Dosing regimen for controlled release PTH compounds

Abstract

To provide a more convenient and safer treatment of hypoparathyroidism with reduced side-effects.SOLUTION: The present invention provides a pharmaceutical composition comprising at least one controlled-release PTH compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment, control, delay or prevention of a condition that can be treated, controlled, delayed or prevented with PTH. The pharmaceutical composition is administered once every 24 hours or less frequently at a dosage of the controlled-release PTH compound that corresponds to 70% or less of the molar equivalent dose of PTH 1-84 administered every 24 hours required to maintain serum calcium within normal levels over the 24-hour period in humans.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to pharmaceutical compositions comprising at least one controlled release PTH compound or a pharma- ceutical acceptable salt, hydrate or solvate thereof for use in the treatment, management, delay or prevention of conditions that can be treated, managed, delayed or prevented with PTH, the compositions being administered no more than once every 24 hours at a dosage of said controlled release PTH compound that corresponds to no more than 70% of the molar equivalent dose required to maintain serum calcium within normal levels in humans over said 24 hour period for PTH 1-84 administered every 24 hours, and to methods of treating, managing, delaying or preventing said conditions. [Background technology]

[0002] Hypoparathyroidism is a rare endocrine disorder of calcium and phosphate metabolism that occurs most often as a result of parathyroid gland injury or removal during thyroid surgery. Hypoparathyroidism is unusual among endocrine disorders and, until recently, was not treated by replacement of the defective hormone, parathyroid hormone, or PTH. Conventional treatments for hypoparathyroidism include large doses of vitamin D and oral calcium supplementation, which are often effective but can increase blood Ca levels, resulting in hypercalcemia and hypocalcemia. 2+ These are accompanied by marked urinary calcium excretion, excessive urinary calcium excretion, nephrocalcinosis, and ectopic calcifications involving blood vessels, the basal ganglia, and the lens of the eye.

[0003] Calcium is the most abundant mineral in the human body, and its tight regulation is required for many biological functions, such as bone mineralization, muscle contraction, nerve conduction, hormone release, and blood clotting. It is particularly important to keep calcium concentrations as stable as possible because various cell systems or organs, including the central nervous system, muscles, and exocrine / endocrine glands, require calcium. 2+ PTH is the master regulator of calcium homeostasis.

[0004] Serum Ca 2+Inappropriately low PTH levels in relation to Ca concentration are a hallmark of hypoparathyroidism. 2+ This leads to a decrease in renal tubular reabsorption of calcium and, concomitantly, an increase in renal tubular reabsorption of phosphate. Therefore, the major biochemical abnormalities of hypoparathyroidism are hypocalcemia and hyperphosphatemia. Clinical features of the disease include symptoms of hypocalcemia, such as perioral numbness, paresthesia, and carpal / pedal muscle spasms. Pharyngeal spasms, tetany, and seizures are serious, potentially life-threatening, complications. Hyperphosphatemia and increased calcium × phosphate products contribute to ectopic deposition of insoluble calcium phosphate complexes in soft tissues, including the vasculature, brain, kidneys, and other organs.

[0005] The standard treatment for hypoparathyroidism is oral calcium and vitamin D supplementation. The goals of treatment are a) to ameliorate the symptoms of hypocalcemia, b) to maintain fasting serum calcium at or slightly below the lower normal range, c) to maintain fasting serum phosphorus at or slightly elevated above the upper normal range, d) to avoid or minimize hypercalciuria, e) to maintain calcium-phosphate products at levels well below the upper normal limit, and f) to avoid ectopic calcification of the kidney (stones and nephrocalcinosis) and other soft tissues.

[0006] Some concerns arise about the long-term use of large doses of calcium and active vitamin D, especially with regard to hypercalciuria, kidney stones, nephrocalcinosis, and ectopic soft tissue calcification. In addition, conventional treatment with calcium and active vitamin D does not alleviate quality of life complaints or reverse the bone remodeling abnormalities characteristic of this disease. In short, improved hypoparathyroidism therapies are greatly needed.

[0007] In 2015, Natpara, PTH(1-84) was approved for the management of hypocalcemia as a once-daily subcutaneous injection as a vitamin D and calcium supplement in patients with hypoparathyroidism. Natpara, PTH(1-84) was approved for the management of hypocalcemia based on a pivotal trial that demonstrated that 42 percent of study participants treated with PTH(1-84) achieved normal blood calcium levels with calcium supplements and reduced doses of active forms of vitamin D, compared with 3 percent of study participants treated with placebo. Time-course follow-up monitoring serum calcium after injection showed that 71 percent of patients treated with PTH(1-84) developed hypercalcemia at one or more measurements during the 24-hour period. PTH(1-84) reduced urinary calcium excretion 2 to 8 hours after injection, but urinary calcium excretion was unchanged beyond 24 hours. Similarly, urinary phosphate excretion was only increased during the first 8 hours after PTH(1-84) injection.

[0008] Although this could be an important advantage in the treatment of this disease, Natpara has not demonstrated the ability to reduce the incidence of hypercalcemia (elevated serum calcium levels), hypocalcemia (low serum calcium) or hypercalciuria (increased urinary calcium) in treated patients compared to conventional therapies.

[0009] Therefore, there is a great need for improved PTH-based therapies for hypoparathyroidism.

[0010] PTH(1-34), or teriparatide, was approved by the FDA in 2002 for the treatment of osteoporosis. PTH(1-34) has been used historically for the treatment of hypoparathyroidism, even though it is not approved for this indication, with patients receiving two or three injections per day. Clinical studies are being conducted with PTH(1-34) administered by pump delivery compared to twice-daily injections to promote more physiological PTH levels. Over a six-month period, pump delivery produced normal steady-state calcium levels with minimal fluctuations, avoiding the elevation of serum and urinary calcium levels that appears immediately after PTH injection. The significant reduction in urinary calcium excretion when PTH(1-34) was administered by pump may indicate that PTH must be continuously exposed to the renal tubules to achieve its renal calcium-sparing effect. Pump delivery of PTH(1-34) achieved simultaneous normalization of bone turnover markers, serum calcium markers, and urinary calcium excretion markers. These results were achieved with a 65 percent lower daily dose of PTH(1-34) and reduced the need for magnesium supplementation compared to a twice-daily PTH(1-34) injection regimen.

[0011] However, continuous pump therapy can be inconvenient and difficult for patients, and it is an object of the present invention to provide a more convenient treatment option that provides continuous exposure to PTH.

[0012] Long-term daily administration of PTH is associated with progressive cortical bone loss due to increased bone metabolism. In a 6-year follow-up study of patients treated with PTH(1-84) (Rubin, JCEM 2016), bone turnover markers remained greater than pretreatment values, peaked in the early years after initiation of PTH(1-84), and then declined but remained significantly higher than baseline values ​​through the 6th year. Bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) was consistent with known site-specific effects of PTH, i.e., increases at the lumbar spine and decreases at the distal third of the radius. The decreases observed at the distal third are consistent with the effects of intermittent PTH, which is known to increase cortical porosity and endosteal resorption. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Rubin, JCEM 2016 Summary of the Invention [Problem to be solved by the invention]

[0014] It is an object of the present invention to provide a method of administering PTH intermittently which provides better control of serum and urinary calcium and serum phosphorus and less increase in bone turnover markers than currently utilized PTH therapies.Preferably, intermittent means on a daily basis or, more preferably, at weekly intervals.

[0015] In both preclinical development programs, Forteo, PTH(1-34), and Natpara, PTH(1-84), a dose-dependent increase in osteosarcoma incidence was observed in rats treated with daily injections of the PTH compound. In the Natpara study, administration of high dose rats was discontinued due to excess mortality in this group, mainly from metastatic osteosarcoma. This is likely due to the sensitivity of rats to the anabolic effects of intermittent PTH. In contrast, continuous exposure to PTH is known to have no significant bone anabolic activity. It is itself an object of the present invention to provide an intermittent PTH replacement therapy that results in an infusion-like profile of PTH, which allows administration of lower doses and results in improved symptom control. Preferably, intermittent means daily, or more preferably or alternatively, at weekly intervals.

[0016] In summary, there is a need for more convenient and safer hypoparathyroidism treatments with reduced side effects.

[0017] SUMMARY OF THE PRESENT EMBODIMENT It is therefore an object of the present invention to at least partially overcome the above mentioned drawbacks. [Means for solving the problem]

[0018] This object is achieved by a pharmaceutical composition comprising at least one controlled release PTH compound or a pharma- ceutical acceptable salt, hydrate or solvate thereof, for use in the treatment, management, delay or prevention of a condition that can be treated, managed, delayed or prevented with PTH, administered no more frequently than once every 24 hours, at a dosage of said controlled release PTH compound that corresponds to no more than 70% of the molar equivalent dose required to maintain serum calcium within normal levels in a human over said 24 hour period for PTH 1-84 administered every 24 hours. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Surprisingly, it has been found that such controlled release PTH compounds are more potent than PTH 1-84 and therefore require a lower molar equivalent to be administered to a patient in a single dose to achieve beneficial serum calcium levels for at least 24 hours, thereby improving efficacy and reducing the risk of side effects.

[0020] PTH 1-84 is understood to be a polypeptide having the sequence of SEQ ID NO:1.

[0021] In the present invention, the following terms are used:

[0022] As used herein, the terms "no more frequently than once every 24 hours" and "at least once every 24 hours" are used interchangeably and mean that the time between two consecutive administrations is 24 hours or more, which means, for example, that there may be 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, or one week between two consecutive administrations.

[0023] The terms "within normal levels" and "within the normal range" as used herein with respect to serum calcium levels refer to calcium levels normally found in subjects of a given species, sex and age, provided as a range given by the lower normal limit and the upper normal limit. For humans, normal levels preferably correspond to serum calcium levels (albumin corrected) greater than 8.5 mg / dL. For humans, the upper normal limit is less than 10.5 mg / dL.

[0024] As used herein, the term "serum calcium greater than 8.5 mg / dL" refers to albumin-corrected calcium concentrations.

[0025] As used herein, the term "albumin corrected" with respect to calcium levels means that the measured serum calcium levels have been corrected for calcium bound to albumin according to the following formula: Albumin-corrected serum calcium (mg / dL) = measured total Ca (mg / dL) + 0.8 (4.0 - serum albumin [g / dL])

[0026] As used herein, the term "uncorrected" with respect to calcium levels means that the measured total calcium concentration (mg / dL) is not corrected for albumin binding of calcium.

[0027] The term "molar equivalent dose" refers to a dose in which a controlled release PTH compound contains the same number of PTH or PTH molecules as a particular dose of PTH 1-84 contains PTH 1-84 molecules. For example, if a controlled release PTH compound contains one PTH molecule or PTH moiety per controlled release PTH compound, a molar equivalent dose is one controlled release PTH compound for every molecule of PTH 1-84. If a controlled release PTH compound contains two PTH molecules or PTH moieties per controlled release PTH compound, a molar equivalent dose is one controlled release PTH compound for every two molecules of PTH 1-84.

[0028] As used herein, the term "controlled release PTH compound" refers to any compound, conjugate, crystal or mixture that contains at least one PTH molecule or PTH substructure, and in which at least one PTH molecule or PTH substructure is released with a release half-life of at least 12 hours.

[0029] As used herein, the terms "release half-life" and "half-life" refer to the time required for half of the total PTH or PTH moieties, respectively, contained in a controlled release PTH compound to be released from said controlled release PTH compound under physiological conditions (i.e., aqueous buffer, pH 7.4, 37° C.).

[0030] The term "PTH" as used herein refers to all PTH polypeptides, preferably from mammalian species, more preferably from human and mammalian species, more preferably from human and murine species, characterized by increasing serum calcium and renal phosphorus excretion, decreasing serum phosphorus and renal calcium excretion, as well as their variants, analogs, orthologs, homologs, and derivatives and fragments thereof. The term "PTH" also refers to all PTH-related polypeptides (PTHrP), such as the polypeptide of SEQ ID NO: 121, that bind to and activate the common PTH / PTHrP1 receptor. Preferably, the term "PTH" refers to the PTH polypeptide of SEQ ID NO: 51, as well as its variants, homologs, and derivatives that exhibit essentially the same biological activity, i.e., increasing serum calcium and renal phosphorus excretion, decreasing serum phosphorus and renal calcium excretion.

[0031] Preferably, the term "PTH" refers to the following peptide sequence: SEQ ID NO:1 (PTH 1-84) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ SEQ ID NO:2 (PTH 1-83) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS SEQ ID NO:3 (PTH 1-82) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK SEQ ID NO:4 (PTH 1-81) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA SEQ ID NO:5 (PTH 1-80) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK SEQ ID NO: 6 (PTH 1-79) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT SEQ ID NO: 7 (PTH 1-78) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL SEQ ID NO:8 (PTH 1-77) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV SEQ ID NO:9 (PTH 1-76) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN SEQ ID NO:10 (PTH 1-75) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV SEQ ID NO:11 (PTH 1-74) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD SEQ ID NO:12 (PTH 1-73) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA SEQ ID NO:13 (PTH 1-72) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK SEQ ID NO:14 (PTH 1-71) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD SEQ ID NO: 15 (PTH 1-70) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA SEQ ID NO:16 (PTH 1-69) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE SEQ ID NO:17 (PTH 1-68) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG SEQ ID NO:18 (PTH 1-67) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL SEQ ID NO:19 (PTH 1-66) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS SEQ ID NO:20 (PTH 1-65) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK SEQ ID NO:21 (PTH 1-64) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE SEQ ID NO:22 (PTH 1-63) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH SEQ ID NO:23 (PTH 1-62) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES SEQ ID NO:24 (PTH 1-61) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE SEQ ID NO:25 (PTH 1-60) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV SEQ ID NO:26 (PTH 1-59) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL SEQ ID NO:27 (PTH 1-58) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV SEQ ID NO:28 (PTH 1-57) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN SEQ ID NO:29 (PTH 1-56) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED SEQ ID NO:30 (PTH 1-55) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE SEQ ID NO:31 (PTH 1-54) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK SEQ ID NO:32 (PTH 1-53) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK SEQ ID NO:33 (PTH 1-52) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR SEQ ID NO:34 (PTH 1-51) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP SEQ ID NO: 35 (PTH 1-50) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR SEQ ID NO:36 (PTH 1-49) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ SEQ ID NO:37 (PTH 1-48) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS SEQ ID NO:38 (PTH 1-47) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG SEQ ID NO:39 (PTH 1-46) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA SEQ ID NO: 40 (PTH 1-45) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD SEQ ID NO: 41 (PTH 1-44) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR SEQ ID NO: 42 (PTH 1-43) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP SEQ ID NO: 43 (PTH 1-42) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA SEQ ID NO: 44 (PTH 1-41) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL SEQ ID NO: 45 (PTH 1-40) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP SEQ ID NO: 46 (PTH 1-39) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA SEQ ID NO: 47 (PTH 1-38) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG SEQ ID NO: 48 (PTH 1-37) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL SEQ ID NO: 49 (PTH 1-36) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA SEQ ID NO:50 (PTH 1-35) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV SEQ ID NO:51 (PTH 1-34) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF SEQ ID NO:52 (PTH 1-33) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN SEQ ID NO:53 (PTH 1-32) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH SEQ ID NO:54 (PTH 1-31) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV SEQ ID NO:55 (PTH 1-30) SVSEIQLMHNLGKHLNSMERVEWLRKKLQD SEQ ID NO:56 (PTH 1-29) SVSEIQLMHNLGKHLNSMERVEWLRKKLQ SEQ ID NO:57 (PTH 1-28) SVSEIQLMHNLGKHLNSMERVEWLRKKL SEQ ID NO:58 (PTH 1-27) SVSEIQLMHNLGKHLNSMERVEWLRKK SEQ ID NO:59 (PTH 1-26) SVSEIQLMHNLGKHLNSMERVEWLRK SEQ ID NO:60 (PTH 1-25) SVSEIQLMHNLGKHLNSMERVEWLR SEQ ID NO: 61 (amidated PTH 1-84) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ; (the C-terminus in this sequence is amidated) SEQ ID NO:62 (amidated PTH 1-83) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS; (the C-terminus in this sequence is amidated) SEQ ID NO:63 (amidated PTH 1-82) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK; (the C-terminus in this sequence is amidated) SEQ ID NO:64 (amidated PTH 1-81) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA; (the C-terminus in this sequence is amidated) SEQ ID NO: 65 (amidated PTH 1-80) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK; (the C-terminus in this sequence is amidated) SEQ ID NO:66 (amidated PTH 1-79) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT; (the C-terminus in this sequence is amidated) SEQ ID NO:67 (amidated PTH 1-78) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL; (the C-terminus in this sequence is amidated) SEQ ID NO:68 (amidated PTH 1-77) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV; (the C-terminus in this sequence is amidated) SEQ ID NO:69 (amidated PTH 1-76) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN; (the C-terminus in this sequence is amidated) SEQ ID NO: 70 (amidated PTH 1-75) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV; (the C-terminus in this sequence is amidated) SEQ ID NO: 71 (amidated PTH 1-74) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD; (the C-terminus in this sequence is amidated) SEQ ID NO: 72 (amidated PTH 1-73) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA; (the C-terminus in this sequence is amidated) SEQ ID NO: 73 (amidated PTH 1-72) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK; (the C-terminus in this sequence is amidated) SEQ ID NO: 74 (amidated PTH 1-71) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD; (the C-terminus in this sequence is amidated) SEQ ID NO: 75 (amidated PTH 1-70) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA; (the C-terminus in this sequence is amidated) SEQ ID NO: 76 (amidated PTH 1-69) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE; (the C-terminus in this sequence is amidated) SEQ ID NO: 77 (amidated PTH 1-68) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG; (the C-terminus in this sequence is amidated) SEQ ID NO: 78 (amidated PTH 1-67) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL; (the C-terminus in this sequence is amidated) SEQ ID NO: 79 (amidated PTH 1-66) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS; (the C-terminus in this sequence is amidated) SEQ ID NO: 80 (amidated PTH 1-65) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK; (the C-terminus in this sequence is amidated) SEQ ID NO: 81 (amidated PTH 1-64) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE; (the C-terminus in this sequence is amidated) SEQ ID NO: 82 (amidated PTH 1-63) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH; (the C-terminus in this sequence is amidated) SEQ ID NO: 83 (amidated PTH 1-62) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES; (the C-terminus in this sequence is amidated) SEQ ID NO: 84 (amidated PTH 1-61) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE; (the C-terminus in this sequence is amidated) SEQ ID NO: 85 (amidated PTH 1-60) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV; (the C-terminus in this sequence is amidated) SEQ ID NO: 86 (amidated PTH 1-59) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL; (the C-terminus in this sequence is amidated) SEQ ID NO: 87 (amidated PTH 1-58) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV; (the C-terminus in this sequence is amidated) SEQ ID NO: 88 (amidated PTH 1-57) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN; (the C-terminus in this sequence is amidated) SEQ ID NO: 89 (amidated PTH 1-56) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED; (the C-terminus in this sequence is amidated) SEQ ID NO: 90 (amidated PTH 1-55) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE; (the C-terminus in this sequence is amidated) SEQ ID NO: 91 (amidated PTH 1-54) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK; (the C-terminus in this sequence is amidated) SEQ ID NO: 92 (amidated PTH 1-53) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK; (the C-terminus in this sequence is amidated) SEQ ID NO: 93 (amidated PTH 1-52) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR; (the C-terminus in this sequence is amidated) SEQ ID NO: 94 (amidated PTH 1-51) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP; (the C-terminus in this sequence is amidated) SEQ ID NO: 95 (amidated PTH 1-50) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR; (the C-terminus in this sequence is amidated) SEQ ID NO: 96 (amidated PTH 1-49) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ; (the C-terminus in this sequence is amidated) SEQ ID NO: 97 (amidated PTH 1-48) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS; (the C-terminus in this sequence is amidated) SEQ ID NO: 98 (amidated PTH 1-47) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG; (the C-terminus in this sequence is amidated) SEQ ID NO: 99 (amidated PTH 1-46) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA; (the C-terminus in this sequence is amidated) SEQ ID NO: 100 (amidated PTH 1-45) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD; (the C-terminus in this sequence is amidated) SEQ ID NO: 101 (amidated PTH 1-44) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR; (the C-terminus in this sequence is amidated) SEQ ID NO: 102 (amidated PTH 1-43) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP; (the C-terminus in this sequence is amidated) SEQ ID NO: 103 (amidated PTH 1-42) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA; (the C-terminus in this sequence is amidated) SEQ ID NO: 104 (amidated PTH 1-41) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL; (the C-terminus in this sequence is amidated) SEQ ID NO: 105 (amidated PTH 1-40) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP; (the C-terminus in this sequence is amidated) SEQ ID NO: 106 (Amidated PTH 1-39) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA; (the C-terminus in this sequence is amidated) SEQ ID NO: 107 (Amidated PTH 1-38) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG; (the C-terminus in this sequence is amidated) SEQ ID NO: 108 (amidated PTH 1-37) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL; (the C-terminus in this sequence is amidated) SEQ ID NO: 109 (amidated PTH 1-36) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA; (the C-terminus in this sequence is amidated) SEQ ID NO: 110 (amidated PTH 1-35) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV; (the C-terminus in this sequence is amidated) SEQ ID NO:111 (amidated PTH 1-34) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF; (the C-terminus in this sequence is amidated) SEQ ID NO: 112 (amidated PTH 1-33) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN; (the C-terminus in this sequence is amidated) SEQ ID NO: 113 (amidated PTH 1-32) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH; (the C-terminus in this sequence is amidated) SEQ ID NO: 114 (amidated PTH 1-31) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV; (the C-terminus in this sequence is amidated) SEQ ID NO: 115 (amidated PTH 1-30) SVSEIQLMHNLGKHLNSMERVEWLRKKLQD; (the C-terminus in this sequence is amidated) SEQ ID NO: 116 (amidated PTH 1-29) SVSEIQLMHNLGKHLNSMERVEWLRKKLQ; (the C-terminus in this sequence is amidated) SEQ ID NO: 117 (amidated PTH 1-28) SVSEIQLMHNLGKHLNSMERVEWLRKKL; (the C-terminus in this sequence is amidated) SEQ ID NO: 118 (amidated PTH 1-27) SVSEIQLMHNLGKHLNSMERVEWLRKK; (the C-terminus in this sequence is amidated) SEQ ID NO: 119 (amidated PTH 1-26) SVSEIQLMHNLGKHLNSMERVEWLRK; (the C-terminus in this sequence is amidated) SEQ ID NO: 120 (amidated PTH 1-25) SVSEIQLMHNLGKHLNSMERVEWLR; (the C-terminus in this sequence is amidated) SEQ ID NO:121 (PTHrP) AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEIRATSEVSPNSKPSPNTKNHPVRFGSDDEGRYLTQETNKVETYKEQPLKTPGKKKKGKPGKRKEQEKKKRRTRSAWLDSGVTGSGLEGDHLSDTSTTSLELDSRRH

[0032] More preferably, the term "PTH" refers to the sequences SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 107, 108, 109, 110, 111, 112, 113, 114 and 115. Even more preferably, the term "PTH" refers to the sequences SEQ ID NOs: 50, 51, 52, 110, 111 and 112. In a particularly preferred embodiment, the term "PTH" refers to the sequence SEQ ID NO: 51.

[0033] The term "PTH polypeptide variant" as used herein refers to a polypeptide from the same species that is different from a reference PTH or PTHrP polypeptide. Preferably, such a reference is a PTH polypeptide sequence, having the sequence of SEQ ID NO: 51. In general, the differences are limited, and thus the amino acid sequences of the reference and the variant are similar throughout and identical in many regions. Preferably, the PTH polypeptide variant is at least 70%, 80%, 90% or 95% identical to the reference PTH or PTHrP polypeptide, preferably the PTH polypeptide of SEQ ID NO: 51. A polypeptide having an amino acid sequence that is at least, for example, 95% "identical" to a query amino acid sequence means that the amino acid sequence of the subject polypeptide is identical to the query sequence, except 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. These 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, or anywhere between these terminal positions, interspersed individually among the residues in the reference sequence, or interspersed among one or more adjacent groups in the reference sequence. The query sequence may be the entire amino acid sequence of the reference sequence, or any fragment designated as described herein. Preferably, the query sequence is the sequence of SEQ ID NO:51.

[0034] Such PTH peptide variants may be naturally occurring variants, such as naturally occurring allelic variants encoded by one of several alternative forms of PTH or PTHrP occupying a given locus in a chromosome or organism, or may be isoforms encoded by naturally occurring splice variants derived from a single primary transcript. Alternatively, the PTH polypeptide variant may be a variant that is not known to occur naturally, but which can be made by mutagenesis methods known in the art.

[0035] It is known in the art that one or more amino acids can be deleted from the N-terminus or C-terminus of a biologically active polypeptide without substantial loss of biological function. Such N- and / or C-terminal deletions are also encompassed by the term PTH polypeptide variant.

[0036] Those skilled in the art also recognize that some amino acid sequences of PTH or PTHrP polypeptide can be changed without significantly affecting the structure or function of said polypeptide.Such variants include deletions, insertions, inversions, repeats and substitutions, which are selected according to general rules known in the art so as to have little effect on activity.For example, guidance on how to make phenotypically silent amino acid substitutions is provided in Bowie et al. (1990), Science 247:1306-1310, which is incorporated herein by reference in its entirety, and the authors of this reference indicate that there are two main approaches to study the tolerance of amino acid sequence to change.

[0037] The term PTH polypeptide also encompasses all PTH or PTHrP polypeptides encoded by PTH or PTHrP analogs, orthologs, and / or species homologs. Those skilled in the art will also recognize that the term PTH polypeptide also encompasses all PTHrP analogs, since PTHrP and PTHrP analogs bind to and activate the common PTH / PTHrP1 receptor. The term "PTH analog" as used herein refers to PTH or PTHrP from different, unrelated organisms that achieve the same function in each organism, but do not originate from an ancestral structure shared by the ancestors of those organisms. Instead, similar PTH and PTHrP have arisen separately and then evolved to perform the same or similar functions. In other words, similar PTH and PTHrP polypeptides are polypeptides that perform the same biological activity, i.e., increase serum calcium and renal phosphorus excretion and decrease serum phosphorus and renal calcium excretion, but have completely different amino acid sequences.

[0038] As used herein, the term "PTH ortholog" refers to PTH or PTHrP in two different species that have evolved to be distinct from each other, although their sequences are related to each other by a common homologous PTH or PTHrP in an ancestral species.

[0039] The term "PTH homolog" as used herein refers to PTH or PTHrP from different organisms that perform the same function in each organism and originate from an ancestral structure shared by the ancestors of those organisms. In other words, homologous PTH polypeptides are polypeptides with identical amino acid sequences that perform the same biological activity, i.e., increasing serum calcium and renal phosphorus excretion and decreasing serum phosphorus and renal calcium excretion. Preferably, a PTH polypeptide homolog may be defined as a polypeptide that exhibits at least 40%, 50%, 60%, 70%, 80%, 90% or 95% identity with a reference PTH or PTHrP polypeptide, preferably the PTH polypeptide of SEQ ID NO:51.

[0040] Thus, a PTH polypeptide according to the invention may, for example, be (i) one in which at least one of the amino acid residues has been replaced with a conserved or non-conserved amino acid residue, preferably a conserved amino acid residue, which may or may not be one encoded by the genetic code, and / or (ii) one in which at least one of the amino acid residues comprises a substituent group, and / or (iii) one in which the PTH polypeptide is fused to another compound, for example a compound for increasing the half-life of the polypeptide (e.g. polyethylene glycol), and / or (iv) one in which further amino acids are fused to the PTH polypeptide, such as an IgG Fc fusion region polypeptide or a leader or secretion sequence, or a sequence used for the purification of the above forms of the polypeptide, or a protein precursor sequence.

[0041] As used herein, the term "PTH polypeptide fragment" refers to any polypeptide that includes a contiguous stretch of a portion of the amino acid sequence of a PTH or PTHrP polypeptide, preferably the polypeptide of SEQ ID NO:51.

[0042] More specifically, a PTH polypeptide fragment comprises at least 6, e.g., at least 8, at least 10, or at least 17 consecutive amino acids of a PTH or PTHrP polypeptide, more preferably of the polypeptide of SEQ ID NO: 51. Furthermore, a PTH polypeptide fragment may be described as a subgenus of PTH or PTHrP polypeptides comprising 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 a PTH or PTHrP polypeptide, preferably of SEQ ID NO: 51. Further included are species of PTH or PTHrP polypeptide fragments at least 6 amino acids in length, as described above, which are further specified with respect to N-terminal and C-terminal positions. All PTH or PTHrP polypeptide fragments at least 6 amino acids in length, as described above, which may be specifically specified by N-terminal and C-terminal positions, are also encompassed as individual species by the term "PTH polypeptide fragment." That is, any combination of N-terminal and C-terminal positions that can be occupied by a fragment of at least 6 contiguous amino acids in length on any given amino acid sequence of a PTH or PTHrP polypeptide, preferably the PTH polypeptide of SEQ ID NO:51, is included in the present invention.

[0043] The term "PTH" also includes poly(amino acid) conjugates having the above sequence, but with a backbone that contains both amide and non-amide bonds, such as ester bonds, such as depsipeptides. A depsipeptide is a chain of amino acid residues whose backbone contains both amide (peptide) and ester bonds. Thus, the term "side chain" as used herein refers to the moiety attached to the alpha-carbon of an amino acid moiety, such as in the case of a polypeptide, when the amino acid moieties are linked by amine bonds, or any carbon atom-containing moiety attached to the backbone of a poly(amino acid) conjugate, such as in the case of a depsipeptide. Preferably, the term "PTH" refers to a polypeptide having a backbone formed by amide (peptide) bonds.

[0044] The term PTH includes the above variants, analogs, orthologs, homologs, derivatives and fragments of PTH or PTHrP, such that all references to a particular position within a reference sequence also include the equivalent position within variants, analogs, orthologs, homologs, derivatives and fragments of the PTH or PTHrP substructure, even if not specifically stated.

[0045] The term "micelle" as used herein refers to an aggregate of amphiphilic molecules dispersed in a liquid colloid. In aqueous solution, typical micelles form aggregates, also called "normal phase micelles," in which the hydrophilic substructure of the surfactant molecule faces toward the surrounding solvent and the hydrophobic substructure of the surfactant faces inward. "Reverse micelles" have the hydrophilic substructure facing inward and the hydrophobic substructure facing toward the surrounding solvent.

[0046] The term "liposome" as used herein refers to a vesicle, preferably a spherical vesicle, having at least one lipid bilayer. Preferably, the liposome comprises phospholipids, even more preferably phosphatidylcholine. The term "liposome" refers to various structures and sizes, such as multilamellar liposome vesicles (MLVs) having more than one concentric lipid bilayer and an average diameter of 100-1000 nm, small unilamellar liposome vesicles (SUVs) having one lipid bilayer and an average diameter of 25-100 nm, large unilamellar liposome vesicles (LUVs) having one lipid bilayer and an average diameter of about 1000 μm, and giant unilamellar vesicles (GUVs) having one lipid bilayer and an average diameter of 1-100 μm. The term "liposome" also includes elastic vesicles, such as transferosomes and ethosomes.

[0047] The term "aquasome" as used herein refers to spherical nanoparticles with diameters between 60 and 300 nm that contain at least three layers of self-assembled structures, i.e., a solid nanocrystalline core covered by an oligomeric film onto which drug molecules of a modified or unmodified drug are adsorbed.

[0048] As used herein, the term "ethosome" refers to a lipid vesicle that contains phospholipids, a relatively high concentration of ethanol and / or isopropanol, and water, and has a size ranging from several tens of nanometers to micrometers.

[0049] As used herein, the term "LeciPlex" refers to a positively charged phospholipid-based vesicular system containing soybean PC, a cationic drug, 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.

[0050] As used herein, the term "niosome" refers to unilamellar or multilamellar vesicles containing a non-ionic surfactant.

[0051] As used herein, the term "pharmacosome" refers to ultramicroscopic vesicles, micelles or hexagonal aggregates made from lipids that are covalently linked to a biologically active moiety.

[0052] As used herein, the term "proniosome" refers to a dry preparation of surfactant-coated carriers that become niosomes upon rehydration and gentle agitation.

[0053] The term "polymersome" as used herein refers to an artificial spherical vesicle that comprises a membrane formed from an amphiphilic synthetic block copolymer and may optionally contain an aqueous solution in its core.Polymersomes have diameters ranging from 50 nm to 5 μm and larger.This term also includes syntosomes, which are polymersomes designed to contain channels that allow certain chemicals to pass through the membrane into or out of the vesicle.

[0054] As used herein, the term "sphingosome" refers to a concentric bilayer vesicle in which the aqueous volume is completely enclosed by a membranous lipid bilayer composed primarily of natural or synthetic sphingolipids.

[0055] As used herein, the term "transferosome" refers to an ultraflexible lipid vesicle containing an aqueous core and formed from a mixture of suitable end-activated lipids with a common polarity that promotes the formation of a highly curved bilayer that renders the transferosome highly deformable.

[0056] As used herein, the term "ufasome" refers to a vesicle that contains unsaturated fatty acids.

[0057] As used herein, the term "polypeptide" refers to a peptide containing 50 or fewer amino acid monomers.

[0058] The term "protein" as used herein refers to a peptide comprising more than 50 amino acid residues. Preferably, the protein comprises at most 20000 amino acid residues, such as at most 15000 amino acid residues, such as at most 10000 amino acid residues, such as at most 5000 amino acid residues, such as at most 4000 amino acid residues, such as at most 3000 amino acid residues, such as at most 2000 amino acid residues, such as at most 1000 amino acid residues.

[0059] As used herein, the term "physiological conditions" refers to an aqueous buffer at 37°C and pH 7.4.

[0060] The term "pharmaceutical composition" as used herein refers to a composition that contains one or more active ingredients, such as at least one controlled release PTH compound, and one or more excipients, as well as any product that is obtained directly or indirectly from the combination, complexation or aggregation of any two or more of the components of said composition, or from the dissociation of one or more of said components, or from other types of reaction or interaction of one or more of said components.Thus, the pharmaceutical composition for use in the present invention encompasses any composition that is produced by mixing one or more controlled release PTH compounds with a pharma-ceutical acceptable excipient.

[0061] As used herein, the term "liquid composition" refers to a mixture comprising a water-soluble controlled-release PTH compound and one or more solvents, such as water.

[0062] The term "suspension composition" refers to a mixture comprising a water-insoluble controlled-release PTH compound and one or more solvents, such as water.

[0063] The term "dry composition" as used herein means that the pharmaceutical composition is provided in a dry form. Suitable drying methods are spray drying and lyophilization, i.e. freeze-drying. Such dry compositions of prodrugs have a maximum of 10%, preferably less than 5%, and more preferably less than 2% residual moisture as determined by Karl Fischer. Preferably, the pharmaceutical composition for use in the present invention is dried by lyophilization.

[0064] As used herein, the term "drug" refers to a substance, such as PTH, used to treat, cure, prevent, or diagnose disease, or to otherwise improve physical or mental well-being. When a drug is conjugated to another moiety, the moiety of the resulting product that is derived from the drug is referred to as a "biologically active moiety."

[0065] The term "prodrug" as used herein refers to a conjugate in which a biologically active moiety is reversibly covalently linked to a special protective group via a reversible linker moiety that contains a reversible bond with the biologically active moiety, the reversible linker moiety also referred to as a "reversible prodrug linker moiety", which changes or removes undesirable properties of the parent molecule. This includes enhancing desirable properties and suppressing undesirable properties of the drug. The special non-toxic protective group is referred to as a "carrier". A prodrug releases the biologically active moiety reversibly covalently linked in the form of its corresponding drug. In other words, a prodrug is a conjugate that contains a biologically active moiety that is reversibly covalently conjugated to a carrier moiety via a reversible prodrug linker moiety, the reversible covalent bond of the carrier to the reversible linker moiety being either direct or via a spacer. Such a conjugate releases the previously conjugated biologically active moiety in the form of a free unmodified drug.

[0066] A "biodegradable bond" or "reversible bond" is a bond that can be degraded, i.e., cleaved, by hydrolysis in the absence of enzymes under physiological conditions (aqueous buffer at pH 7.4, 37° C.) with a half-life in the range of 1 hour to 3 months, preferably 1 hour to 2 months, even more preferably 1 hour to 1 month, even more preferably 1 hour to 3 weeks, and most preferably 1 hour to 2 weeks. Thus, a stable bond is a bond that has a half-life of greater than 3 months under physiological conditions (aqueous buffer at pH 7.4, 37° C.).

[0067] As used herein, the term "traceless prodrug linker" refers to a reversible prodrug linker that, upon cleavage, releases the drug in its free form, i.e., a linker moiety that reversibly covalently links a biologically active moiety to a carrier. As used herein, the term "free form" drug refers to the drug in its unmodified, pharmacologically active form.

[0068] The term "excipient" as used herein refers to a diluent, adjuvant, or vehicle used to administer a therapeutic, e.g., a drug or prodrug. Such pharmaceutical excipients can be sterile liquids, such as water and oils (including those of petroleum, animal, vegetable, or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil, and the like). Water is the preferred excipient when the pharmaceutical composition is administered orally. Saline and aqueous dextrose solutions are the preferred excipients when the pharmaceutical composition is administered intravenously. Saline solutions, and aqueous dextrose and glycerol solutions are preferably used as liquid excipients for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerol, propylene, glycol, water, ethanol, and the like. Pharmaceutical compositions, if desired, may also contain minor amounts of wetting or emulsifying agents, pH buffering agents, such as acetates, succinates, tris, carbonates, phosphates, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), or surfactants, such as Tween, poloxamers, poloxamines, CHAPS, Igepal, or amino acids, such as glycine, lysine, or histidine. These pharmaceutical compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, and the like. Pharmaceutical compositions may also be formulated as suppositories, with traditional binders and excipients, such as triglycerides. Oral formulations can contain standard excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such compositions will contain a therapeutically effective amount of the drug or biologically active moiety, together with a suitable amount of excipients so as to produce the form for proper administration to the patient. The formulation should suit the mode of administration.

[0069] As used herein, the term "reagent" refers to a compound that contains at least one functional group for reaction with a functional group of another compound or a drug. It is understood that a drug that contains a functional group (e.g., a primary or secondary amine or hydroxyl functional group) is also a reagent.

[0070] The term "substructure" as used herein means a portion of a molecule that is missing one or more atoms compared to the corresponding reagent. For example, when a reagent of formula "HXH" reacts with another reagent and becomes part of a reaction product, the corresponding substructure of the reaction product has the structure "HX-" or "-X-", where each "-" indicates a bond to another substructure. Thus, the biologically active substructure is released as a drug from the prodrug.

[0071] When a grouping of atoms or a chemical structure is provided in which a grouping of atoms is attached to two substructures or interrupts a substructure, it is understood that the grouping or chemical structure may be attached to the two substructures in either orientation, unless expressly stated otherwise. For example, the substructure "-C(O)N(R 1 )-" is "-C(O)N(R 1 )-" or "-N(R 1 It may be attached to two substructures or may be interrupted in one substructure as "C(O)-". [ka] teeth, [ka] As such, it may be attached to two substructures or interrupt one substructure.

[0072] As used herein, the term "functional group" means a group of atoms that can react with another group of atoms. Functional groups include, but are not limited to, the following groups: carboxylic acid (-(C=O)OH), primary or secondary amine (-NH, -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 (>NN<), isocyanate, isothiocyanate, phosphate (-O(P=O)OHOH), phosphonate (-O(P=O)OHH), haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, disulfide, sulfonamide, sulfonic acid, vinyl sulfone, vinyl ketone, diazoalkane, oxirane, and aziridine.

[0073] When the controlled release PTH compounds for use in the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharma- ceutically or toxicologically acceptable salts, in particular their pharma- ceutically available salts. Thus, the controlled release PTH compounds for use in the present invention that contain acidic groups can be used in accordance with the present invention, for example as alkali metal salts, alkaline earth metal salts or ammonium salts. More specific 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 controlled release PTH compounds for use in the present invention that contain one or more basic groups, i.e. groups that can be protonated, and such prodrugs can be used in accordance with 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 of converting basic groups into cations are known to those skilled in the art, such as alkylation of amine groups to provide a suitable counterion of positively charged ammonium groups and their salts.When the controlled release PTH compound for use in the present invention contains both acidic and basic groups, the present invention also includes inner salts or betaines (zwitterions) in addition to the salt forms mentioned. The respective salts can be obtained by conventional methods known to those skilled in the art, such as, for example, by contacting these compounds in a solvent or dispersion with an organic or inorganic acid or base, or by anion or cation exchange with other salts. The present invention also includes all salts of the compounds for use according to the invention which are not suitable for use directly in medicines due to their low physiological compatibility, but which can be used, for example, as intermediates in chemical reactions or in the preparation of pharmaceutically acceptable salts.

[0074] The term "pharmaceutical acceptable" means a substance that is not harmful when administered to a patient, and preferably means approved for use in animals, and 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.

[0075] The term "about" used in conjunction with a numerical value herein is used to indicate the numerical value itself plus / minus a range of 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" is used to mean 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 a percentage indicated as "about 20%" does not mean "20% + / - 10%", i.e., a range of 10 to 30%, but rather "about 20%" means a range of 18 to 22%, i.e., a range of plus / minus 10% of the numerical value, which is 20.

[0076] The term "polymer" as used herein refers to a molecule that includes repeating structural units, i.e., monomers, linked by chemical bonds in a linear, cyclic, branched, cross-linked or dendrimeric manner, or a combination thereof, and may be of synthetic or biological origin, or a combination of both. It is understood that a polymer may also include one or more other chemical groups and / or moieties, such as one or more functional groups. Preferably, a soluble polymer has a molecular weight of at least 0.5 kDa, such as a molecular weight of at least 1 kDa, a molecular weight of at least 2 kDa, a molecular weight of at least 3 kDa, or a molecular weight of at least 5 kDa. When the polymer is soluble, it is preferred that it has a molecular weight of at most 1000 kDa, such as at most 750 kDa, such as at most 500 kDa, such as at most 300 kDa, such as at most 200 kDa, such as at most 100 kDa. It is understood that for insoluble polymers, such as hydrogels, a meaningful molecular weight range cannot be provided. It is also understood that proteins are polymers in which amino acids are repeating structural units, even though the side chain of each amino acid can be different.

[0077] As used herein, the term "polymeric" refers to an agent or moiety that includes one or more polymers or polymeric substructures. The polymeric agent or moiety may also optionally include one or more other substructures, such other substructures preferably being 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 heterobicyclyl, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and A bond selected from the group comprising: [ka] (In the formula, The dashed line indicates the bond to the remainder of the moiety or reagent; -R and -R a are each independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.

[0078] Those skilled in the art will understand that the polymerization products resulting from a polymerization reaction do not all have the same molecular weight, but rather exhibit a molecular weight distribution. Therefore, as used herein, molecular weight ranges, molecular weights, ranges of the number of monomers in a polymer, and the number of monomers in a polymer refer to the number average molecular weight and the monomer number average, i.e., the arithmetic average of the molecular weight of the polymer or polymeric substructure, and the arithmetic average of the number of monomers of the polymer or polymeric substructure.

[0079] Thus, for a polymeric moiety that contains "x" monomer units, any integer assigned to "x" corresponds to the arithmetic average number of monomers. Any range of integers assigned to "x" provides a range of integers within which the arithmetic average number of monomers lies. An integer "x" designated as "about x" means that the arithmetic average number of monomers lies within the integer range of x + / - 10%, preferably x + / - 8%, more preferably x + / - 5%, and most preferably x + / - 2%.

[0080] As used herein, the term "number average molecular weight" means the ordinary arithmetic average of the molecular weights of the individual polymers.

[0081] The term "water-soluble" as used herein with respect to a carrier means that when such a carrier is part of a controlled release PTH compound for use in the present invention, at least 1 g of the controlled release PTH compound with such a water-soluble carrier can be dissolved in 1 liter of water at 20° C. to form a homogeneous solution. Thus, the term "water-insoluble" with respect to a carrier means that when such a carrier is part of a controlled release PTH compound for use in the present invention, less than 1 g of the controlled release PTH compound with such a water-insoluble carrier can be dissolved in 1 liter of water at 20° C. to form a homogeneous solution.

[0082] The term "water-soluble" as used herein with respect to a controlled-release PTH compound means that at least 1 g of the controlled-release PTH compound can be dissolved in 1 liter of water at 20° C. to form a homogeneous solution. Thus, the term "water-insoluble" with respect to a controlled-release PTH compound means that less than 1 g of the controlled-release PTH compound can be dissolved in 1 liter of water at 20° C. to form a homogeneous solution.

[0083] As used herein, the term "hydrogel" refers to a hydrophilic or amphiphilic polymeric network composed of homopolymers or copolymers that is insoluble due to the presence of covalent chemical bonds. Crosslinkers provide the structure and physical integrity of the network.

[0084] The term "thermogelling" as used herein means a compound that is 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 low temperatures ranging between about 0°C to about 10°C, but is a more highly viscous compound at higher temperatures ranging between about 30°C to about 40°C, e.g., at about 37°C, at a shear rate of about 0.1 / sec, less than 10,000 cps at about 25°C.

[0085] The term "PEG-based" as used herein with respect to a moiety or reagent means that said moiety or reagent comprises PEG. Preferably, a PEG-based moiety or reagent comprises 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%. The remaining weight percentages of said PEG-based moiety or reagent are other moieties preferably selected from the following moieties and bonds: C 1-50 Alkyl, C 2-50 Alkenyl, C 2-50 Alkynyl, C 3-10cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and A bond selected from the group comprising: [ka] (In the formula, The dashed line indicates the bond to the remainder of the moiety or reagent; -R and -R a are each independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.

[0086] The term "PEG-based comprising at least X% PEG" as used herein with respect to a moiety or reagent means that said moiety or reagent comprises at least X% (w / w) ethylene glycol units (-CH2CHO-), which may be arranged in alternating blocks or may be randomly distributed within said moiety or reagent, preferably all ethylene glycol units of said moiety or reagent are present in one block, with the remaining weight percentage of the PEG-based moiety or reagent being other moieties preferably 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 heterobicyclyl, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and A bond selected from the group comprising: [ka] (In the formula, The dashed line indicates the bond to the remainder of the moiety or reagent; -R and -R a are each independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.

[0087] The term "a hyaluronic acid system containing at least X% hyaluronic acid" is used arbitrarily.

[0088] As used herein, the term "substituted" means that one or more -H atoms of a molecule or moiety have been replaced with another atom or group of atoms, which are referred to as "substituents."

[0089] Preferably, the 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 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 alkynyl, wherein -T 0 , C1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl may be one or more -R x2 and optionally substituted with C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl includes -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 )-, -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, 0 , C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl may be one or more -R x2 and wherein said C is optionally substituted with 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl includes -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 )-, Each T 0 are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; 0 may independently be one or more of the same or different -R x2 and optionally substituted with Each R x2 are 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 C1-6 alkyl, 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R x3 , -R x3a , -R x4 , -R x4a , -R x4b are independently -H and C 1-6 alkyl, 1-6 The alkyl is optionally substituted with one or more halogens, which may be the same or different.

[0090] More preferably, the one or more further 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 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10alkynyl, wherein -T 0 , C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl may be one or more -R x2 and optionally substituted with C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl includes -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 )-, Each-R x1 , -R x1a , -R x1b , -R x3 , -R x3a are independently -H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl, Each T 0 are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; 0 may independently be one or more of the same or different -R x2 and optionally substituted with Each R x2 are independently halogen, -CN, oxo (=O), -COOR x4 , -OR x4 , -C(O)Rx4 , -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, 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R x4 , -R x4a , -R x4b are independently -H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl.

[0091] Even more preferably, the one or more further 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(Rx1 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 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, wherein -T 0 , C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl may be one or more -R x2 and wherein said C is optionally substituted with 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl includes -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 )-, Each-R x1 , -R x1a , -R x1b , -R x2 , -R x3 , -R x3a are independently -H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl, Each T 0 are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; 0 may independently be one or more of the same or different -R x2 is optionally replaced by

[0092] Preferably, up to six -H atoms of an optionally substituted molecule are independently replaced by a substituent, e.g., five -H atoms are independently replaced by a substituent, four -H atoms are independently replaced by a substituent, three -H atoms are independently replaced by a substituent, two -H atoms are independently replaced by a substituent, or one -H atom is replaced by a substituent.

[0093] The term "interposed" means that the moiety is inserted between two carbon atoms or, if the insertion is at the terminal end of the moiety, between a carbon or heteroatom and a hydrogen atom, preferably between a carbon and a hydrogen atom.

[0094] As used herein alone or in combination, the term " 1-4 "Alkyl" means a linear or branched alkyl moiety having 1 to 4 carbon atoms. When present at the terminal end of a molecule, it is a linear or branched C 1-4Examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. 1-4 When bonded by an alkyl, such C 1-4 Examples of alkyl groups are -CH-, -CH-CH-, -CH(CH)-, -CH-CH-CH-, -CH(CH)-, and -C(CH)-. 1-4 Each hydrogen of an alkyl carbon may be optionally replaced by a substituent as defined above. 1-4 The alkyl may be interrupted by one or more moieties as defined below.

[0095] As used herein alone or in combination, the term " 1-6 "Alkyl" means a linear or branched alkyl moiety having 1 to 6 carbon atoms. When present at the terminal end of a molecule, linear and branched C 1-6 Examples of 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. 1-6 When the alkyl group is bonded to the C 1-6 Examples of alkyl groups are -CH-, -CH-CH-, -CH(CH)-, -CH-CH-CH-, -CH(CH)-, and -C(CH)-. 1-6 Each hydrogen atom of the carbon may be optionally replaced by a substituent as defined above. 1-6 The alkyl may be interrupted by one or more moieties as defined below.

[0096] Therefore, "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; C 1-10 , C 1-20 Or C 1-50 Each hydrogen atom of the carbon may be optionally replaced by a substituent as defined above. 1-10 Or C 1-50 The alkyl may be interrupted by one or more moieties as defined below.

[0097] As used herein alone or in combination, the term " 2-6 "Alkenyl" means a straight or branched hydrocarbon moiety containing at least one carbon-carbon double bond having 2 to 6 carbon atoms. When present at the end of the molecule, examples are -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3 and -CH=CH-CH=CH2. When two moieties of the molecule are C 2-6 When bonded by an alkenyl, such C 2-6 An example of an alkenyl is -CH=CH-. 2-6 Each hydrogen atom of the alkenyl moiety may be optionally replaced by a substituent as defined above. 2-6 The alkenyl may be optionally interrupted by one or more moieties as defined below.

[0098] Thus, the term "C" alone or in combination 2-10 alkenyl", "C 2-20 alkenyl" or "C 2-50 "Alkenyl" means a linear or branched hydrocarbon moiety containing at least one carbon-carbon double bond and having 2 to 10, 2 to 20, or 2 to 50 carbon atoms. 2-10 Alkenyl, C 2-20 Alkenyl or C 2-50 Each hydrogen atom of the alkenyl group may be optionally replaced by a substituent as defined above. 2-10 Alkenyl, C 2-20 Alkenyl or C 2-50The alkenyl may be optionally interrupted by one or more moieties as defined below.

[0099] As used herein alone or in combination, the term " 2-6 "Alkynyl" means a straight or branched hydrocarbon moiety containing at least one carbon-carbon triple bond having 2 to 6 carbon atoms. 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 connected by an alkynyl group, an example is -C≡C-. 2-6 Each hydrogen atom of the alkynyl group may be optionally replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-6 The alkynyl may be optionally interrupted by one or more moieties as defined below.

[0100] Thus, the term "C" as used herein alone or in combination 2-10 alkynyl", "C 2-20 alkynyl" or "C 2-50 "Alkynyl" refers to a linear or branched hydrocarbon moiety containing at least one carbon-carbon triple bond, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, respectively. 2-10 Alkynyl, C 2-20 Alkynyl or C 2-50 Each hydrogen atom of the alkynyl group may be optionally 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 The alkynyl may be optionally interrupted by one or more moieties as defined below.

[0101] As mentioned above, C 1-4 Alkyl, C 1-6 Alkyl, C 1-10 Alkyl, C 1-20 Alkyl, C 1-50 Alkyl, C2-6 Alkenyl, C 2-10 Alkenyl, C 2-20 Alkenyl, C 2-50 Alkenyl, C 2-6 Alkynyl, C 2-10 Alkynyl, C 2-20 Alkenyl or C 2-50 The alkynyl may be optionally interrupted by one or more moieties, preferably [ka] (In the formula, The dashed line indicates the bond to the remainder of the moiety or reagent; -R and -R a are each independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl. is selected from the group consisting of:

[0102] 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, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl. 3-10 Each hydrogen atom of a cycloalkyl carbon may be replaced by a substituent as defined above. 3-10 "Cycloalkyl" also includes bridged bicycles such as norbornane or norbornene.

[0103] The term "8-30 membered carbopolycyclyl" or "8-30 membered carbopolycycle" refers to a cyclic moiety having 8-30 ring atoms, with two or more rings, two adjacent rings sharing at least one ring atom, and which may contain up to a maximum number of double bonds (fully saturated, partially saturated or unsaturated, aromatic or non-aromatic rings). Preferably, 8-30 membered carbopolycyclyl refers to a cyclic moiety having 2, 3, 4 or 5 rings, more preferably 2, 3 or 4 rings.

[0104] The term "3- to 10-membered heterocyclyl" or "3- to 10-membered heterocycle" as used herein means a ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, in which at least one ring atom and up to four ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), which may contain up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings) and which is attached to the remainder of the molecule by a carbon or nitrogen atom. Examples of 3- to 10-membered heterocycles include, but are not limited to, aziridine, oxirane, thiirane, azirine, oxirene, thiylene, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazolidine, 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 the 3- to 10-membered heterocyclyl or 3- to 10-membered heterocyclic group may be optionally replaced by a substituent as defined below.

[0105] The term "8-11 membered heterobicyclyl" or "8-11 membered heterobicycle" as used herein means a two-ring heterocyclic moiety having 8 to 11 ring atoms and which may contain up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings), in which at least one ring atom is shared by both rings, and at least one ring atom, up to a maximum of six 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 the ring is bonded to the remainder of the molecule by a carbon or nitrogen atom. Examples of 8-11 membered heterobicycles 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 8-11 membered heterobicycle also includes two ring 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 the 8-11 membered heterobicyclyl or 8-11 membered heterobicycle carbon may be optionally replaced by a substituent as defined below.

[0106] Similarly, the term "8- to 30-membered heteropolycyclyl" or "8- to 30-membered heteropolycycle" refers to a heterocyclic moiety of more than two rings, preferably 3, 4 or 5 rings, having 8 to 30 ring atoms and which may contain up to a maximum number of double bonds (fully saturated, partially saturated or unsaturated, aromatic or non-aromatic rings), in which two adjacent rings share at least one ring atom, and in which at least one ring atom, up to a maximum of 10 ring atoms, is replaced by a heteroatom selected from the group of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and in which the rings are bonded to the remainder of the molecule by a carbon or nitrogen atom.

[0107] structure: [ka] Regarding the partial structure of x / R y together with the atoms to which they are attached, C 3-10 The phrase "form a cycloalkyl or 3- to 10-membered heterocyclyl" is intended to include R x and R y is understood to be meant to form the following structure: [ka] (Wherein, R is C 3-10 cycloalkyl or 3-10 membered heterocyclyl).

[0108] structure: [ka] Regarding the partial structure of x / R y together with the atoms to which they are attached form a ring A" is intended to include R x and R y is also understood to be meant to form the structure: [ka]

[0109] As used herein, "halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.

[0110] In general, the terms "comprise" or "comprising" also encompass "consist" or "consisting of."

[0111] It is understood that human experiments are subject to strict rules. Therefore, more readily available test systems in the form of animal models may be needed to determine the dosage of PTH 1-84 required to maintain serum calcium within normal levels in otherwise hypocalcemic subjects, which preferably refers to serum albumin-corrected calcium levels greater than 8.5 mg / dL and less than 10.5 mg / dL, with 9.5 mg / dL being the optimal level in humans, corresponding to a range of 2.125-2.625 nmol / L, with 2.375 nmol / L being optimal. One such animal model is the thyroparathyroidectomized (TPTX) rat. Thyroparathyroidectomized rats are unable to produce parathyroid hormone, PTH, the key regulator of calcium homeostasis, and as a result develop hypocalcemia.

[0112] However, it is also understood that serum calcium levels may vary between different species, for example between humans and rats, and therefore values ​​need to be corrected to adjust for these interspecies differences in order to achieve comparable results. Thus, when using such animal models, the normal serum calcium levels of that species for a given sex and age must first be determined. For example, Watchorn (Biochem J. 1933; 27(6): 1875-1878) provides the normal range of serum calcium (uncorrected) for male rats as 10.29-13.16 mg / dL, and for female rats as 9.61-14.04 mg / dL. Preferably, the normal serum calcium range is determined as a serum calcium concentration higher than the lower limit of the normal range, for example, higher than 9.6 mg / dL (uncorrected), for female rats, and even more preferably for female rats aged 13-22 weeks. Preferably, the normal serum calcium range is determined as a serum calcium concentration below the upper limit of the normal range, for example, less than 14 mg / dL (uncorrected), for female rats, and more preferably for female rats aged 13-22 weeks.

[0113] Therefore, when performing thyroparathyroidectomy on female rats to obtain TPTX rats, the therapeutically targeted normal range would be greater than 9.6 mg / dL (uncorrected) and preferably less than 14 mg / dL (uncorrected) for such animals aged 13 to 22 weeks.

[0114] Preferably, the pharmaceutical compositions of the invention are for use in the treatment of a condition that can be treated with PTH.

[0115] The pharmaceutical compositions for use according to the invention are administered no more frequently than once every 24 hours, for example every 24 hours, every 48 hours, every 72 hours, every 96 hours, every 120 hours, every 144 hours, once a week, once every two weeks, etc. Preferably, the administration of the pharmaceutical compositions according to the invention is in multiples of 24 hours, i.e. N times in 24 hours, where N is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14.

[0116] In one embodiment, the pharmaceutical composition for use in the present invention is administered once every 24 hours.

[0117] In another embodiment, the pharmaceutical composition for use according to the invention is administered once every 48 hours.

[0118] In another embodiment, the pharmaceutical composition for use according to the invention is administered once every 72 hours.

[0119] In another embodiment, the pharmaceutical composition for use according to the invention is administered once every 96 hours.

[0120] In another embodiment, the pharmaceutical composition for use according to the invention is administered once every 120 hours.

[0121] In another embodiment, the pharmaceutical composition for use according to the invention is administered once every 144 hours.

[0122] In another embodiment, the pharmaceutical composition for use according to the present invention is administered once a week.

[0123] In the present invention, PTH 1-84 is administered every 24 hours. This means that when the pharmaceutical composition containing controlled release PTH compound is administered every 24 hours, both the pharmaceutical composition containing controlled release PTH compound and PTH 1-84 are administered at the same frequency. When the pharmaceutical composition containing controlled release PTH compound is administered at an interval longer than 24 hours, PTH 1-84 is administered more than once within the interval between two consecutive administrations of the pharmaceutical composition containing controlled release PTH compound. In such a case, in order to obtain a basis for determining the molar equivalent dose of the controlled release PTH compound, the total amount of PTH 1-84 is calculated from all administrations performed during said interval between two consecutive administrations of the pharmaceutical composition containing controlled release PTH compound of the present invention.

[0124] The pharmaceutical compositions for use in the present invention are administered by injection. In one embodiment, administration is by intramuscular injection. In another embodiment, administration is by intravenous injection. In another embodiment, administration is by subcutaneous injection.

[0125] It is understood that the method of administration of the controlled release PTH compound and the method of administration of PTH 1-84 are the same, i.e., if PTH 1-84 is administered by subcutaneous injection, the controlled release PTH compound is also administered by subcutaneous injection, and if PTH 1-84 is administered by intramuscular injection, the controlled release PTH compound is also administered by intramuscular injection.

[0126] In one embodiment, the pharmaceutical composition for use in the present invention is administered in a syringe. In another embodiment, the pharmaceutical composition for use in the present invention is administered in a pen-type injector. In another embodiment, the pharmaceutical composition for use in the present invention is administered in an autoinjector.

[0127] In the present invention, the pharmaceutical compositions for use in the present invention are administered at a dosage of the controlled release PTH compound equivalent to no more than 70% of the molar equivalent dose of PTH 1-84 required to maintain serum calcium within the normal range, preferably above 8.5 mg / dL, in humans over a 24 hour period, at a frequency of no more than every 24 hours. Preferably, the pharmaceutical compositions for use in the present invention are administered at a dosage of the controlled release PTH compound which corresponds to no more than 65%, more preferably no more than 60%, even more preferably no more than 55%, even more preferably no more than 50%, even more preferably no more than 45%, even more preferably no more than 40%, even more preferably no more than 35%, and most preferably no more than 30% of the molar equivalent dose of PTH 1-84 required to maintain serum calcium within the normal range, preferably above 8.5 mg / dL, over a 24 hour period in humans.

[0128] Preferably, the PTH compound comprises a PTH molecule or PTH substructure having the sequence of SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114 or SEQ ID NO: 115. More preferably, the PTH molecule or PTH substructure has the sequence of SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 110, SEQ ID NO: 111 or SEQ ID NO: 112.

[0129] In one embodiment, the PTH molecule or PTH substructure has the sequence of SEQ ID NO:50.

[0130] In another embodiment, the PTH molecule or PTH substructure has the sequence of SEQ ID NO:52.

[0131] In another embodiment, the PTH molecule or PTH substructure has the sequence of SEQ ID NO:110.

[0132] In another embodiment, the PTH molecule or PTH substructure has the sequence of SEQ ID NO:111.

[0133] In another embodiment, the PTH molecule or PTH substructure has the sequence of SEQ ID NO:112.

[0134] Most preferably, the PTH molecule or PTH substructure has the sequence of SEQ ID NO:51.

[0135] In one embodiment, the controlled release PTH compound is water insoluble.

[0136] Preferably, the water insoluble controlled release PTH compound is selected from the group consisting of crystals, nanoparticles, microparticles, nanospheres and microspheres.

[0137] In one embodiment, the water-insoluble controlled-release PTH compound is crystalline, comprising at least one PTH molecule or PTH substructure.

[0138] In another embodiment, the water-insoluble controlled-release PTH compound is a nanoparticle comprising at least one PTH molecule or PTH substructure.

[0139] In another embodiment, the water-insoluble controlled-release PTH compound is a microparticle comprising at least one PTH molecule or PTH substructure.

[0140] In another embodiment, the water-insoluble controlled-release PTH compound is a nanosphere comprising at least one PTH molecule or PTH substructure.

[0141] In another embodiment, the water-insoluble controlled-release PTH compound is a microsphere comprising at least one PTH molecule or PTH substructure.

[0142] In one embodiment, the water-insoluble controlled-release PTH compound is a vesicle comprising at least one PTH molecule or PTH substructure. Preferably, such a vesicle comprising at least one PTH molecule or PTH substructure is a micelle, liposome or polymersome.

[0143] In one embodiment, the water-insoluble controlled-release PTH compound is a micelle comprising at least one PTH molecule or PTH substructure.

[0144] In another embodiment, the water-insoluble controlled-release PTH compound is a liposome comprising at least one PTH molecule or PTH substructure.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, ethosomes, ufasomes, sphingosomes, and pharmacosomes.

[0145] In another embodiment, the water insoluble controlled release PTH compound is a polymersome comprising at least one PTH molecule or PTH substructure.

[0146] In another embodiment, the water-insoluble controlled-release PTH compound comprises at least one PTH molecule non-covalently incorporated into a water-insoluble polymer. Preferably, such water insoluble polymers are 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymers, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate ... and poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinylpyrrolidone), silicone, cellulose, carbomethylcellulose, hydroxypropyl methylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate based polymers, xylan, and copolymers thereof.

[0147] In a preferred embodiment, the water-insoluble controlled-release PTH compound comprises at least one PTH molecule non-covalently incorporated into poly(lactic-co-glycolic acid) (PLGA).

[0148] In another embodiment, the water-insoluble controlled-release PTH compound comprises at least one PTH molecule covalently and reversibly conjugated to a water-insoluble polymer. Preferably, such water insoluble polymers are 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymers, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate ... and poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinylpyrrolidone), silicone, cellulose, carbomethylcellulose, hydroxypropyl methylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate based polymers, xylan, and copolymers thereof.

[0149] In one embodiment, such a water insoluble controlled release PTH compound is the conjugate DL (In the formula, -D is a PTH moiety, -L is a reversible prodrug linker moiety, -L 1 - containing said partial structure -L 1 - is linked to the PTH moiety -D via a functional group of PTH, Said-L 1 - is -L 2 -Z', optionally further substituted; -L 2 - is a single chemical bond or a spacer moiety; -Z' is a water-insoluble carrier moiety. It is a compound comprising:

[0150] Many substructures -L 2 -L 1 It is understood that -D is linked to a water-insoluble carrier -Z' and that such controlled release PTH compounds are PTH prodrugs, more specifically, PTH prodrugs linked to a carrier.

[0151] -D, -L 1 -, -L 2 Preferred embodiments of - and -Z' are as described below.

[0152] In a preferred embodiment, the controlled release PTH compound is water soluble.

[0153] In a preferred embodiment, such a water-soluble controlled release PTH compound is a compound of formula (Ia) or (Ib) [ka] (In the formula, -D is a PTH moiety, -L 1 - is a reversible prodrug linker moiety that is reversibly covalently linked to the PTH moiety -D via a functional group of PTH, -L 2 - is a single chemical bond or a spacer moiety; -Z is a water-soluble carrier moiety; x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; y is an integer selected from the group consisting of 1, 2, 3, 4 and 5. or a pharma- ceutically acceptable salt thereof.

[0154] It will be appreciated that the compounds of formula (Ia) and (Ib) are PTH prodrugs, more particularly water-soluble PTH prodrugs.

[0155] Preferably, -D has the sequence SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114 or SEQ ID NO: 115. More preferably, -D has the sequence SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 110, SEQ ID NO: 111 or SEQ ID NO: 112.

[0156] In one embodiment, -D has the sequence of SEQ ID NO:50.

[0157] In another embodiment, -D has the sequence of SEQ ID NO:52.

[0158] In another embodiment, -D has the sequence of SEQ ID NO:110.

[0159] In another embodiment, -D has the sequence of SEQ ID NO:111.

[0160] In another embodiment, -D has the sequence of SEQ ID NO:112.

[0161] Most preferably, -D has the sequence SEQ ID NO:51.

[0162] Substructure-L 1- is conjugated to a functional group in the side chain of an amino acid residue of -D, to the N-terminal amine or C-terminal carboxyl functional group of -D, or to a nitrogen atom in the backbone polypeptide chain of -D. Attachment to either the N- or C-terminus may be direct, through the corresponding amine or carboxyl functional group, respectively, or indirect, in which case the spacer moiety is first conjugated to the amine or carboxyl functional group, and the spacer moiety -L is attached to that functional group. 1 - is conjugated.

[0163] Preferably, -L 1 The amino acid residue of PTH to which - is conjugated contains a functional group selected from the group consisting of carboxylic acid, primary and secondary amines, maleimide, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isocyanate, isothiocyanate, phosphate, phosphonic acid, haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, sulfate, disulfide, vinyl sulfone, vinyl ketone, diazoalkane, oxirane, guanidine and aziridine. 1 The amino acid residue of PTH to which -L is conjugated contains a functional group selected from the group consisting of hydroxyl, primary and secondary amines, and guanidine. Even more preferably, -L 1 The amino acid residue of PTH to which - is conjugated contains primary and secondary amine functional groups. 1 The amino acid residue of PTH to which - is conjugated contains a primary amine functionality.

[0164] Substructure-L 1 When - is conjugated to a functional group of the side chain of an amino acid residue of PTH, said amino acid residue is selected from the group consisting of proteinogenic and non-proteinogenic amino acid residues.

[0165] In one embodiment, -L 1- is conjugated to a functional group in the side chain of a non-proteinogenic amino acid residue of PTH, it being understood that such non-proteinogenic amino acids are not found in the sequence of native PTH or fragments thereof, but are present only in variants and derivatives of PTH.

[0166] In another embodiment, -L 1 - is conjugated to a functional group of the side chain of a proteinogenic amino acid residue of PTH. Preferably, said amino acid is selected from the group consisting of histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid and arginine. Even more preferably, said amino acid is selected from the group consisting of lysine, aspartic acid, arginine and serine. Even more preferably, said amino acid is selected from the group consisting of lysine, arginine and serine.

[0167] In one embodiment, -L 1 - is conjugated to a functional group in the histidine side chain of PTH.

[0168] In another embodiment, -L 1 - is conjugated to a functional group in the lysine side chain of PTH.

[0169] In another embodiment, -L 1 - is conjugated to a functional group in the side chain of tryptophan of PTH.

[0170] In another embodiment, -L 1 - is conjugated to a functional group in the serine side chain of PTH.

[0171] In another embodiment, -L 1 - is conjugated to a functional group in the side chain of threonine of PTH.

[0172] In another embodiment, -L 1 - is conjugated to a functional group in the side chain of tyrosine of PTH.

[0173] In another embodiment, -L 1 - is conjugated to a functional group in the aspartic acid side chain of PTH.

[0174] In another embodiment, -L 1 - is conjugated to a functional group in the glutamic acid side chain of PTH.

[0175] In another embodiment, -L 1 - is conjugated to a functional group in the arginine side chain of PTH.

[0176] It is understood that not all PTH substructures may contain all of these amino acid residues.

[0177] In a preferred embodiment, -L 1 - is conjugated directly to the N-terminal amine functionality of PTH through the corresponding amine functionality, or indirectly, where the spacer moiety is first conjugated to the amine functionality and then the spacer moiety -L 1 Even more preferably, -L 1 - is directly conjugated to the N-terminal amine functionality of PTH.

[0178] In an equally preferred embodiment, -L 1 - is conjugated to the C-terminal amine functionality of PTH either directly through the corresponding carboxyl functionality, in which case the spacer moiety is first conjugated to the carboxyl functionality and then the spacer moiety -L 1 - is conjugated.

[0179] Most preferably, L 1 - is directly conjugated to the N-terminal amine functionality of PTH.

[0180] Substructure-L 1- may be linked to -D by any type of bond provided that it is reversible. 1 - is linked to -D by a bond selected from the group consisting of amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide and acylguanidine. Even more preferably, -L 1 - is linked to -D by a bond selected from the group consisting of amide, ester, carbamate and acylguanidine. Some of these bonds are not themselves reversible, however, in the present invention, -L 1 It is understood that the adjacent groups contained in - make these bonds reversible.

[0181] In one embodiment, -L 1 - is linked to -D via an ester bond.

[0182] In another embodiment, -L 1 - is linked to -D by a carbamate bond.

[0183] In another embodiment, -L 1 - is linked to -D by an acylguanidine.

[0184] In a preferred embodiment, -L 1 - is linked to -D via an amide bond.

[0185] Substructure-L 1 - is a reversible prodrug linker in which the drug, i.e. PTH, is released in its free form, i.e. a traceless prodrug linker. Suitable prodrug linkers are known in the art, such as 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.

[0186] 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.

[0187] Particularly preferred partial structure -L 1 - is disclosed in WO 2009 / 095479 A2. Thus, in a preferred embodiment, the moiety -L 1 - is a compound of formula (II): [ka] (In the formula, The dashed lines indicate bonds to the nitrogen, hydroxyl, or thiol of the PTH moiety -D; -X- is -C(R 4 R 4a )-, -N(R 4 )-, -O-, -C(R 4 R 4a )-C(R 5 R 5a )-, -C(R 5 R 5a )-C(R 4 R 4a )-, -C(R 4 R 4a )-N(R 6 )-, -N(R 6 )-C(R 4 R 4a )-, -C(R 4 R 4a )-O-, -OC(R 4 R 4a )- and -C(R 7 R 7a )-, X 1 is selected from the group consisting of C and S(O); -X 2 - is -C(R 8 R 8a )- and -C(R 8 R8a )-C(R 9 R 9a )-, =X 3 is selected from the group consisting of =O, =S, and =N-CN; -R 1 , -R 1a , -R 2 , -R 2a , -R 4 , -R 4a , -R 5 , -R 5a , -R 6 , -R 8 , -R 8a , -R 9 and -R 9a are independently -H and C 1-6 is selected from the group consisting of alkyl, -R 3 and -R 3a are independently -H and C 1-6 alkyl, where -R 3 and -R 3a When one or both of are other than -H, they are not -H and are not -H. 3 are linked by hybridized carbon atoms, -R 7 is -N(R 10 R 10a ) and -NR 10 -(C=O)-R 11 is selected from the group consisting of -R 7a , -R 10 , -R 10a and -R 11 are each independently -H and C 1-6 is selected from the group consisting of alkyl, In some cases, Pair-R 1a / -R 4a , -R 1a / -R 5a , -R 1a / -R 7a , -R 4a / -R 5a and -R 8a / -R 9a one or more of the following forms a chemical bond; In some cases, Pair-R 1 / -R 1a , -R 2 / -R 2a , -R 4 / -R 4a , -R 5 / -R 5a , -R 8 / -R 8a and -R 9 / -R 9a One or more of the following, together with the atoms to which they are attached, are C 3-10 forming a cycloalkyl or 3- to 10-membered heterocyclyl; In some cases, Pair-R 1 / -R 4 , -R 1 / -R 5 , -R 1 / -R 6 , -R 1 / -R 7a , -R 4 / -R 5 , -R 4 / -R 6 , -R 8 / -R 9 and -R 2 / -R 3 one or more of, together with the atoms to which they are attached, form a ring A; In some cases, -R 3 / -R 3a form, together with the nitrogen atom to which they are attached, a 3- to 10-membered heterocyclic ring; A is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; -L 1 - is -L 2 -Z or -L 2 -Z' and optionally -L 1 - is further substituted, with the proviso that the hydrogen marked with an asterisk in formula (II) is -L 2 -Z or -L 2 is not replaced by -Z' or a substituent, -L2 - is a single chemical bond or spacer, -Z is a water-soluble carrier; -Z' is a water-insoluble carrier.

[0188] Preferably, -L of formula (II) 1 - is one substructure -L 2 -Z or -L 2 -Z' is substituted.

[0189] In one embodiment, -L of formula (II) 1 - is not further substituted.

[0190] -R in formula (II) 3 / -R 3a However, when they are combined with the nitrogen atom to which they are bonded to form a 3- to 10-membered heterocycle, the atom directly bonded to the nitrogen atom is sp 3 It is understood that only such 3- to 10-membered heterocyclic rings can be formed that are hybridized carbon atoms. 3 / -R 3a and the nitrogen atom to which they are attached have the following structure: [ka] (In the formula, The dashed line is -L 1 - represents the bond to the remainder of the ring contains 3 to 10 atoms, including at least one nitrogen atom; and R # and R ## sp 3 represents a hybridized carbon atom).

[0191] It is also understood that the 3- to 10-membered heterocycle may be further substituted.

[0192] -R in formula (II) 3 / -R 3a and the nitrogen atom to which they are attached are the following: [ka] (In the formula, The dashed line indicates the bond to the rest of the molecule; -R is -H and C 1-6 alkyl).

[0193] Optionally, -L of formula (II) 1 - may be further substituted. In general, any substituent may be used as long as it does not affect the principle of cleavage, i.e., the hydrogen with an asterisk in formula (II) is not replaced and the partial structure of formula (II) [ka] The nitrogen in remains part of a primary, secondary or tertiary amine, i.e., -R 3 and -R 3a are each independently -H or sp 3 It is linked to -N< by a hybridized carbon atom.

[0194] In one embodiment, the -R 1 or -R 1a -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 2 or -R 2a -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 3 or -R 3a -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 4 -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 5 or -R 5a -L 2 -Z or -L 2In another embodiment, the -R of formula (II) is substituted with -Z'. 6 -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 7 or -R 7a -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 8 or -R 8a -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 9 or -R 9a -L 2 -Z or -L 2 In another embodiment, -R 10 -L 2 -Z or -L 2 In another embodiment, -R 11 -L 2 -Z or -L 2 -Z' is substituted.

[0195] Preferably, -X- in formula (II) is -C(R 4 R 4a )-, -N(R 4 )- and -C(R 7 R 7a )-.

[0196] In one embodiment, -X- in formula (II) is -C(R 4 R 4a )-.

[0197] In one preferred embodiment, -X- in formula (II) is -C(R 7 R 7a )-.

[0198] Preferably, -R in formula (II) 7 -NR 10 -(C=O)-R 11 It is.

[0199] Preferably, -R in formula (II) 7a is selected from -H, methyl and ethyl. Most preferably, -R in formula (II) 7a is -H.

[0200] Preferably, -R 10 is selected from -H, methyl and ethyl. Most preferably, -R 10 is methyl.

[0201] Preferably, -R 11 is selected from -H, methyl and ethyl. Most preferably, -R 11 is -H.

[0202] Preferably, -R 11 -L 2 -Z or -L 2 -Z' is substituted.

[0203] In another preferred embodiment, -X- in formula (II) is -N(R 4 )-.

[0204] Preferably, -R 4 is selected from the group consisting of -H, methyl and ethyl. 4 is -H.

[0205] Preferably, X in formula (II) 1 is C.

[0206] Preferably, =X in formula (II) 3 is =O.

[0207] Preferably, -X in formula (II) 2 - is -C(R 8 R 8a )-.

[0208] Preferably, -R in formula (II) 8 and -R 8ais independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (II) is 8 and -R 8a At least one of -R in formula (II) is -H. Even more preferably, 8 and-R 8a Both are -H.

[0209] Preferably, -R in formula (II) 1 and -R 1a is independently selected from the group consisting of -H, methyl and ethyl.

[0210] In one preferred embodiment, -R of formula (II) 1 and -R 1a At least one of -R in formula (II) is -H, and more preferably, 1 and-R 1a Both are -H.

[0211] In another preferred embodiment, -R 1 and -R 1a At least one of -R in formula (II) is methyl. 1 and-R 1a Both are methyl.

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

[0213] Preferably, -R in formula (II) 3 and -R 3a is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl.

[0214] In one preferred embodiment, -R of formula (II) 3 and -R 3a At least one of -R in formula (II) is methyl. 3 is methyl, and -R in formula (II) 3a is -H.

[0215] In another preferred embodiment, -R 3 and-R 3a Both are -H.

[0216] Preferably, -D is linked to -L by the nitrogen through the formation of an amide bond. 1 - is linked to.

[0217] In one preferred embodiment, the moiety -L 1 - is a compound of formula (IIa-i): [ka] (In the formula, The dashed line indicates the attachment of the PTH moiety, -D, to the nitrogen by forming an amide bond; -R 1 , -R 1a , -R 2 , -R 2a , -R 3 , -R 3a , -R 7 , -R 7a and -X 2 - is used as defined in relation to formula (II) having Said-L 1 - is -L 2 -Z or -L 2 -Z', and optionally -L 1 - is further substituted, with the proviso that the hydrogen marked with an asterisk in formula (IIa-i) is -L 2 -Z or -L 2 It is not replaced by -Z' or a substituent.

[0218] -R in formula (IIa-i)3 , -R 3a When one or both of are other than -H, they must have sp 3 It is understood that the linkage is through a hybridized carbon atom.

[0219] Preferably, -L of formula (IIa-i) 1 - is one substructure -L 2 -Z or -L 2 -Z' is substituted.

[0220] Preferably, the moiety -L of formula (IIa-i) 1 - is not further substituted.

[0221] Preferably, -R of formula (IIa-i) 1 and -R 1a is independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (IIa-i) is 1 and -R 1a At least one of -R in formula (IIa-i) is -H. Even more preferably, -R in formula (IIa-i) is -H. 1 and-R 1a Both are -H.

[0222] Preferably, -R of formula (IIa-i) 7 -NR 10 -(C=O)-R 11 It is.

[0223] Preferably, -R in formula (II-i) 7a is selected from -H, methyl and ethyl. Most preferably, -R in formula (II-i) 7a is -H.

[0224] Preferably, -R of formula (IIa-i) 10 is selected from -H, methyl and ethyl. Most preferably, -R in formula (IIa-i) 10 is methyl.

[0225] Preferably, -R of formula (IIa-i) 11is selected from -H, methyl and ethyl. Most preferably, -R in formula (IIa-i) 11 is -H.

[0226] Preferably, -R of formula (IIa-i) 11 -L 2 -Z or -L 2 It is replaced by -Z'.

[0227] Preferably, -X of formula (IIa-i) 2 - is -C(R 8 R 8a )-.

[0228] Preferably, -R of formula (IIa-i) 8 and -R 8a is independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (IIa-i) is 8 and -R 8a At least one of -R in formula (IIa-i) is -H. Even more preferably, 8 and-R 8a Both are -H.

[0229] Preferably, -R of formula (IIa-i) 2 and -R 2a is independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (IIa-i) is 2 and -R 2a At least one of -R in formula (IIa-i) is -H. Even more preferably, 2 and-R 2a Both are H.

[0230] Preferably, -R of formula (IIa-i) 3 and -R 3a is independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Even more preferably, -R in formula (IIa-i) is 3 and -R 3a At least one of is methyl.

[0231] Preferably, R of formula (IIa-i) 3 is -H, and -R in formula (IIa-i) 3a is methyl.

[0232] More preferably, the partial structure -L 1 - is a compound of the formula (IIa-ii): [ka] (In the formula, The dashed line indicates the attachment of the PTH moiety, -D, to the nitrogen by forming an amide bond; -R 2 , -R 2a , -R 10 , -R 11 and -X 2 - is used as defined in relation to formula (II) having Said-L 1 - is -L 2 -Z or -L 2 -Z', and optionally -L 1 - is further substituted, provided that the hydrogen marked with an asterisk in formula (IIa-ii) is -L 2 -Z or -L 2 It is not replaced by -Z' or a substituent.

[0233] -R in formula (IIa-ii) 3 , -R 3a When one or both of are other than -H, they must have sp 3 It is understood that the linkage is through a hybridized carbon atom.

[0234] Preferably, -L of formula (IIa-ii) 1 - is one substructure -L 2 -Z or -L 2 -Z' is substituted.

[0235] Preferably, the partial structure -L of formula (IIa-ii) 1 - is not further substituted.

[0236] Preferably, -X in formula (IIa-ii) 2 - is -C(R 8 R 8a )-.

[0237] Preferably, -R of formula (IIa-ii) 8 and -R 8a is independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (IIa-ii) is 8 and -R 8a At least one of -R in formula (IIa-ii) is -H. Even more preferably, 8 and-R 8a Both are -H.

[0238] Preferably, -R of formula (IIa-ii) 3 and -R 3a is independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Even more preferably, -R in formula (IIa-ii) is 3 and -R 3a At least one of is methyl.

[0239] Preferably, -R of formula (IIa-ii) 3 is -H, and -R in formula (IIa-ii) 3a is methyl.

[0240] Preferably, -R of formula (IIa-ii) 10 is selected from -H, methyl and ethyl. Most preferably, -R in formula (IIa-ii) 10 is methyl.

[0241] Preferably, -R of formula (IIa-ii) 11 is selected from -H, methyl and ethyl. Most preferably, -R in formula (IIa-ii) 11 is -H.

[0242] Preferably, -R of formula (IIa-ii) 11 -L 2-Z or -L 2 It is replaced by -Z'.

[0243] In an even more preferred embodiment, the moiety -L 1 - is represented by the formula (IIa-ii'): [ka] (In the formula, The dashed line indicates the attachment of the PTH moiety, D, to the nitrogen by forming an amide bond; The dashed line with an asterisk indicates -L 2 - indicates a bond to -R 3 , -R 3a , -R 10 and -X 2 - is used as defined in relation to formula (II) having Said-L 1 - is optionally further substituted, with the proviso that the hydrogen marked with an asterisk in formula (IIa-ii') is not replaced by a substituent.

[0244] -R in formula (IIa-ii') 3 , -R 3a When one or both of are other than -H, they must have sp 3 It is understood that the linkage is through a hybridized carbon atom.

[0245] Preferably, the partial structure -L of formula (IIa-ii′) 1 - is not further substituted.

[0246] Preferably, -X in formula (IIa-ii') 2 - is -C(R 8 R 8a )-.

[0247] Preferably, -R in formula (IIa-ii') 8 and -R 8ais independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (IIa-ii') is 8 and -R 8a At least one of -R in formula (IIa-ii') is -H. 8 and-R 8a Both are -H.

[0248] Preferably, -R in formula (IIa-ii') 3 and -R 3a is independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Even more preferably, -R in formula (IIa-ii') is 3 and -R 3a At least one of is methyl.

[0249] Preferably, -R in formula (IIa-ii') 3 is -H, and -R in formula (IIa-ii') 3a is methyl.

[0250] Preferably, -R in formula (IIa-ii') 10 is selected from -H, methyl and ethyl. Most preferably, -R in formula (IIa-ii') 10 is methyl.

[0251] Even more preferably, the moiety -L 1 - is a compound of formula (IIa-iii): [ka] where the dashed line indicates attachment of the PTH moiety, -D, to the nitrogen by forming an amide bond. having Said-L 1 - is -L 2 -Z or -L 2 -Z', Said-L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIa-iii) is -L 2 -Z or -L2 It is not replaced by -Z' or a substituent.

[0252] -R in formula (IIa-iii) 3 , -R 3a When one or both of are other than -H, they must have sp 3 It is understood that the linkage is through a hybridized carbon atom.

[0253] Preferably, -L of formula (IIa-iii) 1 - is one substructure -L 2 -Z or -L 2 -Z' is substituted.

[0254] Preferably, the moiety -L of formula (IIa-iii) 1 - is not further substituted.

[0255] Most preferably, the moiety -L 1 - is a group represented by the formula (IIa-iii'): [ka] (In the formula, The dashed line indicates the attachment of the PTH moiety, D, to the nitrogen by forming an amide bond; The dashed line with an asterisk indicates -L 2 - indicates a bond to -R 2 , -R 2a , -R 3 , -R 3a , and -X 2 - is used as defined in relation to formula (II) having Said-L 1 - is optionally further substituted, with the proviso that the hydrogen marked with an asterisk in formula (IIa-iii') is not replaced by a substituent.

[0256] -R in formula (IIa-iii') 3 , -R 3aWhen one or both of are other than -H, they must have sp 3 It is understood that the linkage is through a hybridized carbon atom.

[0257] Preferably, the partial structure -L of formula (IIa-iii') 1 - is not further substituted.

[0258] In another preferred embodiment, the moiety -L 1 - is a compound of the formula (IIb-i): [ka] (In the formula, The dashed line indicates the attachment of the PTH moiety, -D, to the nitrogen by forming an amide bond; -R 1 , -R 1a , -R 2 , -R 2a , -R 3 , -R 3a , -R 4 , and -X 2 are used as defined for formula (II). having Said-L 1 - is -L 2 -Z or -L 2 -Z', and -L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIb-i) is -L 2 -Z or -L 2 It is not replaced by -Z' or a substituent.

[0259] -R in formula (IIb-i) 3 , -R 3a When one or both of are other than -H, they must have sp 3 It is understood that the linkage is through a hybridized carbon atom.

[0260] Preferably, -L of formula (IIb-i) 1 - is one substructure -L2 -Z or -L 2 -Z' is substituted.

[0261] Preferably, the partial structure -L of formula (IIb-i) 1 - is not further substituted.

[0262] Preferably, -R of formula (IIb-i) 1 and -R 1a is independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (IIb-i) is 1 and -R 1a At least one of -R in formula (IIb-i) is methyl. 1 and-R 1a Both are methyl.

[0263] Preferably, -R of formula (IIb-i) 4 is selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (IIb-i) 4 is -H.

[0264] Preferably, -X in formula (IIb-i) 2 - is -C(R 8 R 8a )-.

[0265] Preferably, -R of formula (IIb-i) 8 and -R 8a is independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (IIb-i) is 8 and -R 8a At least one of -R in formula (IIb-i) is -H. Even more preferably, 8 and-R 8a Both are -H.

[0266] Preferably, -R of formula (IIb-i) 2 and -R 2a is independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (IIb-i) is2 and -R 2a At least one of -R in formula (IIb-i) is -H. Even more preferably, 2 and-R 2a Both are H.

[0267] Preferably, -R of formula (IIb-i) 3 and -R 3a is independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Even more preferably, -R in formula (IIb-i) is 3 and -R 3a At least one of -R in formula (IIb-i) is -H. Even more preferably, 3 and-R 3a Both are -H.

[0268] More preferably, the partial structure -L 1 - is a compound of the formula (IIb-ii): [ka] (In the formula, The dashed line indicates the attachment of the PTH moiety, -D, to the nitrogen by forming an amide bond; -R 2 , -R 2a , -R 3 , -R 3a and -X 2 - is used as defined in relation to formula (II) having Said-L 1 - is -L 2 -Z or -L 2 -Z', and optionally -L 1 - is further substituted, with the proviso that the hydrogen marked with an asterisk in formula (IIb-ii) is -L 2 -Z or -L 2 It is not replaced by -Z' or a substituent.

[0269] -R in formula (IIb-ii) 3 , -R 3aWhen one or both of are other than -H, they must have sp 3 It is understood that the linkage is through a hybridized carbon atom.

[0270] Preferably, -L of formula (IIb-ii) 1 - is one substructure -L 2 -Z or -L 2 -Z' is substituted.

[0271] Preferably, the partial structure -L of formula (IIb-ii) 1 - is not further substituted.

[0272] Preferably, -X in formula (IIb-ii) 2 - is -C(R 8 R 8a )-.

[0273] Preferably, -R in formula (IIb-ii) 8 and -R 8a is independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (IIb-ii) is 8 and -R 8a At least one of -R in formula (IIb-ii) is -H. 8 and-R 8a Both are -H.

[0274] Preferably, -R in formula (IIb-ii) 2 and -R 2a is independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (IIb-ii) is 2 and -R 2a At least one of -R in formula (IIb-ii) is -H. 2 and-R 2a Both are H.

[0275] Preferably, -R in formula (IIb-ii) 3 and -R 3ais independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Even more preferably, -R in formula (IIb-ii) is 3 and -R 3a At least one of -R in formula (IIb-ii) is -H. 3 and-R 3a Both are -H.

[0276] Even more preferably, the moiety -L 1 - is represented by the formula (IIb-ii'): [ka] (In the formula, The dashed line indicates the attachment of the PTH moiety, -D, to the nitrogen by forming an amide bond; -R 2 , -R 2a , -R 3a and -X 2 - is used as defined in relation to formula (II) having Said-L 1 - is -L 2 -Z or -L 2 -Z', and optionally -L 1 - is further substituted, with the proviso that the hydrogen marked with an asterisk in formula (IIb-ii') is -L 2 -Z or -L 2 It is not replaced by -Z' or a substituent.

[0277] -R in formula (IIb-ii') 3a If is other than -H, it must have sp 3 It is understood that the linkage is through a hybridized carbon atom.

[0278] Preferably, the partial structure -L of formula (IIb-ii′) 1 - is not further substituted.

[0279] Preferably, -X in formula (IIb-ii') 2- is -C(R 8 R 8a )-.

[0280] Preferably, -R in formula (IIb-ii') 8 and -R 8a is independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (IIb-ii') is 8 and -R 8a At least one of -R in formula (IIb-ii') is -H. 8 and-R 8a Both are -H.

[0281] Preferably, -R in formula (IIb-ii') 2 and -R 2a is independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R in formula (IIb-ii') is 2 and -R 2a At least one of -R in formula (IIb-ii') is -H. 2 and-R 2a Both are -H.

[0282] Preferably, -R in formula (IIb-ii') 3a is selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. 3a is -H.

[0283] Even more preferably, the moiety -L 1 - is a compound of the formula (IIb-iii): [ka] (In the formula, The dashed line indicates the attachment of the PTH moiety -D to the nitrogen by forming an amide bond. having Said-L 1 - is -L 2 -Z or -L 2-Z', and optionally -L 1 - is further substituted, with the proviso that the hydrogen marked with an asterisk in formula (IIb-iii) is -L 2 -Z or -L 2 It is not replaced by -Z' or a substituent.

[0284] -R in formula (IIb-iii) 3 , -R 3a When one or both of are other than -H, they must have sp 3 It is understood that the linkage is through a hybridized carbon atom.

[0285] Preferably, -L of formula (IIb-iii) 1 - is one substructure -L 2 -Z or -L 2 It is replaced by -Z'.

[0286] Preferably, the partial structure -L of formula (IIb-iii) 1 - is not further substituted.

[0287] Most preferably, the moiety -L 1 - is a compound of the formula (IIb-iii'): [ka] (In the formula, The dashed line indicates the attachment of the PTH moiety, -D, to the nitrogen by forming an amide bond; The dashed line with an asterisk indicates -L 2 - indicates a bond to having Said-L 1 - is optionally further substituted, with the proviso that the hydrogen marked with an asterisk in formula (IIb-iii') is -L 2 -Z or -L 2 It is not replaced by -Z' or a substituent.

[0288] The nitrogen adjacent to the dashed line marked with an asterisk in formula (IIb-iii') is sp3 -L by hybridized carbon atom 2 It is understood that the linker is connected to -.

[0289] Preferably, the partial structure -L of formula (IIb-iii') 1 - is not further substituted.

[0290] Another preferred substructure -L 1 - is disclosed in WO2016 / 020373A1. Thus, in another preferred embodiment, the moiety -L 1 - is a compound of formula (III): [ka] (In the formula, The dashed lines indicate attachment by forming an amide or ester bond to a primary or secondary amine or hydroxyl of the PTH moiety, -D, respectively; -R 1 , -R 1a , -R 2 , -R 2a , -R 3 and -R 3a are, independently of each other, -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, independently of each other, -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 , -R7a , -R 8 , -R 8a , -R 8b , -R 9 , -R 9a , -R 9b are, independently of each other, -H, halogen, -CN, -COOR 10 , -OR 10 , -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, wherein said -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl may be one or more -R 11 and optionally substituted with C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl includes -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 )-, Each-R 10 , -R 10a , -R 10b are independently -H, -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 alkynyl, 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl may be one or more -R 11 and wherein said C is optionally substituted with 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl includes -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 )-, Each T is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl, each T being independently selected from the group consisting of one or more of the same or different -R 11 and optionally substituted with Each-R 11 are each independently halogen, -CN, oxo (=O), -COOR 13 , -OR 13 , -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, 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R 12 , -R 12a , -R 13 , -R 13a , -R 13b are independently -H and C 1-6 alkyl, 1-6the alkyl is optionally substituted with one or more halogens which may be the same or different; In some cases, Pair-R 1 / -R 1a , -R 2 / -R 2a , -R 3 / -R 3a , -R 6 / -R 6a , -R 7 / -R 7a One or more of the following, together with the atoms to which they are attached, are C 3-10 forming a cycloalkyl or 3- to 10-membered heterocyclyl; In some cases, 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 7one or more of, together with the atoms to which they are attached, form a ring A; A is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl. having Said-L 1 - is -L 2 -Z or -L 2 -Z', and optionally -L 1 - is further substituted, -L 2 - is a single chemical bond or spacer, -Z is a water-soluble carrier; -Z' is a water-insoluble carrier.

[0291] -L in formula (III) 1 The optional further substituents of - are preferably as described above.

[0292] Preferably, -L of formula (III) 1 - is one substructure -L 2 -Z or -L 2 -Z' is substituted.

[0293] In one embodiment, -L of formula (III) 1 - is not further substituted.

[0294] -L 1 Further preferred embodiments for - are disclosed in EP 1536334 B1, WO 2009 / 009712 A1, WO 2008 / 034122 A1, WO 2009 / 143412 A2, WO 2011 / 082368 A2, and U.S. Pat. No. 8,618,124 B2, which are hereby incorporated by reference in their entirety.

[0295] -L 1Further preferred embodiments of -L are disclosed in U.S. Pat. No. 8,946,405 B2 and U.S. Pat. No. 8,754,190 B2, which are incorporated herein by reference in their entirety. Accordingly, preferred moieties -L 1 - is a compound of formula (IV): [ka] (In the formula, The dashed line indicates a bond to the PTH moiety, -D, said bond being through a functional group of -D selected from the group consisting of -OH, -SH and -NH; m is 0 or 1; -R 1 and -R 2 At least one or both of are, independently of each other, -CN, -NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, -C(O)R 3 , -S(O)R 3 , -S(O)2R 3 , and -SR 4 is selected from the group consisting of -R 1 and -R 2 is selected from the group consisting of: -H, optionally substituted alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; -R 3 is -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 9 and -N(R 9 ) 2 selected from the group consisting of -R 4is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; Each-R 5 is independently selected from the group consisting of: -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; -R 9 is selected from the group consisting of -H and optionally substituted alkyl; -Y- is absent and -X- is -O- or -S-; or -Y- is -N(Q)CH2- and -X- is -O-; Q is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; In some cases, -R 1 and R 2 may combine to form a 3- to 8-membered ring, and In some cases, both -R 9 together with the nitrogen to which they are attached form a heterocyclic ring) having Said-L 1 - is -L 2 -Z or -L 2 -Z', and optionally -L 1 - is further substituted, -L 2 - is a single chemical bond or spacer, -Z is a water-soluble carrier; -Z' is a water-insoluble carrier.

[0296] The terms used exclusively in connection with formula (IV) have the following meanings: As used herein, the term "alkyl" includes straight-chained, branched or cyclic saturated hydrocarbon groups of 1 to 8 carbons, or, in some embodiments, 1 to 6 or 1 to 4 carbon atoms.

[0297] The term "alkoxy" includes an alkyl group linked to an oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and the like.

[0298] The term "alkenyl" includes non-aromatic unsaturated hydrocarbons having a carbon-carbon double bond.

[0299] The term "alkynyl" includes non-aromatic unsaturated hydrocarbon groups having a carbon-carbon triple bond.

[0300] The term "aryl" includes aromatic hydrocarbon groups of 6 to 18 carbons, preferably 6 to 10 carbons, including groups such as phenyl, naphthyl, and anthracenyl. The term "heteroaryl" includes aromatic rings containing 3 to 15 carbon atoms and containing at least one N, O, or S atom, preferably 3 to 7 carbon atoms and containing at least one N, O, or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and the like.

[0301] 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 will be referred to as alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that an alkylene moiety is between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which it is coupled.

[0302] The term "halogen" includes bromo, fluoro, chloro and iodo.

[0303] The term "heterocyclic ring" refers to a 4-8 membered aromatic or non-aromatic ring containing from 3 to 7 carbon atoms and at least one N, O or S atom. Examples are piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine and tetrahydrofuranyl, as well as the exemplary groups provided above for the term "heteroaryl".

[0304] When the ring system is optionally substituted, suitable substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or further rings, each of which is optionally further substituted. Optional substituents for any of the groups, including those listed above, include halo, nitro, cyano, -OR, -SR, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -SOR, -SONR2, -SON2NR2, where each R is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or two R groups together with the atoms to which they are attached form a ring.

[0305] Preferably, -L in formula (IV) 1 - is one substructure -L 2 -Z or -L 2 It is replaced by -Z'.

[0306] -L 1 Further preferred embodiments of - are disclosed in WO2013 / 036857A1, which is incorporated herein by reference in its entirety. Accordingly, preferred moieties -L 1 - is a compound of formula (V): [ka] (In the formula, The dashed line indicates a bond to the PTH moiety, -D, where the bond is through the amine functionality of -D; -R 1is an optionally substituted C1-C6 linear, branched or cyclic alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an alkoxy, and -NR 5 2, -R 2 is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; -R 3 is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; -R 4 is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; Each-R 5 are independently selected from the group consisting of: -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl, or when taken together, two -R 5 can be cycloalkyl or cycloheteroalkyl) having Said-L 1 - is -L 2 -Z or -L 2 -Z', and optionally -L 1 - is further substituted, -L 2 - is a single chemical bond or spacer, -Z is a water-soluble carrier; -Z' is a water-insoluble carrier.

[0307] The terms used exclusively in connection with formula (V) have the following meanings: "Alkyl", "alkenyl" and "alkynyl" include straight-chain, branched or cyclic hydrocarbon groups of 1 to 8, or 1 to 6, or 1 to 4 carbons, 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, they contain 1 to 6 C.

[0308] "Aryl" includes aromatic hydrocarbon groups of 6 to 18 carbons, preferably 6 to 10 carbons, including groups such as phenyl, naphthyl, and anthracenyl. "Heteroaryl" includes aromatic rings containing 3 to 15 carbons and at least one N, O, or S atom, preferably 3 to 7 carbons and at least one N, O, or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and the like.

[0309] The term "substituted" refers to an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group that contains 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 linear, branched, and cyclic), lower haloalkyl (including fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl), OH, lower alkoxy (including linear, branched, and cyclic), SH, lower alkylthio (including linear, 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, thio, aryloxy ... may be selected from carbamates, thioureas, ketenes, sulfones, sulfonamides, aryls (including phenyl, naphthyl and anthracenyl), heteroaryls (including 5-membered heteroaryls such as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole and tetrazole, 6-membered heteroaryls such as pyridine, pyrimidine and pyrazine, and fused heteroaryls such as benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzisoxazole and benzisothiazole).

[0310] Preferably, -L in formula (V) 1 - is one substructure -L 2 -Z or -L 2 -Z' is substituted.

[0311] -L 1 Further preferred embodiments of -L are disclosed in U.S. Pat. No. 7,585,837 B2, which is incorporated herein by reference in its entirety. Accordingly, preferred moieties -L 1 - is a compound of formula (VI): [ka] (In the formula, The dashed line indicates a bond to the PTH moiety, -D, where the bond is through the amine functionality of -D; R 1 and R 2 are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkaryl, aralkyl, halogen, nitro, -SO3H, -SO2NHR 5 , amino, ammonium, carboxyl, PO3H2, and OPO3H2; R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl and aryl; Said-L 1 - is -L 2 -Z or -L 2 -Z', and optionally -L 1 - is further substituted, -L 2 - is a single chemical bond or spacer, -Z is a water-soluble carrier; -Z' is a water-insoluble carrier.

[0312] Suitable substituents for 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 (eg, phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (eg, aromatic 4- to 7-membered heterocycle), or halogen moiety.

[0313] The terms used exclusively in connection with formula (VI) have the following meanings: The terms "alkyl", "alkoxy", "alkoxyalkyl", "aryl", "alkaryl" and "aralkyl" refer to alkyl groups of 1 to 8, preferably 1 to 4, carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl, and aryl groups of 6 to 10 carbon atoms, such as phenyl and naphthyl. The term "halogen" includes bromo, fluoro, chloro and iodo.

[0314] Preferably, -L of formula (VI) 1 - is one substructure -L 2 -Z or -L 2 It is replaced by -Z'.

[0315] -L 1 Further preferred embodiments of -L are disclosed in WO2002 / 089789A1, which is incorporated herein by reference in its entirety. Accordingly, preferred moieties -L 1 - is a group represented by the formula (VII): [ka] (In the formula, The dashed line indicates a bond to the PTH moiety, -D, where the bond is through the amine functionality of -D; L1 is a bifunctional linking group, Y1 and Y2 are independently O, S or NR 7 and R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 3-12 Branched alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl, aryl, substituted aryl, aralkyl, C 1-6 Heteroalkyl, substituted C 1-6 Heteroalkyl, C 1-6 Alkoxy, phenoxy and C 1-6heteroalkoxy; When Ar is included in formula (VII), it is a partial structure forming a polysubstituted aromatic hydrocarbon or a polysubstituted heterocyclic group. X is a chemical bond, a moiety that is actively transported into a target cell, a hydrophobic moiety, or a combination thereof; Y is 0 or 1. having Said-L 1 - is -L 2 -Z or -L 2 -Z', and optionally -L 1 - is further substituted, -L 2 - is a single chemical bond or a spacer moiety; -Z is a water-soluble carrier; -Z' is a water-insoluble carrier.

[0316] The terms used exclusively in connection with formula (VII) have the following meanings: The term "alkyl" includes, for example, alkoxy, C 3-8 Linear, branched, substituted C, including cycloalkyl or substituted cycloalkyl 1-12 It is understood to include alkyl.

[0317] The term "substituted" shall be understood to include the addition of, as well as the replacement of, one or more atoms contained in a functional group or compound with one or more different atoms.

[0318] 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- shall be understood to include fluoro, chloro, iodo, and bromo.

[0319] Preferably, -L in formula (VII) 1 - is one substructure -L 2 -Z or -L 2 It is replaced by -Z'.

[0320] In another preferred embodiment, -L 1 - is a substructure of formula (VIII) [ka] (In the formula, The dashed line with an asterisk indicates attachment to the nitrogen of the PTH moiety, -D, by forming an amide bond; The unmarked dashed line is -L 1 - indicates the bond to the remainder of Including, Said-L 1 - is -L 2 -Z or -L 2 -Z', and optionally -L 1 - is further substituted, -L 2 - is a single chemical bond or spacer, -Z is a water-soluble carrier; -Z' is a water-insoluble carrier.

[0321] Preferably, -L of formula (VIII) 1 - is one substructure -L 2 -Z or -L 2 -Z' is substituted.

[0322] In one embodiment, -L of formula (VIII) 1 - is not further substituted.

[0323] In another preferred embodiment, -L 1 - is a substructure of formula (IX) [ka] (In the formula, The dashed line with an asterisk indicates attachment by forming a carbamate bond to the nitrogen of the PTH moiety, -D; The unmarked dashed line is -L 1 - indicates the bond to the remainder of Including, Said-L 1 - is -L 2 -Z or -L 2 -Z', and optionally -L 1 - is further substituted, -L 2 - is a single chemical bond or spacer, -Z is a water-soluble carrier; -Z' is a water-insoluble carrier.

[0324] Preferably, -L of formula (IX) 1 - is one substructure -L 2 -Z or -L 2 -Z' is substituted.

[0325] In one embodiment, -L of formula (IX) 1 - is not further substituted.

[0326] In the prodrugs for use in the present invention, -L 2 - is a chemical bond or a spacer moiety.

[0327] In one embodiment, -L 2 - is a chemical bond.

[0328] In another embodiment, -L 2 - is a spacer moiety.

[0329] -L 2 If - is other than a single chemical bond, -L 2 - is 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, wherein -T-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl may be one or more -R y2 and optionally substituted with C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl includes -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(Ry3 )C(O)N(R y3a )- and -OC(O)N(R y3 )-, -R y1 and -R y1a are, independently of each other, -H, -T, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 alkynyl, 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl may be one or more of the same or different -Ry 2 and wherein said C is optionally substituted with 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl includes -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 )-, Each T is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl, each T being independently selected from the group consisting of one or more of the same or different -R y2 and optionally substituted with Each R y2 are independently halogen, -CN, oxo (=O), -COOR y5 , -OR y5 , -C(O)Ry5 , -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, 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b are independently -H and C 1-6 alkyl, 1-6 The alkyl is optionally substituted with one or more halogens, which may be the same or different.

[0330] -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(Ry1 )-, -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, wherein -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl may be one or more -R y2 Optionally substituted with C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl includes -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 )-, -R y1 and -R y1a are, independently of each other, -H, -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 alkynyl, 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl may be one or more -R y2and wherein said C is optionally substituted with 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl includes -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 )-, Each T is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl, each T being independently selected from the group consisting of one or more of the same or different -R y2 and optionally substituted with -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 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)Ry5a , -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 is optionally substituted with one or more halogens which may be the same or different; Each-R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b are independently -H and C 1-6 alkyl, 1-6 The alkyl is optionally substituted with one or more halogens, which may be the same or different.

[0331] -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, wherein -T-, C1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl may be one or more -R y2 and optionally substituted with C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl includes -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 )-, -R y1 and -R y1a are independently -H, -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 alkynyl, Each T is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; -R y2 are independently halogen and C 1-6 is selected from the group consisting of alkyl, 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,1-6 The alkyl is optionally substituted with one or more halogens, which may be the same or different.

[0332] Even more preferably, -L 2 - is -O-, -T- and -C(O)N(R y1 )-, optionally interrupted by one or more groups independently selected from 1-20 is an alkyl chain, 1-20 The alkyl chains are -OH, -T and -C(O)N(R y6 R y6a ) wherein said -R y1 , -R y6 , -R y6a are independently H and C 1-4 alkyl, wherein T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 It is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl.

[0333] Preferably, -L 2 has a molecular weight in the range of 14 g / mol to 750 g / mol.

[0334] Preferably, -L 2 - comprises a substructure selected from the following: [ka] TIFF0007646888000034.tif93164 (in the formula, The dashed line is -L 2 -, -L 1 each of -, -Z and / or -Z' represents a bond to the remainder; -R and -R a are each independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.

[0335] In one preferred embodiment, -L 2 - has a chain length of 1 to 20 atoms.

[0336] Substructure-L 2 As used herein, the term "chain length" refers to -L 1 -L at the shortest connection between - and -Z 2 -Refers to the number of atoms.

[0337] Preferably, -L 2 - is a group represented by the formula (i) [ka] (In the formula, The dashed line with an asterisk indicates -L 1 - indicates a bond to The unmarked dashed line indicates a bond to -Z or -Z'; n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18. and optionally, this moiety of formula (i) is further substituted.

[0338] Preferably, n in formula (i) is selected from the group consisting of 3, 4, 5, 6, 7, 8, and 9. Even more preferably, n in formula (i) is 4, 5, 6 or 7. In one embodiment, n in formula (i) is 4. In another embodiment, n in formula (i) is 5. In another embodiment, n in formula (i) is 6.

[0339] In another preferred embodiment, the moiety -L 1 -L 2 is selected from the group consisting of: [ka] (In the formula, The unmarked dashed line indicates attachment to the nitrogen of the PTH moiety, -D, by forming an amide bond; The dashed line with an asterisk indicates the bond to -Z or -Z').

[0340] In one preferred embodiment, the moiety -L 1 -L 2 -teeth, [ka] TIFF0007646888000038.tif61122 (in the formula, The unmarked dashed line indicates attachment to the nitrogen of the PTH moiety, -D, by forming an amide bond; The dashed line with an asterisk indicates a bond to -Z or -Z'. is selected from the group consisting of:

[0341] In a preferred embodiment, the moiety -L 1 -L2- has the formula (IIca-ii).

[0342] In another preferred embodiment, the moiety -L 1 -L 2 has the formula (IIcb-iii).

[0343] Preferably, the controlled release PTH compound for use in the present invention has the formula (Ia) where x=1.

[0344] Carrier-Z is C 8-24Preferably, -Z is a polymer, preferably 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate ... and poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinylpyrrolidone), silicone, cellulose, carbomethylcellulose, hydroxypropyl methylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate based polymers, xylan, and copolymers thereof.

[0345] Preferably, -Z has a molecular weight in the range of 5 to 200 kDa. Even more preferably, -Z 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 has a molecular weight of about 20 kDa. In another equally preferred embodiment, -Z has a molecular weight of about 40 kDa.

[0346] In one embodiment, such water-soluble carrier-Z comprises a protein.Preferred protein is selected from the group consisting of carboxyl-terminal polypeptide of chorionic gonadotropin as described in US Patent Application Publication No. 2012 / 0035101 A1, which is incorporated herein by reference, albumin, XTEN sequence as described in WO 2011123813 A2, which is incorporated herein by reference, proline / alanine random coil sequence as described in WO 2011 / 144756 A1, which is incorporated herein by reference, proline / alanine / serine random coil sequence as described in WO 2008 / 155134 A1 and WO 2013 / 024049 A1, which are incorporated herein by reference, and Fc fusion protein.

[0347] In one embodiment, -Z is polysarcosine.

[0348] In another preferred embodiment, -Z comprises poly(N-methylglycine).

[0349] In particularly preferred embodiments, -Z comprises a random coil protein substructure.

[0350] In a preferred embodiment, -Z comprises one random coil protein substructure.

[0351] In another preferred embodiment, -Z comprises two random coil protein substructures.

[0352] In another preferred embodiment, -Z comprises three random coil protein substructures.

[0353] In another preferred embodiment, -Z comprises four random coil protein substructures.

[0354] In another preferred embodiment, -Z comprises five random coil protein substructures.

[0355] In another preferred embodiment, -Z comprises six random coil protein substructures.

[0356] In another preferred embodiment, -Z comprises seven random coil protein substructures.

[0357] In another preferred embodiment, -Z comprises eight random coil protein substructures.

[0358] Preferably, such random coil protein substructures comprise at least 25 amino acid residues and at most 2000 amino acids. Even more preferably, such random coil protein substructures comprise at least 30 amino acid residues and at most 1500 amino acid residues. Even more preferably, such random coil protein substructures comprise at least 50 amino acid residues and at most 500 amino acid residues.

[0359] In a preferred embodiment, -Z comprises a random coil protein substructure 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 said random coil protein substructure 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 random coil protein substructure are proline residues. Preferably, such random coil protein substructures are as described in WO 2011 / 144756 A1, the entire contents of which are incorporated herein by reference. Even more preferably, -Z comprises at least one substructure 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, as disclosed in WO 2011 / 144756, which is incorporated herein by reference. Such random coil protein containing alanine and proline containing substructures will be referred to as "PA" or "PA substructures".

[0360] Thus, -Z includes a PA moiety.

[0361] In an equally preferred embodiment, -Z comprises a random coil protein substructure, 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 said random coil protein substructure 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 random coil protein substructure are proline residues. Preferably, such random coil protein substructures are as described in WO 2008 / 155134 A1, the entire contents of which are incorporated herein by reference. Even more preferably, -Z comprises at least one substructure 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 WO 2008 / 155134 A1, which is incorporated herein by reference. Substructures that include such random coil protein substructures containing alanine, serine and proline will be referred to as "PAS" or "PAS substructures".

[0362] Thus, -Z contains a PAS moiety.

[0363] In an equally preferred embodiment, -Z comprises a random coil protein substructure, wherein 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 said random coil protein substructure are selected from alanine, glycine and proline. A substructure comprising such a random coil protein substructure comprising alanine, glycine and proline will be referred to as "PAG" or "PAG substructure".

[0364] Thus, -Z includes a PAG moiety.

[0365] In an equally preferred embodiment, -Z comprises a random coil protein substructure, wherein 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 said random coil protein substructure are selected from proline and glycine. A substructure comprising such a random coil protein substructure containing proline and glycine will be referred to as "PG" or "PG substructure".

[0366] Preferably, such a PG moiety comprises a moiety of formula (a-0): [(Gly) p -Pro-(Gly) q ] r (a-0) (In the formula, 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 ranging from 10 to 1000; However, at least one of p and q is at least 1.

[0367] Preferably, p in formula (a-0) is selected from the group consisting of 1, 2, and 3.

[0368] Preferably, q in formula (a-0) is selected from 0, 1 and 2.

[0369] Even more preferably, the PG moiety has the sequence of SEQ ID NO: 122: GGPGGPGPGGPGGPGPGGPG Includes.

[0370] Even more preferably, the PG moiety has the sequence of formula (a-0-a): (GGPGGPGPGGPGGPGPGGPG) v (a-0-a) wherein v is an integer ranging from 1 to 50.

[0371] It is understood that the sequence of formula (a-0-a) includes repeats of v of the sequence of SEQ ID NO:122.

[0372] Thus, -Z contains a PG moiety.

[0373] In an equally preferred embodiment, -Z comprises a random coil protein substructure, wherein 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 said random coil protein substructure are selected from alanine, glycine, serine, threonine, glutamate and proline. Preferably, such a random coil protein substructure is as described in WO 2010 / 091122 A1, which is incorporated herein by reference. Even more preferably, -Z comprises SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184, as disclosed in WO 2010 / 091122 A1, which is incorporated herein by reference; 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, 19, 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.Substructures that include such random coil protein substructures that include alanine, glycine, serine, threonine, glutamate, and proline are referred to as "XTEN" or "XTEN substructures" consistent with their designation in WO 2010 / 091122 A1.

[0374] Thus, -Z includes an XTEN moiety.

[0375] In another preferred embodiment, -Z comprises a fatty acid derivative. Preferred fatty acid derivatives are those disclosed in WO 2005 / 027978 A2 and WO 2014 / 060512 A1, which are incorporated herein by reference.

[0376] In another preferred embodiment, -Z is a hyaluronic acid based polymer.

[0377] In one embodiment, -Z is a carrier as disclosed in WO 2012 / 02047 A1, which is incorporated herein by reference.

[0378] In another embodiment, -Z is a carrier as described in WO 2013 / 024048 A1, which is incorporated herein by reference.

[0379] In another preferred embodiment, -Z is a PEG-based polymer, such as a linear, branched, or multi-arm PEG-based polymer.

[0380] In one embodiment, -Z is a linear PEG-based polymer.

[0381] In another embodiment, -Z is a multi-arm PEG-based polymer. Preferably, -Z is a multi-arm PEG-based polymer having at least four PEG-based arms.

[0382] Preferably, such a multi-arm PEG-based polymer-Z comprises multiple moieties -L 2 -L 1-D, and preferably each of the moieties -L 2 -L 1 -D is linked to the end of an arm, preferably to the end of an arm. Preferably, such a multi-arm PEG-based polymer -Z has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 moieties -L 2 -L 1 Even more preferably, such a multi-arm PEG-based polymer -Z is linked to 2, 3, 4, 6 or 8 moieties -L. 2 -L 1 Even more preferably, such a multi-arm PEG-based polymer -Z is linked to 2, 4 or 6 moieties -L. 2 -L 1 and even more preferably, such multi-arm PEG-based polymer-Z is linked to 4 or 6 moieties -L 2 -L 1 -D, and most preferably such a multi-arm PEG-based polymer-Z is linked to four moieties -L 2 -L 1 -Connected to D.

[0383] Preferably, such a multi-arm PEG-based polymer-Z is a multi-arm PEG derivative, such as a 4-arm-PEG derivative, in particular a 4-arm-PEG containing a pentaerythritol core, an 8-arm-PEG derivative containing a hexaglycerin core, and an 8-arm-PEG derivative containing a tripentaerythritol core, as listed, for example, in the product list of JenKem Technology, USA (obtained by download from http: / / www.jenkemusa.com / Pages / PEGProducts.aspx on December 18, 2014). More preferably, the water-soluble PEG-based carrier-Z is 4-arm PEG amine containing a pentaerythritol core: [ka] (n is in the range of 20 to 500), 8-arm PEG amine with a hexaglycerol core: [ka] (n is in the range of 20 to 500, R=hexaglycerol or tripentaerythritol core structure), and 6-arm PEG amines containing a sorbitol or dipentaerythritol core: [ka] (n is in the range of 20 to 500, R = containing a sorbitol or dipentaerythritol core The dashed lines in these formulas indicate the bond to the remainder of the PTH prodrug.

[0384] In a preferred embodiment, -Z is a branched PEG-based polymer. In one embodiment, -Z is a branched PEG-based polymer having 1, 2, 3, 4, 5 or 6 branch points. Preferably, -Z is a branched PEG-based polymer having 1, 2 or 3 branch points. In one embodiment, -Z is a branched PEG-based polymer having 1 branch point. In another embodiment, -Z is a branched PEG-based polymer having 2 branch points. In another embodiment, -Z is a branched PEG-based polymer having 3 branch points.

[0385] The branch points are preferably selected from the group consisting of -N<, -CH< and >C<.

[0386] Preferably, such branched PEG-based moieties-Z have a molecular weight of at least 10 kDa.

[0387] In one embodiment, such branched moiety-Z has a molecular weight in the range of 10 kDa to 500 kDa, more preferably in the range of 10 kDa to 250 kDa, even more preferably in the range of 10 kDa to 150 kDa, even more preferably in the range of 12 kDa to 100 kDa, and most preferably in the range of 15 kDa to 80 kDa.

[0388] Preferably, such branched substructure-Z has a molecular weight in the range of 10 kDa to 80 kDa. In one embodiment, the molecular weight is about 10 kDa. In another embodiment, the molecular weight of such branched substructure-Z is about 20 kDa. In another embodiment, the molecular weight of such branched substructure-Z is about 30 kDa. In another embodiment, the molecular weight of such branched substructure-Z is about 40 kDa. In another embodiment, the molecular weight of such branched substructure-Z is about 50 kDa. In another embodiment, the molecular weight of such branched substructure-Z is about 60 kDa. In another embodiment, the molecular weight of such branched substructure-Z is about 70 kDa. In another embodiment, the molecular weight of such branched substructure-Z is about 80 kDa. Most preferably, such branched substructure-Z has a molecular weight of about 40 kDa.

[0389] Preferably, -Z or -Z' comprises the following moiety: [ka]

[0390] In an equally preferred embodiment, -Z comprises an amide bond.

[0391] Preferably, -Z comprises a moiety of formula (a): [ka] (In the formula, The dashed line is -L 2 represents a bond to - or to the remainder of -Z, BP ais a branch point selected from the group consisting of -N<, -CR< and >C<, -R is -H and C 1-6 is selected from the group consisting of alkyl, a is BP a is 0 when -N< or -CR<, and n is BP a 1 if >C<, -S a -, -S a' -, -S a'' -and-S a''' - are, independently of each other, a chemical bond or C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 alkynyl, 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl may be one or more -R 1 and wherein said C is optionally substituted with 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl includes -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 phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl, each -T- being independently selected from the group consisting of one or more of the same or different -R1 and optionally substituted with Each-R 1 are independently 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, 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R 2 , -R 2a , -R 3 , -R 3a and -R 3b are independently -H and C 1-6 alkyl, 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; -P a' , -P a'' and -P a'''are independently polymeric substructures).

[0392] In one embodiment, the BP of formula (a) a is -N<.

[0393] In another embodiment, the BP of formula (a) a is >C<.

[0394] In a preferred embodiment, the BP of formula (a) a is -CR<. Preferably, -R is -H. Thus, a in formula (a) is preferably 0.

[0395] In one embodiment, the -S a - is a chemical bond.

[0396] In another embodiment, the -S a - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 alkynyl, 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl includes -T-, -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 )-, where -T- is 3- to 10-membered heterocyclyl, -R 4 and -R 4a is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl.

[0397] Preferably, the -S of formula (a) a - is C 1-10 alkyl, optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)-, and -O-.

[0398] In one embodiment, the -S a' - is a chemical bond.

[0399] In another embodiment, the -S a' - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 alkynyl, 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl includes -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 )-, wherein said -R 4 and -R 4a is independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. a' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, which include -O-, -C(O)-, and -C(O)N(R 4 )-.

[0400] In one embodiment, the -S a'' - is a chemical bond.

[0401] In another embodiment, the -S a'' - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 alkynyl, 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl includes -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 )-, wherein said -R 4 and -R 4a is independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. a'' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, which include -O-, -C(O)-, and -C(O)N(R 4 )-.

[0402] In one embodiment, the -S a''' - is a chemical bond.

[0403] In another embodiment, the -S a''' - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 alkynyl,1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl includes -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 )-, wherein said -R 4 and -R 4a is independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. a''' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, which include -O-, -C(O)-, and -C(O)N(R 4 )-.

[0404] Preferably, -P of formula (a) a' , -P a'' and -P a'''are, independently, 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate ... and poly(propyloxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinylpyrrolidone), silicone, cellulose, carbomethylcellulose, hydroxypropylmethylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate based polymers, xylan, and copolymers thereof.

[0405] More preferably, -P of formula (a) a' , -P a'' and -P a''' Independently, the -P of formula (a) contains a PEG-based moiety. a' , -P a'' and -P a'''comprises, independently, a PEG-based moiety that comprises at least 20% PEG, 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.

[0406] Preferably, P of formula (a) a' , -P a'' and -P a''' independently have a molecular weight in the range of 5 kDa to 50 kDa, more preferably in the range of 5 kDa to 40 kDa, even more preferably in the range of 7.5 kDa to 35 kDa, even more preferably in the range of 7.5 to 30 kDa, and even more preferably in the range of 10 to 30 kDa.

[0407] In one embodiment, P of formula (a) a' , -P a'' and -P a''' has a molecular weight of approximately 5 kDa.

[0408] In another embodiment, P of formula (a) a' , -P a'' and -P a''' has a molecular weight of approximately 7.5 kDa.

[0409] In another embodiment, P of formula (a) a' , -P a'' and -P a''' has a molecular weight of approximately 10 kDa.

[0410] In another embodiment, P of formula (a) a' , -P a'' and -P a''' has a molecular weight of approximately 12.5 kDa.

[0411] In another embodiment, P of formula (a) a' , -P a'' and -P a''' has a molecular weight of approximately 15 kDa.

[0412] In another embodiment, P of formula (a) a' , -P a'' and -P a''' has a molecular weight of approximately 20 kDa.

[0413] In one embodiment, -Z comprises one moiety of formula (a).

[0414] In another embodiment, -Z comprises two moieties of formula (a).

[0415] In another embodiment, -Z comprises three moieties of formula (a).

[0416] Preferably, -Z is a moiety of formula (a).

[0417] More preferably, -Z comprises a moiety of formula (b): [ka] (In the formula, The dashed line is -L 2 represents a bond to - or to the remainder of -Z, m and p each independently represent an integer in the range of 150 to 1000, preferably an integer in the range of 150 to 500, more preferably an integer in the range of 200 to 500, and most preferably an integer in the range of 400 to 500).

[0418] Preferably, m and p in formula (b) are the same integer.

[0419] Most preferably, m and p in formula (b) are about 450.

[0420] Preferably, -Z is a moiety of formula (b).

[0421] Carrier-Z' is a water-insoluble polymer, more preferably a hydrogel. Preferably, such hydrogel is selected from the group consisting of 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate ... hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinylpyrrolidone), silicone, cellulose, carbomethylcellulose, hydroxypropyl methylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate based polymers, xylan, and copolymers thereof.

[0422] When Carrier-Z' is a hydrogel, Carrier-Z' is preferably a hydrogel containing PEG or hyaluronic acid. Most preferably, such a hydrogel contains PEG.

[0423] Even more preferably, Carrier-Z' is a hydrogel as described in WO 2006 / 003014 A2, WO 2011 / 012715 A1 or WO 2014 / 056926 A1, the entireties of which are incorporated herein by reference.

[0424] In another embodiment, -Z' is a polymer network formed by physical aggregation of polymer chains, said physical aggregation preferably resulting from hydrogen bonding, crystallization, helix formation or complexation. In one embodiment, such a polymer network is a thermogelling polymer.

[0425] When the controlled release PTH compound for use in the present invention is a prodrug, its total mass is preferably at least 10 kDa, such as at least 12 kDa, such as at least 15 kDa, such as at least 20 kDa, or such as at least 30 kDa.When the controlled release PTH compound is a water-soluble prodrug, its total mass is preferably at most 250 kDa, such as at most 200 kDa, 180 kDa, 150 kDa, or 100 kDa.When the controlled release PTH compound is water-insoluble, it is understood that no meaningful upper molecular weight limit can be obtained.

[0426] In a preferred embodiment, the controlled release PTH compound has the formula (IIe-i): [ka] (In the formula, The unmarked dashed line indicates attachment to the nitrogen of the PTH moiety, -D, by forming an amide bond; Dashed lines with asterisks represent substructures [ka] represents a bond to m and p are independently integers ranging from 400 to 500.

[0427] Preferably, -D is attached to the PTH prodrug of formula (IIe-i) through the N-terminal amine functionality of the PTH moiety.

[0428] In another preferred embodiment, the PTH prodrug for use in the present invention has the formula (IIf-i): [ka] (In the formula, The unmarked dashed line indicates attachment to the nitrogen of the PTH moiety, -D, by forming an amide bond; Dashed lines with asterisks represent substructures [ka] represents a bond to m and p are independently integers ranging from 400 to 500.

[0429] Preferably, -D is attached to the PTH prodrug of formula (IIf-i) through the N-terminal amine functionality of the PTH moiety.

[0430] In preferred embodiments, the residual activity of the controlled release PTH prodrug form is less than 10%, more preferably less than 1%, even more preferably less than 0.1%, even more preferably less than 0.01%, even more preferably less than 0.001%, and most preferably less than 0.0001%.

[0431] The term "residual activity" as used herein refers to the activity exhibited by a PTH prodrug with a PTH moiety bound to a carrier, relative to the activity exhibited by the corresponding free PTH. In this context, "activity" refers to binding to the activation domain of the PTH / PTHrP1 receptor, which results in the activation of adenylate cyclase to generate cAMP, phospholipase C to generate intracellular calcium, or the activation of osteoblast expression of RANKL (which binds to RANK (receptor activator of nuclear factor kB)) on osteoclasts. It is understood that the measurement of the residual activity of a PTH prodrug for use in the present invention requires time for a certain amount of PTH to be released from the PTH prodrug, and such released PTH may distort the measurement results of the PTH prodrug. Therefore, it is customary to test the residual activity of a prodrug using a conjugate in which the drug moiety, in this case PTH, is irreversibly, i.e. stably, bound to a carrier, and which is as close as possible to the structure of the PTH prodrug for which the residual activity is to be measured.

[0432] Preferably, a pharmaceutical composition comprising at least one controlled release PTH compound for use according to the invention has a pH in the range of pH 3 to pH 8. More preferably, the pharmaceutical composition has a pH in the range of pH 4 to pH 6. Most preferably, the pharmaceutical composition has a pH in the range of pH 4 to pH 5.

[0433] In one embodiment, the pharmaceutical composition comprising at least one controlled release PTH compound for use in the present invention is a liquid or suspension formulation. It is understood that said pharmaceutical composition is a suspension formulation when the controlled release PTH compound for use in the present invention is water-insoluble.

[0434] In another embodiment, the pharmaceutical composition comprising at least one controlled release PTH compound for use in the present invention is a dry formulation that is reconstituted prior to administration to a patient.

[0435] Such liquid, suspension, dry or reconstituted pharmaceutical compositions comprise at least one excipient. Excipients used in parenteral formulations can be classified, for example, as buffers, isotonicity adjusting agents, preservatives, stabilizers, absorption inhibitors, oxidation protection agents, thickening / viscosifying agents, or other auxiliary agents. However, in some cases, an excipient may have a dual or triple function. Preferably, the at least one excipient included in the pharmaceutical composition for use according to the invention is selected from the group consisting of: (i) Buffers: physiologically acceptable buffers to maintain pH within a desired range, such as sodium phosphate, bicarbonate, succinate, histidine, citrate and acetate, sulfate, nitrate, chloride, pyruvate. Acid suppressants, such as Mg(OH)2 or ZnCO3, may also be used; (ii) Isotonicity adjusting agents: to minimize pain that may result from cell damage due to osmotic pressure differences at the injection depot. Glycerin and sodium chloride are examples. Effective concentrations can be determined by osmometry using an assumed osmolality of 285-315 mOsmol / kg for serum; (iii) Preservatives and / or antimicrobial agents: Multi-dose parenteral formulations require the addition of preservatives in sufficient concentrations to minimize the patient's risk of infection upon injection, and corresponding regulatory requirements have been 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; (iv) Stabilizers: stabilization is achieved by enhancing the protein stabilizing power, by destabilizing the denatured state, or by direct binding of excipients 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, dendrimers, PEG or PVP, or protamine or HSA, may be used; (v) Absorption inhibitors: mainly ionic or non-ionic surfactants or other proteins or soluble polymers, such as poloxamer (Pluronic F-68), PEG dodecyl ether (Brij 35), polysorbate 20 and 80, dextran, polyethylene glycol, PEG-polyhistidine, BSA and HSA, and gelatin, are used to coat or competitively adsorb to the inner surface of the formulation container. The excipient concentration and type selected depends on the effect to be avoided, but typically a monolayer of surfactant is formed at the interface just above the CMC value; (vi) Oxidant protection agents: 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; (vii) Thickening or viscosity increasing agents: in the case of suspensions, they retard settling of particles in vials and syringes, are used to aid mixing and resuspension of the particles, and to make the suspension easier to inject (i.e., less force on the syringe plunger). Suitable thickening or viscosity increasing agents are, for example, carbomer thickeners, such as Carbopol 940, Carbopol Ultrez 10; cellulose derivatives, such as hydroxypropylmethylcellulose (hypromellose, HPMC) or diethylaminoethylcellulose (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), terpolymers of D,L-lactide, glycolide and caprolactone; poloxamers; hydrophilic poly(oxyethylene) blocks and hydrophobic poly(oxypropylene) blocks to form poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) triblocks (e.g., Pluronic®); polyether ester copolymers, such as polyethylene glycol terephthalate / polybutylene terephthalate copolymers; sucrose acetate isobutyrate (SAIB); dextran or its derivatives. conductors; combinations of dextran and PEG; polydimethylsiloxane; collagen; chitosan; polyvinyl alcohol (PVA) and derivatives; polyalkylimides; poly(acrylamide-co-diallyldimethylammonium (DADMA)); polyvinylpyrrolidone (PVP); glycosaminoglycans (GAGs), 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 poloxamers mentioned above may exhibit inverse thermogelation behavior (a fluid state at room temperature to facilitate administration, and a gel state above the sol-gel transition temperature at body temperature after injection); (viii) Spreading or Diffusion Agents: regulate the permeability of connective tissue by hydrolysis of components of the extracellular matrix in the interstitial space (e.g., but not limited to, hyaluronic acid, a polysaccharide found in the intercellular spaces of connective tissue). Spreading agents, such as, but not limited to, hyaluronidase, temporarily reduce the viscosity of the extracellular matrix, facilitating the diffusion of injected drugs; and (ix) Other auxiliaries: wetting agents, viscosity modifiers, antibiotics, hyaluronidase, etc. Hyaluronic acid and acids and bases such as sodium hydroxide are auxiliaries required for pH adjustment during production.

[0436] A further aspect of the invention is a method for treating, managing, delaying or preventing one or more conditions that can be treated, managed, delayed or prevented with PTH in a mammalian patient, comprising the step of administering a pharmaceutical composition comprising at least one controlled-release PTH compound or a pharma- ceutical acceptable salt, hydrate or solvate thereof no more than once every 24 hours, at a dosage of said controlled-release PTH compound that corresponds to no more than 70% of the molar equivalent dose required to maintain serum calcium within normal levels over a 24-hour period for PTH 1-84 administered at the same dosing frequency.

[0437] Preferably, the mammalian patient is a human patient.

[0438] For example, preferred embodiments of the controlled release PTH compound, the administration frequency, ie the time between two injections, the administration method, and the dosage are as described above.

[0439] Preferably, the conditions that can be treated, managed, delayed or prevented with PTH are selected from the group consisting of hypoparathyroidism, hyperphosphatemia, osteoporosis, fracture repair, osteomalacia, osteomalacia and osteoporosis in patients with hypophosphatasia, steroid-induced osteoporosis, male osteoporosis, arthritis, osteoarthritis, osteogenesis imperfecta, fibrous dysplasia, rheumatoid arthritis, Paget's disease, hypercalcemia associated with malignant tumors, osteopenia, periodontal disease, bone fracture, alopecia, chemotherapy-induced alopecia, and thrombocytopenia. More preferably, the conditions that can be treated, managed, delayed or prevented with PTH are selected from the group consisting of hypoparathyroidism, hyperphosphatemia, fracture repair, arthritis, osteoarthritis, rheumatoid arthritis, osteopenia, periodontal disease, bone fracture, alopecia, chemotherapy-induced alopecia, and thrombocytopenia.

[0440] Most preferably, the condition is hypoparathyroidism. EXAMPLES

[0441] Materials and Methods Side-chain protected PTH(1-34) (SEQ ID NO:51) on TCP resin with a Boc-protected N-terminus and an ivDde-protected side chain of Lys26 (synthesized with the Fmoc strategy) was obtained from a custom peptide synthesis provider.

[0442] Side-chain protected PTH(1-34) on TCP resin with an Fmoc-protected N-terminus (synthesized with the Fmoc strategy) was obtained from a custom peptide synthesis provider.

[0443] PEG 2x20 kDa maleimide, Sunbright GL2-400MA, was purchased from NOF Europe NV, Grobbendonk, Belgium. S-Trityl-6-mercaptohexanoic acid was purchased from Polypeptide, Strasbourg, France. HATU was obtained from Merck Biosciences GmbH, Schwalbach / Ts, Germany. Fmoc-N-Me-Asp(OBn)-OH was obtained from Peptide International Inc., Louisville, KY, USA. Fmoc-Aib-OH was purchased from Iris Biotech GmbH, Marktredwitz, Germany. All other chemicals and reagents were purchased from Sigma Aldrich GmbH, Taufkirchen, Germany, unless a different supplier is named.

[0444] Compound 11a (examples 11-15) was synthesized according to the procedure described in patent WO29095479A2, example 1.

[0445] Syringes equipped with polyethylene frits (MultiSynTech GmbH, Witten, Germany) were used as reaction vessels or for washing steps of the peptide resin.

[0446] General procedure for removal of ivDde protecting group from side-chain protected PTH on resin: The resin was pre-swollen in DMF for 30 min and the solvent was discarded. The ivDde group was removed by incubating the resin with DMF / hydrazine hydrate 4 / 1 (v / v, 2.5 mL / g resin) for 8 x 15 min. A fresh DMF / hydrazine hydrate solution was used for each step. Finally, the resin was washed with DMF (10 x), DCM (10 x) and dried under vacuum.

[0447] General procedure for removal of the Fmoc protecting group from on-resin protected PTH: The resin was pre-swollen in DMF for 30 min and the solvent was discarded. The Fmoc group was removed by incubating the resin with DMF / piperidine / DBU 96 / 2 / 2 (v / v / v, 2.5 mL / g resin) for 3×10 min. A fresh DMF / piperidine / DBU solution was used for each step. Finally, the resin was washed with DMF (10×), DCM (10×) and dried under vacuum.

[0448] RP-HPLC purification: For preparative RP-HPLC, a Waters 600 controller and a 2487 Dual Absorbance Detector were used, equipped with the following columns: Waters XBridge™ BEH300 Prep C18 5 μm, 150×10 mm, flow rate 6 mL / min, or Waters XBridge™ BEH300 Prep C18 10 μm, 150×30 mm, flow rate 40 mL / min. A linear gradient of solvent system A (water containing 0.1% TFA v / v) and solvent system B (acetonitrile containing 0.1% TFA v / v) was used. If not otherwise stated, the HPLC fractions containing the product were pooled and lyophilized.

[0449] Flash Chromatography Flash chromatography purification was performed on an Isolera One system from Biotage AB, Sweden using Biotage KP-Sil silica cartridges with n-heptane and ethyl acetate as eluents. Products were detected at 254 nm.

[0450] Ion exchange chromatography: Ion exchange chromatography (IEX) was performed using an Amersham Bioscience AEKTAbasic system (Amersham Bioscience / GE Healthcare) equipped with a MacroCap SP cation exchange column. 17 mM acetic acid pH 4.5 (solvent A) and 17 mM acetic acid, 1 M NaCl, pH 4.5 (solvent B) were used as mobile phases.

[0451] Size Exclusion Chromatography: Size exclusion chromatography (SEC) was performed using an Amersham Bioscience AEKTAbasic system (Amersham Bioscience / GE Healthcare) equipped with a HiPrep 26 / 10 desalting column, with 0.1% (v / v) acetic acid used as the mobile phase.

[0452] Analysis method Ultra-performance LC (UPLC)-MS analyses were performed on a Waters Acquity system equipped with a Waters BEH300 C18 column (2.1 × 50 mm, particle size 1.7 μm, flow rate: 0.25 mL / min, Solvent A: water containing 0.04% TFA (v / v), Solvent B: acetonitrile containing 0.05% TFA (v / v)) coupled to a LTQ Orbitrap Discovery mass spectrometer from Thermo Scientific or coupled to a Waters Micromass ZQ.

[0453] Quantitative measurements of serum calcium (sCa), urinary calcium, and serum phosphorus (sP) were performed using a Roche-Hitachi P800 modular biochemistry analyzer.

[0454] [Example 1] Synthesis of linker reagent 1f Linker reagent 1f was synthesized according to the following scheme:

[0455] [ka] TIFF0007646888000050.tif52154

[0456] To a solution of N-methyl-N-Boc-ethylenediamine (2 g, 11.48 mmol) and NaCNBH3 (819 mg, 12.63 mmol) in MeOH (20 mL) was added 2,4,6-trimethoxybenzaldehyde (2.08 g, 10.61 mmol) in portions. The mixture was stirred at room temperature for 90 min, acidified with 3M HCl (4 mL) and stirred for an additional 15 min. The reaction mixture was added to saturated NaHCO3 solution (200 mL) and extracted five times with DCM. The combined organic phases were dried over Na2SO4 and the solvent was evaporated under vacuum. The obtained N-methyl-N-Boc-N'-Tmob-ethylenediamine 1a was dried under high vacuum and used in the next reaction step without further purification. Yield: 3.76 g (11.48 mmol, 89% purity, 1a: double Tmob protected product = 8:1) MS: m / z 355.22=[M+H] + , (calculated monoisotopic mass = 354.21).

[0457] To a solution of 1a (2 g, 5.65 mmol) in DCM (24 mL) was added COMU (4.84 g, 11.3 mmol), N-Fmoc-N-Me-Asp(OBn)-OH (2.08 g, 4.52 mmol) and 2,4,6-collidine (2.65 mL, 20.34 mmol). The reaction mixture was stirred at room temperature for 3 h, diluted with DCM (250 mL) and washed three times with 0.1 M H2SO4 (100 mL) and three times with saturated brine (100 mL). The aqueous phase was re-extracted with DCM (100 mL). The combined organic phase was dried over Na2SO4, filtered and the residue was concentrated to a volume of 24 mL. 1b was purified using flash chromatography. Yield: 5.31 g (148%, 6.66 mmol) MS: m / z 796.38=[M+H] + , (calculated monoisotopic mass = 795.37).

[0458] To a solution of 1b (5.31 g, ~4.52 mmol with respect to N-Fmoc-N-Me-Asp(OBn)-OH) in THF (60 mL) was added DBU (1.8 mL, 3% v / v). The solution was stirred at room temperature for 12 min, diluted with DCM (400 mL) and washed three times with 0.1 M H2SO4 (150 mL) and three times with saturated brine (150 mL). The aqueous phase was re-extracted with DCM (100 mL). The combined organic phases were dried over Na2SO4 and filtered. 1c was isolated by evaporation of the solvent and used in the next reaction without further purification. MS: m / z 574.31=[M+H] + , (calculated monoisotopic mass = 573.30).

[0459] 1c (5.31 g, 4.52 mmol, crude) was dissolved in acetonitrile (26 mL) and COMU (3.87 g, 9.04 mmol), 6-tritylmercaptohexanoic acid (2.12 g, 5.42 mmol) and 2,4,6-collidine (2.35 mL, 18.08 mmol) were added. The reaction mixture was stirred at room temperature for 4 h, diluted with DCM (400 mL) and washed three times with 0.1 M H2SO4 (100 mL) and three times with saturated brine (100 mL). The aqueous phase was re-extracted with DCM (100 mL). The combined organic phase was dried over Na2SO4, filtered and 1d was isolated by evaporation of the solvent. Product 1d was purified using flash chromatography. Yield: 2.63g (62%, purity 94%) MS: m / z 856.41=[M+H] + , (calculated monoisotopic mass = 855.41).

[0460] To a solution of 1d (2.63 g, 2.78 mmol) in i-PrOH (33 mL) and H2O (11 mL) was added LiOH (267 mg, 11.12 mmol) and the reaction mixture was stirred for 70 min at room temperature. The mixture was diluted with DCM (200 mL) and washed three times with 0.1 M H2SO4 (50 mL) and three times with saturated brine (50 mL). The aqueous phase was re-extracted with DCM (100 mL). The combined organic phase was dried over Na2SO4, filtered and 1e was isolated by evaporation of the solvent. 1e was purified using flash chromatography. Yield: 2.1g (88%) MS: m / z 878.4=[M+Na] + , (calculated monoisotopic mass = 837.40).

[0461] To a solution of 1e (170 mg, 0.198 mmol) in anhydrous DCM (4 mL) was added DCC (123 mg, 0.59 mmol) and a catalytic amount of DMAP. After 5 min, N-hydroxy-succinimide (114 mg, 0.99 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered, the solvent was removed under vacuum and the residue was dissolved in 90% acetonitrile + 0.1% TFA (3.4 mL). The crude mixture was purified by RP-HPLC. The product fractions were neutralized with 0.5 M pH 7.4 phosphate buffer and concentrated. The remaining aqueous phase was extracted with DCM and 1f was isolated by evaporation of the solvent. Yield: 154mg (81%) MS: m / z 953.4=[M+H] + , (calculated monoisotopic mass = 952.43).

[0462] [Example 2] Synthesis of linker reagent 2g

[0463] [ka]

[0464] 4-Methoxytritylphenylmethyl chloride (3.00 g, 9.71 mmol) was dissolved in DCM (20 mL) and added dropwise to a stirred solution of ethylenediamine 2a (6.5 mL, 97.3 mmol) in DCM (20 mL). The reaction mixture was stirred for 2 h at room temperature, then diluted with diethyl ether (300 mL) and washed three times with saturated brine / 0.1 M NaOH 30 / 1 (v / v) and once with saturated brine. The organic phase was dried over Na2SO4 and 2b was isolated by evaporation of the solvent. Yield: 3.18g (98%)

[0465] The Mmt-protected intermediate 2b (3.18 g, 9.56 mmol) was dissolved in DCM (30 mL). 6-(tritylthio)-hexanoic acid (4.48 g, 11.5 mmol), PyBOP (5.67 g, 10.9 mmol) and DIPEA (5.0 mL, 28.6 mmol) were added and the mixture was stirred for 30 min at room temperature. The solution was diluted with diethyl ether (250 mL) and washed three times with saturated brine / 0.1 M NaOH 30 / 1 (v / v) and once with saturated brine. The organic phase was dried over Na2SO4 and the solvent was removed under vacuum. 2c was purified using flash chromatography. Yield: 5.69g (85%) MS: m / z 705.4=[M+H] + , (calculated monoisotopic mass = 704.34).

[0466] Compound 2c (3.19 g, 4.53 mmol) was dissolved in anhydrous THF (50 mL), 1M BH3·THF solution in THF (8.5 mL, 8.5 mmol) was added, and the mixture was stirred for 16 h at room temperature. An additional 1M BH3·THF solution in THF (14 mL, 14.0 mmol) was added, and the mixture was stirred for another 16 h at room temperature. Methanol (8.5 mL) and N,N'-dimethyl-ethylenediamine (3.00 mL, 27.9 mmol) were added, and the mixture was heated at reflux for 3 h. The mixture was allowed to cool, and ethyl acetate (300 mL) was added. The solution was washed twice with aqueous Na2CO3 and twice with aqueous NaHCO3. The organic phase was dried over Na2SO4, and the solvent was removed under vacuum to give 2d. Yield: 3.22g (103%) MS: m / z 691.4=[M+H] + , (calculated monoisotopic mass = 690.36).

[0467] Di-tert-butyl dicarbonate (2.32 g, 10.6 mmol) and DIPEA (3.09 mL, 17.7 mmol) were dissolved in DCM (5 mL) and added to a solution of 2d (2.45 g, 3.55 mmol) in DCM (5 mL). The mixture was stirred for 30 min at room temperature. The solution was concentrated in vacuo and purified by flash chromatography to give product 2e. Yield: 2.09g (74%) MS: m / z 791.4=[M+H] + , (calculated monoisotopic mass = 790.42).

[0468] Compound 2e (5.01 g, 6.34 mmol) was dissolved in acetonitrile (80 mL). 0.4 M aqueous HCl (80 mL) was added followed by acetonitrile (20 mL) and the mixture was stirred for 1 h at room temperature. The pH was adjusted to pH 5.5 by addition of 5 M aqueous NaOH. The organic solvent was removed in vacuum and the remaining aqueous solution was extracted four times with DCM. The combined organic phases were dried over Na2SO4 and the solvent was removed in vacuum to give 2f. Yield: 4.77g (95%) MS: m / z 519.3=[M+H] + , (calculated monoisotopic mass = 518.30).

[0469] Compound 2f (5.27 g, 6.65 mmol) was dissolved in DCM (30 mL) and added to a solution of p-nitrophenyl chloroformate (2.01 g, 9.98 mmol) in DCM (25 mL). 2,4,6-trimethylpyridine (4.38 mL, 33.3 mmol) was added and the solution was stirred for 45 min at room temperature. The solution was concentrated in vacuo and purified by flash chromatography to give product 2g. Yield: 4.04g (89%) MS: m / z 706.32=[M+Na] + , (calculated monoisotopic mass = 683.30).

[0470] [Example 3] Synthesis of persistent S1 PTH(1-34) conjugate 3

[0471] [ka] Side-chain protected PTH (1-34) on TCP resin with Fmoc-protected N-terminus was deprotected according to the procedure given in Materials and Methods. A solution of 6-tritylmercaptohexanoic acid (62.5 mg, 160 μmol), PyBOP (80.1 mg, 154 μmol) and DIPEA (53 μL, 306 μmol) in DMF (2 mL) was added to 0.21 g (51 μmol) of resin. The suspension was stirred for 80 min at room temperature. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Cleavage of the peptide from the resin and removal of the protecting groups was achieved by adding 10 mL of cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole and stirring the suspension for 1 h at room temperature. Crude 3 was precipitated into pre-cooled diethyl ether (−18° C.). The precipitate was dissolved in ACN / water and purified by RP-HPLC. The product fractions were lyophilized. Yield: 36mg (14%), 3*8TFA MS: m / z 1062.31=[M+4H] 4+ , ([M+4H] 4+ Calculated monoisotopic mass for = 1062.30).

[0472] [Example 4] Synthesis of persistent K26 PTH(1-34) conjugate 4

[0473] [ka] The ivDde of side-chain protected PTH(1-34) on TCP resin with Boc-protected N-terminus and ivDde-protected side chain of Lys26 was deprotected according to the procedure given in Materials and Methods. A solution of 6-tritylmercaptohexanoic acid (107 mg, 273 μmol), PyBOP (141 mg, 273 μmol) and DIPEA (93 μL, 545 μmol) in DMF (3 mL) was added to 0.80 g (90.9 μmol) of resin. The suspension was stirred for 1 h at room temperature. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Cleavage of the peptide from the resin and removal of the protecting groups was achieved by adding 6 mL of cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole and stirring the suspension for 1 h at room temperature. Crude 4 was precipitated in pre-cooled diethyl ether (-18 °C). The precipitate was dissolved in ACN / water and purified by RP-HPLC. The product fraction was lyophilized. Yield: 40mg (8%), 4*8TFA MS: m / z 1062.30=[M+4H] 4+ , ([M+4H] 4+ Calculated monoisotopic mass for = 1062.30).

[0474] [Example 5] Synthesis of transient S1 PTH(1-34) conjugates

[0475] [ka] The Fmoc of side-chain protected PTH(1-34) on TCP resin with Fmoc-protected N-terminus was deprotected according to the procedure given in Materials and Methods. A solution of Fmoc-Aib-OH (79 mg, 244 μmol), PyBOP (127 mg, 244 μmol) and DIPEA (64 μL, 365 μmol) in DMF (1.5 mL) was added to 0.60 g (61 μmol) of resin. The suspension was stirred for 16 h at room temperature. The resin was washed 10 times with DMF and Fmoc deprotected as described above. A solution of 2 g (167 mg, 244 μmol) and DIPEA (64 μL, 365 μmol) in DMF (1.5 mL) was added to the resin. The suspension was stirred for 24 h at room temperature. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Cleavage of the peptide from the resin and removal of the protecting groups was achieved by adding 7 mL of cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole and stirring the suspension for 1 h at room temperature. Crude 5 was precipitated into pre-cooled diethyl ether (-18 °C). The precipitate was dissolved in ACN / water and purified by RP-HPLC. The product fraction was lyophilized. Yield: 78mg (24%), 5*9TFA MS: m / z 1101.59=[M+4H] 4+ , ([M+4H] 4+ Calculated monoisotopic mass for = 1101.57).

[0476] [Example 6] Synthesis of transient S1 PTH(1-34) conjugate 6

[0477] [ka] The Fmoc of side-chain protected PTH(1-34) on TCP resin with Fmoc-protected N-terminus was deprotected according to the procedure given in Materials and Methods. A solution of Fmoc-Aib-OH (32 mg, 102 μmol), PyBOP (53 mg, 102 μmol) and DIPEA (27 μL, 152 μmol) in DMF (3 mL) was added to 0.25 g (25 μmol) of resin. The suspension was shaken for 1 h at room temperature. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Fmoc deprotection was carried out as described above. A solution of 2 g (69 mg, 102 μmol) and DIPEA (27 μL, 152 μmol) in DMF (3 mL) was added to the resin. The suspension was stirred for 1.5 h at room temperature. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Cleavage of the peptide from the resin and removal of the protecting groups was achieved by adding 3 mL of cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole and stirring the suspension for 1 h at room temperature. Crude 6 was precipitated into pre-cooled diethyl ether (-18 °C). The precipitate was dissolved in ACN / water and purified by RP-HPLC. The product fraction was lyophilized. Yield: 25mg (18%), 6*9TFA MS: m / z 1098.75=[M+4H] 4+ , ([M+4H] 4+ Calculated monoisotopic mass for = 1098.07).

[0478] [Example 7] Synthesis of transient S1 PTH(1-34) conjugate 7

[0479] [ka] The Fmoc of side-chain protected PTH(1-34) on TCP resin with Fmoc-protected N-terminus was deprotected according to the procedure given in Materials and Methods. A solution of Fmoc-Ser(Trt)-OH (117 mg, 205 μmol), PyBOP (108 mg, 207 μmol) and DIPEA (53 μL, 305 μmol) in DMF (2 mL) was added to 0.50 g (51 μmol) of resin. The suspension was stirred for 1 h at room temperature. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Fmoc deprotection was carried out as described above. A solution of 2 g (144 mg, 211 μmol) and DIPEA (53 μL, 305 μmol) in DMF (1.8 mL) was added to the resin. The suspension was shaken for 7 h at room temperature. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Cleavage of the peptide from the resin and removal of the protecting groups was achieved by adding 6 mL of cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole and stirring the suspension for 1 h at room temperature. Crude 7 was precipitated into pre-cooled diethyl ether (-18 °C). The precipitate was dissolved in ACN / water and purified by RP-HPLC. The product fraction was lyophilized. Yield: 54mg (20%), 7*9TFA MS: m / z 1102.08=[M+4H] 4+ , ([M+4H] 4+ Calculated monoisotopic mass for = 1102.07).

[0480] [Example 8] Synthesis of transient S1 PTH(1-34) conjugate 8

[0481] [ka] The Fmoc of side-chain protected PTH(1-34) on TCP resin with Fmoc-protected N-terminus was deprotected according to the procedure given in Materials and Methods. A solution of Fmoc-Leu-OH (36 mg, 102 μmol), PyBOP (53 mg, 102 μmol) and DIPEA (27 μL, 152 μmol) in DMF (3 mL) was added to 0.25 g (25 μmol) of resin. The suspension was stirred for 1 h at room temperature. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Fmoc deprotection was carried out as described above. A solution of 2 g (69 mg, 102 μmol) and DIPEA (27 μL, 152 μmol) in DMF (3 mL) was added to the resin. The suspension was stirred for 1.5 h at room temperature. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Cleavage of the peptide from the resin and removal of the protecting groups was achieved by adding 3 mL of cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole and stirring the suspension for 1 h at room temperature. Crude 8 was precipitated into pre-cooled diethyl ether (-18 °C). The precipitate was dissolved in ACN / water and purified by RP-HPLC. The product fraction was lyophilized. Yield: 31mg (22%), 8*9TFA MS: m / z 1109.32=[M+4H] 4+ , ([M+4H] 4+ Calculated monoisotopic mass for = 1108.58).

[0482] [Example 9] Synthesis of transient S1 PTH(1-34) conjugate 9

[0483] [ka] The Fmoc of side-chain protected PTH(1-34) on TCP resin with Fmoc-protected N-terminus was deprotected according to the procedure given in Materials and Methods. A solution of 1e (182 mg, 213 μmol), PyBOP (111 mg, 213 μmol) and DIPEA (93 μL, 532 μmol) in DMF (5 mL) was added to 2.00 g (107 μmol) of resin. The suspension was stirred for 16 h at room temperature. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Cleavage of the peptide from the resin and removal of the protecting groups was achieved by adding 20 mL of cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole and stirring the suspension for 1 h at room temperature. Crude 9 was precipitated into pre-cooled diethyl ether (−18 °C). The precipitate was dissolved in ACN / water and purified by RP-HPLC. The product fractions were lyophilized. Yield: 47mg (8%), 9*9TFA MS: m / z 1108.58=[M+4H] 4+ , ([M+4H] 4+ Calculated monoisotopic mass for = 1108.57).

[0484] [Example 10] Synthesis of transient K26 PTH(1-34) conjugate 10

[0485] [ka] The ivDde of side-chain protected PTH(1-34) on TCP resin with Boc-protected N-terminus and ivDde-protected side chain of Lys26 was deprotected according to the procedure given in Materials and Methods. A solution of 1f (867 mg, 910 μmol) and DIPEA (0.24 mL, 1.36 mmol) in DMF (5 mL) was added to 1.91 g (227 μmol) of resin. The suspension was stirred for 1 h at room temperature. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Cleavage of the peptide from the resin and removal of the protecting groups was achieved by adding 20 mL of cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole and shaking the suspension for 1 h at room temperature. Crude 10 was precipitated into pre-cooled diethyl ether (−18° C.). The precipitate was dissolved in ACN / water and purified by RP-HPLC. The product fractions were lyophilized. Yield: 92mg (7%), 10*9TFA MS: m / z 1108.58=[M+4H] 4+ , ([M+4H] 4+ Calculated monoisotopic mass for = 1108.57).

[0486] [Example 11] Synthesis of low molecular weight temporary S1 PEG conjugate 11b

[0487] [ka] TIFF0007646888000061.tif130127To 0.5 mL of a 20 mg / mL solution of thiol 5 (10 mg, 1.84 μmol) in 1 / 1 (v / v) acetonitrile / water containing 0.1% TFA (v / v), 0.15 mL of 0.5 M NaH2PO4 buffer (pH 7.4) was added. The solution was incubated for 10 min at room temperature, after which 238 μL of a 10 mg / mL solution of maleimide 11a (2.4 mg, 2.21 μmol) in 1 / 1 (v / v) acetonitrile / water containing 0.1% TFA (v / v) was added. The solution was incubated for 20 min at room temperature. 10 μL TFA was added and the mixture was purified by RP-HPLC. The product fraction was lyophilized to give 11b. Yield: 3.1mg (26%), 11b*9TFA MS: m / z 1097.00=[M+4H] 4+ , ([M+5H] 5+ Calculated monoisotopic mass for = 1096.99).

[0488] [Example 12] Synthesis of low molecular weight temporary S1 PEG conjugate 12

[0489] [ka] Conjugate 12 was synthesized as described for 11b by using thiol 6 (10 mg, 1.85 μmol) and maleimide 11a (2.4 mg, 2.21 μmol). Yield: 10mg (83%), 12*9TFA MS: m / z 1094.20=[M+4H] 4+ , ([M+4H] 4+ Calculated monoisotopic mass for = 1094.19).

[0490] [Example 13] Synthesis of low molecular weight temporary S1 PEG conjugate 13

[0491] [ka] Conjugate 13 was synthesized as described for 11b by using thiol 7 (10 mg, 1.84 μmol) and maleimide 11a (2.4 mg, 2.21 μmol). Yield: 8mg (67%), 13*9TFA MS: m / z 1097.40=[M+5H] 5+ , ([M+5H] 5+ Calculated monoisotopic mass for = 1097.39).

[0492] [Example 14] Synthesis of low molecular weight temporary S1 PEG conjugate 14

[0493] [ka] Conjugate 14 was synthesized as described for 11b by using thiol 8 (10 mg, 1.83 μmol) and maleimide 11a (2.4 mg, 2.21 μmol). Yield: 4mg (33%), 14*9TFA MS: m / z 1378.01=[M+4H] 4+ , ([M+4H] 4+ Calculated monoisotopic mass for = 1378.00).

[0494] [Example 15] Synthesis of low molecular weight temporary K26 PEG conjugate 15

[0495] [ka] TIFF0007646888000066.tif38144 Conjugate 15 was synthesized as described for 11b by using thiol 10 (5.2 mg, 0.95 μmol) and maleimide 11a (1.23 mg, 1.14 μmol). Yield: 2.1mg (33%), 15*9TFA MS: m / z 1102.60=[M+5H]5+ , ([M+5H] 5+ Calculated monoisotopic mass for = 1102.59).

[0496] [Example 16] Synthesis of persistent 2x20kDa S1 PEG conjugate 16

[0497] [ka] 772 μL of a solution containing thiol 3 (19.4 mg / mL, 15 mg, 3.54 μmol) and 2.5 mg / mL Boc-L-Met in 1 / 1 (v / v) acetonitrile / water containing 0.1% TFA (v / v) was added to 1.87 mL of a solution containing PEG 2x20kDa maleimide (Sunbright GL2-400MA, 187 mg, 4.32 μmol) and 2.5 mg / mL Boc-L-Met in water containing 0.1% TFA (v / v). 0.5 M NaH2PO4 buffer (0.66 mL, pH 7.0) was added and the mixture was stirred for 30 min at room temperature. 10 μL of a 270 mg / mL solution of 2-mercaptoethanol in water was added. The mixture was stirred for 5 min at room temperature and 0.33 mL 1 M HCl was added. Conjugate 16 was purified by IEX and then by RP-HPLC using a linear gradient of solvent system A (water containing 0.1% AcOH v / v) and solvent system B (acetonitrile containing 0.1% AcOH v / v). The product-containing fractions were lyophilized to dryness. Yield: 97 mg (2.01 μmol, 57%) conjugate 16*8AcOH

[0498] [Example 17] Synthesis of persistent 2x20kDa K26 PEG conjugate 17

[0499] [ka] Conjugate 17 was prepared as described for 16 by reaction of thiol 4 (15 mg, 3.53 μmol) with PEG 2x20 kDa maleimide (Sunbright GL2-400MA, 187 mg, 4.32 μmol). Yield: 80 mg (1.79 μmol, 51%) conjugate 17*8AcOH

[0500] [Example 18] Synthesis of transient 2x20kDa S1 PEG conjugate 18

[0501] [ka] Conjugate 18 was prepared as described for 16 by reaction of thiol 5 (37 mg, 8.40 μmol) with PEG 2x20kDa maleimide (Sunbright GL2-400MA, 445 mg, 9.24 μmol). The reaction was stopped by adding 50 μL TFA without prior addition of 2-mercaptoethanol. Conjugate 18 was purified by IEX and then by SEC for desalting. The product-containing fractions were lyophilized. Yield: 161 mg (3.33 μmol, 40%) conjugate 18*9AcOH

[0502] [Example 19] Synthesis of transient 2x20kDa S1 PEG conjugate 19

[0503] [ka] Conjugate 19 was prepared as described for 16 by reaction of thiol 7 (27 mg, 6.14 μmol) with PEG 2x20 kDa maleimide (Sunbright GL2-400MA, 325 mg, 7.50 μmol). Yield: 249mg (5.16μmol, 84%) conjugate 19*9AcOH

[0504] [Example 20] Synthesis of transient 2x20kDa S1 PEG conjugate 20

[0505] [ka] Conjugate 20 was prepared as described for 16 by reaction of thiol 9 (38 mg, 8.59 μmol) with PEG 2x20kDa maleimide (Sunbright GL2-400MA, 455 mg, 9.45 μmol). The reaction was stopped by adding 50 μL TFA without prior addition of 2-mercaptoethanol. Conjugate 20 was purified by IEX and then by SEC for desalting. The product-containing fractions were lyophilized. Yield: 194mg (4.01μmol, 47%) Conjugate 20*9AcOH

[0506] [Example 21] Synthesis of transient 2x20kDa K26 PEG conjugate 21

[0507] [ka] Conjugate 21 was prepared as described for 16 by reaction of thiol 10 (34 mg, 7.58 μmol) with PEG 2x20 kDa maleimide (Sunbright GL2-400MA, 401 mg, 9.26 μmol). Yield: 256 mg (5.30 μmol, 70%) conjugate 21*9AcOH

[0508] [Example 22] Pharmacodynamic effects of daily subcutaneous injections of conjugate 18 or PTH(1-84) in thyroparathyroidectomized (TPTx) rats during a 28-day study. This study was performed to test and compare the effects of daily subcutaneous injections of compound 18 and the current standard of care, PTH(1-84), in an animal disease model suitable for studying the treatment of hypoparathyroidism (HP). Rats subjected to blunt dissection thyroparathyroidectomy (TPTx) are unable to produce parathyroid hormone, PTH, the master regulator of calcium homeostasis. Therefore, TPTx rats develop hypocalcemia and hyperphosphatemia, characteristic of HP. Seventeen-week-old female SD TPTx rats (n=9 / group) were subcutaneously dosed with compound 18 (5 μg PTH equivalents / kg / d; 1.2 nmol / kg / d in 10 mM acetate, 46 g / L mannitol, pH 4.0), PTH(1-84) (70 μg PTH equivalents / kg / d; 7.3 nmol / kg / d in 10 mM citrate, 39.0 g / L mannitol, pH 5.0) or vehicle for 28 days. In addition, a group of sham-operated rats (n=9) representing normal physiological background controls also received vehicle. Serum calcium (sCa) and phosphorus (sP) levels in the animals were measured pre- and post-dosing on days 1, 6, 12 and 27. In addition, bone turnover markers (P1NP and CTx) were measured and bone quality was assessed ex vivo by pQCT.

[0509] Results: On day 1, mean sCa in TPTx rats before dosing was 8.3 mg / dL compared to 10.9 mg / dL in sham-operated control rats. sP values ​​were 8.7 mg / dL and 5.9 mg / dL, respectively. Compound 18 administered daily at 1.2 nmol / kg raised sCa to near-normal levels within a few days of dosing, while lowering sP. On day 12 (day 5 at steady state with Compound 18), sCa was stable at normal levels (10.7 mg / dL) in this group of animals (compound 18 / sham control ratio = 1.01) in contrast to the hypocalcemic levels (8.1 mg / dL) measured in PTH(1-84)-treated rats (PTH(1-84) / sham control ratio = 0.76). In addition, 24-hour urinary Ca excretion on day 12 was comparable between compound 18-treated and sham-treated animals. Bone mineral density (BMD) and bone mineral content (BMC) were increased in TPTx controls as seen in HP patients. Treatment with compound 18 decreased BMD, BMC and area with concomitant increase in CTx compared to sham and vehicle-treated TPTx animals. A significant increase in cancellous BMD was observed in animals treated with PTH(1-84) compared to both control groups.

[0510] We conclude that compound 18, even at a dosage as low as less than 20% of the molar equivalent of the PTH(1-84) dose tested here, can maintain sCa levels for 24 hours at levels comparable to those in sham control animals (here corresponding to normal levels). In contrast, PTH(1-84) at 7.3 nmol / kg / day did not result in an increase in sCa compared to levels in vehicle-injected TPTx rats. However, little increase in sP was observed in animals administered PTH(1-84). This confirms the exposure and response to PTH(1-84) in rats. After 28 days of treatment with compound 18, trabecular and cortical bone BMD in vertebrae was within the normal range, while anabolic effects on trabecular and cortical bone of vertebrae were observed for PTH(1-84).

[0511] Abbreviation: ACN Acetonitrile AcOH Acetic acid Aib 2-aminoisobutyric acid BMD bone density Bn Benzyl Boc tert-Butyloxycarbonyl COMU (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate cAMP cyclic adenosine monophosphate d day DBU 1,3-Diazabicyclo[5.4.0]undecene DCC N,N'-dicyclohexylcarbodiimide DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMAP Dimethylamino-pyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DTT Dithiothreitol EDTA Ethylenediaminetetraacetic acid eq stoichiometric equivalent ESI-MS Electrospray Ionization Mass Spectrometry Et Ethyl Fmoc 9-Fluorenylmethyloxycarbonyl Glu-C Endoproteinase Glu-C h time HATU O(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HP hypoparathyroidism HPLC High Performance Liquid Chromatography ivDde 4,4-Dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl LC Liquid Chromatography LTQ Linear Trap Quadrupole Lys-C Endoproteinase Lys-C LLOQ Lower limit of quantification Mal 3-Maleimidopropyl Me Methyl MeOH Methanol min Mmt Monomethoxytrityl MS mass spectrometry / mass spectrometry m / z mass-to-charge ratio OtBu tert-butyloxy PEG Poly(ethylene glycol) pH Hydrogen ion power PK Pharmacokinetics Pr Propyl PTH Parathyroid hormone PyBOP Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate Q-TOF Quadrupole Time-of-Flight RP-HPLC Reversed-phase high-performance liquid chromatography rt room temperature sCa Serum calcium SIM Single Ion Monitoring SEC Size Exclusion Chromatography sc subcutaneous sP Serum phosphate t 1 / 2 Half-life TCP Trityl Chloride Polystyrene TES Triethylsilane TFA Trifluoroacetic acid THF Tetrahydrofuran Tmob 2,4,6-trimethoxybenzyl TPTx Thyroid parathyroidectomy Trt Triphenylmethyl, Trityl ULOQ Upper limit of quantitation UPLC Ultra High Performance Liquid Chromatography UV ultraviolet light ZQ Single Quadrupole The present invention includes the following embodiments. (Embodiment 1) A pharmaceutical composition comprising at least one controlled release PTH compound or a pharma- ceutical acceptable salt, hydrate or solvate thereof, for use in the treatment, management, delay or prevention of a condition that can be treated, managed, delayed or prevented with PTH, the composition being administered every 24 hours. 1-84, wherein the pharmaceutical composition is administered no more than once every 24 hours at a dosage of the controlled release PTH compound equivalent to no more than 70% of the molar equivalent dose required to maintain serum calcium within normal levels over said 24 hour period in a human. (Embodiment 2) The pharmaceutical composition for use according to embodiment 1, wherein the composition is administered once every 24 hours. (Embodiment 3) The pharmaceutical composition for use according to embodiment 1, wherein the composition is administered once a week. (Embodiment 4) The pharmaceutical composition for use according to any one of embodiments 1 to 3, which is administered by injection. (Embodiment 5) The pharmaceutical composition for use according to any one of embodiments 1 to 4, which is administered by subcutaneous injection. (Embodiment 6) The pharmaceutical composition for use according to any one of embodiments 1 to 5, which is administered by a pen injection. (Embodiment 7) The pharmaceutical composition for use according to any one of embodiments 1 to 6, wherein said dosage is no more than 60% of the molar equivalent dose of PTH 1-84 required to maintain serum calcium within normal levels in humans over a 24 hour period. (Embodiment 8) 8. The pharmaceutical composition for use according to any one of the preceding embodiments, wherein said PTH compound comprises a PTH molecule or PTH substructure having the sequence of SEQ ID NO:51. (Embodiment 9) The pharmaceutical composition for use according to any one of embodiments 1 to 8, wherein said controlled release PTH compound is water insoluble. (Embodiment 10) The pharmaceutical composition for use according to embodiment 9, wherein said water-insoluble controlled-release PTH compound comprises at least one PTH molecule non-covalently incorporated into poly(lactic-co-glycolic acid). (Embodiment 11) The pharmaceutical composition for use according to any one of embodiments 1 to 8, wherein said controlled release PTH compound is water soluble. (Embodiment 12) The water-soluble controlled release PTH compound is a compound of formula (Ia) or (Ib)

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Claims

1. A pharmaceutical composition for treating hypoparathyroidism comprising at least one controlled release PTH compound or a pharma- ceutical acceptable salt, hydrate or solvate thereof, administered by subcutaneous injection no more than once every 24 hours at a dosage of said controlled release PTH compound equivalent to no more than 40% of the molar equivalent dose required to maintain an albumin-corrected serum calcium level greater than 8.5 mg / dL in a human over said 24 hour period for PTH 1-84 of SEQ ID NO: 1 administered subcutaneously every 24 hours, wherein said controlled release PTH compound is represented by the formula (IIf-i): 【Chemistry 1】 (In the formula, The unmarked dashed line indicates attachment to the nitrogen of the PTH moiety by forming an amide bond, the PTH moiety having the sequence of SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114 or SEQ ID NO:115; Dashed lines with asterisks represent substructures 【Chemistry 2】 represents a bond to m and p are independently integers ranging from 150 to 1000. The pharmaceutical composition is a water-soluble conjugate of

2. 10. The pharmaceutical composition of claim 1, which is administered once every 24 hours.

3. The pharmaceutical composition of claim 1 administered once every 48 hours.

4. 10. The pharmaceutical composition of claim 1, which is administered once weekly.

5. The pharmaceutical composition according to any one of claims 1 to 4, which is administered by means of a pen injection device.

6. The pharmaceutical composition of claim 1, wherein the dosage of the controlled release PTH compound corresponds to 30% or less of a molar equivalent dose of PTH 1-84.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the PTH partial structure has the sequence of SEQ ID NO:

51.

8. The pharmaceutical composition according to any one of claims 1 to 7, having a pH in the range from pH 3 to pH 8.

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