Jaffe-Lichtenstein syndrome, Marfan syndrome, McCune-Albright syndrome, osteopetrosis and osteopathia striata.

[0697] In another embodiment, the medicament is used for the treatment of ophthalmic diseases, such as glaucoma and / or ocular hypertension.

[0698] In another embodiment, the medicament is used for the treatment of cancers associated with the overactivation of FGFR3, such as multiple myeloma, myeloproliferative syndrome, leukemia, plasma cell leukemia, lymphoma, glioblastoma, prostate cancer, bladder cancer or breast cancer.

[0699] In another embodiment, the medicament is used for the treatment of vascular smooth muscle disorders, preferably selected from the group consisting of hypertension, restenosis, arteriosclerosis, acute decompensated heart failure, congestive heart failure, cardiac edema, renal edema, hepatic edema, acute renal failure and chronic renal failure.

[0700] In another embodiment, the medicament is used for the treatment of hemorrhagic shock.

[0701] Preferably, the medicament is used for the treatment of the achondroplasia phenotype, selected from the group consisting of growth retardation, cranial deformation, orthodontic defects, cervical spinal cord compression, spinal stenosis, hydrocephalus, hearing loss due to chronic otitis media, cardiovascular diseases, neurological diseases and obesity.

[0702] Most preferably, the medicament is used for the treatment of achondroplasia.

[0703] Another aspect of the present invention is a pharmaceutical composition comprising the sustained-release CNP agonist of the present invention or at least one sustained-release CNP agonist for use in a method of treating a disease that can be treated with a CNP agonist.

[0704] Preferably, the disease is selected from the group consisting of achondroplasia, hypochondroplasia, short stature, dwarfism, osteochondrodysplasia, lethal dysplasia, osteogenesis imperfecta, achondrogenesis, stippled chondrodysplasia, homozygous achondroplasia, campomelic dysplasia, congenital lethal hypophosphatasia, perinatal lethal osteogenesis imperfecta, short rib polydactyly syndrome, rhizomelic chondrodysplasia punctata, Jansen metaphyseal dysplasia, congenital spondyloepiphyseal dysplasia, osteogenesis imperfecta, torsional dysplasia of bone, congenital femoral shortening, Langer mesomelic dysplasia, Nievergelt mesomelic dysplasia, Robinow syndrome, Reinhardt syndrome, acroosteolysis, peripheral osteolysis, Kneist dysplasia, fibrochondrogenesis, Roberts syndrome, distal mesomelic dysplasia, micromelia, Morquio syndrome, Kneist syndrome, dysplastic dysplasia of bone, spondyloepiphyseal metaphyseal dysplasia, neurofibromatosis, Legius syndrome, Leopard syndrome, Noonan syndrome, hereditary gingival fibromatosis, neurofibromatosis type 1, Legius syndrome, cardiofaciocutaneous syndrome, Costello syndrome, SHOX deficiency, idiopathic short stature, growth hormone deficiency, osteoarthritis, cleidocranial dysplasia, craniosynostosis (e.g., Muenke syndrome, Crouzon syndrome, Apert syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome, or Crouzonodermoskeletal syndrome), polydactyly (finger abnormalities), brachydactyly, camptodactyly, polydactyly, syndactyly, arthrochalasia dysplasia, enchondroma, fibrous dysplasia of bone, hereditary multiple exostoses, hypophosphatemic rickets, Yaffe-Lichtenstein syndrome, Marfan syndrome, McCune-Albright syndrome, osteopetrosis and osteopathia striata.

[0705] In another embodiment, the disease is an ophthalmic disease, such as glaucoma and / or ocular hypertension.

[0706] In another embodiment, the disease is cancer, such as FGFR3 overactivation in multiple myeloma, myeloproliferative syndrome, leukemia, plasma cell leukemia, lymphoma, glioblastoma, prostate cancer, bladder cancer or breast cancer.

[0707] In another embodiment, the disease is a vascular smooth muscle disorder preferably selected from the group consisting of hypertension, restenosis, arteriosclerosis, acute decompensated heart failure, congestive heart failure, cardiac edema, renal edema, hepatic edema, acute renal failure, and chronic renal failure.

[0708] In another embodiment, the disease is hemorrhagic shock.

[0709] In another embodiment, the disease is a achondroplasia phenotype selected from the group consisting of growth retardation, cranial deformation, orthodontic defect, cervical spinal cord compression, spinal stenosis, hydrocephalus, hearing loss due to chronic otitis media, cardiovascular disease, neurological disease, and obesity.

[0710] Most preferably, the disease is achondroplasia.

[0711] In one embodiment, the patient undergoing the treatment method of the present invention is a mammalian patient, preferably a human patient. In one embodiment, this human patient is an adult. In a preferred embodiment, the human patient is a pediatric patient.

[0712] Another aspect of the present invention is the use of a sustained-release CNP agonist of the present invention or a pharmaceutical composition comprising at least one sustained-release CNP agonist for the manufacture of a medicament for treating a disease that can be treated with CNP.

[0713] Preferably, the disease is selected from the group consisting of achondrogenesis, hypochondrogenesis, short stature, dwarfism, osteochondrodysplasia, lethal dysplasia, osteogenesis imperfecta, achondrogenesis, stippled chondrodysplasia, homozygous achondroplasia, campomelic dysplasia, congenital lethal hypophosphatasia, perinatal lethal osteogenesis imperfecta, short rib polydactyly syndrome, rhizomelic stippled chondrodysplasia, Jansen metaphyseal dysplasia, congenital spondyloepiphyseal dysplasia, osteogenesis imperfecta, torsional osteodysplasia, congenital femoral shortening, Langer mesomelic dysplasia, Nievergelt mesomelic dysplasia, Robinow syndrome, Reinhardt syndrome, acroosteolysis, distal osteolysis, Kneist osteochondrodysplasia, fibrochondrogenesis, Roberts syndrome, distal mesomelic dysplasia, micromelia, Morquio syndrome, Kneist syndrome, dysplastic osteodysplasia, spondyloepiphyseal metaphyseal dysplasia, neurofibromatosis, Legius syndrome, Leopard syndrome, Noonan syndrome, hereditary gingival fibromatosis, neurofibromatosis type 1, Legius syndrome, cardiofaciocutaneous syndrome, Costello syndrome, SHOX deficiency, idiopathic short stature, growth hormone deficiency, osteoarthritis, cleidocranial dysplasia, craniosynostosis (e.g., Muenke syndrome, Crouzon syndrome, Apert syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome, or Crouzonodermoskeletal syndrome), syndactyly, brachydactyly, camptodactyly, polydactyly, syndactyly, segmental dysplasia, enchondroma, fibrous dysplasia, hereditary multiple exostoses, hypophosphatemic rickets, Jaffe-Lichtenstein syndrome, Marfan syndrome, McCune-Albright syndrome, osteopetrosis, and osteopathia striata.

[0714] In another embodiment, the disease is an ophthalmic disease, such as glaucoma and / or ocular hypertension.

[0715] In another embodiment, the disease is cancer, such as FGFR3 overactivation associated with multiple myeloma, myeloproliferative syndrome, leukemia, plasma cell leukemia, lymphoma, glioblastoma, prostate cancer, bladder cancer, or breast cancer.

[0716] In another embodiment, the disease is a vascular smooth muscle disorder preferably selected from the group consisting of hypertension, restenosis, arteriosclerosis, acute decompensated heart failure, congestive heart failure, cardiac edema, renal edema, hepatic edema, acute renal failure and chronic renal failure.

[0717] In another embodiment, the disease is hemorrhagic shock.

[0718] In another embodiment, the disease is a achondroplasia phenotype selected from the group consisting of growth retardation, cranial deformation, orthodontic defect, cervical spinal cord compression, spinal stenosis, hydrocephalus, hearing loss due to chronic otitis media, cardiovascular disease, neurological disease and obesity.

[0719] Most preferably, the disease is achondroplasia.

[0720] In one embodiment, the disease to be treated with the sustained-release CNP agonist or a pharmaceutical composition comprising at least one sustained-release CNP agonist of the present invention occurs in a mammalian patient, preferably in a human patient. In one embodiment, the human patient is an adult. In a preferred embodiment, the human patient is a pediatric patient.

[0721] A further aspect of the present invention is a method of treating, managing, delaying or preventing in a mammalian patient, preferably a human patient, in need of treatment of one or more diseases that can be treated with a CNP agonist, comprising administering to the patient in need thereof a therapeutically effective amount of a sustained-release CNP agonist or a pharmaceutical composition comprising at least one sustained-release CNP agonist of the present invention. In one embodiment, the human patient is an adult. In a preferred embodiment, the human patient is a pediatric patient.

[0722] Preferably, one or more diseases that can be treated with the CNP are selected from the group consisting of achondrogenesis, hypochondrogenesis, short stature, dwarfism, osteochondrodysplasia, lethal dysplasia, osteogenesis imperfecta, achondrogenesis, stippled chondrodysplasia, homozygous achondroplasia, campomelic dysplasia, congenital lethal hypophosphatasia, perinatal lethal osteogenesis imperfecta, short rib polydactyly syndrome, rhizomelic chondrodysplasia punctata, Jansen metaphyseal chondrodysplasia, congenital spondyloepiphyseal dysplasia, osteogenesis imperfecta, torsional dysplasia, congenital femoral shortening, Langer mesomelic dysplasia, Nievergelt mesomelic dysplasia, Robinow syndrome, Reinhardt syndrome, acroosteolysis, distal osteolysis, Kneist dysplasia, fibrochondrogenesis, Roberts syndrome, distal mesomelic dysplasia, micromelia, Morquio syndrome, Kneist syndrome, dysplastic dysplasia, spondyloepiphyseal metaphyseal dysplasia, neurofibromatosis, Legius syndrome, Leopard syndrome, Noonan syndrome, hereditary gingival fibromatosis, neurofibromatosis type 1, Legius syndrome, cardiofaciocutaneous syndrome, Costello syndrome, SHOX deficiency, idiopathic short stature, growth hormone deficiency, osteoarthritis, cleidocranial dysplasia, craniosynostosis (e.g., Muenke syndrome, Crouzon syndrome, Apert syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome, or Crouzonodermoskeletal syndrome), syndactyly, brachydactyly, camptodactyly, polydactyly, syndactyly, segmental dysplasia, enchondroma, fibrous dysplasia, hereditary multiple exostoses, hypophosphatemic rickets, Jaffe-Lichtenstein syndrome, Marfan syndrome, McCune-Albright syndrome, osteopetrosis, and osteopathia striata.

[0723] In another embodiment, one or more diseases that can be treated with the CNP are ophthalmic diseases, such as glaucoma and / or ocular hypertension.

[0724] In another embodiment, one or more diseases that can be treated with the CNP are cancers, such as those associated with overactivation of FGFR3 in multiple myeloma, myeloproliferative syndromes, leukemia, plasma cell leukemia, lymphoma, glioblastoma, prostate cancer, bladder cancer, or breast cancer.

[0725] In another embodiment, one or more diseases that can be treated with said CNP are vascular smooth muscle disorders preferably selected from the group consisting of hypertension, restenosis, arteriosclerosis, acute decompensated heart failure, congestive heart failure, cardiac edema, renal edema, hepatic edema, acute renal failure and chronic renal failure.

[0726] In another embodiment, one or more diseases that can be treated with said CNP is hemorrhagic shock.

[0727] In another embodiment, one or more diseases that can be treated with CNP are achondroplasia phenotypes selected from the group consisting of growth retardation, craniofacial deformities, orthodontic defects, cervical spinal cord compression, spinal stenosis, hydrocephalus, hearing loss due to chronic otitis media, cardiovascular diseases, neurological diseases and obesity.

[0728] Most preferably, one or more diseases that can be treated with CNP is achondroplasia.

[0729] A further aspect of the present invention is a method of administering a pharmaceutical composition comprising the sustained release CNP agonist of the present invention or at least one sustained release CNP agonist, by topical, enteral or parenteral administration, and by intra-articular, peri-articular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardiac, transtracheal, subepidermal, subcapsular, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion, direct delivery to the brain by an implantable device (e.g., an Ommaya Reservoir) that enables delivery of the present invention to brain tissue or cerebrospinal fluid, direct intraventricular injection or infusion, injection or infusion into the brain or brain-related regions, injection into the subchoroidal space, retrobulbar injection and eye drops, including topical, injection or infusion methods, preferably by subcutaneous injection, comprising the step of administering a pharmaceutical composition comprising the sustained release CNP agonist of the present invention or at least one sustained release CNP agonist.

[0730] In a preferred embodiment, the present invention relates to a pharmaceutical composition for use in the treatment of achondroplasia by subcutaneous injection, comprising a sustained-release CNP agonist of the present invention or a pharmaceutical composition comprising at least one sustained-release CNP agonist.

[0731] In a further aspect, the present invention relates to a pharmaceutical composition comprising at least one sustained-release CNP agonist of the present invention or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises at least one further bioactive moiety or agent.

[0732] The at least one further bioactive moiety or agent can be in its free form (i.e., in the form of a free drug), in the form of a stable conjugate, or in the form of a sustained-release compound.

[0733] In one embodiment, the at least one further bioactive moiety or agent is a drug in its free form, i.e., the pharmaceutical composition of the present invention comprises at least one sustained-release CNP agonist and at least one further agent.

[0734] Preferably, the at least one further agent is selected from the group consisting of antihistamines; human anti-FGFR3 antibodies; soluble human fibroblast growth factor receptor 3; tyrosine kinase inhibitors; statins; CNP agonists; growth hormone; IGF-1; ANP; BNP; inhibitors of peptidases and proteases; and inhibitors of NPR-C.

[0735] A preferred antihistamine is meclizine.

[0736] A preferred tyrosine kinase inhibitor is NVP-BGJ398.

[0737] A preferred statin is rosuvastatin.

[0738] A preferred CNP agonist for the at least one further agent is vosoritide.

[0739] Preferred inhibitors of peptidases and proteases are NEP and furin inhibitors.

[0740] Preferred inhibitors for NEP are thiolphan and candoxatril.

[0741] Preferred inhibitors of NPR-C are the fragment of SEQ ID NO: 98 (FGIPMDRIGRNPR) and antibody B701.

[0742] Preferred inhibitors of tyrosine kinase are as disclosed in U.S. Patent Nos. 6,329,375 and 6,344,459 (incorporated herein by reference).

[0743] In one embodiment, the at least one additional agent is an antihistamine.

[0744] In another embodiment, the at least one additional agent is a human anti-FGFR3 antibody.

[0745] In another embodiment, the at least one additional agent is a soluble form of human fibroblast growth factor receptor 3 (sFGFR3).

[0746] In another embodiment, the at least one additional agent is a tyrosine kinase inhibitor.

[0747] In another embodiment, the at least one additional agent is a statin.

[0748] In another embodiment, the at least one additional agent is a growth hormone.

[0749] In another embodiment, the at least one additional agent is a CNP agonist.

[0750] In another embodiment, the at least one additional agent is IGF-1.

[0751] In another embodiment, the at least one additional agent is ANP.

[0752] In another embodiment, the at least one additional agent is BNP.

[0753] In another embodiment, the at least one additional agent is an inhibitor of peptidases and proteases.

[0754] In another embodiment, the at least one additional agent is an inhibitor of NPR-C.

[0755] In another embodiment, the at least one additional bioactive moiety or agent is in the form of a stable conjugate.

[0756] In one embodiment, the at least one additional bioactive moiety in the form of a stable conjugate comprises at least one bioactive moiety covalently bound, directly or via a spacer moiety, via a stable linkage to a polymer moiety, preferably a water-soluble polymer moiety.

[0757] Preferably, such a polymer moiety, more preferably a water-soluble polymer moiety, is selected from the group consisting of 2-methacryloyloxyethyl phosphorylcholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amideamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxy methacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organic phosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinyl methyl ethers), poly(vinyl pyrrolidones), silicones, celluloses, carboxymethyl celluloses, hydroxypropyl methyl celluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon-based polymers, xylans, and copolymers thereof.

[0758] In another embodiment, said at least one further bioactive moiety in the form of a stable conjugate is covalently bound to the albumin-binding moiety via a stable linker. Preferably, said albumin-binding moiety is a C 8-24 alkyl moiety or a fatty acid derivative. Preferred fatty acid derivatives are those disclosed in WO2005 / 027978A2 and WO2014 / 060512A1 (incorporated herein by reference).

[0759] Preferably, said at least one further bioactive moiety in the form of a stable conjugate comprises a bioactive moiety selected from the group consisting of an antihistamine; a human anti-FGFR3 antibody; soluble human fibroblast growth factor receptor 3 (sFGFR3); a tyrosine kinase inhibitor; statins; a CNP agonist; growth hormone; IGF-1; ANP; BNP; inhibitors of peptidases and proteases; and an inhibitor of NPR-C.

[0760] A preferred antihistamine is meclozine.

[0761] A preferred tyrosine kinase inhibitor is NVP-BGJ398.

[0762] A preferred statin is rosuvastatin.

[0763] A preferred CNP agonist for said at least one further bioactive moiety is vosoritide.

[0764] Preferred inhibitors of peptidases and proteases are NEP and furin inhibitors.

[0765] Preferred inhibitors for NEP are thiorphan and candoxatril.

[0766] Preferred inhibitors of NPR-C are the fragment of SEQ ID NO: 98 (FGIPMDRIGRNPR) and antibody B701.

[0767] Preferred inhibitors of tyrosine kinase are disclosed in U.S. Patent Nos. 6,329,375 and 6,344,459, which are incorporated herein by reference.

[0768] In one embodiment, the at least one additional bioactive moiety in the form of a stable conjugate comprises an antihistamine moiety.

[0769] In another embodiment, the at least one additional bioactive moiety in the form of a stable conjugate comprises a human anti-FGFR3 antibody moiety.

[0770] In another embodiment, the at least one additional bioactive moiety in the form of a stable conjugate comprises a soluble form of human fibroblast growth factor receptor 3 (sFGFR3) moiety.

[0771] In another embodiment, the at least one additional bioactive moiety in the form of a stable conjugate comprises a tyrosine kinase inhibitor moiety.

[0772] In another embodiment, the at least one additional bioactive moiety in the form of a stable conjugate comprises a statin moiety.

[0773] In another embodiment, the at least one additional bioactive moiety in the form of a stable conjugate comprises a growth hormone moiety.

[0774] In another embodiment, the at least one additional bioactive moiety in the form of a stable conjugate comprises a CNP agonist moiety.

[0775] In another embodiment, the at least one additional bioactive moiety in the form of a stable conjugate comprises an IGF-1 moiety.

[0776] In another embodiment, the at least one additional bioactive moiety in the form of a stable conjugate comprises an ANP moiety.

[0777] In another embodiment, the at least one additional bioactive moiety in the form of a stable conjugate comprises a BNP moiety.

[0778] In another embodiment, the at least one additional bioactive moiety in the form of a stable conjugate comprises inhibitors of peptidases and proteases moieties.

[0779] In another embodiment, the at least one additional bioactive moiety in the form of a stable conjugate comprises an inhibitor of the NPR-C moiety.

[0780] In another embodiment, the at least one additional bioactive moiety or agent is in the form of a sustained release compound.

[0781] Preferably, the at least one additional bioactive moiety or agent in the form of a sustained release compound comprises at least one bioactive moiety or agent selected from the group consisting of: antihistamines; human anti-FGFR3 antibodies; soluble human fibroblast growth factor receptor 3; statins; CNP agonists; growth hormone; IGF-1; ANP; BNP; inhibitors of peptidases and proteases; inhibitors of tyrosine kinases; and inhibitors of NPR-C.

[0782] A preferred antihistamine is meclozine.

[0783] A preferred tyrosine kinase inhibitor is NVP-BGJ398.

[0784] A preferred statin is rosuvastatin.

[0785] A preferred CNP agonist for the at least one additional agent is vosoritide.

[0786] Preferred inhibitors of peptidases and proteases are NEP and furin inhibitors.

[0787] Preferred inhibitors of NEP are thiolphan and candoxatril.

[0788] Preferred inhibitors of NPR-C are the fragment of SEQ ID NO: 98 (FGIPMDRIGRNPR) and antibody B701.

[0789] Preferred inhibitors of tyrosine kinases are those disclosed in U.S. Patent Nos. 6329375 and 6344459 (incorporated herein by reference).

[0790] In one embodiment, the at least one further bioactive moiety or agent in sustained release form comprises an antihistamine moiety or agent.

[0791] In another embodiment, the at least one further bioactive moiety or agent in sustained release form comprises a human anti-FGFR3 antibody moiety or agent.

[0792] In another embodiment, the at least one further bioactive moiety or agent in sustained release form comprises a soluble form of human fibroblast growth factor receptor 3 (sFGFR3) moiety or agent.

[0793] In another embodiment, the at least one further bioactive moiety or agent in sustained release form comprises a tyrosine kinase inhibitor moiety or agent.

[0794] In another embodiment, the at least one further bioactive moiety or agent in sustained release form comprises a statin moiety or agent.

[0795] In another embodiment, the at least one further bioactive moiety or agent in sustained release form comprises a growth hormone moiety or agent.

[0796] In another embodiment, the at least one further bioactive moiety or agent in sustained release form comprises a CNP agonist moiety or agent.

[0797] In another embodiment, the at least one additional bioactive moiety or agent in sustained release form comprises an IGF-1 moiety or agent.

[0798] In another embodiment, the at least one additional bioactive moiety or agent in sustained release form comprises an ANP moiety or agent.

[0799] In another embodiment, the at least one additional bioactive moiety or agent in sustained release form comprises a BNP moiety or agent.

[0800] In another embodiment, the at least one additional bioactive moiety or agent in sustained release form comprises inhibitors of peptidases and proteases moieties or agents.

[0801] In another embodiment, the at least one additional bioactive moiety or agent in sustained release form comprises an NPR-C moiety or inhibitor of an agent.

[0802] In one embodiment, the at least one additional bioactive moiety or agent in the form of a sustained release compound is water-insoluble.

[0803] Preferably, such water-insoluble sustained release compounds are selected from the group consisting of crystals, nanoparticles, microparticles, nanospheres and microspheres.

[0804] In one embodiment, the at least one additional bioactive moiety or agent in the form of a water-insoluble sustained release compound is a crystal comprising at least one agent or bioactive moiety.

[0805] In another embodiment, the at least one additional bioactive moiety or agent in the form of a water-insoluble sustained release compound is a nanoparticle comprising at least one agent or bioactive moiety.

[0806] In another embodiment, said at least one further bioactive moiety or agent in the form of a water-insoluble sustained release compound is microparticles comprising at least one agent or bioactive moiety.

[0807] In another embodiment, said at least one further bioactive moiety or agent in the form of a water-insoluble sustained release compound is nanospheres comprising at least one agent or bioactive moiety.

[0808] In another embodiment, said at least one further bioactive moiety or agent in the form of a water-insoluble sustained release compound is microspheres comprising at least one agent or bioactive moiety.

[0809] In one embodiment, said at least one further bioactive moiety or agent in the form of a water-insoluble sustained release compound is a medium comprising at least one agent or bioactive moiety. Preferably, such a medium comprising at least one agent or bioactive moiety is micelles, liposomes or polymersomes.

[0810] In one embodiment, said at least one further bioactive moiety or agent in the form of a water-insoluble sustained release compound is micelles comprising at least one agent or bioactive moiety.

[0811] In another embodiment, said at least one further bioactive moiety or agent in the form of a water-insoluble sustained release compound is liposomes comprising at least one agent or bioactive moiety. Preferably, such liposomes are selected from the group consisting of aquasomes; nonionic surfactant media such as niosomes and proniosomes; cationic liposomes such as LeciPlex; transfersomes; ethosomes; ufasomes; sphingosomes; and pharmacosomes.

[0812] In another embodiment, said at least one further bioactive moiety or agent in the form of a water-insoluble sustained-release compound is a polymersome comprising at least one agent or bioactive moiety.

[0813] In another embodiment, said at least one further bioactive moiety or agent in the form of a water-insoluble sustained release compound comprises at least one bioactive moiety or agent non-covalently embedded in a water-insoluble polymer. Preferably, such water-insoluble polymers include polymers selected from the group consisting of 2-methacryloyl-oxyethyl phosphorylcholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amide amines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxy methacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organic phosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinyl methyl ethers), poly(vinyl pyrrolidones), silicones, celluloses, carboxymethyl celluloses, hydroxypropyl methyl celluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon-based polymers, xylans, and copolymers thereof.

[0814] In a preferred embodiment, said at least one further bioactive moiety or agent in the form of a water-insoluble sustained-release compound comprises at least one agent or bioactive moiety non-covalently embedded in poly(lactic-co-glycolic acid) (PLGA).

[0815] In another embodiment, said at least one further bioactive moiety or agent in the form of a water-insoluble sustained release compound comprises at least one bioactive moiety covalently and reversibly bound to an insoluble polymer. Preferably, such water-insoluble polymers include polymers selected from the group consisting of 2-methacryloyl-oxyethyl phosphorylcholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amideamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxy methacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organic phosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinyl methyl ethers), poly(vinyl pyrrolidones), silicones, celluloses, carboxymethyl celluloses, hydroxypropyl methyl celluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon-based polymers, xylans, and copolymers thereof.

[0816] Preferably, said at least one additional bioactive moiety or agent in the form of a water-insoluble sustained-release compound comprises at least one bioactive moiety or agent selected from the group consisting of: an antihistamine; a human anti-FGFR3 antibody; a soluble form of human fibroblast growth factor receptor 3; a tyrosine kinase inhibitor; statins; a CNP agonist; growth hormone; IGF-1; ANP; BNP; an inhibitor of peptidases and proteases; and an inhibitor of NPR-C.

[0817] A preferred antihistamine is meclozine.

[0818] A preferred tyrosine kinase inhibitor is NVP-BGJ398.

[0819] A preferred statin is rosuvastatin.

[0820] A preferred CNP agonist for said at least one additional agent is vosoritide.

[0821] Preferred inhibitors of peptidases and proteases are NEP and furin inhibitors.

[0822] Preferred inhibitors for NEP are thiorphan and candoxatril.

[0823] Preferred inhibitors of NPR-C are t...

Claims

1. A method for synthesizing a compound represented by the following formula 11i, 【Chemical 1】 wherein the method includes a step of reacting a compound represented by the following formula 11h with a solution containing PEG 2x10 kDa maleimide, [Chemical Formula 2] where [Chemical Formula 3] is CNP-38 represented by SEQ ID NO: 24, and the dashed line indicates a bond to the remainder of the compound represented by formula 11i, method.

2. The method according to claim 1, wherein the solution further contains water and 0.1% TFA (v / v).

3. The method according to claim 1 or 2, wherein the method further includes adding 0.5 M lactate buffer.

4. The method according to claim 3, wherein the pH of the buffer is 4.

5. The method according to claim 3 or 4, further including stirring the mixture at room temperature for 4 hours after adding the buffer.

6. The method according to any one of claims 1 to 5, wherein the compound represented by formula 11i is purified by RP-HPLC.

7. A compound represented by the following formula 11h, 【Chemical Formula 4】 where 【Chemical Formula 5】 is CNP-38 represented by SEQ ID NO: 24, and the dashed line indicates a bond to the remainder of the compound represented by formula 11h, compound.

8. A method for synthesizing a compound represented by the following formula 11h, 【Chemical Formula 6】 wherein the method includes a step of reacting a compound represented by the following formula 11g with a solution containing TFA, MSA, DTT, water and thioanisole in a ratio of 100 / 5 / 3 / 2 / 1 (v / v / w / v / v), [Chemical Formula 7] where -Dmb is 2,4-dimethoxybenzyl, 【Chemical Formula 8】 is CNP-38 represented by SEQ ID NO: 24, and the dashed line indicates a bond to the remainder of the compound represented by formula 11h or 11g, method.

9. The method according to claim 8, further including cooling the solution containing TFA, MSA, DTT, water and thioanisole before adding the compound represented by formula 11g.

10. The method according to claim 8 or 9, further including isolating the compound represented by formula 11h by precipitation in pre-cooled ether.

11. The method according to any one of claims 8 to 10, wherein the compound represented by formula 11h is purified by RP-HPLC.

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