Gradual dose setting for controlled release PTH compounds

Abstract

This invention provides a pharmaceutical composition for use in intermittent administration of PTH, which offers improved management of serum and urinary calcium and serum phosphorus levels, and less increase in bone turnover markers compared to currently used PTH therapy. [Solution] A pharmaceutical composition is provided comprising a controlled-release PTH compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which is administered according to a dosage plan in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in increments of 25% or less.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition comprising a controlled-release PTH compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof for use in methods of treating, managing, delaying, or preventing conditions that can be treated, managed, delayed, or prevented by PTH, wherein the controlled-release PTH compound is administered according to a dosing schedule in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in increments of 25% or less. [Background technology]

[0002] Hypoparathyroidism is a rare endocrine disorder affecting calcium and phosphate metabolism, most often resulting from parathyroid damage or removal during thyroid surgery. Hypoparathyroidism is unusual among endocrine disorders and, until recently, was not treated with supplementation of the deficient hormone, parathyroid hormone (PTH). Conventional treatments for hypoparathyroidism include high doses of vitamin D and oral calcium supplementation, which is often effective but can lead to hypercalcemia and hypocalcemia of the blood (ca). 2+ It is accompanied by marked fluctuations, excessive urinary calcium excretion, nephrocalcemia, and ectopic calcification, including that of blood vessels, basal ganglia, and the lens of the eye.

[0003] Calcium is the most abundant mineral in the human body, and its precise regulation is required for many biological functions, such as bone mineralization, muscle contraction, nerve conduction, hormone release, and blood clotting. Maintaining the most stable calcium concentration possible is especially important because various cell systems or organs, including the central nervous system, muscles, and exocrine / endocrine glands, require Ca 2+ This is because it reacts strongly to even small fluctuations. PTH is a major regulator of calcium homeostasis.

[0004] Serum Ca 2+ Inappropriately low or simply low PTH levels in relation to concentration are characteristic of hypoparathyroidism, Ca 2+This leads to decreased reabsorption of calcium by the renal tubules and, at the same time, increased reabsorption of phosphate by the renal tubules. Therefore, the main biochemical abnormalities of hypoparathyroidism are hypocalcemia and hyperphosphatemia. The clinical features of this disease include symptoms of hypocalcemia, such as numbness around the mouth, paresthesia, and carpal / foot muscle spasms. Pharyngospasm, tetany, and epileptic 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 vascular system, brain, kidneys, and other organs.

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

[0006] Several concerns arise regarding the long-term use of high doses of calcium and activated vitamin D, particularly for hypercalciuria, kidney stones, nephrocalcinosis, and ectopic soft tissue calcification. Furthermore, conventional treatments with calcium and activated vitamin D do not alleviate quality-of-life complaints or improve the bone remodeling abnormalities specific to this disease. In short, improved hypoparathyroidism therapy is desperately needed.

[0007] In 2015, Natpara, PTH(1-84) was approved for 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 crucial clinical trial that demonstrated that 42 percent of participants treated with PTH(1-84) achieved normal blood calcium levels with reduced doses of calcium supplement and active form of vitamin D, compared to 3 percent of participants treated with placebo. Time-course tracking of serum calcium after injection showed that 71 percent of patients treated with PTH(1-84) developed hypercalcemia with one or more measurements within a 24-hour period. PTH(1-84) reduced urinary calcium excretion 2–8 hours after injection, but there was no change in urinary calcium excretion after 24 hours. Similarly, urinary phosphate excretion increased only during the first 8 hours after PTH(1-84) injection.

[0008] While this could be considered a significant advantage in treating this disease, Natpara has not demonstrated that it can reduce the incidence of hypercalcemia (elevated serum calcium levels), hypocalcemia (low serum calcium levels), or hypercalciuria (increased urinary calcium) in treated patients compared to conventional treatments.

[0009] Therefore, improved PTH-based treatments for hypoparathyroidism are in great need.

[0010] PTH(1-34), or teriparatide, was approved by the FDA in 2002 for the treatment of osteoporosis. PTH(1-34) has long been used for the treatment of hypoparathyroidism, despite not being approved for this indication, with patients receiving injections two or three times daily. Clinical studies have been conducted using pump-delivered PTH(1-34) compared to twice-daily injections to promote more physiological PTH levels. Over six months, pump delivery produced normal steady-state calcium levels with minimal fluctuation, avoiding the elevation of serum and urinary calcium levels that appears immediately after PTH injection. The significant decrease 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 a renal calcium-conserving 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 at a dose 65 percent lower than the 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 is inconvenient and difficult for patients; therefore, the object of the present invention is to provide a more convenient treatment option that results in continuous exposure to PTH.

[0012] Long-term daily administration of PTH is associated with progressive cortical osteopenia 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 higher than pre-treatment levels, peaked in the first few years after initiation of PTH(1-84), and then declined, but remained significantly higher than baseline levels until year 6. BMD measured by DXA was consistent with the known site-specific effects of PTH, namely an increase in the lumbar spine and a decrease in the distal one-third of the radius. The decrease observed in the distal one-third is consistent with the known effects of intermittent PTH, which increase cortical porosity and endosteal resorption. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Rubin, JCEM 2016 [Overview of the project] [Problems that the invention aims to solve]

[0014] The object of the present invention is to provide a method of intermittently administering PTH that improves the management of serum and urinary calcium and serum phosphorus compared to currently used PTH therapies, and reduces the increase in bone turnover markers. Preferably, intermittently means every day, or more preferably at weekly intervals.

[0015] In both the Forteo, PTH(1-34) and Natpara, PTH(1-84) preclinical development programs, a dose-dependent increase in osteosarcoma incidence was observed in rats treated with daily injections of PTH compounds. In the Natpara study, administration to high-dose rats was discontinued due to an excessive number of deaths, primarily from metastatic osteosarcoma, in this group. This is thought to be due to the rats' sensitivity to the anabolic effects of intermittent PTH. In contrast, it is known that continuous exposure to PTH does not have significant anabolic activity. It is an object of the present invention to provide an intermittent PTH replacement therapy that results in an infusion-like profile of PTH, which leads to improved symptom control with the administration of lower doses. Preferably, intermittent means daily, or more preferably weekly.

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

[0017] Therefore, an object of the present invention is to overcome the above-mentioned drawbacks at least partially. [Means for solving the problem]

[0018] This objective is achieved with a pharmaceutical composition comprising a controlled-release PTH compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof for use in methods of treating, managing, delaying, or preventing conditions that can be treated, managed, delayed, or prevented by PTH, wherein the pharmaceutical composition comprising the controlled-release PTH compound is administered according to a dosing schedule in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in increments of 25% or less.

[0019] Surprisingly, such controlled-release PTH compounds are more potent than PTH 1-84, and it has been found that dose adjustments of pharmaceutical compositions containing such controlled-release PTH compounds can be made with fewer increments than dose adjustments of pharmaceutical compositions containing PTH 1-84, which involve doubling or halving the dose in response to hypocalcemia or hypercalcemia, respectively, to reach the correct dose. A typical starting dose is 50 μg / day, which is gradually reduced to 25 μg / day (50%) in cases of hypercalcemia, or gradually increased to 75 μg / day (50%) first, and then to 100 μg / day (33.3%) in cases of hypocalcemia where most subjects require 75 or 100 μg / day.

[0020] In this invention, the following terms are used:

[0021] As used herein, the term "increment" refers to an increase or decrease in the amount of the controlled-release PTH compound based on a previously administered dose of the same controlled-release PTH compound, and this increase or decrease is expressed as a specific percentage based on the weight of the controlled-release PTH compound.

[0022] As used herein, the term “controlled-release PTH compound” refers to any compound, conjugate, crystal, or mixture comprising at least one PTH molecule or substructure, wherein at least one PTH molecule or substructure is released with an release half-life of at least 12 hours.

[0023] As used herein, the terms “release half-life” and “half-life” refer to the time required for all or half of all PTH or PTH substructures contained in each controlled-release PTH compound to be released from the controlled-release PTH compound under physiological conditions (i.e., aqueous buffer, pH 7.4, 37°C).

[0024] As used herein, the term "PTH" refers to all PTH polypeptides, preferably from mammalian species, more preferably from humans and mammalian species, more preferably from humans and murine species, as well as their variants, analogs, orthologues, homologs, and derivatives and fragments, characterized by increasing serum calcium and renal phosphorus excretion and decreasing serum phosphorus and renal calcium excretion. The term "PTH" also refers to all PTHrP polypeptides that bind to and activate the common PTH / PTHrP1 receptor, such as the polypeptide of SEQ ID NO: 121. 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, namely increasing serum calcium and renal phosphorus excretion and decreasing serum phosphorus and renal calcium excretion.

[0025] Preferably, the term "PTH" refers to the following peptide sequence: Sequence ID 1 (PTH 1-84) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ Sequence ID 2 (PTH 1-83) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS Sequence ID 3 (PTH 1-82) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK Sequence ID 4 (PTH 1-81) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA Sequence ID 5 (PTH 1-80) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK Sequence ID 6 (PTH 1-79) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT Sequence ID 7 (PTH 1-78) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL Sequence ID 8 (PTH 1-77) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV Sequence ID 9 (PTH 1-76) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN Sequence ID 10 (PTH 1-75) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV Sequence ID 11 (PTH 1-74) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD Sequence ID 12 (PTH 1-73) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA Sequence ID 13 (PTH 1-72) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK Sequence ID 14 (PTH 1-71) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD Sequence ID 15 (PTH 1-70) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA Sequence ID 16 (PTH 1-69) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE Sequence ID 17 (PTH 1-68) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG Sequence ID 18 (PTH 1-67) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL Sequence ID 19 (PTH 1-66) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS Sequence ID 20 (PTH 1-65) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK Sequence ID 21 (PTH 1-64) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE Sequence ID 22 (PTH 1-63) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH Sequence ID 23 (PTH 1-62) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES Sequence ID 24 (PTH 1-61) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE Sequence ID 25 (PTH 1-60) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV Sequence ID 26 (PTH 1-59) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL Sequence ID 27 (PTH 1-58) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV Sequence ID 28 (PTH 1-57) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN Sequence ID 29 (PTH 1-56) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED Sequence ID 30 (PTH 1-55) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE Sequence ID 31 (PTH 1-54) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK Sequence ID 32 (PTH 1-53) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK Sequence ID 33 (PTH 1-52) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR Sequence ID 34 (PTH 1-51) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP Sequence ID 35 (PTH 1-50) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR Sequence ID 36 (PTH 1-49) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ Sequence ID 37 (PTH 1-48) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS Sequence ID 38 (PTH 1-47) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG Sequence ID 39 (PTH 1-46) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA Sequence ID 40 (PTH 1-45) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD Sequence ID 41 (PTH 1-44) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR Sequence ID 42 (PTH 1-43) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP Sequence ID 43 (PTH 1-42) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA Sequence ID 44 (PTH 1-41) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL Sequence ID 45 (PTH 1-40) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP Sequence ID 46 (PTH 1-39) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA Sequence ID 47 (PTH 1-38) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG Sequence ID 48 (PTH 1-37) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL Sequence ID 49 (PTH 1-36) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA Sequence ID 50 (PTH 1-35) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV Sequence ID 51 (PTH 1-34) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF Sequence ID 52 (PTH 1-33) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN Sequence ID 53 (PTH 1-32) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH Sequence ID 54 (PTH 1-31) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV Sequence ID 55 (PTH 1-30) SVSEIQLMHNLGKHLNSMERVEWLRKKLQD Sequence ID 56 (PTH 1-29) SVSEIQLMHNLGKHLNSMERVEWLRKKLQ Sequence ID 57 (PTH 1-28) SVSEIQLMHNLGKHLNSMERVEWLRKKL Sequence ID 58 (PTH 1-27) SVSEIQLMHNLGKHLNSMERVEWLRKK Sequence ID 59 (PTH 1-26) SVSEIQLMHNLGKHLNSMERVEWLRK Sequence ID 60 (PTH 1-25) SVSEIQLMHNLGKHLNSMERVEWLR Sequence ID No. 61 (amidate PTH 1-84) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ; (The C-terminus of this sequence is amidated.) Sequence ID No. 62 (Amidated PTH 1-83) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS; (The C-terminus of this sequence is amidated.) Sequence ID No. 63 (Amidated PTH 1-82) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK; (The C-terminus of this sequence is amidated.) Sequence ID No. 64 (amidate PTH 1-81) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA; (The C-terminus of this sequence is amidated.) Sequence ID No. 65 (Amidated PTH 1-80) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK; (The C-terminus of this sequence is amidated.) Sequence ID No. 66 (amidate PTH 1-79) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT; (The C-terminus of this sequence is amidated.) Sequence ID No. 67 (Amidated PTH 1-78) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL; (The C-terminus of this sequence is amidated.) Sequence ID No. 68 (amidate PTH 1-77) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV; (The C-terminus of this sequence is amidated.) Sequence ID No. 69 (amidate PTH 1-76) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN; (The C-terminus of this sequence is amidated.) Sequence ID No. 70 (amidate PTH 1-75) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV; (The C-terminus of this sequence is amidated.) Sequence ID No. 71 (amidate PTH 1-74) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD; (The C-terminus of this sequence is amidated.) Sequence ID No. 72 (amidate PTH 1-73) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA; (The C-terminus of this sequence is amidated.) Sequence ID No. 73 (Amidated PTH 1-72) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK; (The C-terminus of this sequence is amidated.) Sequence ID No. 74 (amidate PTH 1-71) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD; (The C-terminus of this sequence is amidated.) Sequence ID No. 75 (amidate PTH 1-70) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA; (The C-terminus of this sequence is amidated.) Sequence ID No. 76 (amidate PTH 1-69) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE; (The C-terminus of this sequence is amidated.) Sequence ID No. 77 (amidate PTH 1-68) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG; (The C-terminus of this sequence is amidated.) Sequence ID No. 78 (amidate PTH 1-67) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL; (The C-terminus of this sequence is amidated.) Sequence ID 79 (amidate PTH 1-66) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS; (The C-terminus of this sequence is amidated.) Sequence ID No. 80 (amidate PTH 1-65) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK; (The C-terminus of this sequence is amidated.) Sequence ID No. 81 (amidate PTH 1-64) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE; (The C-terminus of this sequence is amidated.) Sequence ID No. 82 (amidate PTH 1-63) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH; (The C-terminus of this sequence is amidated.) Sequence ID No. 83 (Amidated PTH 1-62) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES; (The C-terminus of this sequence is amidated.) Sequence ID No. 84 (Amidated PTH 1-61) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE; (The C-terminus of this sequence is amidated.) Sequence ID No. 85 (Amidated PTH 1-60) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV; (The C-terminus of this sequence is amidated.) Sequence ID No. 86 (Amidated PTH 1-59) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL; (The C-terminus of this sequence is amidated.) Sequence ID No. 87 (Amidated PTH 1-58) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV; (The C-terminus of this sequence is amidated.) Sequence ID No. 88 (Amidated PTH 1-57) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN; (The C-terminus of this sequence is amidated.) Sequence ID No. 89 (Amidated PTH 1-56) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED; (The C-terminus of this sequence is amidated.) Sequence ID No. 90 (amidate PTH 1-55) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE; (The C-terminus of this sequence is amidated.) Sequence ID No. 91 (amidate PTH 1-54) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK; (The C-terminus of this sequence is amidated.) Sequence ID No. 92 (Amidated PTH 1-53) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK; (The C-terminus of this sequence is amidated.) Sequence ID No. 93 (Amidated PTH 1-52) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR; (The C-terminus of this sequence is amidated.) Sequence ID No. 94 (Amidated PTH 1-51) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP; (The C-terminus of this sequence is amidated.) Sequence ID 95 (amidated PTH 1-50) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR; (The C-terminus of this sequence is amidated.) Sequence ID No. 96 (Amidated PTH 1-49) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ; (The C-terminus of this sequence is amidated.) Sequence ID No. 97 (Amidated PTH 1-48) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS; (The C-terminus of this sequence is amidated.) Sequence ID No. 98 (Amidated PTH 1-47) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG; (The C-terminus of this sequence is amidated.) Sequence ID 99 (amidate PTH 1-46) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA; (The C-terminus of this sequence is amidated.) Sequence ID No. 100 (amidate PTH 1-45) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD; (The C-terminus of this sequence is amidated.) Sequence ID No. 101 (amidate PTH 1-44) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR; (The C-terminus of this sequence is amidated.) Sequence ID No. 102 (amidate PTH 1-43) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP; (The C-terminus of this sequence is amidated.) Sequence ID No. 103 (Amidated PTH 1-42) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA; (The C-terminus of this sequence is amidated.) Sequence ID No. 104 (amidate PTH 1-41) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL; (The C-terminus of this sequence is amidated.) Sequence ID No. 105 (amidate 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 of this sequence is amidated.) Sequence ID No. 108 (amidate PTH 1-37) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL; (The C-terminus of this sequence is amidated.) Sequence ID No. 109 (Amidated PTH 1-36) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA; (The C-terminus of this sequence is amidated.) Sequence ID No. 110 (amidate PTH 1-35) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV; (The C-terminus of this sequence is amidated.) Sequence ID No. 111 (amidate PTH 1-34) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF; (The C-terminus of this sequence is amidated.) Sequence ID No. 112 (amidate PTH 1-33) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN; (The C-terminus of this sequence is amidated.) Sequence ID No. 113 (amidate PTH 1-32) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH; (The C-terminus of this sequence is amidated.) Sequence ID No. 114 (amidate PTH 1-31) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV; (The C-terminus of this sequence is amidated.) Sequence ID No. 115 (Amidated PTH 1-30) SVSEIQLMHNLGKHLNSMERVEWLRKKLQD; (The C-terminus of this sequence is amidated.) Sequence ID No. 116 (amidate PTH 1-29) SVSEIQLMHNLGKHLNSMERVEWLRKKLQ; (The C-terminus of this sequence is amidated.) Sequence ID No. 117 (Amidated PTH 1-28) SVSEIQLMHNLGKHLNSMERVEWLRKKL; (The C-terminus of this sequence is amidated.) Sequence ID No. 118 (amidate PTH 1-27) SVSEIQLMHNLGKHLNSMERVEWLRKK; (The C-terminus of this sequence is amidated.) Sequence ID No. 119 (amidate PTH 1-26) SVSEIQLMHNLGKHLNSMERVEWLRK; (The C-terminus of this sequence is amidated.) Sequence ID No. 120 (amidate PTH 1-25) SVSEIQLMHNLGKHLNSMERVEWLR; (The C-terminus of this sequence is amidated.) Sequence ID 121 (PTHrP) AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEIRATSEVSPNSKPSPNTKNHPVRFGSDDEGRYLTQETNKVETYKEQPLKTPGKKKKGKPGKRKEQEKKKRRTRSAWLDSGVTGSGLEGDHLSDTSTTSLELDSRRH

[0026] More preferably, the term "PTH" refers to the sequence of sequence numbers 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 sequence of sequence numbers 50, 51, 52, 110, 111, and 112. In a particularly preferred embodiment, the term "PTH" refers to the sequence of sequence number 51.

[0027] As used herein, the term “PTH polypeptide variant” refers to a polypeptide from the same species that is different from the reference PTH or PTHrP polypeptide. Preferably, such reference is a PTH polypeptide sequence having the sequence of SEQ ID NO: 51. Generally, the differences are limited, and therefore 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 the query amino acid sequence means that the amino acid sequence of the target polypeptide is identical to the query sequence, except that it may contain no more than 5 amino acid changes for every 100 amino acids of the query amino acid sequence. These modifications of the reference sequence may be located at the amino-terminus (N-terminus) or carboxy-terminus (C-terminus) of the reference amino acid sequence, or they may be individually scattered among residues in the reference sequence, or scattered among one or more adjacent groups in the reference sequence, or they may be located at any position between these terminal positions. The query sequence may be the entire amino acid sequence of the reference sequence, or any fragment as specified herein. Preferably, the query sequence is the sequence of SEQ ID NO: 51.

[0028] Such PTH peptide variants may be naturally occurring variants, such as naturally occurring allele variants encoded by one of several alternative forms of PTH or PTHrP occupying a given locus on a chromosome or organism, or they may be isoforms encoded by naturally occurring splice variants derived from a single primary transcript. Alternatively, the PTH polypeptide variant may be a variant not known to exist naturally, which can be produced by mutagenesis methods known in the art.

[0029] 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 substantially losing its biological function. Such N and / or C-terminal deletions are also encompassed by the term PTH polypeptide variant.

[0030] Those skilled in the art will also recognize that the amino acid sequence of a portion of a PTH or PTHrP polypeptide can be altered without significantly affecting the structure or function of the 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 methods for making 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 show that there are two main approaches to studying the tolerance of amino acid sequences to alteration.

[0031] 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 encompasses all PTHrP analogs, since PTHrP and PTHrP analogs bind to and activate the common PTH / PTHrP1 receptor. As used herein, the term "PTH analogue" refers to PTH or PTHrP from different, unrelated organisms that perform the same function in each organism but do not originate from a common ancestral structure shared by the ancestors of those organisms. Rather, similar PTH and PTHrP arose separately and subsequently evolved to perform the same or similar functions. In other words, similar PTH and PTHrP polypeptides are polypeptides that perform the same biological activity, namely increasing serum calcium and renal phosphorus excretion and decreasing serum phosphorus and renal calcium excretion, but have entirely different amino acid sequences.

[0032] As used herein, the term "PTH ortholog" refers to PTHs or PTHrPs within two different species that have evolved to be distinct from each other, although their sequences are related by a common homologous PTH or PTHrP in the ancestral species.

[0033] As used herein, the term "PTH homolog" refers to PTH or PTHrP from different organisms that perform the same function in each organism and originate from an ancestral structure common to the ancestors of those organisms. In other words, homologous PTH 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, and have exactly the same amino acid sequence. Preferably, a PTH polypeptide homolog can 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.

[0034] Accordingly, the PTH polypeptide according to the present invention may, for example, (i) have at least one amino acid residue substituted with a conserved or non-conserved amino acid residue, preferably a conserved amino acid residue, and such substituted amino acid residue may or may not be encoded by the genetic code, and / or (ii) have at least one amino acid residue containing a substituent, and / or (iii) have the PTH polypeptide fused with another compound, for example, a compound for increasing the half-life of the polypeptide (e.g., polyethylene glycol), and / or (iv) have further amino acids fused to the PTH polypeptide, such as an IgG Fc fusion region polypeptide or a leader or secretion sequence, or a sequence used for purifying the polypeptide of the above form, or a protein precursor sequence.

[0035] As used herein, the term "PTH polypeptide fragment" refers to any polypeptide comprising a contiguous range of a portion of the amino acid sequence of a PTH or PTHrP polypeptide, preferably the polypeptide of SEQ ID NO: 51.

[0036] More specifically, a PTH polypeptide fragment comprises at least six, e.g., at least eight, at least ten, or at least 17 consecutive amino acids of a PTH or PTHrP polypeptide, more preferably the polypeptide of SEQ ID NO: 51. Furthermore, a PTH polypeptide fragment may be described as a subgenus of a PTH or PTHrP polypeptide comprising at least six amino acids, where “at least six” is defined as any integer between six and an integer representing the C-terminal amino acid of a PTH or PTHrP polypeptide, preferably the polypeptide of SEQ ID NO: 51. Further includes species of PTH or PTHrP polypeptide fragments of at least six amino acids in length, as described above, which are further specified with respect to the N-terminal and C-terminal positions. All PTH or PTHrP polypeptide fragments of at least six amino acids in length, as described above, which may be specifically specified by the N-terminal and C-terminal positions, are also included in the term “PTH polypeptide fragment” as individual species. In other words, the present invention includes any combination of N-terminal and C-terminal positions that can be occupied by a fragment of at least six consecutive amino acids on any given amino acid sequence of a PTH or PTHrP polypeptide, preferably the PTH polypeptide of SEQ ID NO: 51.

[0037] The term "PTH" includes poly(amino acid) conjugates having the sequence described above, but also having a backbone containing 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) bonds and ester bonds. Therefore, as used herein, the term "side chain" refers to a substructure bonded to the alpha-carbon of an amino acid substructure when the amino acid substructures are linked by amine bonds, for example in the case of a polypeptide, or to any carbon-carbon-containing substructure bonded 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.

[0038] The term PTH includes the above variants, analogs, orthologues, homologs, derivatives, and fragments of PTH or PTHrP; therefore, all references to specific positions within the reference sequence also include equivalent positions within variants, analogs, orthologues, homologs, derivatives, and fragments of the PTH or PTHrP substructure, even if not specifically stated.

[0039] As used herein, the term "micelle" refers to an aggregate of amphiphilic molecules dispersed in a liquid colloid. In aqueous solutions, typical micelles form aggregates, also called "normal-phase micelles," in which the hydrophilic substructure of the surfactant molecule faces the surrounding solvent and the hydrophobic substructure of the surfactant faces inward. "Reverse micelles" have both an inwardly facing hydrophilic substructure and a hydrophobic substructure facing the surrounding solvent.

[0040] As used herein, the term "liposome" refers to a vesicle having at least one lipid bilayer, preferably a spherical vesicle. Preferably, the liposome contains phospholipids, more preferably phosphatidylcholine. The term "liposome" refers to a variety of structures and sizes, such as multilayer liposomal vesicles (MLVs) having one or more concentric lipid bilayers and an average diameter of 100-1000 nm, small monolayer liposomal vesicles (SUVs) having one lipid bilayer and an average diameter of 25-100 nm, large monolayer liposomal vesicles (LUVs) having one lipid bilayer and an average diameter of about 1000 μm, and giant monolayer 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.

[0041] As used herein, the term "aquasome" refers to spherical nanoparticles having a diameter of 60 to 300 nm, comprising at least three layers of self-assembling structures, i.e., a solid-phase nanocrystalline core covered with an oligomeric film on which drug molecules of a modified or unmodified drug are adsorbed.

[0042] As used herein, the term "ethosome" refers to a lipid vesicle containing phospholipids, as well as relatively high concentrations of ethanol and / or isopropanol, and water, and having a size ranging from tens of nanometers to micrometers.

[0043] As used herein, the term "LeciPlex" refers to a positively charged phospholipid vesicle system comprising soybean PC, a cationic agent, 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.

[0044] As used herein, the term "niosome" refers to a monolayer or multilayer vesicle containing a nonionic surfactant.

[0045] As used herein, the term "pharmacosome" refers to a microvesicle, micelle, or hexagonal aggregate derived from lipids covalently bound to a biologically active substructure.

[0046] As used herein, the term "proniosome" refers to a dried formulation of a surfactant-coated carrier that becomes a niosome upon rehydration and gentle stirring.

[0047] As used herein, the term "polymerosome" refers to an artificial spherical vesicle containing a membrane formed from an amphiphilic synthetic block copolymer, which may sometimes contain an aqueous solution within its core. Polymerosomes have a wide range of diameters, from 50 nm to 5 μm and larger. The term also includes syntosomes, which are polymerosomes designed to contain channels that allow certain chemical substances to enter or leave the vesicle through the membrane.

[0048] As used herein, the term "sphingosome" refers to a concentric bilayer vesicle in which the aqueous volume is completely encapsulated by a membrane-like lipid bilayer composed primarily of natural or synthetic sphingolipids.

[0049] As used herein, the term "transferosome" refers to a highly flexible lipid vesicle containing an aqueous core, formed from a mixture of suitable terminally activated lipids having a common polarity, the common polarity of which promotes the formation of a highly curved bilayer, and this curved bilayer makes the transferosome highly deformable.

[0050] As used herein, the term "ufasome" refers to a vesicle containing unsaturated fatty acids.

[0051] As used herein, the term "polypeptide" refers to a peptide containing 50 or fewer amino acid monomers.

[0052] As used herein, the term "protein" refers to a peptide containing more than 50 amino acid residues. Preferably, a protein contains up to 20,000 amino acid residues, for example, up to 15,000 amino acid residues, for example, up to 10,000 amino acid residues, for example, up to 5,000 amino acid residues, for example, up to 4,000 amino acid residues, for example, up to 3,000 amino acid residues, for example, up to 2,000 amino acid residues, for example, up to 1,000 amino acid residues.

[0053] As used herein, the term "physiological conditions" refers to an aqueous buffer solution at 37°C and pH 7.4.

[0054] As used herein, the term “pharmaceutical composition” means a composition containing one or more active ingredients, such as at least one controlled-release PTH compound, and one or more excipients, and any products obtained directly or indirectly from combinations, complexes, or aggregations of any two or more components of the composition, or from the dissociation of one or more of the components, or from other types of reactions or interactions of one or more of the components. Accordingly, the pharmaceutical compositions of the present invention encompass any composition produced by mixing one or more controlled-release PTH compounds with pharmaceutically acceptable excipients.

[0055] 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.

[0056] The term "suspension composition" refers to a mixture containing a water-insoluble controlled-release PTH compound and one or more solvents, such as water.

[0057] As used herein, the term “dried composition” means that the pharmaceutical composition is provided in a dry form. Preferred drying methods are spray drying and freeze-drying. Such a dried composition of a prodrug has a residual moisture content of up to 10%, preferably less than 5%, and more preferably less than 2%, as determined by Karl Fischer. Preferably, the pharmaceutical composition of the present invention is dried by freeze-drying.

[0058] As used herein, the term “drug” refers to a substance used to treat, cure, prevent or diagnose a disease, or to otherwise improve physical or mental well-being. When a drug is conjugated with another substructure, the substructure of the resulting product derived from that drug is called the “bioactive substructure.”

[0059] As used herein, the term “prodrug” refers to a conjugate in which a bioactive substructure is reversibly covalently linked to a special protecting group via a reversible linker substructure that includes a reversible bond to the bioactive substructure, the reversible linker substructure also referred to as the “reversible prodrug linker substructure,” and the special protecting group alters or removes undesirable properties of the parent molecule. This includes enhancing desirable properties and suppressing undesirable properties of the drug. The special non-toxic protecting group is referred to as the “carrier.” A prodrug releases a reversibly covalently bonded bioactive substructure in the form of its corresponding drug. In other words, a prodrug is a conjugate containing a bioactive substructure reversibly covalently conjugated to a carrier substructure via a reversible prodrug linker substructure, where the reversible covalent bond of the carrier to the reversible linker substructure is either direct or spacer-mediated. Such a conjugate releases the previously conjugated bioactive substructure in the form of a free, unmodified drug.

[0060] A "biodegradable bond" or "reversible bond" is a bond that can be decomposed by hydrolysis in the absence of enzymes under physiological conditions (aqueous buffer solution at pH 7.4, 37°C), i.e., cleaved, 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. Therefore, a stable bond is a bond that has a half-life longer than 3 months under physiological conditions (aqueous buffer solution at pH 7.4, 37°C).

[0061] As used herein, the term "trace-free prodrug linker" refers to a reversible prodrug linker that releases the drug in its free form upon cleavage; that is, a linker substructure that reversibly covalently links a bioactive substructure to a carrier. As used herein, the term "free form" refers to the drug in its unmodified, pharmacologically active form.

[0062] As used herein, the term “excipient” refers to a substance that is therapeutically useful, such as a diluent, adjuvant, or vehicle used to administer a drug or prodrug. Such pharmaceutical excipients may be sterile solutions, such as water and oils (including, but not limited to, peanut oil, soybean oil, mineral oil, sesame oil, etc., including those of petroleum, animal, plant, or synthetic origin). Water is a preferred excipient when the pharmaceutical composition is administered orally. When the pharmaceutical composition is administered intravenously, saline and dextrose aqueous solutions are preferred excipients. Salt solutions, as well as dextrose and glycerol aqueous solutions, are preferably used as liquid excipients for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, and ethanol. Pharmaceutical compositions may, as needed, contain small amounts of wetting or emulsifying agents, pH buffers 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, poloxamer, poloxamine, CHAPS, Igepal, or amino acids such as glycine, lysine, or histidine. These pharmaceutical compositions can take the form of liquids, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. Pharmaceutical compositions may also be formulated as suppositories using conventional binders and excipients, such as triglycerides. Oral formulations may contain standard excipients, such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such compositions would contain a therapeutically effective amount of drug or bioactive substructure, along with suitable amounts of excipients to produce a dosage form for appropriate administration to the patient. The formulation should be appropriate for the method of administration.

[0063] As used herein, the term “reagent” means a compound containing at least one functional group for reaction with the functional group of another compound or drug. Drugs containing a functional group (e.g., a primary or secondary amine or a hydroxyl functional group) are also understood to be reagents.

[0064] As used herein, the term "substructure" refers to a part of a molecule that lacks 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 the reaction product, the corresponding substructure of that 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.

[0065] When an arrangement or chemical structure of atomic groups is provided in which an atomic group is bonded to two substructures or interposed in one substructure, it is understood that, unless otherwise explicitly stated, the arrangement or chemical structure may be bonded to the two substructures in either orientation. For example, the substructure "-C(O)N(R 1 )-" is "-C(O)N(R 1 )-" or "-N(R 1 As ")C(O)-", it may be bonded to two substructures, or it may be inserted into one substructure. Similarly, substructure [ka] teeth, [ka] They may be bonded to two substructures or inserted into one substructure.

[0066] As used herein, the term "functional group" refers to an atomic group that can react with other atomic groups. Functional groups include, but are not limited to, the following: carboxylic acids (-(C=O)OH), primary or secondary amines (-NH2, -NH-), maleimides, thiols (-SH), sulfonic acids (-(O=S=O)OH), carbonates, carbamates (-O(C=O)N<), hydroxyls (-OH), aldehydes (-(C=O)H), ketones (-(C=O)-), hydrazines (>NN<), isocyanates, isothiocyanates, phosphoric acids (-O(P=O)OHOH), phosphonic acids (-O(P=O)OHH), haloacetyls, alkyl halides, acryloyls, aryl fluorides, hydroxylamines, disulfides, sulfonamides, sulfonic acids, vinyl sulfones, vinyl ketones, diazoalkanes, oxiranes, and aziridines.

[0067] If the controlled-release PTH compounds of the present invention contain one or more acidic or basic groups, the present invention also includes corresponding pharmaceutically or toxicologically acceptable salts thereof, in particular pharmaceutically usable salts thereof. Accordingly, controlled-release PTH compounds of the present invention containing 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 detailed examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine, etc.) or amino acids. There may also be controlled-release PTH compounds of the present invention containing one or more basic groups, i.e., protonable groups, and such prodrugs can be used in accordance with the present invention in the form of inorganic or organic acids and their addition salts. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenolpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. Further methods for converting basic groups to cations, such as alkylation of amine groups to provide suitable counterions for positively charged ammonium groups and their salts, are known to those skilled in the art. When the controlled-release PTH compound of the present invention contains both an acidic and a basic group, the present invention also includes intramolecular salts or betaines (zwitterionic) in addition to the salt forms mentioned. Each salt can be obtained by conventional methods known to those skilled in the art, for example, by contacting these compounds with organic or inorganic acids or bases in a solvent or dispersion, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention, which, due to their low physiological compatibility, are not directly suitable for use in pharmaceuticals, but can be used, for example, as intermediates in chemical reactions or in the production of pharmaceutically acceptable salts.

[0068] The term "medically acceptable" means a substance that does not cause harm when administered to a patient and is preferably approved for use in animals, preferably for use in humans, by a regulatory body, such as the EMA (Europe) and / or the FDA (United States) and / or any other national regulatory body.

[0069] In this specification, the term “about” as used in combination with a number is used to indicate not only the number itself, but also a range of plus / minus 10% or less of the number, more preferably 8% or less of the number, even more preferably 5% or less of the number, and most preferably 2% or less of the number. 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. A percentage indicated as “about 20%” is understood not to mean “20%+ / -10%”, i.e., a range of 10 to 30%, but rather that “about 20%” means a range of 18 to 22%, i.e., plus / minus 10% of the number 20.

[0070] As used herein, the term "polymer" means a molecule containing repeating structural units, i.e., monomers, linked by chemical bonds in a linear, cyclic, branched, cross-linked or dendrimer-like manner or in combinations thereof, which may be of synthetic origin, of biological origin, or a combination of both. It is understood that polymers may also contain one or more other chemical groups and / or substructures, such as, for example, one or more functional groups. Preferably, soluble polymers have a molecular weight of at least 0.5 kDa, for example, at least 1 kDa, at least 2 kDa, at least 3 kDa, or at least 5 kDa. When the polymer is soluble, it preferably has a molecular weight of up to 1000 kDa, for example, up to 750 kDa, for example, up to 500 kDa, for example, up to 300 kDa, for example, up to 200 kDa, for example, up to 100 kDa. It is understood that for insoluble polymers such as hydrogels, a meaningful molecular weight range cannot be provided. Proteins are also understood to be polymers in which the amino acids are the repeating structural units, even though the side chains of each amino acid may be different.

[0071] As used herein, the term "polymeric" means a reagent or substructure containing one or more polymers or polymer substructures. The polymeric reagent or substructure may optionally also contain one or more other substructures, and such other substructures are preferably selected from the group consisting of: · C 1-50 alkyl, C 2-50 alkenyl, C 2-50 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and · bonds selected from the group comprising:

Chemical formula

[0072] Those skilled in the art will understand that polymerization products obtained from polymerization reactions do not necessarily all have the same molecular weight, but rather exhibit a molecular weight distribution. Therefore, as used herein, molecular weight range, molecular weight, monomer number range in a polymer, and monomer number in a polymer refer to the number-average molecular weight and monomer number average, i.e., the arithmetic mean of the molecular weight of the polymer or polymer substructure and the arithmetic mean of the number of monomers in the polymer or polymer substructure.

[0073] Therefore, in the case of a polymer substructure containing "x" monomer units, any integer substituted for "x" corresponds to the arithmetic mean number of the monomers. Any range of integers substituted for "x" provides an integer range in which the arithmetic mean number of the monomers resides. An integer "x" expressed as "approximately x" means that the arithmetic mean number of the monomers resides within the integer range of x+ / -10%, preferably x+ / -8%, more preferably x+ / -5%, and most preferably x+ / -2%.

[0074] As used herein, the term "number-mean molecular weight" refers to the usual arithmetic mean of the molecular weights of individual polymers.

[0075] With respect to a carrier, the term "water-soluble" as used herein means that, if such a carrier is part of the controlled-release PTH compound of the present invention, at least 1 g of the controlled-release PTH compound containing such a water-soluble carrier can be dissolved in 1 liter of water at 20°C to form a homogeneous solution. Therefore, with respect to a carrier, the term "water-insoluble" means that, if such a carrier is part of the controlled-release PTH compound of the present invention, less than 1 g of the controlled-release PTH compound containing such a water-insoluble carrier can be dissolved in 1 liter of water at 20°C to form a homogeneous solution.

[0076] As used herein, the term "hydrogel" refers to a hydrophilic or amphiphilic polymer network composed of homopolymers or copolymers that are insoluble due to the presence of covalent chemical bonds. Crosslinking agents provide the network structure and physical integrity.

[0077] As used herein, the term "thermal gelling" refers to a compound that is a liquid or low-viscosity solution having a viscosity of less than 500 cps at 25°C with a shear rate of about 0.1 / second at low temperatures in the range of about 0°C to about 10°C, but is a compound with a higher viscosity of less than 10,000 cps at about 25°C with a shear rate of about 0.1 / second at higher temperatures in the range of about 30°C to about 40°C, for example, about 37°C.

[0078] As used herein with respect to a substructure or reagent, the term "PEG-based" means that the substructure or reagent contains PEG. Preferably, the PEG-based substructure or reagent contains at least 90% (w / w) PEG, such as at least 10% (w / w) PEG, for example at least 20% (w / w) PEG, for example at least 30% (w / w) PEG, for example at least 40% (w / w) PEG, for example at least 50% (w / w), for example at least 60% (w / w) PEG, for example at least 70% (w / w) PEG, for example at least 80% (w / w) PEG, for example at least 95%, etc. The remaining weight percentage of the PEG-based substructure or reagent is other substructures preferably selected from the following substructures and bindings: ·C 1-50 Alkyl, C 2-50 Alkenil, C 2-50 Alkinyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and • Joins selected from the group including the following: [ka] (In the formula, The dashed line indicates binding to the substructure or the remainder of the reagent. -R and -R a (These are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl, and hexyl).

[0079] As used herein with respect to a substructure or reagent, the term "PEG system containing at least X% PEG" means that the substructure or reagent contains at least X% (w / w) ethylene glycol units (-CH2CH2O-), which may be arranged in alternating blocks or randomly distributed within the substructure or reagent, preferably all ethylene glycol units of the substructure or reagent are located within a single block, and the remaining weight percentage of the PEG system substructure or reagent is other substructures preferably selected from the following substructures and combinations: ·C 1-50 Alkyl, C 2-50 Alkenil, C 2-50 Alkinyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and • Joins selected from the group including the following: [ka] (In the formula, The dashed line indicates binding to the substructure or the remainder of the reagent. -R and -R a (These are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl, and hexyl).

[0080] The term "hyaluronic acid-based product containing at least X% hyaluronic acid" is used as appropriate.

[0081] As used herein, the term "substituted" means that one or more -H atoms in a molecule or substructure are replaced by another atom or group of atoms, and such other atom or group of atoms is referred to as a "substituent."

[0082] Preferably, one or more further optional substituents are halogen, -CN, -COOR, independently of each other. 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 A group consisting of alkynnyls is selected, where -T 0 , C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is the same or different -R of one or more R's. x2 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl has -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3)-, -S(O)2N(R x3 )-, -S(O)N(R x3 )-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-, -N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )- from the group consisting of one or more groups selected may optionally intervene, -R x1 , -R x1a , -R x1b are, independently of each other, -H, -T 0 , C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl selected from the group consisting of, said -T 0 , C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl are optionally substituted with one or more -R x2 and the C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl may contain -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )(R x3 )-, -S(O)2N(R x3 )-, -S(O)N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-, -N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )- from the group consisting of one or more groups selected may optionally intervene, each T 0These are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl, each of the above T 0 These are independently one or more -Rs, the same or different. x2 It is sometimes replaced by, Each R x2 These are, independently, halogen, -CN, oxo (=O), and -COOR. x4 , -OR x4 , -C(O)R x4 ,-C(O)N(R x4 R x4a ), -S(O)2N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O)2R x4 ,-S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO2, -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O)2R x4a , -N(R x4 )S(O)R x4a , -N(R x4 )C(O)OR x4a , -N(R x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ), and C 1-6 Selected from the group consisting of alkyl groups, the C 1-6 Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. Each-R x3 ,-R x3a ,-R x4 ,-R x4a ,-R x4b These are independently -H and C 1-6Selected from the group consisting of alkyl groups, the C 1-6 Alkyl is sometimes substituted with one or more halogens, one or more of the same or different.

[0083] More preferably, one or more further optional substituents may be halogen, -CN, or -COOR, independently of each other. x1 , -OR x1 , -C(O)R x1 ,-C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 ,-S(O)R x1 , -N(R x1 )S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O)2R x1a , -N(R x1 )S(O)R x1a , -N(R x1 )C(O)OR x1a , -N(R x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 , C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 A group consisting of alkynnyls is selected, where -T 0 , C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl is the same or different -R of one or more R's. x2 In some cases, it is replaced by C 1-10 Alkyl, C 2-10 Alkenyl and C2-10 Alkinyl has -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 One or more groups selected from the group consisting of )- are interspersed, Each-R x1 ,-R x1a ,-R x1b ,-R x3 ,-R x3a These are independently -H, halogen, and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls, Each T 0 These are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl, each of the above T 0 These are independently one or more -Rs, the same or different. x2 It is sometimes replaced by, Each R x2 These are, independently, halogen, -CN, oxo (=O), and -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(Rx4a 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 Selected from the group consisting of alkyl groups, the C 1-6 Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. Each-R x4 ,-R x4a ,-R x4b These are independently -H, halogen, and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls.

[0084] More preferably, one or more further optional substituents may be halogen, -CN, -COOR, independently of each other. 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 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 A group consisting of alkynnyls is selected, where -T 0 , C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl is the same or different -R of one or more R's. x2 It is sometimes replaced by the aforementioned C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl has -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 One or more groups selected from the group consisting of )- are interspersed, Each-R x1 ,-R x1a ,-R x1b ,-R x2 ,-R x3 ,-R x3a These are independently -H, halogen, and C 1-6 Alkyl, C2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls, Each T 0 These are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl, each of the above T 0 These are independently one or more -Rs, the same or different. x2 It is sometimes replaced.

[0085] Preferably, up to six -H atoms of the optionally substituted molecule are independently replaced by substituents, for example, five -H atoms are independently replaced by substituents, four -H atoms are independently replaced by substituents, three -H atoms are independently replaced by substituents, two -H atoms are independently replaced by substituents, or one -H atom is independently replaced by a substituent.

[0086] The term "inserted" means that a substructure is inserted between two carbon atoms, or, if the insertion is at the end of the substructure, between a carbon or heteroatom and a hydrogen atom, preferably between a carbon and a hydrogen atom.

[0087] The term "C" as used herein, either alone or in combination with other terms. 1-4 "Alkyl" refers to a linear or branched alkyl substructure having 1 to 4 carbon atoms. When present at the end of a molecule, it is linear or branched. 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. The two substructures of the molecule are C 1-4 If bonded by alkyl, such C 1-4 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. 1-4Each hydrogen atom of the alkyl carbon may optionally be replaced by a substituent as defined above. 1-4 The alkyl group may have one or more substructures as defined below.

[0088] The term "C" as used herein, either alone or in combination with other terms. 1-6 "Alkyl" refers to a linear or branched alkyl substructure having 1 to 6 carbon atoms. When present at the end of a molecule, it can be linear or branched. 1-6 Examples of alkyl groups include 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. The two substructures of the molecule are C 1-6 If bonded by an alkyl group, such C 1-6 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. 1-6 Each hydrogen atom of carbon may be replaced by a substituent as defined above. 1-6 The alkyl group may have one or more substructures as defined below.

[0089] Therefore, "C 1-10 Alkyl," "C 1-20 "Alkyl" or "C 1-50 "Alkyl" refers to an alkyl chain having 1 to 10, 1 to 20, or 1 to 50 carbon atoms, respectively. 1-10 , C 1-20 or C 1-50 Each hydrogen atom of carbon may be replaced by a substituent as defined above. 1-10 or C 1-50 The alkyl group may have one or more substructures as defined below.

[0090] The term "C" as used herein, either alone or in combination with other terms. 2-6 An "alkenyl" refers to a linear or branched hydrocarbon substructure having 2 to 6 carbon atoms and containing at least one carbon-carbon double bond. When present at the ends of a molecule, examples include -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3, and -CH=CH-CH=CH2. Two substructures of a molecule are C 2-6 When bonded by an alkenyl, such C 2-6 An example of an alkenil is -CH=CH-. 2-6 Each hydrogen atom in the alkenyl substructure may be replaced by a substituent as defined above. 2-6 An alkenil may have one or more substructures, as defined below, interspersed within it.

[0091] Therefore, the term "C" can be used alone or in combination with other terms. 2-10 Alkenil, "C 2-20 "Alkenil" or "C 2-50 "Alkenyl" refers to a linear or branched hydrocarbon substructure having 2 to 10, 2 to 20, or 2 to 50 carbon atoms and containing at least one carbon-carbon double bond. 2-10 Alkenil, 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. In some cases, C 2-10 Alkenil, C 2-20 Alkenyl or C 2-50 An alkenil may have one or more substructures, as defined below, interspersed within it.

[0092] The term "C" as used herein, either alone or in combination with other terms. 2-6"Alkynyl" refers to a linear or branched hydrocarbon substructure having 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. When present at the end of a molecule, examples include -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, and CH2-C≡C-CH3. When two substructures of a molecule are linked by an alkynyl group, an example is -C≡C-. 2-6 Each hydrogen atom of the alkynyl group may optionally be replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-6 An alkynyl may have one or more substructures, as defined below, interspersed within it.

[0093] Therefore, the term "C" used herein, either alone or in combination, is used herein. 2-10 Alkinyl, C 2-20 "Alkinyl" or "C 2-50 "Alkynyl" refers to a linear or branched hydrocarbon substructure containing at least one carbon-carbon triple bond, each having 2-10, 2-20, or 2-50 carbon atoms, respectively. 2-10 Alkinyl, C 2-20 Alkinyl or C 2-50 Each hydrogen atom of the alkynyl group may optionally be replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-10 Alkinyl, C 2-20 Alkinyl or C 2-50 An alkynyl may have one or more substructures, as defined below, interspersed within it.

[0094] As mentioned above, C 1-4 Alkyl, C 1-6 Alkyl, C 1-10 Alkyl, C 1-20 Alkyl, C 1-50 Alkyl, C 2-6 Alkenil, C 2-10 Alkenil, C 2-20 Alkenil, C 2-50 Alkenil, C 2-6 Alkinyl, C 2-10Alkinyl, C 2-20 Alkenyl or C 2-50 The alkynyl may optionally have one or more substructures interspersed within it, and the one or more substructures are preferably [ka] (In the formula, The dashed line indicates binding to the substructure or the remainder of the reagent. -R and -R a (These are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl, and hexyl.) It is selected from the group consisting of the following.

[0095] The term "C" as used herein 3-10 "Cycloalkyl" means a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. 3-10 Each hydrogen atom of a cycloalkyl carbon may be replaced by a substituent as defined above. 3-10 "Cycloalkyl" also includes cross-linked birings such as norbornane or norbornene.

[0096] The term "8-30 membered carbopolycyclil" or "8-30 membered carbon polycyclic" refers to a cyclic substructure having 8 to 30 ring atoms, in which two adjacent rings share 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, an 8-30 membered carbopolycyclil refers to a cyclic substructure with 2, 3, 4, or 5 rings, more preferably 2, 3, or 4 rings.

[0097] As used herein, the terms “3- to 10-membered heterocyclyl” or “3- to 10-membered heterocycle” mean a ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, wherein at least one ring atom and up to four ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and which may contain up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings), and the remainder of the molecule is bonded by carbon or nitrogen atoms. Examples of 3- to 10-membered heterocycles include, but are not limited to, aziridine, oxirane, thiirane, azirine, oxilen, thiirane, azetidine, oxetane, thietan, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazoline, isothiazoline, thiadiazole, thiadiazole, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazoline, isothiazoline, thiadiazole, thiadiazole, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazoline, sulforane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyridine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidin, diazepane, azepine, and homopiperazine. Each hydrogen atom of a 3- to 10-membered heterocyclyl or 3- to 10-membered heterocyclic group may optionally be replaced by a substituent as defined below.

[0098] As used herein, the terms “8-11 membered heterobicyryl” or “8-11 membered heterobicyclic” mean a two-ring heterocyclic substructure having 8 to 11 ring atoms and potentially containing up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated aromatic or non-aromatic rings), wherein at least one ring atom is shared by both rings, and at least one ring atom, up to a maximum of six ring atoms, are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the rings are bonded to the remainder of the molecule by carbon or nitrogen atoms. Examples of 8- to 11-membered heterobicyclic rings include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzimidazole, benzimidazolin, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, and pteridine. The term 8- to 11-membered heterobicyclic ring also includes bicyclic spiro structures such as 1,4-dioxa-8-azaspiro[4.5]decane, or bridging heterocyclic rings such as 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom of an 8- to 11-membered heterobicyclyl or 8- to 11-membered heterobicyclic carbon may optionally be replaced by substituents as defined below.

[0099] Similarly, the term “8-30 membered heteropolycyclil” or “8-30 membered heteropolycycle” means a heterocyclic substructure having two or more rings, preferably three, four, or five rings, having 8 to 30 ring atoms and potentially containing up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings), wherein two adjacent rings share at least one ring atom, and at least one ring atom, up to a maximum of ten 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 the ring is bonded to the remainder of the molecule by carbon or nitrogen atoms.

[0100] structure: [ka] Regarding the substructure, "Pair R x / R y Together with the atoms to which they are bonded, C 3-10 The phrase "forms a cycloalkyl or 3-10 membered heterocycline" is R x and R y However, it is understood that this means forming the following structure: [ka] (In the formula, R is C 3-10 (They are cycloalkyl or 3-10 membered heterocyclines.)

[0101] structure: [ka] Regarding the substructure, "Pair R x / R y The phrase "they, together with the atoms to which they are bonded, form ring A" is R x and R y However, it is also understood that this means forming the following structure: [ka]

[0102] As used herein, "halogen" means fluoro, chloro, bromo, or iodine. Generally, fluoro or chloro halogens are preferred.

[0103] Generally, the terms "include" or "including" also include "consist of" or "consist of."

[0104] Preferably, the pharmaceutical composition containing the controlled-release PTH compound is administered according to a dosing plan in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in increments of 20% or less, more preferably 15% or less, and most preferably 10% or less.

[0105] In one embodiment, a pharmaceutical composition containing a controlled-release PTH compound is administered according to a dosing schedule in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in 25% increments.

[0106] More preferably, the pharmaceutical composition containing the controlled-release PTH compound is administered according to a dosing schedule in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in 20% increments.

[0107] More preferably, the pharmaceutical composition containing the controlled-release PTH compound is administered according to a dosing schedule in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in 15% increments.

[0108] Most preferably, the pharmaceutical composition containing the controlled-release PTH compound is administered according to a dosing schedule in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in 10% increments.

[0109] Preferably, the pharmaceutical product containing the controlled-release PTH compound is administered to the patient at a frequency of once every 24 hours or less, for example, every 24 hours, every 36 hours, every 48 hours, every 60 hours, every 72 hours, every 84 hours, every 96 hours, every 108 hours, every 120 hours, every 132 hours, every 144 hours, every 156 hours, once a week, once every two weeks.

[0110] In one embodiment, a pharmaceutical composition containing a controlled-release PTH compound is administered every 24 hours.

[0111] In another embodiment, the pharmaceutical composition containing the controlled-release PTH compound is administered every 48 hours.

[0112] In another embodiment, the pharmaceutical composition containing the controlled-release PTH compound is administered every 72 hours.

[0113] In another embodiment, the pharmaceutical composition containing the controlled-release PTH compound is administered every 96 hours.

[0114] In another embodiment, the pharmaceutical composition containing the controlled-release PTH compound is administered every 120 hours.

[0115] In another embodiment, the pharmaceutical composition containing the controlled-release PTH compound is administered every 144 hours.

[0116] In another embodiment, the pharmaceutical composition containing the controlled-release PTH compound is administered once a week.

[0117] Preferably, the pharmaceutical composition containing the PTH compound is administered to the patient by subcutaneous administration, preferably by subcutaneous injection.

[0118] In one embodiment, the pharmaceutical composition for use of the present invention is administered by syringe. In another embodiment, the pharmaceutical composition for use of the present invention is administered by pen-type syringe. In yet another embodiment, the pharmaceutical composition for use of the present invention is administered by auto-injector.

[0119] Preferably, the controlled-release PTH compound includes a PTH molecule or substructure having the sequence of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 107, 108, 109, 110, 111, 112, 113, 114, or 115. More preferably, the controlled-release PTH molecule or substructure has the sequence of SEQ ID NOs: 50, 51, 52, 110, 111, or 112.

[0120] In one embodiment, the PTH molecule or substructure has the sequence of SEQ ID NO: 50.

[0121] In another embodiment, the PTH molecule or substructure has the sequence of SEQ ID NO: 52.

[0122] In another embodiment, the PTH molecule or substructure has the sequence of SEQ ID NO: 110.

[0123] In another embodiment, the PTH molecule or substructure has the sequence of SEQ ID NO: 111.

[0124] In another embodiment, the PTH molecule or substructure has the sequence of SEQ ID NO: 112.

[0125] Most preferably, the PTH molecule or substructure has the sequence of SEQ ID NO: 51.

[0126] In one embodiment, the controlled-release PTH compound is water-insoluble.

[0127] Preferably, the water-insoluble controlled-release PTH compound is selected from the group consisting of crystals, nanoparticles, microparticles, nanospheres, and microspheres.

[0128] In one embodiment, the water-insoluble controlled-release PTH compound is a crystal containing at least one PTH molecule or substructure.

[0129] In another embodiment, the water-insoluble controlled-release PTH compound is a nanoparticle comprising at least one PTH molecule or substructure.

[0130] In another embodiment, the water-insoluble controlled-release PTH compound is a microparticle comprising at least one PTH molecule or substructure.

[0131] In another embodiment, the water-insoluble controlled-release PTH compound is a nanosphere comprising at least one PTH molecule or substructure.

[0132] In another embodiment, the water-insoluble controlled-release PTH compound is a microsphere comprising at least one PTH molecule or substructure.

[0133] In one embodiment, the water-insoluble controlled-release PTH compound is a vesicle containing at least one PTH molecule or substructure. Preferably, such a vesicle containing at least one PTH molecule or substructure is a micelle, liposome, or polymerosome.

[0134] In one embodiment, the water-insoluble controlled-release PTH compound is a micelle containing at least one PTH molecule or substructure.

[0135] In another embodiment, the water-insoluble controlled-release PTH compound is a liposome comprising at least one PTH molecule or substructure. Preferably, such liposomes are selected from the group consisting of aquasomes, nonionic surfactant vesicles, e.g., niosomes and proniosomes, cationic liposomes, e.g., LeciPlex, transferosomes, etosomes, uphasomes, sphingosomes, and pharmacosomes.

[0136] In another embodiment, the water-insoluble controlled-release PTH compound is a polymerosome comprising at least one PTH molecule or substructure.

[0137] In another embodiment, the water-insoluble controlled-release PTH compound comprises at least one PTH molecule or substructure incorporated non-covalently into a water-insoluble polymer. Preferably, such water-insoluble polymers include 2-methacryloyloxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amideamine), poly(amino acid), poly(acid 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 The polymers include polymers selected from the group consisting of poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic acid-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 its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate polymers, xylan, and copolymers thereof.

[0138] In a preferred embodiment, the water-insoluble controlled-release PTH compound comprises at least one PTH molecule or substructure non-covalently incorporated into poly(lactic acid-coglycolic acid) (PLGA).

[0139] In another embodiment, the water-insoluble controlled-release PTH compound comprises at least one PTH molecule reversibly conjugated covalently to a water-insoluble polymer. Preferably, such water-insoluble polymers include 2-methacryloyloxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amideamine), poly(amino acid), poly(acid 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 The polymers include polymers selected from the group consisting of poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic acid-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 its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate polymers, xylan, and copolymers thereof.

[0140] In one embodiment, such a water-insoluble controlled-release PTH compound is conjugated DL (In the formula, -D is a PTH substructure, -L is a reversible pro-drag linker substructure -L 1 - containing said partial structure -L 1 - is linked to the PTH substructure-D via the functional group of PTH, Said-L 1 - is -L 2 It is replaced with -Z', and in some cases further replaced. -L 2 - is a single chemical bond or spacer substructure. -Z' is a water-insoluble support substructure. It is a compound containing [a specific compound].

[0141] Multiple substructures - L 2 -L 1 It is understood that -D is linked to a water-insoluble carrier -Z', and that such a controlled-release PTH compound is a PTH prodrug, more specifically, a PTH prodrug linked to a carrier.

[0142] -D, -L 1 -, -L 2 Preferred embodiments of - and -Z' are described below.

[0143] In a preferred embodiment, the controlled-release PTH compound is water-soluble.

[0144] 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 substructure, -L 1 - is a reversible prodrug linker substructure linked to the PTH substructure-D via the functional group of PTH, -L 2 - is a single chemical bond or spacer substructure. -Z is a water-soluble carrier substructure, 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 pharmaceutically acceptable salt thereof.

[0145] It is understood that the compounds of formulas (Ia) and (Ib) are PTH prodrugs, more specifically water-soluble PTH prodrugs.

[0146] Preferably, -D has the sequence of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 107, 108, 109, 110, 111, 112, 113, 114, or 115. More preferably, -D has the sequence of SEQ ID NOs: 50, 51, 52, 110, 111, or 112.

[0147] In one embodiment, -D has the sequence of sequence number 50.

[0148] In another embodiment, -D has the sequence of sequence number 52.

[0149] In another embodiment, -D has the sequence of sequence number 110.

[0150] In another embodiment, -D has the sequence of sequence number 111.

[0151] In another embodiment, -D has the sequence of sequence number 112.

[0152] Most preferably, -D has the sequence of sequence number 51.

[0153] Substructure-L 1- is conjugated to the functional group of the side chain of the amino acid residue of -D, to the N-terminal amine functional group or C-terminal carboxyl functional group of -D, or to the nitrogen atom in the skeletal polypeptide chain of -D. The bond to either the N-terminus or C-terminus may be direct or indirect by the corresponding amine or carboxyl functional group, in which case the spacer substructure first conjugates to the amine or carboxyl functional group, and then the spacer substructure -L conjugates to that functional group. 1 - is conjugated.

[0154] Preferably, -L 1 -The amino acid residue of the PTH conjugated by - contains a functional group selected from the group consisting of carboxylic acids, primary and secondary amines, maleimides, thiols, sulfonic acids, carbonates, carbamates, hydroxyls, aldehydes, ketones, hydrazines, isocyanates, isothiocyanates, phosphoric acids, phosphonic acids, haloacetyls, alkyl halides, acryloyls, aryl fluorides, hydroxylamines, sulfates, disulfides, vinyl sulfones, vinyl ketones, diazoalkanes, oxiranes, guanidines, and aziridines. More preferably, -L 1 - The amino acid residue of the PTH conjugated by - contains a functional group selected from the group consisting of hydroxyl, primary and secondary amines, and guanidine. More preferably, -L 1 -The amino acid residues of the PTH conjugated by - contain primary and secondary amine functional groups. Most preferably, -L 1 - The amino acid residue of the PTH conjugated with this group contains a primary amine functional group.

[0155] Substructure-L 1 -However, if it is conjugated to a functional group of the side chain of an amino acid residue of PTH, the amino acid residue is selected from the group consisting of protein-constituting amino acid residues and non-protein-constituting amino acid residues.

[0156] In one embodiment, -L 1- is conjugated to the functional group of the side chain of a non-protein constituent amino acid residue of PTH. Such non-protein constituent amino acids are not found in the sequence or fragments of natural PTH, and are understood to be present only in variants, analogs, orthologues, homologs, and derivatives of PTH.

[0157] In another embodiment, -L 1 - is conjugated to the functional group of the side chain of the protein constituent amino acid residue of PTH. Preferably, the amino acid is selected from the group consisting of histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid, and arginine. More preferably, the amino acid is selected from the group consisting of lysine, aspartic acid, arginine, and serine. Even more preferably, the amino acid is selected from the group consisting of lysine, arginine, and serine.

[0158] In one embodiment, -L 1 - is conjugated to the functional group of the histidine side chain of PTH.

[0159] In another embodiment, -L 1 - is conjugated to the functional group of the lysine side chain of PTH.

[0160] In another embodiment, -L 1 - is conjugated to the functional group of the tryptophan side chain of PTH.

[0161] In another embodiment, -L 1 - is conjugated to the functional group of the serine side chain of PTH.

[0162] In another embodiment, -L 1 - is conjugated to the functional group of the threonine side chain of PTH.

[0163] In another embodiment, -L 1 - is conjugated to the functional group of the tyrosine side chain of PTH.

[0164] In another embodiment, -L 1 - is conjugated to the functional group of the aspartic acid side chain of PTH.

[0165] In another embodiment, -L 1 - is conjugated to the functional group of the glutamic acid side chain of PTH.

[0166] In another embodiment, -L 1 - is conjugated to the functional group of the arginine side chain of PTH.

[0167] It should be understood that not all PTH substructures can contain all of these amino acid residues.

[0168] In a preferred embodiment, -L 1 - is either directly conjugated to the N-terminal amine functional group of PTH by the corresponding amine functional group, or indirectly conjugated in this case, the spacer substructure first conjugates to the amine functional group, and then the spacer substructure -L conjugates to that functional group. 1 - is conjugated. More preferably, -L 1 - is directly conjugated with the N-terminal amine functional group of PTH.

[0169] Similarly, in a preferred embodiment, -L 1 - is either directly conjugated to the C-terminal amine functional group of PTH by the corresponding carboxyl functional group, or indirectly conjugated in this case, the spacer substructure first conjugates to the carboxyl functional group, and then the spacer substructure -L conjugates to that functional group. 1 - is conjugated.

[0170] Most preferably, L 1 - is directly conjugated with the N-terminal amine functional group of PTH.

[0171] Substructure-L1 - may be linked to -D by any type of bond, provided that it is reversible. Preferably, -L 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. More preferably, -L 1 - is linked to -D by a bond selected from the group consisting of amides, esters, carbamates, and acylguanidines. Some of these bonds are not reversible in themselves, however, in this invention -L 1 It is understood that the adjacent groups contained within the - make these bonds reversible.

[0172] In one embodiment, -L 1 - is linked to -D by an ester bond.

[0173] In another embodiment, -L 1 - is linked to -D by a carbamate bond.

[0174] In another embodiment, -L 1 - is linked to -D by acylguanidine.

[0175] In a preferred embodiment, -L 1 - is linked to -D by an amide bond.

[0176] Substructure-L 1 - is a reversible prodrug linker in which the drug, namely PTH, is released in its free form, i.e., a traceless prodrug linker. Suitable prodrug linkers, such as the reversible prodrug linker substructures disclosed in WO 2005 / 099768 A2, WO 2006 / 136586 A2, WO 2011 / 089216 A1 and WO 2013 / 024053 A1, which are incorporated herein by reference, are known in the art.

[0177] 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.

[0178] Particularly preferred substructure - L 1 - is disclosed in WO 2009 / 095479 A2. Therefore, in a preferred embodiment, substructure-L 1 - is equation (II): [ka] (In the formula, The dashed lines indicate the bonding of the PTH substructure -D to nitrogen, hydroxyl, or thiol. -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 Selected from the group consisting of )-, X 1 It is selected from the group consisting of C and S(O), -X 2 - is -C(R 8 R 8a )- and -C(R 8R 8a )-C(R 9 R 9a Selected from the group consisting of )-, =X 3 It 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 ,-R 9a These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, -R 3 ,-R 3a These are independently -H and C 1-6 Selected from the group consisting of alkyl, except -R 3 ,-R 3a If one or both of them are not -H, then they are SP to the N to which they are bonded. 3 Linked by hybrid carbon atoms, -R 7 is -N(R 10 R 10a ) and -NR 10 -(C=O)-R 11 Selected from the group consisting of, -R 7a ,-R 10 ,-R 10a ,-R 11 These are, independently of each other, -H and C 1-6 Selected from the group consisting of alkyl groups, Depending on the circumstances, Pair-R 1a / -R 4a ,-R 1a / -R 5a ,-R 1a / -R 7a ,-R 4a / -R 5a ,-R 8a / -R 9a One or more of them form a chemical bond, Depending on the circumstances, Pair-R 1 / -R 1a ,-R 2 / -R 2a ,-R 4 / -R 4a ,-R 5 / -R 5a ,-R 8 / -R 8a ,-R 9 / -R 9a One or more of them, together with the atom they are bonded to, C 3-10 Forming cycloalkyl or 3-10 membered heterocyclines, Depending on the circumstances, 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 ,-R 2 / -R 3 One or more of these, together with the atoms to which they are bonded, form ring A. Depending on the case, -R 3 / -R 3a These, together with the nitrogen atoms to which they are bonded, form a 3- to 10-membered heterocycle. A is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 (Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl), -L 1 - is -L 2 -Z or -L 2 -Z' is used as a substitution, and in some cases, -L 1 - is further substituted, except that the hydrogen with an asterisk in formula (II) is -L 2 -Z or -L 2 -Z' or substitutions are not replaced, -L2 - is a single chemical bond or spacer, -Z is a water-soluble carrier, -Z' is a water-insoluble carrier.

[0179] Preferably, -L of formula (II) 1 - is one substructure - L 2 -Z or -L 2 It is replaced with -Z'.

[0180] In one embodiment, formula (II) -L 1 - has not been further replaced.

[0181] -R in equation (II) 3 / -R 3a However, when they combine with the nitrogen atom to which they are bonded to form a 3- to 10-membered heterocycle, the atom directly bonded to the nitrogen is SP 3 It is understood that only such 3- to 10-membered heterocycles, which are hybrid carbon atoms, can be formed. In other words, -R 3 / -R 3a Such 3- to 10-membered heterocycles, formed by these atoms and the nitrogen atoms to which they are bonded, have the following structure: [ka] (In the formula, The dashed line is -L 1 - indicates the connection to the remainder, The ring contains 3 to 10 atoms, including at least one nitrogen atom, and R # and R ## SP 3 (Represents hybrid carbon atoms).

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

[0183] -R in equation (II) 3 / -R 3a Exemplary embodiments of preferred 3- to 10-membered heterocycles formed by these atoms and the nitrogen atoms to which they are bonded are as follows: [ka] (In the formula, The dashed line indicates the bond to the rest of the molecule. -R is -H and C 1-6 (Selected from the group consisting of alkyl groups).

[0184] Depending on the case, -L in equation (II) 1 - may be further substituted. In general, any substituent may be used as long as it does not affect the principle of cleavage, that is, the hydrogen with an asterisk in formula (II) is not substituted, and the substructure of formula (II) [ka] The nitrogen remains as part of the primary, secondary, or tertiary amine, i.e., -R 3 and -R 3a These are either -H independently of each other, or SP 3 It is linked to -N< by hybridized carbon atoms.

[0185] In one embodiment, the -R of formula (II) 1 or -R 1a is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 2 or -R 2a is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 3 or -R 3a is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 4 is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 5 or -R 5a is, -L 2 -Z or -L 2It is substituted with -Z'. In another embodiment, -R in formula (II) 6 is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 7 or -R 7a is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 8 or -R 8a is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 9 or -R 9a is, -L 2 -Z or -L 2 -Z' is substituted. In another embodiment, -R 10 is, -L 2 -Z or -L 2 -Z' is substituted. In another embodiment, -R 11 is, -L 2 -Z or -L 2 It is replaced with -Z'.

[0186] Preferably, -X- in formula (II) is -C(R 4 R 4a )-,-N(R 4 )- and -C(R 7 R 7a Selected from the group consisting of )-.

[0187] In one embodiment, -X- in formula (II) is -C(R 4 R 4a )-is.

[0188] In one preferred embodiment, -X- in formula (II) is -C(R 7 R 7a )-is.

[0189] Preferably, -R of formula (II) 7 -NR 10 -(C=O)-R 11 That is the case.

[0190] Preferably, -R of formula (II) 7a is selected from -H, methyl and ethyl. Most preferably, -R of formula (II). 7a It is -H.

[0191] Preferably, -R 10 is selected from -H, methyl, and ethyl. Most preferably, -R 10 It is methyl.

[0192] Preferably, -R 11 is selected from -H, methyl, and ethyl. Most preferably, -R 11 It is -H.

[0193] Preferably, -R 11 is, -L 2 -Z or -L 2 It is replaced with -Z'.

[0194] In another preferred embodiment, -X- in formula (II) is -N(R 4 )-is.

[0195] Preferably, -R 4 is selected from the group consisting of -H, methyl, and ethyl. Preferably, -R 4 It is -H.

[0196] Preferably, X in formula (II) 1 It is C.

[0197] Preferably, equation (II) = X 3 The answer is = O.

[0198] Preferably, -X in formula (II) 2 - is -C(R 8 R 8a )-is.

[0199] Preferably, -R of formula (II) 8 and -R 8aThe is independently selected from the group consisting of -H, methyl, and ethyl. More preferably, the -R of formula (II). 8 and -R 8a At least one of them is -H. More preferably, -R of formula (II). 8 and -R 8a Both are -H.

[0200] Preferably, -R of formula (II) 1 and -R 1a This is independently selected from the group consisting of -H, methyl, and ethyl.

[0201] In one preferred embodiment, -R of formula (II) 1 and -R 1a At least one of them is -H, and more preferably -R of formula (II). 1 and -R 1a Both are -H.

[0202] In another preferred embodiment, -R of formula (II) 1 and -R 1a At least one of them is methyl, more preferably -R of formula (II). 1 and -R 1a Both are methyl.

[0203] Preferably, -R of formula (II) 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. More preferably, the -R of formula (II). 2 and -R 2a At least one of them is -H. More preferably, -R of formula (II). 2 and -R 2a Both are H.

[0204] Preferably, -R of formula (II) 3 and -R 3a This is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl.

[0205] In one preferred embodiment, -R of formula (II) 3 and -R 3a At least one of them is methyl, more preferably -R of formula (II). 3 It is methyl, and -R of formula (II) 3a It is -H.

[0206] In another preferred embodiment, -R of formula (II) 3 and -R 3a Both are -H.

[0207] Preferably, -D forms an amide bond with nitrogen, thereby creating -L 1 It is linked to -

[0208] In one preferred embodiment, substructure-L 1 - is equation (IIa-i): [ka] (In the formula, The dashed line indicates the bonding of the PTH substructure -D to 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 for equation (II). It has, Said-L 1 - is -L 2 -Z or -L 2 -Z' is substituted, and in some cases, the aforementioned -L 1 - is further substituted, except that the hydrogen with an asterisk in equation (IIa-i) is -L 2 -Z or -L 2 -Z' or substitutions cannot replace it.

[0209] Preferably, -L of formula (IIa-i) 1 - is one substructure - L 2 -Z or -L 2 It is replaced with -Z'.

[0210] Preferably, the substructure of formula (IIa-i) - L 1 - has not been further replaced.

[0211] Preferably, -R in formula (IIa-i) 1 and -R 1a The is independently selected from the group consisting of -H, methyl, and ethyl. More preferably, the -R of formula (IIa-i). 1 and -R 1a At least one of them is -H. More preferably, -R of formula (IIa-i). 1 and -R 1a Both are -H.

[0212] Preferably, -R in formula (IIa-i) 7 -NR 10 -(C=O)-R 11 That is the case.

[0213] Preferably, the -R in formula (II-i) 7a is selected from -H, methyl and ethyl. Most preferably, -R of formula (II-i) 7a It is -H.

[0214] Preferably, -R in formula (IIa-i) 10 is selected from -H, methyl and ethyl. Most preferably, -R of formula (IIa-i) 10 It is methyl.

[0215] Preferably, -R in formula (IIa-i) 11 is selected from -H, methyl and ethyl. Most preferably, -R of formula (IIa-i) 11 It is -H.

[0216] Preferably, -R in formula (IIa-i) 11 is, -L 2-Z or -L 2 It is replaced with -Z'.

[0217] Preferably, -X in formula (IIa-i) 2 - is -C(R 8 R 8a )-is.

[0218] Preferably, -R in formula (IIa-i) 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. More preferably, the -R of formula (IIa-i). 8 and -R 8a At least one of them is -H. More preferably, -R of formula (IIa-i). 8 and -R 8a Both are -H.

[0219] Preferably, -R in formula (IIa-i) 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. More preferably, the -R of formula (IIa-i). 2 and -R 2a At least one of them is -H. More preferably, -R of formula (IIa-i). 2 and -R 2a Both are H.

[0220] Preferably, -R in formula (IIa-i) 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. More preferably, the -R of formula (IIa-i). 3 and -R 3a At least one of them is methyl.

[0221] Preferably, R in formula (IIa-i) 3 This is -H, and -R in equation (IIa-i). 3a It is methyl.

[0222] More preferably, substructure-L 1- is equation (IIa-ii): [ka] (In the formula, The dashed line indicates the bonding of the PTH substructure -D to nitrogen by forming an amide bond. -R 2 ,-R 2a ,-R 10 ,-R 11 and -X 2 - is used as defined for equation (II). It has, Said-L 1 - is -L 2 -Z or -L 2 -Z' is substituted, and in some cases, the aforementioned -L 1 - is further substituted, except that the hydrogen with an asterisk in equation (IIa-ii) is -L 2 -Z or -L 2 -Z' or substitutions cannot replace it.

[0223] Preferably, the -L in formula (IIa-ii) 1 - is one substructure - L 2 -Z or -L 2 It is replaced with -Z'.

[0224] Preferably, the substructure of formula (IIa-ii) - L 1 - has not been further replaced.

[0225] Preferably, -X in formula (IIa-ii) 2 - is -C(R 8 R 8a )-is.

[0226] Preferably, the -R in formula (IIa-ii) 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. More preferably, the -R of formula (IIa-ii). 8 and -R 8aAt least one of them is -H. More preferably, -R of formula (IIa-ii). 8 and -R 8a Both are -H.

[0227] Preferably, the -R in formula (IIa-ii) 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. More preferably, the -R of formula (IIa-ii) 3 and -R 3a At least one of them is methyl.

[0228] Preferably, the -R in formula (IIa-ii) 3 This is -H, and -R in equation (IIa-ii). 3a It is methyl.

[0229] Preferably, the -R in formula (IIa-ii) 10 is selected from -H, methyl and ethyl. Most preferably, -R of formula (IIa-ii) 10 It is methyl.

[0230] Preferably, the -R in formula (IIa-ii) 11 is selected from -H, methyl and ethyl. Most preferably, -R of formula (IIa-ii) 11 It is -H.

[0231] Preferably, the -R in formula (IIa-ii) 11 is, -L 2 -Z or -L 2 It is replaced with -Z'.

[0232] In a more preferred embodiment, substructure-L 1 - is equation (IIa-ii'): [ka] (In the formula, The dashed line indicates the bonding of D, a PTH substructure, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates -L 2 - indicates binding to -R 3 ,-R 3a ,-R 10 and -X 2 - is used as defined for equation (II). It has, Said-L 1 The hyphens are sometimes further substituted, except that the hydrogen atoms with asterisks in formula (IIa-ii') are not replaced by substituents.

[0233] Preferably, the substructure of formula (IIa-ii') - L 1 - has not been further replaced.

[0234] Preferably, -X in formula (IIa-ii') 2 - is -C(R 8 R 8a )-is.

[0235] Preferably, the -R in formula (IIa-ii') 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. More preferably, the -R of formula (IIa-ii'). 8 and -R 8a At least one of them is -H. More preferably, -R of formula (IIa-ii'). 8 and -R 8a Both are -H.

[0236] Preferably, the -R in formula (IIa-ii') 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. More preferably, the -R of formula (IIa-ii'). 3 and -R 3a At least one of them is methyl.

[0237] Preferably, the -R in formula (IIa-ii') 3 This is -H, and -R in equation (IIa-ii').3a It is methyl.

[0238] Preferably, the -R in formula (IIa-ii') 10 is selected from -H, methyl and ethyl. Most preferably, -R of formula (IIa-ii'). 10 It is methyl.

[0239] More preferably, substructure-L 1 - is equation (IIa-iii): [ka] (In the formula, the dashed line indicates the bonding of the PTH substructure -D to nitrogen by forming an amide bond.) It has, Said-L 1 - is -L 2 -Z or -L 2 It is replaced with -Z', Said-L 1 - may be further substituted in some cases, except that the hydrogen with an asterisk in formula (IIa-iii) is -L 2 -Z or -L 2 -Z' or substitutions cannot replace it.

[0240] Preferably, the -L of formula (IIa-iii) 1 - is one substructure - L 2 -Z or -L 2 It is replaced with -Z'.

[0241] Preferably, the substructure of formula (IIa-iii) - L 1 - has not been further replaced.

[0242] Most preferably, substructure-L 1 - is equation (IIa-iii'): [ka] (In the formula, The dashed line indicates the bonding of D, a PTH substructure, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates -L 2 - indicates binding to -R 2 ,-R 2a ,-R 3 ,-R 3a , and -X 2 - is used as defined for equation (II). It has, Said-L 1 - may be further substituted in some cases, except that the hydrogen atoms with an asterisk in formula (IIa-iii') are not replaced by substituents.

[0243] Preferably, the substructure of formula (IIa-iii') - L 1 - has not been further replaced.

[0244] In another preferred embodiment, substructure-L 1 - is equation (IIb-i): [ka] (In the formula, The dashed line indicates the bonding of the PTH substructure -D to nitrogen by forming an amide bond. -R 1 ,-R 1a ,-R 2 ,-R 2a ,-R 3 ,-R 3a ,-R 4 , and -X 2 (This is used as defined with respect to equation (II)) It has, Said-L 1 - is -L 2 -Z or -L 2 -Z' is substituted, and the aforementioned -L 1 - is sometimes further substituted, except that the hydrogen with the asterisk in formula (IIb-i) is -L 2 -Z or -L 2-Z' or substitutions cannot replace it.

[0245] Preferably, -L of formula (IIb-i) 1 - is one substructure - L 2 -Z or -L 2 It is replaced with -Z'.

[0246] Preferably, the substructure of formula (IIb-i) - L 1 - has not been further replaced.

[0247] Preferably, the -R in formula (IIb-i) 1 and -R 1a The is independently selected from the group consisting of -H, methyl, and ethyl. More preferably, the -R of formula (IIb-i). 1 and -R 1a At least one of them is methyl. More preferably, -R of formula (IIb-i) 1 and -R 1a Both are methyl.

[0248] Preferably, the -R in formula (IIb-i) 4 is selected from the group consisting of -H, methyl, and ethyl. More preferably, -R of formula (IIb-i) 4 It is -H.

[0249] Preferably, -X in formula (IIb-i) 2 - is -C(R 8 R 8a )-is.

[0250] Preferably, the -R in formula (IIb-i) 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. More preferably, the -R of formula (IIb-i). 8 and -R 8a At least one of them is -H. More preferably, -R of formula (IIb-i). 8 and -R 8a Both are -H.

[0251] Preferably, the -R in formula (IIb-i) 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. More preferably, the -R of formula (IIb-i). 2 and -R 2a At least one of them is -H. More preferably, -R of formula (IIb-i). 2 and -R 2a Both are H.

[0252] Preferably, the -R in formula (IIb-i) 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. More preferably, the -R of formula (IIb-i). 3 and -R 3a At least one of them is -H. More preferably, -R of formula (IIb-i). 3 and -R 3a Both are -H.

[0253] More preferably, substructure-L 1 - is equation (IIb-ii): [ka] (In the formula, The dashed line indicates the bonding of the PTH substructure -D to nitrogen by forming an amide bond. -R 2 ,-R 2a ,-R 3 ,-R 3a and -X 2 - is used as defined for equation (II). It has, Said-L 1 - is -L 2 -Z or -L 2 -Z' is substituted, and in some cases, the aforementioned -L 1 - is further substituted, except that the hydrogen with an asterisk in formula (IIb-ii) is -L 2 -Z or -L 2 -Z' or substitutions cannot replace it.

[0254] Preferably, -L in formula (IIb-ii) 1 - is a single substructure -L 2 -Z or -L 2 - is replaced by -Z'

[0255] Preferably, the substructure -L in formula (IIb-ii) 1 - is further unsubstituted

[0256] Preferably, -X in formula (IIb-ii) 2 - is -C(R 8 R 8a )-

[0257] Preferably, -R in formula (IIb-ii) 8 and -R 8a are independently selected from the group consisting of -H, methyl, and ethyl. More preferably, at least one of -R 8 and -R 8a in formula (IIb-ii) is -H. Even more preferably, both -R 8 and -R 8a in formula (IIb-ii) are -H

[0258] Preferably, -R in formula (IIb-ii) 2 and -R 2a are independently selected from the group consisting of -H, methyl, and ethyl. More preferably, at least one of -R 2 and -R 2a in formula (IIb-ii) is -H. Even more preferably, both -R 2 and -R 2a in formula (IIb-ii) are H

[0259] Preferably, -R in formula (IIb-ii) 3 and -R 3a are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. Even more preferably, -R 3 and -R 3aAt least one of them is -H. More preferably, -R of formula (IIb-ii) 3 and -R 3a are both -H.

[0260] More preferably, the substructure -L 1 - is of formula (IIb-ii'):

Chemical formula

[0261] Preferably, the substructure -L of formula (IIb-ii') 1 - is not further substituted.

[0262] Preferably, -X of formula (IIb-ii') 2 - is -C(R 8 R 8a )-.

[0263] Preferably, -R of formula (IIb-ii') 8 and -R 8a are independently selected from the group consisting of -H, methyl and ethyl. More preferably, -R of formula (IIb-ii') 8 [[ID=7e]]and -R 8aAt least one of them is -H. More preferably, -R of formula (IIb-ii'). 8 and -R 8a Both are -H.

[0264] Preferably, the -R in formula (IIb-ii') 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. More preferably, the -R of formula (IIb-ii'). 2 and -R 2a At least one of them is -H. More preferably, -R of formula (IIb-ii'). 2 and -R 2a Both are -H.

[0265] Preferably, the -R in formula (IIb-ii') 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. More preferably, the -R of formula (IIb-ii'). 3 and -R 3a At least one of them is -H. More preferably, -R of formula (IIb-ii'). 3 and -R 3a Both are -H.

[0266] More preferably, substructure-L 1 - is equation (IIb-iii): [ka] (In the formula, The dashed line indicates the bonding of the PTH substructure -D to nitrogen by forming an amide bond. It has, Said-L 1 - is -L 2 -Z or -L 2 -Z' is substituted, and in some cases, the aforementioned -L 1 - is further substituted, except that the hydrogen with an asterisk in formula (IIb-iii) is -L 2 -Z or -L 2-Z' or substitutions cannot replace it.

[0267] Preferably, -L of formula (IIb-iii) 1 - is one substructure - L 2 -Z or -L 2 It is replaced with -Z'.

[0268] Preferably, the substructure of formula (IIb-iii) - L 1 - has not been further replaced.

[0269] Most preferably, substructure-L 1 - is equation (IIb-iii'):

[0270] [ka] (In the formula, The dashed line indicates the bonding of the PTH substructure -D to nitrogen by forming an amide bond. -R 2 ,-R 2a ,-R 3 ,-R 3a and -X 2 - is used as defined for equation (II). It has, Said-L 1 - is -L 2 -Z or -L 2 -Z' is substituted, and in some cases, the aforementioned -L 1 - is further substituted, except that the hydrogen with an asterisk in formula (IIb-iii') is -L 2 -Z or -L 2 -Z' or substitutions cannot replace it.

[0271] Preferably, the substructure of formula (IIb-iii') - L 1 - has not been further replaced.

[0272] Another preferred substructure - L 1- is disclosed in WO2016 / 020373A1. Thus, in another preferred embodiment, the substructure -L 1 - is of formula (III):

Chemical formula

[0273] -L in equation (III) 1 Any further optional substituents are preferably as described above.

[0274] Preferably, -L of formula (III) 1 - is one substructure - L 2 -Z or -L 2 It is replaced with -Z'.

[0275] In one embodiment, formula (III) -L 1 - has not been further replaced.

[0276] -L 1 Further preferred embodiments of - are disclosed in European Patent No. 1536334B1, WO2009 / 009712A1, WO2008 / 034122A1, WO2009 / 143412A2, WO2011 / 082368A2, and U.S. Patent No. 8,618,124B2, which are incorporated herein by reference in their entirety.

[0277] -L 1 Further preferred embodiments of - are disclosed in U.S. Patent No. 8,946,405B2 and U.S. Patent No. 8,754,190B2, which are incorporated herein by reference in their entirety. Therefore, preferred substructure-L 1 - is equation (IV): [ka] (In the formula, The dashed line indicates a bond to the PTH substructure -D, and this bond is due to a functional group of -D selected from the group consisting of -OH, -SH, and -NH2. m is either 0 or 1. -R1 and -R 2 At least one or both of these 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 Selected from the group consisting of, -R 1 and -R 2 One or only one of these is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl. -R 3 -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 9 and -N(R 9 Selected from the group consisting of )2, -R 4 This is selected from the group consisting of optionally substituted alkyls, optionally substituted aryls, optionally substituted arylalkyls, optionally substituted heteroaryls, and optionally substituted heteroarylalkyls. Each-R 5 These are 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 This is selected from the group consisting of -H and optionally substituted alkyl groups, -Y- does not exist, and -X- is either -O- or -S-, or -Y- is -N(Q)CH2-, and -X- is -O-, Q is selected from the group consisting of optionally substituted alkyls, optionally substituted aryls, optionally substituted arylalkyls, optionally substituted heteroaryls, and optionally substituted heteroarylalkyls. Depending on the case, -R 1 and R 2 They may also come together to form a 3-8 membered ring, and Depending on the case, both -R 9 (These atoms, together with the nitrogen atoms they are bonded to, form a heterocyclic ring.) It has, Said-L 1 - is -L 2 -Z or -L 2 -Z' is substituted, and in some cases, the aforementioned -L 1 - has been further replaced, -L 2 - is a single chemical bond or spacer, -Z is a water-soluble carrier, -Z' is a water-insoluble carrier.

[0278] The term used exclusively in relation to formula (IV) has the following meanings: The term "alkyl" as used herein includes linear, branched, or cyclic saturated hydrocarbon groups comprising 1 to 8 carbon atoms, or in some embodiments, 1 to 6 or 1 to 4 carbon atoms.

[0279] The term "alkoxy" includes alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and similar groups.

[0280] The term "alkenyl" includes non-aromatic unsaturated hydrocarbons that have a carbon-carbon double bond.

[0281] The term "alkynyl" includes non-aromatic unsaturated hydrocarbons that have a carbon-carbon triple bond.

[0282] The term "aryl" includes aromatic hydrocarbon groups with 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, including groups such as phenyl, naphthyl, and anthracenyl. The term "heteroaryl" includes aromatic rings with 3 to 15 carbon atoms and at least one N, O, or S atom, preferably 3 to 7 carbon atoms 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 similar groups.

[0283] In some cases, alkenyl, alkynyl, aryl, or heteroaryl substructures may be coupled to the remainder of the molecule by an alkylene bond. Substituents under these circumstances are referred to as alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that the alkylene substructure lies between the alkenyl, alkynyl, aryl, or heteroaryl substructure and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is coupled.

[0284] The term "halogen" includes bromo, fluoro, chloro, and iodine.

[0285] The term "heterocyclic ring" refers to a 4-8 member aromatic or aromatic ring containing 3-7 carbon atoms and at least one N, O, or S atom. Examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the good example groups provided above for the term "heteroaryl."

[0286] When the ring system is optionally substituted, preferred substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or further rings, each of which may be further substituted. Optional substituents for any of the above groups include halo, nitro, cyano, -OR, -SR, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -SO2R, -SONR2, and -SO2NR2, where each R is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or two R groups together with the atom to which they are bonded form a ring.

[0287] Preferably, -L of formula (IV) 1 - is one substructure - L 2 -Z or -L 2 It is replaced with -Z'.

[0288] -L 1 Further preferred embodiments of - are disclosed in WO2013 / 036857A1, which is incorporated herein by reference in its entirety. Therefore, preferred substructure-L 1 - is equation (V): [ka] (In the formula, The dashed line indicates a bond to the PTH substructure -D, and this bond is due to the amine functional group of -D. -R 1 These include optionally substituted C1-C6 linear, branched, or cyclic alkyl groups, optionally substituted aryl groups, optionally substituted heteroaryl groups, alkoxy groups, and -NR groups. 5 Selected from a group consisting of 2, -R 2 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. -R 3This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. -R 4 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. Each-R 5 These are independently selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl, or together, two -R 5 (This can be a cycloalkyl or cycloheteroalkyl group.) It has, Said-L 1 - is -L 2 -Z or -L 2 -Z' is substituted, and in some cases, the aforementioned -L 1 - has been further replaced, -L 2 - is a single chemical bond or spacer, -Z is a water-soluble carrier, -Z' is a water-insoluble carrier.

[0289] The term used exclusively in relation to the expression (V) has the following meanings: "Alkyl," "alkenyl," and "alkynyl" refer to linear, branched, or cyclic hydrocarbon groups comprising 1 to 8, 1 to 6, or 1 to 4 carbon atoms, wherein alkyl is a saturated hydrocarbon, alkenyl contains one or more carbon-carbon double bonds, and alkynyl contains one or more carbon-carbon triple bonds. Unless otherwise specified, these contain 1 to 6 carbon atoms.

[0290] "Aryl" includes aromatic hydrocarbon groups with 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, including groups such as phenyl, naphthyl, and anthracenin. "Heteroaryl" includes aromatic rings with 3 to 15 carbon atoms and at least one N, O, or S atom, preferably 3 to 7 carbon atoms 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 similar groups.

[0291] 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 halogens (including F, Cl, Br, and I), lower alkyls (including linear, branched, and cyclic), lower haloalkyls (including fluoroalkyls, chloroalkyls, bromoalkyls, and iodoalkyls), OH, lower alkoxys (including linear, branched, and cyclic), SH, lower alkylthios (including linear, branched, and cyclic), aminos, alkylaminos, dialkylaminos, silyls (including alkylsilyls, alkoxysilyls, and arylsilyls), nitros, cyanos, carbonyls, carboxylic acids, carboxylic acid esters, carboxylic acid amides, aminocarbonyls, aminoacyls, carbamates, ureas, and thios. The following can be selected: carbamates, thioureas, ketenes, sulfones, sulfonamides, aryls (including phenyl, naphthyl, and anthracenyl), and heteroaryls (including five-membered heteroaryls such as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole, and tetrazole; six-membered heteroaryls such as pyridine, pyrimidine, and pyrazine; and condensed heteroaryls such as benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzoisoxazole, and benzoisothiazole).

[0292] Preferably, -L of formula (V) 1 - is one substructure - L 2 -Z or -L 2 It is replaced with -Z'.

[0293] -L 1 Further preferred embodiments of - are disclosed in U.S. Patent No. 7,585,837 B2, which is incorporated herein by reference in its entirety. Therefore, preferred substructure-L 1 - is equation (VI): [ka] (In the formula, The dashed line indicates a bond to the PTH substructure -D, and this bond is due to the amine functional group of -D. R 1 and R 2 These are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkalyl, aralkyl, halogen, nitro, -SO3H, -SO2HH 5 Selected from the group consisting of amino, ammonium, carboxyl, PO3H2 and OPO3H2, R 3 , R 4 and R 5 It independently has (selected from the group consisting of hydrogen, alkyl and aryl), Said-L 1 - is -L 2 -Z or -L 2 -Z' is substituted, and in some cases, the aforementioned -L 1 - has been further replaced, -L 2 - is a single chemical bond or spacer, -Z is a water-soluble carrier, -Z' is a water-insoluble carrier.

[0294] Preferred substituents for formula (VI) are alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g., C 2-6Alkenyl), Alkinyl (for example, C 2-6 The substructures are alkynyl, aryl (e.g., phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (e.g., aromatic 4-7 membered heterocycle), or halogen substructures.

[0295] The term used exclusively in relation to formula (VI) has the following meanings: The terms "alkyl," "alkoxy," "alkoxyalkyl," "aryl," "alkalil," and "aralkyl" refer to alkyl groups with 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, and butyl, and aryl groups with 6 to 10 carbon atoms, such as phenyl and naphthyl. The term "halogen" includes bromo, fluoro, chloro, and iodine.

[0296] Preferably, -L of formula (VI) 1 - is one substructure - L 2 -Z or -L 2 It is replaced with -Z'.

[0297] -L 1 Further preferred embodiments of - are disclosed in WO2002 / 089789A1, which is incorporated herein by reference in its entirety. Therefore, preferred substructure-L 1 - is equation (VII): [ka] (In the formula, The dashed line indicates a bond to the PTH substructure -D, and this bond is due to the amine functional group of -D. L1 is a bifunctional bonding 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 These are, independently, hydrogen and C 1-6Alkyl, C 3-12 Branched alkyl, C 3-8 Cycloalkyl, C 1-6 Substituting 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 1-6 Selected from the group consisting of heteroalkoxys, When Ar is included in formula (VII), it is a substructure that forms a polysubstituted aromatic hydrocarbon or a polysubstituted heterocyclic group. X is a chemical bond, a substructure that is actively transported to the target cell, a hydrophobic substructure, or a combination thereof. Y is either 0 or 1. It has, Said-L 1 - is -L 2 -Z or -L 2 -Z' is substituted, and in some cases, the aforementioned -L 1 - has been further replaced, -L 2 - is a single chemical bond or spacer substructure. -Z is a water-soluble carrier, -Z' is a water-insoluble carrier.

[0298] The term used exclusively in relation to formula (VII) has the following meanings: The term "alkyl" is used, for example, in alkoxy, C 3-8 Linear, branched, and substituted carbon atoms, including cycloalkyl or substituted cycloalkyl groups. 1-12 It is understood that it contains alkyl groups.

[0299] The term "substituted" shall be understood to include the addition of one or more atoms contained in a functional group or compound, and the replacement of one or more different atoms.

[0300] Substituted alkyls include carboxyalkyls, aminoalkyls, dialkylaminos, hydroxyalkyls, and mercaptoalkyls; substituted cycloalkyls include substructures such as 4-chlorocyclohexyl; aryls include substructures such as naphthyl; substituted aryls include substructures such as 3-bromophenyl; aralkyls include substructures such as toluyl; heteroalkyls include substructures such as ethylthiophene; substituted heteroalkyls include substructures such as 3-methoxythiophene; alkoxys include substructures such as methoxy; and phenoxys include substructures such as 3-nitrophenoxy. Halos are understood to include fluoro, chloro, iodine, and bromo.

[0301] Preferably, -L of formula (VII) 1 - is one substructure - L 2 -Z or -L 2 It is replaced with -Z'.

[0302] In another preferred embodiment, -L 1 - is a substructure of equation (VIII) [ka] (In the formula, The dashed lines with asterisks indicate the bonding of the PTH substructure -D to nitrogen by forming an amide bond. Dashed lines without a mark are -L 1 (Indicates connection to the remainder) Includes, Said-L 1 - is -L 2 -Z or -L 2 -Z' is substituted, and in some cases, the aforementioned -L 1 - has been further replaced, and here, -L 2 - is a single chemical bond or spacer, -Z is a water-soluble carrier, -Z' is a water-insoluble carrier.

[0303] Preferably, the -L of formula (VIII) 1 - is one substructure - L 2 -Z or -L 2 It is replaced with -Z'.

[0304] In one embodiment, formula (VIII) -L 1 - has not been further replaced.

[0305] In another preferred embodiment, -L 1 - is a substructure of equation (IX) [ka] (In the formula, The dashed lines with asterisks indicate bonding by forming a carbamate bond to the nitrogen of the PTH substructure -D. Dashed lines without a mark are -L 1 (Indicates connection to the remainder) Includes, Said-L 1 - is -L 2 -Z or -L 2 -Z' is substituted, and in some cases, the aforementioned -L 1 - has been further replaced, -L 2 - is a single chemical bond or spacer, -Z is a water-soluble carrier, -Z' is a water-insoluble carrier.

[0306] Preferably, -L of formula (IX) 1 - is one substructure - L 2 -Z or -L 2 It is replaced with -Z'.

[0307] In one embodiment, the -L of formula (IX) 1 - has not been further replaced.

[0308] In the prodrug of the present invention, -L 2 - represents a chemical bond or spacer substructure.

[0309] In one embodiment, -L 2 - represents a chemical bond.

[0310] In another embodiment, -L 2 - is a spacer substructure.

[0311] -L 2 -If it is anything 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 A group consisting of alkynnyls is selected, where -T-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is the same or different -R of one or more R's. y2 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -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 )- may intersect with one or more groups selected from the group consisting of, -R y1 and -R y1a These are -H, -T, and C, which are independent of each other. 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynyl, -T, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more of the same or different -Ry 2 It is sometimes replaced by the aforementioned C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) y4 )-,-S(O)2N(R y4 )-,-S(O)N(R y4 )-, -S(O)2-, -S(O)-, -N(R y4 )S(O)2N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-,-N(R y4 )C(O)N(R y4a )-, and -OC(O)N(R y4 )- may intersect with one or more groups selected from the group consisting of, Each T independently consists of phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C. 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, each T independently has one or more identical or different -R y2 It is sometimes replaced by, Each R y2 These are, independently, halogen, -CN, oxo (=O), and -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 Selected from the group consisting of alkyl groups, the C 1-6 Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. Each-R y3 ,-R y3a ,-R y4 ,-R y4a ,-R y5 ,-R y5a and -R y5b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, the C 1-6 Alkyl is sometimes substituted with one or more halogens, one or more of the same or different.

[0312] -L 2 -If it is anything other than a single chemical bond, -L 2 - is more preferably -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-,-S(O)2N(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 Selected from alkinyl, where -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl is the same or different -R of one or more R's. y2 In some cases, it is replaced by C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) y3 )-,-S(O)2N(R y3 )-,-S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-,-N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- may intersect with one or more groups selected from the group consisting of, -R y1 and -R y1a These are -H, -T, and C, which are independent of each other. 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynyl, -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl is the same or different -R of one or more R's. y2It is sometimes replaced by the aforementioned C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) y4 )-,-S(O)2N(R y4 )-,-S(O)N(R y4 )-, -S(O)2-, -S(O)-, -N(R y4 )S(O)2N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-,-N(R y4 )C(O)N(R y4a )-, and -OC(O)N(R y4 )- may intersect with one or more groups selected from the group consisting of, Each T independently consists of phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C. 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, each T independently has one or more identical or different -R y2 It is sometimes replaced by, -R y2 These are halogen, -CN, oxo (=O), and -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 Selected from the group consisting of alkyl groups, the C 1-6 Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. Each-R y3 ,-R y3a ,-R y4 ,-R y4a ,-R y5 ,-R y5a and -R y5b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, the C 1-6 Alkyl is sometimes substituted with one or more halogens, one or more of the same or different.

[0313] -L 2 -If it is anything other than a single chemical bond, -L 2 - is more preferably -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-,-S(O)2N(R y1 )-,-S(O)N(R y1 )-, -S(O)2-, -S(O)-, -N(R y1 )S(O)2N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-,-N(R y1 )C(O)N(R y1a )-,-OC(O)N(R y1 )-, C 1-50 Alkyl, C 2~50 Alkenyl and C 2~50 A group consisting of alkynnyls is selected, where -T-, C1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is the same or different -R of one or more R's. y2 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) y3 )-,-S(O)2N(R y3 )-,-S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-,-N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- may intersect with one or more groups selected from the group consisting of, -R y1 and -R y1a These are independently -H, -T, and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyls, Each T independently consists of phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C. 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, -R y2 These are, independently, halogen and C 1-6 Selected from the group consisting of alkyl groups, Each-R y3 ,-R y3a ,-R y4 ,-R y4a ,-R y5 ,-R y5a and -R y5b These are, independently of each other, -H and C 1-6 Selected from the group consisting of alkyl groups, the C1-6 Alkyl is sometimes substituted with one or more halogens, one or more of the same or different.

[0314] More preferably, -L 2 - is -O-, -T- and -C(O)N(R y1 )- where one or more elements selected independently of C may interrupt 1-20 It is an alkyl chain, and the C 1-20 The alkyl chain consists of -OH, -T, and -C(O)N(R) y6 R y6a ) is optionally substituted with one or more groups independently selected from -R y1 ,-R y6 ,-R y6a H and C are independent of each other. 1-4 Selected from the group consisting of alkyl groups, where T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 The group is selected from cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl.

[0315] Preferably, -L 2 - has a molecular weight in the range of 14 g / mol to 750 g / mol.

[0316] Preferably, -L 2 - includes a substructure selected from the following: [ka] (In the formula, The dashed line is -L 2 -, -L 1 - indicates the binding to the remainder of -Z and / or -Z', respectively. -R and -R a (These are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl, and hexyl).

[0317] In one preferred embodiment, -L 2- has a chain length of 1 to 20 atoms.

[0318] Substructure-L 2 -In this specification, the term "chain length" is used with respect to -L 1 -L exists at the shortest connection point between - and -Z. 2 - Refers to the number of atoms.

[0319] Preferably, -L 2 - is equation (i) [ka] (In the formula, The dashed line with an asterisk indicates -L 1 - indicates binding to Unmarked dashed lines indicate connections 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. It has the substructure of this formula (i), and in some cases, the substructure of this formula (i) is further substituted.

[0320] Preferably, n in formula (i) is selected from the group consisting of 3, 4, 5, 6, 7, 8, and 9. 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 yet another embodiment, n in formula (i) is 6.

[0321] In one embodiment, partial structure -L 1 -L 2 - is selected from the following group: [ka] JPEG2026082916000036.jpg46113 (in the formula, The unmarked dashed lines indicate the bonding of the PTH substructure -D to nitrogen by forming an amide bond. (A dashed line with an asterisk indicates a connection to -Z or -Z').

[0322] In one preferred embodiment, substructure-L 1 -L 2 -teeth, [ka] (In the formula, The unmarked dashed lines indicate the bonding of the PTH substructure -D to nitrogen by forming an amide bond. (A dashed line with an asterisk indicates a connection to -Z or -Z'.) It is selected from the group consisting of the following.

[0323] In a preferred embodiment, substructure-L 1 -L2- has the equation (IIca-ii).

[0324] In another preferred embodiment, substructure-L 1 -L 2 - has the equation (IIcb-iii).

[0325] Preferably, the controlled-release PTH compound of the present invention has equation (Ia) where x=1.

[0326] Carrier-Z is C 8-24Contains alkyl or polymer. Preferably, -Z is a polymer, preferably 2-methacryloyloxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amideamine), poly(amino acid), poly(acid 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), The polymers include polymers selected from the group consisting of poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic acid-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 its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate polymers, xylan, and copolymers thereof.

[0327] Preferably, -Z has a molecular weight in the range of 5 to 200 kDa. More preferably, -Z has a molecular weight in the range of 8 to 100 kDa, more preferably 10 to 80 kDa, more preferably 12 to 60 kDa, and 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.

[0328] In one embodiment, such a water-soluble carrier-Z comprises a protein. Preferred proteins are selected from the group consisting of chorionic gonadotropin carboxyl-terminal polypeptides such as those described in U.S. Patent Application Publication No. 2012 / 0035101A1 incorporated herein by reference, albumin, XTEN sequences such as those described in WO 2011123813 A2 incorporated herein by reference, proline / alanine random coil sequences such as those described in WO 2011 / 144756 A1 incorporated herein by reference, proline / alanine / serine random coil sequences such as those described in WO 2008 / 155134 A1 and WO 2013 / 024049 A1 incorporated herein by reference, and Fc fusion proteins.

[0329] In one embodiment, -Z is polysarcosine.

[0330] In another preferred embodiment, -Z comprises poly(N-methylglycine).

[0331] In a particularly preferred embodiment, -Z comprises a random coil protein substructure.

[0332] In one preferred embodiment, -Z comprises a single random coil protein substructure.

[0333] In another preferred embodiment, -Z comprises two random coil protein substructures.

[0334] In another preferred embodiment, -Z comprises three random coil protein substructures.

[0335] In another preferred embodiment, -Z comprises four random coil protein substructures.

[0336] In another preferred embodiment, -Z comprises five random coil protein substructures.

[0337] In another preferred embodiment, -Z comprises six random coil protein substructures.

[0338] In another preferred embodiment, -Z comprises seven random coil protein substructures.

[0339] In another preferred embodiment, -Z comprises eight random coil protein substructures.

[0340] Preferably, such a random coil protein substructure contains at least 25 amino acid residues and up to 2000 amino acids. More preferably, such a random coil protein substructure contains at least 30 amino acid residues and up to 1500 amino acid residues. Even more preferably, such a random coil protein substructure contains at least 50 amino acid residues and up to 500 amino acid residues.

[0341] In a preferred embodiment, -Z comprises the random coil protein substructure in which at least 80%, preferably at least 85%, more preferably at least 90%, more preferably at least 95%, more preferably at least 98%, and most preferably at least 99% of the total number of amino acids forming the random coil protein substructure are selected from alanine and proline. More preferably, at least 10%, but less than 75%, preferably less than 65%, of the total number of amino acid residues in such a random coil protein substructure are proline residues. Preferably, such a random coil protein substructure is like that described in WO 2011 / 144756 A1, which is incorporated herein by reference in its entirety. More preferably, -Z includes at least one substructure selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 51, and 61, as disclosed in WO 2011 / 144756, which is incorporated herein by reference. Such substructures containing alanine and proline, which include random coil proteins, will be referred to as "PA" or "PA substructure".

[0342] Therefore, -Z includes the PA substructure.

[0343] In a similarly preferred embodiment, -Z comprises the random coil protein substructure in which at least 80%, preferably at least 85%, more preferably at least 90%, more preferably at least 95%, more preferably at least 98%, and most preferably at least 99% of the total number of amino acids forming the random coil protein substructure are selected from alanine, serine, and proline. More preferably, at least 4%, but less than 40%, of the total number of amino acid residues in such a random coil protein substructure are proline residues. Preferably, such a random coil protein substructure is like that described in WO 2008 / 155134 A1, which is incorporated herein by reference in its entirety. More preferably, -Z includes at least one substructure selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 42, 44, 46, 50, 52, 54, and 56, as disclosed in WO 2008 / 155134 A1, which is incorporated herein by reference. A substructure including such a random coil protein substructure containing alanine, serine, and proline will be referred to as a "PAS" or "PAS substructure".

[0344] Therefore, -Z includes the PAS substructure.

[0345] Similarly, in a preferred embodiment, -Z comprises the random coil protein substructure, wherein at least 80%, preferably at least 85%, more preferably at least 90%, more preferably at least 95%, more preferably at least 98%, and most preferably at least 99% of the total number of amino acids forming the random coil protein substructure are selected from alanine, glycine, and proline. A substructure comprising such a random coil protein substructure containing alanine, glycine, and proline will be referred to as "PAG" or "PAG substructure".

[0346] Therefore, -Z includes a PAG substructure.

[0347] In a similarly preferred embodiment, -Z comprises the random coil protein substructure, wherein at least 80%, preferably at least 85%, more preferably at least 90%, more preferably at least 95%, more preferably at least 98%, and most preferably at least 99% of the total number of amino acids forming the random coil protein substructure are selected from proline and glycine. Such a substructure comprising a random coil protein substructure containing proline and glycine will be referred to as "PG" or "PG substructure".

[0348] Preferably, such a PG substructure includes the substructure 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 in the range of 10 to 1000. However, at least one of p and q is at least 1.

[0349] Preferably, p in formula (a-0) is selected from the group consisting of 1, 2, and 3.

[0350] Preferably, q in formula (a-0) is selected from 0, 1, and 2.

[0351] More preferably, the PG substructure is the sequence of sequence number 122: GGGGPGPGGPGGPGPGPGGPG Includes.

[0352] More preferably, the PG substructure is an arrangement of formula (a-0-a) (GGPGGPGPGGPGGPGPGGPG) v (a-0-a) This array includes such that v is an integer in the range of 1 to 50.

[0353] It is understood that the array in expression (a-0-a) contains iterations of v in the array at sequence number 122.

[0354] Therefore, -Z includes the PG substructure.

[0355] In a similarly preferred embodiment, -Z comprises the random coil protein substructure, wherein at least 80%, preferably at least 85%, more preferably at least 90%, more preferably at least 95%, more preferably at least 98%, and most preferably at least 99% of the total number of amino acids forming the random coil protein substructure are selected from alanine, glycine, serine, threonine, glutamate, and proline. Preferably, such a random coil protein substructure is one of those described in WO 2010 / 091122 A1 incorporated herein by reference. More preferably, -Z comprises Sequence IDs 182, 183, and 184 disclosed in WO2010 / 091122A1 incorporated herein by reference; SEQ ID NOs: 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 2 19, comprising at least one substructure selected from the group consisting of SEQ ID NOs: 220, 221, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 1715, 1716, 1718, 1719, 1720, 1721, and 1722. Substructures comprising such random coil protein substructures containing alanine, glycine, serine, threonine, glutamate, and proline are subject to WO 2010 / 091122 A1 In accordance with the terminology used in that context, we will refer to it as "XTEN" or "XTEN substructure."

[0356] Therefore, -Z includes the XTEN substructure.

[0357] 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.

[0358] In another preferred embodiment, -Z is a hyaluronic acid-based polymer.

[0359] In one embodiment, -Z is a carrier such as that disclosed in WO 2012 / 02047 A1, which is incorporated herein by reference.

[0360] In another embodiment, -Z is a carrier as described in WO 2013 / 024048 A1, which is incorporated herein by reference.

[0361] In another preferred embodiment, -Z is a PEG-based polymer, such as a linear, branched, or multi-armed PEG-based polymer.

[0362] In one embodiment, -Z is a linear PEG-based polymer.

[0363] In another embodiment, -Z is a multi-arm PEG polymer. Preferably, -Z is a multi-arm PEG polymer having at least four PEG arms.

[0364] Preferably, such a multi-armed PEG polymer-Z has a number of substructures-L 2 -L 1 -Connected to D, preferably each substructure -L 2 -L 1-D is connected to the end of the arm, preferably to the end of the arm. Preferably, such multi-arm PEG polymer-Z is part of substructure-L 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16. 2 -L 1 - is linked to D. More preferably, such a multi-armed PEG polymer-Z has 2, 3, 4, 6 or 8 substructures-L 2 -L 1 - is linked to D. More preferably, such a multi-armed PEG polymer-Z has 2, 4, or 6 substructures-L 2 -L 1 - is linked to D, and more preferably such multi-arm PEG polymer-Z has 4 or 6 substructures-L 2 -L 1 - is linked to D, and most preferably such multi-arm PEG polymer-Z has four substructures - L 2 -L 1 It is linked to -D.

[0365] Preferably, such multi-arm PEG polymer-Z is a multi-arm PEG derivative, such as a 4-arm PEG derivative, particularly 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 in the product list of JenKem Technology, USA (downloaded from http: / / www.jenkemusa.com / Pages / PEGProducts.aspx on December 18, 2014). More preferably, the water-soluble PEG carrier-Z is 4-arm PEGamine containing pentaerythritol core: [ka] (n is in the range of 20 to 500) 8-arm PEGamine containing a hexaglycerin core: [ka] (n is in the range of 20 to 500) R = hexaglycerin or tripentaerythritol core structure), and 6-arm PEGamine containing sorbitol or dipentaerythritol core: [ka] (n is in the range of 20 to 500) (R = contains sorbitol or dipentaerythritol core) The formula includes a substructure selected from the above, and the dashed lines in these formulas indicate binding to the remainder of the PTH prodrug.

[0366] In a preferred embodiment, -Z is a branched PEG polymer. In one embodiment, -Z is a branched PEG polymer having 1, 2, 3, 4, 5, or 6 branching points. Preferably, -Z is a branched PEG polymer having 1, 2, or 3 branching points. In one embodiment, -Z is a branched PEG polymer having 1 branching point. In another embodiment, -Z is a branched PEG polymer having 2 branching points. In yet another embodiment, -Z is a branched PEG polymer having 3 branching points.

[0367] The branching point is preferably selected from the group consisting of -N<, -CH<, and >C<.

[0368] Preferably, such branched PEG-based substructure-Z has a molecular weight of at least 10 kDa.

[0369] In one embodiment, such a branched substructure-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.

[0370] 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.

[0371] Preferably, -Z or -Z' includes the following substructure: [ka]

[0372] Similarly, in a preferred embodiment, -Z includes an amide bond.

[0373] Preferably, -Z includes a substructure of formula (a): [ka] (In the formula, The dashed line is -L 2 - Indicates a bond to the remainder of -Z, BP a This is a branch point selected from the group consisting of -N<, -CR<, and >C<, -R is -H and C 1-6 Selected from the group consisting of alkyl groups, a is BP a If -N < or -CR <, then it is 0, and n is BP a If >C< then it is 1, -S a -, -Sa' -, -S a'' -and-S a''' - is a chemical bond, independently of each other, or C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynyl, the C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is the same or different -R of one or more R's. 1 It is sometimes replaced by the aforementioned C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -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 )- may intersect with one or more groups selected from the group consisting of, Each -T- is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, each of the -T- independently has one or more -R, one or the same. 1 It is sometimes replaced by, Each-R 1 These are, independently, halogen, -CN, oxo (=O), and -COOR. 3 , -OR 3 , -C(O)R 3 ,-C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a), -S(O)N(R 3 R 3a ), -S(O)2R 3 ,-S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R 3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ), and C 1-6 Selected from the group consisting of alkyl groups, the C 1-6 Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. Each-R 2 ,-R 2a ,-R 3 ,-R 3a and -R 3b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, the C 1-6 Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. -P a' , -P a'' and -P a''' (These are, independently, polymer substructures.)

[0374] In one embodiment, formula (a) BP a -N < .

[0375] In another embodiment, the BP of formula (a) a It is >C<.

[0376] In a preferred embodiment, BP of formula (a) a is -CR<. Preferably, -R is -H. Therefore, a in equation (a) is preferably 0.

[0377] In one embodiment, the -S of formula (a) a - represents a chemical bond.

[0378] In another embodiment, the -S of formula (a) a - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynyl, the C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) 4 )-,-S(O)2N(R 4 )-,-S(O)N(R 4 )-, -S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-,-N(R 4 )C(O)N(R 4a )-, and -OC(O)N(R 4 )- may optionally be interposed by one or more chemical groups selected from the group consisting of -T-, where -T- is a 3- to 10-membered heterocycline and -R 4 and -R 4a This is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl.

[0379] Preferably, -S of formula (a) a - is C 1-10 It is selected from the group consisting of alkyl groups, which may include one or more chemical groups selected from the group consisting of -T-, -C(O)-, and -O-.

[0380] In one embodiment, the -S of formula (a)a' - represents a chemical bond.

[0381] In another embodiment, the -S of formula (a) a' - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyl, this C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyls include -C(O)O-, -O-, -C(O)-, and -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 )- and one or more chemical groups selected from the group consisting of -R may be interspersed, and the -R 4 and -R 4a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. Preferably, the -S of formula (a) a' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, and these include -O-, -C(O)- and -C(O)N(R 4 )- may include one or more chemical groups selected from the group consisting of ).

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

[0383] In another embodiment, the -S of formula (a) a'' - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyl, this C 1-10 Alkyl, C2-10 Alkenyl and C 2-10 Alkinyls include -C(O)O-, -O-, -C(O)-, and -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 )- and one or more chemical groups selected from the group consisting of -R may be interspersed, and the -R 4 and -R 4a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. Preferably, the -S of formula (a) a'' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, and these include -O-, -C(O)- and -C(O)N(R 4 )- may include one or more chemical groups selected from the group consisting of ).

[0384] In one embodiment, the -S of formula (a) a''' - represents a chemical bond.

[0385] In another embodiment, the -S of formula (a) a''' - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyl, this C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyls include -C(O)O-, -O-, -C(O)-, and -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 )- and one or more chemical groups selected from the group consisting of -R may be interspersed, and the -R 4 and -R 4a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. Preferably, the -S of formula (a) a''' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, and these include -O-, -C(O)- and -C(O)N(R 4 )- may include one or more chemical groups selected from the group consisting of ).

[0386] Preferably, -P in formula (a) a' , -P a'' and -P a'''These are independently 2-methacryloyloxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amideamine), poly(amino acid), poly(acid 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), poly(hydroxy The polymers include polymers selected from the group consisting of propyl oxazoline, poly(iminocarbonate), poly(lactic acid), poly(lactic acid-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 its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate polymers, xylan, and copolymers thereof.

[0387] More preferably, -P of formula (a) a' , -P a'' and -P a''' It independently includes a PEG-based substructure. More preferably, the -P of formula (a) a' , -P a'' and -P a'''It independently comprises a PEG-based substructure containing at least 20% PEG, more preferably at least 30%, more preferably at least 40% PEG, more preferably at least 50% PEG, more preferably at least 60% PEG, more preferably at least 70% PEG, more preferably at least 80% PEG, and most preferably at least 90% PEG.

[0388] Preferably, P in formula (a) a' , -P a'' and -P a''' Each of these molecules independently has 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.

[0389] In one embodiment, P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 5 kDa.

[0390] In another embodiment, P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 7.5 kDa.

[0391] In another embodiment, P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 10 kDa.

[0392] In another embodiment, P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 12.5 kDa.

[0393] In another embodiment, P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 15 kDa.

[0394] In another embodiment, P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 20 kDa.

[0395] In one embodiment, -Z includes one substructure of formula (a).

[0396] In another embodiment, -Z includes two substructures of formula (a).

[0397] In another embodiment, -Z includes three substructures of formula (a).

[0398] Preferably, -Z is a substructure of equation (a).

[0399] More preferably, -Z includes the substructure of equation (b): [ka] (In the formula, The dashed line is -L 2 - Indicates a bond to the remainder of -Z, m and p are independent integers in the range of 150 to 1000, preferably in the range of 150 to 500, more preferably in the range of 200 to 500, and most preferably in the range of 400 to 500).

[0400] Preferably, m and p in equation (b) are the same integer.

[0401] Most preferably, m and p in formula (b) are about 450.

[0402] Preferably, -Z is a substructure of equation (b).

[0403] The carrier-Z' is a water-insoluble polymer, more preferably a hydrogel. Preferably, such a hydrogel is 2-methacryloyloxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amideamine), poly(amino acid), poly(acid 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), poly( The polymers include polymers selected from the group consisting of hydroxypropyl oxazoline, poly(iminocarbonate), poly(lactic acid), poly(lactic acid-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 its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate polymers, xylan, and copolymers thereof.

[0404] If the carrier-Z' is a hydrogel, it is preferably a hydrogel containing PEG or hyaluronic acid. Most preferably, such a hydrogel contains PEG.

[0405] More preferably, the carrier-Z' is a hydrogel as described in WO 2006 / 003014 A2, WO 2011 / 012715 A1 or WO 2014 / 056926 A1, which are incorporated herein by reference in their entirety.

[0406] In another embodiment, -Z' is a polymer network formed by the physical aggregation of polymer chains, which preferably results from hydrogen bonding, crystallization, helix formation, or complex formation. In one embodiment, such a polymer network is a thermogelling polymer.

[0407] If the controlled-release PTH compound of the present invention is a prodrug, its total mass is preferably at least 10 kDa, for example at least 12 kDa, for example at least 15 kDa, for example at least 20 kDa, or for example at least 30 kDa. If the controlled-release PTH compound is a water-soluble prodrug, its total mass is preferably up to 250 kDa, for example up to 200 kDa, 180 kDa, 150 kDa, or 100 kDa. If the controlled-release PTH compound is water-insoluble, it is understood that a meaningful upper limit on molecular weight cannot be obtained.

[0408] In a preferred embodiment, the controlled-release PTH compound has formula (IIe-i): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the PTH substructure -D to nitrogen by forming an amide bond. A dashed line with an asterisk indicates a substructure. [ka] This shows the bond to, and in the formula, m and p are independent integers in the range of 400 to 500.

[0409] Preferably, -D is bonded to the PTH prodrug of formula (IIe-i) by the N-terminal amine functional group of the PTH substructure.

[0410] In another preferred embodiment, the PTH prodrug of the present invention has the formula (IIf-i): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the PTH substructure -D to nitrogen by forming an amide bond. A dashed line with an asterisk indicates a substructure. [ka] This shows the bond to, and in the formula, m and p are independent integers in the range of 400 to 500.

[0411] Preferably, -D is bonded to the PTH prodrug of formula (IIf-i) by the N-terminal amine functional group of the PTH substructure.

[0412] In preferred embodiments, the residual activity of the controlled-release PTH in 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%.

[0413] As used herein, the term “residual activity” refers to the activity exhibited by a PTH prodrug in which a PTH substructure is bound to a carrier, as opposed to the activity exhibited by the corresponding free PTH. In this context, “activity” refers to binding to the PTH / PTHrP1 receptor, resulting in activation of adenylyl cyclase to produce cAMP, activation of phospholipase C to produce intramolecular calcium, or activation of the PTH / PTHrP1 receptor to the osteoblast expression of RANKL (which binds to RANK (a receptor activator for nuclear factor kB)) on osteoclasts. It is understood that measuring the residual activity of the PTH prodrug of the present invention takes time for a certain amount of PTH to be released from the PTH prodrug of the present invention, and such released PTH can 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 substructure, in this case PTH, is irreversibly, i.e., stably bound to a carrier, and which approximates as closely as possible the structure of the PTH prodrug whose residual activity is to be measured.

[0414] Preferably, the pharmaceutical composition comprising at least one controlled-release PTH compound of the present 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.

[0415] In one embodiment, a pharmaceutical composition comprising at least one controlled-release PTH compound of the present invention is a liquid or suspension formulation. The pharmaceutical composition is understood to be a suspension formulation when the controlled-release PTH compound of the present invention is water-insoluble.

[0416] In another embodiment, the pharmaceutical composition comprising at least one controlled-release PTH compound of the present invention is a dried formulation that is reconstituted before administration to a patient.

[0417] Such liquid, suspension, dried, or reconstituted pharmaceutical compositions contain at least one excipient. Excipients used in parenteral formulations may be classified, for example, as buffers, isotonic modifiers, preservatives, stabilizers, absorption inhibitors, antioxidants, thickeners / viscosity enhancers, or other adjuvants. However, in some cases, one excipient may have a dual or triple function. Preferably, the at least one excipient included in the pharmaceutical composition of the present invention is selected from the group consisting of: (i) Buffering agents: Physiologically acceptable buffering agents to maintain pH within a desired range, such as sodium phosphate, bicarbonate, succinate, histidine, citrate and acetate, sulfate, nitrate, chloride, and pyruvate. Acid inhibitors, such as Mg(OH)2 or ZnCO3, may also be used; (ii) Isotonic modifiers: These are used to minimize pain that may result from cell damage caused by osmotic pressure differences at the injection depot. Examples include glycerin and sodium chloride. The effective concentration can be determined by osmotic measurement using an assumed molar osmotic concentration of 285–315 mOsmol / kg for serum; (iii) Preservatives and / or antibacterial agents: Parenteral formulations for multiple doses require the addition of preservatives at sufficient concentrations to minimize the risk of infection in patients by injection, and corresponding regulatory requirements have been established. Typical preservatives include m-cresol, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenylmercury nitrate, thimerosal, sorbic acid, potassium sorbate, benzoic acid, chlorocresol, and benzalkonium chloride; (iv) Stabilizers: Stabilization is achieved by enhancing the protein's stabilizing ability, by destabilizing the denatured state, or by direct binding of the excipient to the protein. Stabilizers may include amino acids, e.g., alanine, arginine, aspartic acid, glycine, histidine, lysine, proline; sugars, e.g., glucose, sucrose, trehalose; polyols, e.g., glycerol, mannitol, sorbitol; salts, e.g., potassium phosphate, sodium sulfate; chelating agents, e.g., EDTA, hexaphosphates; ligands, e.g., divalent metal ions (zinc, calcium, etc.); other salts or organic molecules, e.g., phenolic derivatives. In addition, oligomers or polymers, e.g., cyclodextrin, dextran, dendrimers, PEG or PVP, or protamine or HSA may also be used. (v) Absorption inhibitors: Primarily ionic or nonionic 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 for coating the inner surface of the formulation container or for competitive adsorption to the inner surface. The selected excipient concentration and type depend on the action to be avoided, but typically a single layer of surfactant is formed at the interface just above the CMC value; (vi) Antioxidant agents: Antioxidants such as ascorbic acid, ectoin, 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) Thickeners or viscosity enhancers: In the case of suspensions, these are used to delay the sedimentation of particles in the vial and syringe, to facilitate the mixing and resuspension of particles, and to make the suspension easier to inject (i.e., with less force on the syringe plunger). Suitable thickeners or viscosity enhancers include, for example, carbomer thickeners, e.g., Carbopol 940, Carbopol Ultrez 10; cellulose derivatives, e.g., hydroxypropyl methylcellulose (hypromellose, HPMC) or diethylaminoethylcellulose (DEAE or DEAE-C); colloidal magnesium silicate (Veegum) or sodium silicate; hydroxyapatite gel; tricalcium phosphate gel; xanthan gum; carrageenan, e.g., Satia gum UTC 30; Aliphatic poly(hydroxy acids), e.g., poly(D,L- or L-lactic acid) (PLA) and poly(glycolic acid) (PGA) and copolymers thereof (PLGA), terpolymers of D,L-lactide, glycolide and caprolactone; poloxamers; hydrophilic poly(oxyethylene) blocks and hydrophobic poly(oxypropylene) blocks for constituting poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) triblocks (e.g., Pluronic®); polyether ester copolymers, e.g., polyethylene glycol terephthalate / polybutylene terephthalate copolymer; sucrose acetate isobutyrate (SAIB); dextran or its derivatives Conductors; combinations of dextran and PEG; polydimethylsiloxane; collagen; chitosan; polyvinyl alcohol (PVA) and its derivatives; polyalkylimides; poly(acrylamide-co-diallyldimethylammonium (DADMA)); polyvinylpyrrolidone (PVP); glycosaminoglycans (GAG), such as dermatan sulfate, chondroitin sulfate, keratan sulfate, heparin, heparan sulfate, hyaluronan; and ABA triblock or AB block copolymer, which consists 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 described above may exhibit reverse thermal gelation behavior (a fluid state at room temperature to facilitate administration, and a gel state at temperatures higher than the sol-gel transition temperature at body temperature after injection). (viii) Spreading or diffusing agents: These regulate the permeability of connective tissue by hydrolysis of components of the extracellular matrix in the interstitial space (e.g., hyaluronic acid, a polysaccharide found in the intercellular space of connective tissue, for example, but not limited to these). Spreading agents, for example, hyaluronidase, for example, but not limited to these, temporarily reduce the viscosity of the extracellular matrix and promote the diffusion of injected drugs; and (ix) Other auxiliary agents: Wetters, viscosity modifiers, antibiotics, hyaluronidase, etc. Acids and bases such as hyaluronic acid and sodium hydroxide are auxiliary agents necessary for pH adjustment during manufacturing.

[0418] In another embodiment, the present invention relates to a method for treating, managing, delaying or preventing a condition that can be treated, managed, delayed or prevented by PTH, comprising the step of administering a controlled-release PTH compound in accordance with a dosing schedule in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in increments of 25% or less.

[0419] Preferably, the pharmaceutical composition containing the controlled-release PTH compound is administered according to a dosing plan in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in increments of 20% or less, more preferably 15% or less, and most preferably 10% or less.

[0420] In one embodiment, a pharmaceutical composition containing a controlled-release PTH compound is administered according to a dosing schedule in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in 25% increments.

[0421] More preferably, the pharmaceutical composition containing the controlled-release PTH compound is administered according to a dosing schedule in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in 20% increments.

[0422] More preferably, the pharmaceutical composition containing the controlled-release PTH compound is administered according to a dosing schedule in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in 15% increments.

[0423] Most preferably, the pharmaceutical composition containing the controlled-release PTH compound is administered according to a dosing schedule in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in 10% increments.

[0424] Preferably, the pharmaceutical product containing the controlled-release PTH compound is administered to the patient at least every 24 hours, for example, every 24 hours, every 36 hours, every 48 hours, every 60 hours, every 72 hours, every 84 hours, every 96 hours, every 108 hours, every 120 hours, every 132 hours, every 144 hours, or every 156 hours, once a week or once every two weeks.

[0425] In one embodiment, a pharmaceutical composition containing a controlled-release PTH compound is administered every 24 hours.

[0426] In another embodiment, the pharmaceutical composition containing the controlled-release PTH compound is administered every 48 hours.

[0427] In another embodiment, the pharmaceutical composition containing the controlled-release PTH compound is administered every 72 hours.

[0428] In another embodiment, the pharmaceutical composition containing the controlled-release PTH compound is administered every 96 hours.

[0429] In another embodiment, the pharmaceutical composition containing the controlled-release PTH compound is administered every 120 hours.

[0430] In another embodiment, the pharmaceutical composition containing the controlled-release PTH compound is administered every 144 hours.

[0431] In another embodiment, the pharmaceutical composition containing the controlled-release PTH compound is administered once a week.

[0432] Preferably, the pharmaceutical composition containing the PTH compound is administered to the patient by subcutaneous administration, preferably by subcutaneous injection.

[0433] Preferred embodiments of the controlled-release PTH compound are as described above.

[0434] Preferably, 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, fractures, alopecia, chemotherapy-induced alopecia, and thrombocytopenia. More preferably, 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, fractures, alopecia, chemotherapy-induced alopecia, and thrombocytopenia.

[0435] Most preferably, the condition is hypoparathyroidism.

[0436] Preferably, the patient receiving the treatment method of the present invention is a mammalian patient, and preferably a human patient. [Examples]

[0437] Materials and methods Side-chain protected PTH(1-34) (SEQ ID NO: 51) (synthesized using the Fmoc strategy) on TCP resin, having a Boc-protected N-terminus and an ivDde-protected side chain of Lys26, was obtained from a custom peptide synthesis supplier.

[0438] Side-chain protected PTH(1-34) on TCP resin with Fmoc-protected N-terminus (synthesized using the Fmoc strategy) was obtained from a custom peptide synthesis supplier.

[0439] 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 otherwise specified by a different supplier.

[0440] Compound 11a (Examples 11-15) was synthesized according to the procedure described in Patent WO29095479A2, Example 1.

[0441] Syringes equipped with polyethylene frit (MultiSynTech GmbH, Witten, Germany) were used as reaction vessels or in the washing process of the peptide resin.

[0442] General procedure for removing ivDde protecting groups from side-chain protecting PTHs on resin: The resin was pre-swelled in DMF for 30 minutes, and the solvent was discarded. The ivDde groups were removed by incubating the resin with DMF / hydrazine hydrate 4 / 1 (v / v, 2.5 mL / g resin) for 8 × 15 minutes. A fresh DMF / hydrazine hydrate solution was used after each step. Finally, the resin was washed with DMF (10 ×) and DCM (10 ×) and dried under vacuum.

[0443] General procedure for removing Fmoc protecting groups from protective PTH on resin: The resin was pre-swelled in DMF for 30 minutes, and the solvent was discarded. The Fmoc groups were removed by incubating the resin with DMF / piperidine / DBU 96 / 2 / 2 (v / v / v, 2.5 mL / g resin) for 3 × 10 minutes. A fresh DMF / piperidine / DBU solution was used for each step. Finally, the resin was washed with DMF (10 ×) and DCM (10 ×) and dried under vacuum.

[0444] RP-HPLC purification: For preparative RP-HPLC, a Waters 600 controller and 2487 Dual Absorbance Detector were used, fitted with the following columns: Waters XBridge® BEH300 Prep C18 5μm, 150×10mm, flow rate 6mL / min, or Waters XBridge® BEH300 Prep C18 10μm, 150×30mm, flow rate 40mL / min. A linear gradient was used between solvent system A (water containing 0.1% TFA v / v) and solvent system B (acetonitrile containing 0.1% TFA v / v). Unless otherwise specified, the HPLC fractions containing the product were pooled and lyophilized.

[0445] Flash chromatography Flash chromatography purification was performed using a Biotage KP-Sil silica cartridge with n-heptane and ethyl acetate as eluents on an Isolera One system from Biotage AB, Sweden. The product was detected at 254 nm.

[0446] 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.

[0447] 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. 0.1% (v / v) acetic acid was used as the mobile phase.

[0448] Analysis method Ultrafast LC (UPLC)-MS analysis was 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)) connected to either a Thermo Scientific LTQ Orbitrap Discovery mass spectrometer or a Waters Micromass ZQ.

[0449] [Example 1] Synthesis of linker reagent 1f Linker reagent 1f was synthesized according to the following scheme:

[0450] [ka]

[0451] 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), 2,4,6-trimethoxybenzaldehyde (2.08 g, 10.61 mmol) was gradually added. The mixture was stirred at room temperature for 90 minutes, acidified with 3 M HCl (4 mL), and stirred for another 15 minutes. The reaction mixture was added to a saturated NaHCO3 solution (200 mL) and extracted five times by DCM. The combined organic phase was dried over Na2SO4, and the solvent was evaporated under vacuum. The resulting N-methyl-N-Boc-N'-Tmob-ethylenediamine 1a was dried under high vacuum and used in the next reaction step without further purification. Yield: 3.76g (11.48 mmol, purity 89%, 1a:double Tmob protected product = 8:1) MS:m / z 355.22=[M+H] + (Calculated monoisotopic mass = 354.21).

[0452] To a solution of 1a (2 g, 5.65 mmol) in DCM (24 mL), 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) were added. The reaction mixture was stirred at room temperature for 3 hours, diluted with DCM (250 mL), and washed three times with 0.1 M H2SO4 (100 mL) and three times with saturated saline (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: 5.31g (148%, 6.66 mmol) MS:m / z 796.38=[M+H] + (Calculated monoisotopic mass = 795.37).

[0453] To a solution of 1b (5.31 g, maximum 4.52 mmol with respect to N-Fmoc-N-Me-Asp(OBn)-OH) in THF (60 mL), DBU (1.8 mL, 3% v / v) was added. The solution was stirred at room temperature for 12 minutes, diluted with DCM (400 mL), and washed three times with 0.1 M H2SO4 (150 mL) and three times with saturated saline (150 mL). The aqueous phase was re-extracted with DCM (100 mL). The combined organic phase was 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).

[0454] 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 hours, diluted with DCM (400 mL), and washed three times with 0.1 M H2SO4 (100 mL) and three times with saturated saline (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).

[0455] LiOH (267 mg, 11.12 mmol) was added to a solution of 1d (2.63 g, 2.78 mmol) in i-PrOH (33 mL) and H2O (11 mL), and the reaction mixture was stirred at room temperature for 70 minutes. The mixture was diluted with DCM (200 mL) and washed three times with 0.1 M H2SO4 (50 mL) and three times with saturated saline (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).

[0456] To a solution of 1e (170 mg, 0.198 mmol) in anhydrous DCM (4 mL), DCC (123 mg, 0.59 mmol) and a catalytic amount of DMAP were added. After 5 minutes, N-hydroxysuccinimide (114 mg, 0.99 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. 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 fraction was neutralized with 0.5 M pH 7.4 phosphate buffer and concentrated. The residual aqueous phase was extracted with DCM, and 1f was isolated by evaporation of the solvent. Yield: 154 mg (81%) MS:m / z 953.4=[M+H] + (Calculated monoisotopic mass = 952.43).

[0457] [Example 2] Synthesis of 2g of linker reagent

[0458] [ka] JPEG2026082916000050.jpg110152

[0459] 4-Methoxytritylphenyl methyl chloride (3.00 g, 9.71 mmol) was dissolved in DCM (20 mL) and added dropwise to a solution of ethylenediamine 2a (6.5 mL, 97.3 mmol) in DCM (20 mL) with stirring. The reaction mixture was stirred at room temperature for 2 hours, then diluted with diethyl ether (300 mL) and washed three times with saturated saline / 0.1 M NaOH 30 / 1 (v / v) and once with saturated saline. The organic phase was dried over Na2SO4, and 2b was isolated by evaporation of the solvent. Yield: 3.18g (98%)

[0460] Mmt-protecting 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 at room temperature for 30 minutes. The solution was diluted with diethyl ether (250 mL) and washed three times with saturated saline / 0.1 M NaOH 30 / 1 (v / v) and once with saturated saline. 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).

[0461] Compound 2c (3.19 g, 4.53 mmol) was dissolved in anhydrous THF (50 mL), and 1 M BH3·THF solution in THF (8.5 mL, 8.5 mmol) was added. The mixture was stirred at room temperature for 16 hours. A further 1 M BH3·THF solution in THF (14 mL, 14.0 mmol) was added, and the mixture was stirred at room temperature for another 16 hours. Methanol (8.5 mL) and N,N'-dimethylethylenediamine (3.00 mL, 27.9 mmol) were added, and the mixture was heated under reflux for 3 hours. The mixture was allowed to stand and 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 obtain 2d. Yield: 3.22g (103%) MS:m / z 691.4=[M+H] + (Calculated monoisotopic mass = 690.36).

[0462] 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 at room temperature for 30 minutes. The solution was concentrated under vacuum and purified by flash chromatography to obtain product 2e. Yield: 2.09g (74%) MS:m / z 791.4=[M+H] + (Calculated monoisotopic mass = 790.42).

[0463] Compound 2e (5.01 g, 6.34 mmol) was dissolved in acetonitrile (80 mL). 0.4 M aqueous HCl (80 mL), followed by acetonitrile (20 mL), was added, and the mixture was stirred at room temperature for 1 hour. The pH was adjusted to 5.5 by adding 5 M aqueous NaOH. The organic solvent was removed under vacuum, and the remaining aqueous solution was extracted four times by DCM. The combined organic phase was dried over Na2SO4, and the solvent was removed under vacuum to obtain 2f. Yield: 4.77g (95%) MS:m / z 519.3=[M+H] + (Calculated monoisotopic mass = 518.30).

[0464] 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 at room temperature for 45 minutes. The solution was concentrated under vacuum and purified by flash chromatography to obtain 2 g of product. Yield: 4.04g (89%) MS:m / z 706.32=[M+Na] + (Calculated monoisotopic mass = 683.30).

[0465] [Example 3] Synthesis of Permanent S1 PTH(1-34) Conjugate 3

[0466] [ka] Side-chain protected PTH(1-34) on a TCP resin with an Fmoc-protected N-terminus was deprotected according to the procedure given in "Materials and Methods". A solution of 6-trityl mercaptohexanoic 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 the resin. The suspension was stirred at room temperature for 80 minutes. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. 10 mL of the cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole was added, and the suspension was stirred at room temperature for 1 hour to cleave the peptide and remove the protecting group from the resin. Crude 3 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 freeze-dried. Yield: 36 mg (14%), 3*8 TFA MS:m / z 1062.31=[M+4H] 4+ , ([M+4H] 4+ The calculated monoisotopic mass for this is 1062.30.

[0467] [Example 4] Synthesis of Permanent K26 PTH(1-34) Conjugate 4

[0468] [ka] The ivDde of side-chain protected PTH(1-34) on a TCP resin having a Boc-protected N-terminus and a Lys26 ivDde-protected side chain was deprotected according to the procedure given in "Materials and Methods". A solution of 6-trityl mercaptohexanoic 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 the resin. The suspension was stirred at room temperature for 1 hour. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. The peptide was cleaved and the protecting group removed from the resin by adding 6 mL of the cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole and stirring the suspension at room temperature for 1 hour. Crude compound 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 freeze-dried. Yield: 40 mg (8%), 4*8 TFA MS:m / z 1062.30=[M+4H] 4+ , ([M+4H] 4+ The calculated monoisotopic mass for this is 1062.30.

[0469] [Example 5] Synthesis of temporary S1 PTH(1-34) conjugates

[0470] [ka] The Fmoc of side-chain protected PTH(1-34) on TCP resin having an 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 the resin. The suspension was stirred at room temperature for 16 hours. The resin was washed 10 times with DMF and the Fmoc was 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 at room temperature for 24 hours. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. 7 mL of the cleavage cocktail 100 / 3 / 3 / 2 / 1(v / w / v / v / v) TFA / DTT / TES / water / thioanisole was added, and the suspension was stirred at room temperature for 1 hour to cleave the peptide from the resin and remove the protecting groups. Crude 5 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 freeze-dried. Yield: 78 mg (24%), 5*9 TFA MS:m / z 1101.59=[M+4H] 4+ , ([M+4H] 4+ The calculated monoisotopic mass for this is 1101.57.

[0471] [Example 6] Temporary S1 PTH(1-34) Conjugate 6 Synthesis

[0472] [ka] The Fmoc of side-chain protected PTH(1-34) on TCP resin having an 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 the resin. The suspension was shaken at room temperature for 1 hour. The resin was washed 10 times with DMF and 10 times with DCM, and dried under vacuum. Deprotection of Fmoc was performed 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 at room temperature for 1.5 hours. The resin was washed 10 times with DMF and 10 times with DCM, and dried under vacuum. 3 mL of the cleavage cocktail 100 / 3 / 3 / 2 / 1(v / w / v / v / v) TFA / DTT / TES / water / thioanisole was added, and the suspension was stirred at room temperature for 1 hour to cleave the peptide from the resin and remove the protecting groups. Crude 6 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 freeze-dried. Yield: 25 mg (18%), 6*9 TFA MS:m / z 1098.75=[M+4H] 4+ , ([M+4H] 4+ The calculated monoisotopic mass for this is 1098.07.

[0473] [Example 7] Temporary S1 PTH(1-34) Conjugate 7 Synthesis

[0474] [ka] The Fmoc of side-chain protected PTH(1-34) on TCP resin having an 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 the resin. The suspension was stirred at room temperature for 1 hour. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Deprotection of Fmoc was performed 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 at room temperature for 7 hours. The resin was washed 10 times with DMF and 10 times with DCM, and dried under vacuum. 6 mL of the cleavage cocktail 100 / 3 / 3 / 2 / 1(v / w / v / v / v) TFA / DTT / TES / water / thioanisole was added, and the suspension was stirred at room temperature for 1 hour to cleave the peptide and remove the protecting groups from the resin. Crude 7 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 freeze-dried. Yield: 54 mg (20%), 7*9 TFA MS:m / z 1102.08=[M+4H] 4+ , ([M+4H] 4+ The calculated monoisotopic mass for this is 1102.07).

[0475] [Example 8] Synthesis of temporary S1 PTH(1-34) conjugate 8

[0476] [ka] The Fmoc of side-chain protected PTH(1-34) on TCP resin having an 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 the resin. The suspension was stirred at room temperature for 1 hour. The resin was washed 10 times with DMF and 10 times with DCM, and dried under vacuum. Deprotection of Fmoc was performed 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 at room temperature for 1.5 hours. The resin was washed 10 times with DMF and 10 times with DCM, and dried under vacuum. 3 mL of the cleavage cocktail 100 / 3 / 3 / 2 / 1(v / w / v / v / v) TFA / DTT / TES / water / thioanisole was added, and the suspension was stirred at room temperature for 1 hour to cleave the peptide from the resin and remove the protecting groups. Crude 8 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 freeze-dried. Yield: 31 mg (22%), 8*9 TFA MS:m / z 1109.32=[M+4H] 4+ , ([M+4H] 4+ The calculated monoisotopic mass for this is 1108.58.

[0477] [Example 9] Temporary S1 PTH(1-34) Conjugate 9 Synthesis

[0478] [ka] The Fmoc of side-chain protected PTH(1-34) on a TCP resin having an 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 the resin. The suspension was stirred at room temperature for 16 hours. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. 20 mL of the cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole was added, and the suspension was stirred at room temperature for 1 hour to cleave the peptide and remove the protecting group from the resin. The crude product 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 freeze-dried. Yield: 47 mg (8%), 9*9 TFA MS:m / z 1108.58=[M+4H] 4+ , ([M+4H] 4+ The calculated monoisotopic mass for this is 1108.57.

[0479] [Example 10] Temporary K26 PTH(1-34) Conjugate 10 Synthesis

[0480] [ka] The ivDde of side-chain protected PTH(1-34) on a TCP resin having a Boc-protected N-terminus and a Lys26 ivDde-protected side chain 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 the resin. The suspension was stirred at room temperature for 1 hour. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. 20 mL of the cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole was added, and the suspension was shaken at room temperature for 1 hour to cleave the peptide and remove the protecting group from the resin. Crude 10 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 freeze-dried. Yield: 92 mg (7%), 10*9 TFA MS:m / z 1108.58=[M+4H] 4+ , ([M+4H] 4+ The calculated monoisotopic mass for this is 1108.57.

[0481] [Example 11] Synthesis of low molecular weight transient S1 PEG conjugate 11b

[0482] [ka] To 0.5 mL of a 20 mg / mL solution of 1 / 1(v / v) acetonitrile / water thiol 5 (10 mg, 1.84 μmol) containing 0.1% TFA (v / v), 0.15 mL of 0.5 M NaH2PO4 buffer (pH 7.4) was added. The solution was incubated at room temperature for 10 minutes, and then 238 μL of a 10 mg / mL solution of 1 / 1(v / v) acetonitrile / water maleimide 11a (2.4 mg, 2.21 μmol) containing 0.1% TFA (v / v) was added. The solution was incubated at room temperature for 20 minutes. 10 μL of TFA was added, and the mixture was purified by RP-HPLC. The product fraction was lyophilized to obtain 11b. Yield: 3.1 mg (26%), 11b*9TFA MS:m / z 1097.00=[M+4H] 4+ , ([M+5H] 5+ The calculated monoisotopic mass for this is 1096.99.

[0483] [Example 12] Synthesis of low molecular weight transient S1 PEG conjugate 12

[0484] [ka] Conjugate 12 was synthesized using thiol 6 (10 mg, 1.85 μmol) and maleimide 11a (2.4 mg, 2.21 μmol) as described for 11b. Yield: 10 mg (83%), 12*9 TFA MS:m / z 1094.20=[M+4H] 4+ , ([M+4H] 4+ The calculated monoisotopic mass for this is 1094.19.

[0485] [Example 13] Synthesis of low molecular weight transient S1 PEG conjugate 13

[0486] [ka] Conjugate 13 was synthesized using thiol 7 (10 mg, 1.84 μmol) and maleimide 11a (2.4 mg, 2.21 μmol) as described for 11b. Yield: 8 mg (67%), 13*9 TFA MS:m / z 1097.40=[M+5H] 5+ , ([M+5H] 5+ The calculated monoisotopic mass for this is 1097.39.

[0487] [Example 14] Synthesis of low molecular weight transient S1 PEG conjugate 14

[0488] [ka] Conjugate 14 was synthesized using thiol 8 (10 mg, 1.83 μmol) and maleimide 11a (2.4 mg, 2.21 μmol) as described for 11b. Yield: 4 mg (33%), 14*9 TFA MS:m / z 1378.01=[M+4H] 4+ , ([M+4H] 4+ The calculated monoisotopic mass for this is 1378.00.

[0489] [Example 15] Synthesis of low molecular weight transient K26 PEG conjugate 15

[0490] [ka] Conjugate 15 was synthesized using thiol 10 (5.2 mg, 0.95 μmol) and maleimide 11a (1.23 mg, 1.14 μmol) as described for 11b. Yield: 2.1 mg (33%), 15*9 TFA MS:m / z 1102.60=[M+5H] 5+ , ([M+5H] 5+ The calculated monoisotopic mass for this is 1102.59.

[0491] [Example 16] Synthesis of persistent 2x20kDa S1 PEG conjugate 16

[0492] [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 2x20 kDa 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). 0.66 mL of 0.5 M NaH2PO4 buffer (pH 7.0) was added, and the mixture was stirred at room temperature for 30 minutes. 10 μL of a 270 mg / mL solution of 2-mercaptoethanol in water was added. The mixture was stirred at room temperature for 5 minutes, and 0.33 mL of 1 M HCl was added. Conjugate 16 was purified by IEX, and then further purified by RP-HPLC using a linear gradient between solvent system A (water containing 0.1% AcOH v / v) and solvent system B (acetonitrile containing 0.1% AcOH v / v). The product-containing fraction was freeze-dried. Yield: 97 mg (2.01 μmol, 57%) Conjugate 16*8 AcOH

[0493] [Example 17] Synthesis of persistent 2x20kDa K26 PEG conjugate 17

[0494] [ka] Conjugate 17 was prepared as described in section 16 by reacting 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*8 AcOH

[0495] [Example 18] Synthesis of temporary 2x20kDa S1 PEG conjugate 18

[0496] [ka] Conjugate 18 was prepared as described in section 16 by the reaction of thiol 5 (37 mg, 8.40 μmol) with PEG 2x20 kDa maleimide (Sunbright GL2-400MA, 445 mg, 9.24 μmol). The reaction was stopped by adding 50 μL of TFA without prior addition of 2-mercaptoethanol. Conjugate 18 was purified by IEX and then by SEC for desalting. The product-containing fraction was freeze-dried. Yield: 161 mg (3.33 μmol, 40%) Conjugate 18*9AcOH

[0497] [Example 19] Synthesis of temporary 2x20kDa S1 PEG conjugate 19

[0498] [ka] Conjugate 19 was prepared as described in section 16 by reacting thiol 7 (27 mg, 6.14 μmol) with PEG 2x20 kDa maleimide (Sunbright GL2-400MA, 325 mg, 7.50 μmol). Yield: 249 mg (5.16 μmol, 84%) Conjugate 19*9AcOH

[0499] [Example 20] Synthesis of temporary 2x20kDa S1 PEG conjugate 20

[0500] [ka] Conjugate 20 was prepared as described in section 16 by the reaction of thiol 9 (38 mg, 8.59 μmol) with PEG 2x20 kDa maleimide (Sunbright GL2-400MA, 455 mg, 9.45 μmol). The reaction was stopped by adding 50 μL of TFA without prior addition of 2-mercaptoethanol. Conjugate 20 was purified by IEX and then by SEC for desalting. The product-containing fraction was freeze-dried. Yield: 194 mg (4.01 μmol, 47%) Conjugate 20*9AcOH

[0501] [Example 21] Synthesis of temporary 2x20kDa K26 PEG conjugate 21

[0502] [ka] Conjugate 21 was prepared as described in section 16 by the 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

[0503] [Example 22] Dose Range Establishment Study - Dose Adjustment Study on Daily Subcutaneous Injection of TransCon PTH in Cynomolgus Monkeys Methods: This study was conducted to test the hypothesis of dose adjustment for TransCon PTH in 25% increments in response to hypocalcemia or hypercalcemia. The study was conducted in male and female cynomolgus monkeys. Four groups, each consisting of one male and one female, were administered at doses of 0.2, 0.5, 1.0, and 2.0 μg / kg / day for 4 weeks, respectively. Serum calcium (sCa) levels in these animals were measured before administration and on days -6, 1, 3, 7, 8, 12, 14, 16, 19, 23, 26, 28, and 29 after administration.

[0504] Results: Daily subcutaneous administration of TransCon PTH at doses of 0.2, 0.5, and 1.0 μg / kg / day over 28 days was well tolerated and accompanied by the expected sporadic, slight increases in sCa levels (1.05x to a maximum of 1.12x compared to pre-study levels). On day 3, sCa levels in males and females administered at 2.0 μg / kg / day increased to severe hypercalcemia levels (maximum 1.42x and 1.34x, respectively, compared to pre-study levels). Administration was discontinued in these two animals, followed by a drug-free period. On day 23, administration was resumed at 1.5 μg / kg / day for one week (25% dose reduction). On day 23 (the first day of administration after the drug-free period), increases in calcium were observed in males at all time points (1.05x to 1.12x compared to pre-study levels), with peak concentrations reached 4 hours after administration. On day 26, an increase was observed in both males and females (up to 1.17x compared to pre-study levels). On day 29, the calcium increase was still present in both males and females.

[0505] Conclusion: The dose of controlled-release PTH compound administered subcutaneously to male and female cynomolgus monkeys was successfully adjusted (reduced) by a 25% increment as a measure against hypercalcemia. sCa levels in the animals were lower after administration of the 25% reduced dose compared to administration of the original higher dose.

[0506] Abbreviation: ACN Acetonitrile Acetic acid (ACOH) 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 Dimethylaminopyridine 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-dioxocyclohexa-1-ylidene)-3-methylbutyl LC (Reset Chromatography) LTQ Linear Trap Quadrupole Lys-C endoproteinase Lys-C LLOQ Lower limit of quantitation 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 concentration) PK (Pharmacokinetics) Pr Propyl PTH (parathyroid hormone) PyBOP Benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate Q-TOF Quadrupole Flight Time Type RP-HPLC (Reverse-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 quantification UPLC Ultra-High-Speed ​​Liquid Chromatography UV ultraviolet light ZQ Single Quadrupole

[0507] [Sequence List] SEQUENCE LISTING <110> Ascendis Pharma Bone Diseases A / S <120> Incremental dose finding in controlled-release PTH compounds <130> PA26-033 <150> EP 16191453.6 <151> 2016-09-29 <160> 122 <170> PatentIn version 3.5 <210> 1 <211> 84 <212> PRT <213> Homo sapiens <400> 1 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys 65 70 75 80 Ala Lys Ser Gln <210> 2 <211> 83 <212> PRT <213> Artificial Sequence <220> <223> Human PTH 1-83 <400> 2 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys 65 70 75 80 Ala Lys Ser <210> 3 <211> 82 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-82 <400> 3 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys 65 70 75 80 Ala Lys <210> 4 <211> 81 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-81 <400> 4 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys 65 70 75 80 Ala <210> 5 <211> 80 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-80 <400> 5 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys 65 70 75 80 <210> 6 <211> 79 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-79 <400> 6 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr 65 70 75 <210> 7 <211> 78 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-78 <400> 7 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu 65 70 75 <210> 8 <211> 77 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-77 <400> 8 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val 65 70 75 <210> 9 <211> 76 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-76 <400> 9 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn 65 70 75 <210> 10 <211> 75 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-75 <400> 10 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val 65 70 75 <210> 11 <211> 74 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-74 <400> 11 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp 65 70 <210> 12 <211> 73 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-73 <400> 12 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala 65 70 <210> 13 <211> 72 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-72 <400> 13 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys 65 70 <210> 14 <211> 71 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-71 <400> 14 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp 65 70 <210> 15 <211> 70 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-70 <400> 15 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala 65 70 <210> 16 <211> 69 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-69 <400> 16 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu 65 <210> 17 <211> 68 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-68 <400> 17 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly 65 <210> 18 <211> 67 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-67 <400> 18 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu 65 <210> 19 <211> 66 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-66 <400> 19 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser 65 <210> 20 <211> 65 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-65 <400> 20 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys 65 <210> 21 <211> 64 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-64 <400> 21 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 <210> 22 <211> 63 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-63 <400> 22 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His 50 55 60 <210> 23 <211> 62 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-62 <400> 23 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser 50 55 60 <210> 24 <211> 61 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-61 <400> 24 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu 50 55 60 <210> 25 <211> 60 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-60 <400> 25 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val 50 55 60 <210> 26 <211> 59 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-59 <400> 26 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu 50 55 <210> 27 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-58 <400> 27 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val 50 55 <210> 28 <211> 57 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-57 <400> 28 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn 50 55 <210> 29 <211> 56 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-56 <400> 29 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp 50 55 <210> 30 <211> 55 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-55 <400> 30 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu 50 55 <210> 31 <211> 54 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-54 <400> 31 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys 50 <210> 32 <211> 53 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-53 <400> 32 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys 50 <210> 33 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-52 <400> 33 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg 50 <210> 34 <211> 51 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-51 <400> 34 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro 50 <210> 35 <211> 50 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-50 <400> 35 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg 50 <210> 36 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-49 <400> 36 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln <210> 37 <211> 48 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-48 <400> 37 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 <210> 38 <211> 47 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-47 <400> 38 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly 35 40 45 <210> 39 <211> 46 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-46 <400> 39 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala 35 40 45 <210> 40 <211> 45 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-45 <400> 40 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp 35 40 45 <210> 41 <211> 44 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-44 <400> 41 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg 35 40 <210> 42 <211> 43 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-43 <400> 42 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro 35 40 <210> 43 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-42 <400> 43 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala 35 40 <210> 44 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> human PTH-41 <400> 44 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu 35 40 <210> 45 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-40 <400> 45 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro 35 40 <210> 46 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-39 <400> 46 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala 35 <210> 47 <211> 38 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-38 <400> 47 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly 35 <210> 48 <211> 37 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-37 <400> 48 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu 35 <210> 49 <211> 36 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-36 <400> 49 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala 35 <210> 50 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-35 <400> 50 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val 35 <210> 51 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-34 <400> 51 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe <210> 52 <211> 33 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-33 <400> 52 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn <210> 53 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-32 <400> 53 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 <210> 54 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-31 <400> 54 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val 20 25 30 <210> 55 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-30 <400> 55 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp 20 25 30 <210> 56 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-29 <400> 56 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln 20 25 <210> 57 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-28 <400> 57 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu 20 25 <210> 58 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-27 <400> 58 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys 20 25 <210> 59 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-26 <400> 59 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys 20 25 <210> 60 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> human PTH 1-25 <400> 60 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg 20 25 <210> 61 <211> 84 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-84 <220> <221> MOD_RES <222> (84)..(84) <223> AMIDATION <400> 61 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys 65 70 75 80 Ala Lys Ser Gln <210> 62 <211> 83 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-83 <220> <221> MOD_RES <222> (83)..(83) <223> AMIDATION <400> 62 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys 65 70 75 80 Ala Lys Ser <210> 63 <211> 82 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-82 <220> <221> MOD_RES <222> (82)..(82) <223> AMIDATION <400> 63 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys 65 70 75 80 Ala Lys <210> 64 <211> 81 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-81 <220> <221> MOD_RES <222> (81)..(81) <223> AMIDATION <400> 64 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys 65 70 75 80 Ala <210> 65 <211> 80 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-80 <220> <221> MOD_RES <222> (80)..(80) <223> AMIDATION <400> 65 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys 65 70 75 80 <210> 66 <211> 79 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-79 <220> <221> MOD_RES <222> (79)..(79) <223> AMIDATION <400> 66 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr 65 70 75 <210> 67 <211> 78 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-78 <220> <221> MOD_RES <222> (78)..(78) <223> AMIDATION <400> 67 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu 65 70 75 <210> 68 <211> 77 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-77 <220> <221> MOD_RES <222> (77)..(77) <223> AMIDATION <400> 68 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val 65 70 75 <210> 69 <211> 76 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-76 <220> <221> MOD_RES <222> (76)..(76) <223> AMIDATION <400> 69 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn 65 70 75 <210> 70 <211> 75 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-75 <220> <221> MOD_RES <222> (75)..(75) <223> AMIDATION <400> 70 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val 65 70 75 <210> 71 <211> 74 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-74 <220> <221> MOD_RES <222> (74)..(74) <223> AMIDATION <400> 71 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp 65 70 <210> 72 <211> 73 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-73 <220> <221> MOD_RES <222> (73)..(73) <223> AMIDATION <400> 72 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala 65 70 <210> 73 <211> 72 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-72 <220> <221> MOD_RES <222> (72)..(72) <223> AMIDATION <400> 73 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys 65 70 <210> 74 <211> 71 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-71 <220> <221> MOD_RES <222> (71)..(71) <223> AMIDATION <400> 74 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp 65 70 <210> 75 <211> 70 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-70 <220> <221> MOD_RES <222> (70)..(70) <223> AMIDATION <400> 75 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala 65 70 <210> 76 <211> 69 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-69 <220> <221> MOD_RES <222> (69)..(69) <223> AMIDATION <400> 76 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu 65 <210> 77 <211> 68 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-68 <220> <221> MOD_RES <222> (68)..(68) <223> AMIDATION <400> 77 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly 65 <210> 78 <211> 67 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-67 <220> <221> MOD_RES <222> (67)..(67) <223> AMIDATION <400> 78 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu 65 <210> 79 <211> 66 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-66 <220> <221> MOD_RES <222> (66)..(66) <223> AMIDATION <400> 79 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser 65 <210> 80 <211> 65 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-65 <220> <221> MOD_RES <222> (65)..(65) <223> AMIDATION <400> 80 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys 65 <210> 81 <211> 64 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-64 <220> <221> MOD_RES <222> (64)..(64) <223> AMIDATION <400> 81 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 <210> 82 <211> 63 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-63 <220> <221> MOD_RES <222> (63)..(63) <223> AMIDATION <400> 82 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His 50 55 60 <210> 83 <211> 62 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-62 <220> <221> MOD_RES <222> (62)..(62) <223> AMIDATION <400> 83 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser 50 55 60 <210> 84 <211> 61 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-61 <220> <221> MOD_RES <222> (61)..(61) <223> AMIDATION <400> 84 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu 50 55 60 <210> 85 <211> 60 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-60 <220> <221> MOD_RES <222> (60)..(60) <223> ACETYLATION <400> 85 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val 50 55 60 <210> 86 <211> 59 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-59 <220> <221> MOD_RES <222> (59)..(59) <223> AMIDATION <400> 86 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu 50 55 <210> 87 <211> 58 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-58 <220> <221> MOD_RES <222> (58)..(58) <223> AMIDATION <400> 87 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val 50 55 <210> 88 <211> 57 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-57 <220> <221> MOD_RES <222> (57)..(57) <223> AMIDATION <400> 88 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn 50 55 <210> 89 <211> 56 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-56 <220> <221> MOD_RES <222> (56)..(56) <223> AMIDATION <400> 89 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp 50 55 <210> 90 <211> 55 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-55 <220> <221> MOD_RES <222> (55)..(55) <223> AMIDATION <400> 90 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu 50 55 <210> 91 <211> 54 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-54 <220> <221> MOD_RES <222> (54)..(54) <223> AMIDATION <400> 91 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys 50 <210> 92 <211> 53 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-53 <220> <221> MOD_RES <222> (53)..(53) <223> AMIDATION <400> 92 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys 50 <210> 93 <211> 52 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-52 <220> <221> MOD_RES <222> (52)..(52) <223> AMIDATION <400> 93 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg 50 <210> 94 <211> 51 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-51 <220> <221> MOD_RES <222> (51)..(51) <223> AMIDATION <400> 94 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro 50 <210> 95 <211> 50 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-50 <220> <221> MOD_RES <222> (50)..(50) <223> AMIDATION <400> 95 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg 50 <210> 96 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-49 <220> <221> MOD_RES <222> (49)..(49) <223> AMIDATION <400> 96 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln <210> 97 <211> 48 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-48 <220> <221> MOD_RES <222> (48)..(48) <223> AMIDATION <400> 97 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 <210> 98 <211> 47 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-47 <220> <221> MOD_RES <222> (47)..(47) <223> AMIDATION <400> 98 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly 35 40 45 <210> 99 <211> 46 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-46 <220> <221> MOD_RES <222> (46)..(46) <223> AMIDATION <400> 99 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala 35 40 45 <210> 100 <211> 45 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-45 <220> <221> MOD_RES <222> (45)..(45) <223> AMIDATION <400> 100 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp 35 40 45 <210> 101 <211> 44 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-44 <220> <221> MOD_RES <222> (44)..(44) <223> AMIDATION <400> 101 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg 35 40 <210> 102 <211> 43 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-43 <220> <221> MOD_RES <222> (43)..(43) <223> AMIDATION <400> 102 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro 35 40 <210> 103 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-42 <220> <221> MOD_RES <222> (42)..(42) <223> AMIDATION <400> 103 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala 35 40 <210> 104 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-41 <220> <221> MOD_RES <222> (41)..(41) <223> AMIDATION <400> 104 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu 35 40 <210> 105 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-40 <220> <221> MOD_RES <222> (40)..(40) <223> AMIDATION <400> 105 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro 35 40 <210> 106 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-39 <220> <221> MOD_RES <222> (39)..(39) <223> AMIDATION <400> 106 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala 35 <210> 107 <211> 38 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-38 <220> <221> MOD_RES <222> (38)..(38) <223> AMIDATION <400> 107 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly 35 <210> 108 <211> 37 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-37 <220> <221> MOD_RES <222> (37)..(37) <223> AMIDATION <400> 108 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu 35 <210> 109 <211> 36 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-36 <220> <221> MOD_RES <222> (36)..(36) <223> AMIDATION <400> 109 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala 35 <210> 110 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-35 <220> <221> MOD_RES <222> (35)..(35) <223> AMIDATION <400> 110 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val 35 <210> 111 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-34 <220> <221> MOD_RES <222> (34)..(34) <223> AMIDATION <400> 111 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe <210> 112 <211> 33 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-33 <220> <221> MOD_RES <222> (33)..(33) <223> AMIDATION <400> 112 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn <210> 113 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-32 <220> <221> MOD_RES <222> (32)..(32) <223> AMIDATION <400> 113 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 <210> 114 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-31 <220> <221> MOD_RES <222> (31)..(31) <223> AMIDATION <400> 114 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val 20 25 30 <210> 115 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-30 <220> <221> MOD_RES <222> (30)..(30) <223> AMIDATION <400> 115 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp 20 25 30 <210> 116 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-29 <220> <221> MOD_RES <222> (29)..(29) <223> AMIDATION <400> 116 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln 20 25 <210> 117 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-28 <220> <221> MOD_RES <222> (28)..(28) <223> AMIDATION <400> 117 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu 20 25 <210> 118 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-27 <220> <221> MOD_RES <222> (27)..(27) <223> AMIDATION <400> 118 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys 20 25 <210> 119 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-26 <220> <221> MOD_RES <222> (26)..(26) <223> AMIDATION <400> 119 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys 20 25 <210> 120 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> amidated human PTH 1-25 <220> <221> MOD_RES <222> (25)..(25) <223> AMIDATION <400> 120 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg 20 25 <210> 121 <211> 141 <212> PRT <213> Homo sapiens <400> 121 Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln 1 5 10 15 Asp Leu Arg Arg Arg Phe Phe Leu His His Leu Ile Ala Glu Ile His 20 25 30 Thr Ala Glu Ile Arg Ala Thr Ser Glu Val Ser Pro Asn Ser Lys Pro 35 40 45 Ser Pro Asn Thr Lys Asn His Pro Val Arg Phe Gly Ser Asp Asp Glu 50 55 60 Gly Arg Tyr Leu Thr Gln Glu Thr Asn Lys Val Glu Thr Tyr Lys Glu 65 70 75 80 Gln Pro Leu Lys Thr Pro Gly Lys Lys Lys Lys Gly Lys Pro Gly Lys 85 90 95 Arg Lys Glu Gln Glu Lys Lys Lys Arg Arg Thr Arg Ser Ala Trp Leu 100 105 110 Asp Ser Gly Val Thr Gly Ser Gly Leu Glu Gly Asp His Leu Ser Asp 115 120 125 Thr Ser Thr Thr Ser Leu Glu Leu Asp Ser Arg Arg His 130 135 140 <210> 122 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> Artificial random coil <400> 122 Gly Gly Pro Gly Gly Pro Gly Pro Gly Gly Pro Gly Gly Pro Gly Pro 1 5 10 15 Gly Gly Pro Gly 20

Claims

1. A pharmaceutical composition comprising a controlled-release PTH compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof for use in methods of treating, managing, delaying, or preventing conditions that can be treated, managed, delayed, or prevented by PTH, wherein the controlled-release PTH compound is administered according to a dosing plan in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in increments of 25% or less.

2. The pharmaceutical composition according to claim 1, wherein the controlled-release PTH compound is administered according to a dosage plan in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in increments of 20% or less.

3. The pharmaceutical composition according to claim 1 or 2, wherein the controlled-release PTH compound is administered according to a dosage plan in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in increments of 15% or less.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the controlled-release PTH compound is administered according to a dosage plan in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in increments of 10% or less.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the controlled-release PTH compound is administered according to a dosing plan in which dose adjustments corresponding to hypocalcemia or hypercalcemia are made in 10% increments.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition containing the controlled-release PTH compound is administered to a patient at a frequency of once every 24 hours or less.

7. A pharmaceutical composition according to any one of claims 1 to 6, administered to a patient once every 24 hours.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition containing the PTH compound is administered to a patient by subcutaneous administration.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the release-controlled PTH compound comprises a PTH molecule or substructure having the sequence of SEQ ID NO:

51.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the release-controlled PTH compound is water-insoluble.

11. The pharmaceutical composition according to claim 10, wherein the water-insoluble release-controlled PTH compound is selected from the group consisting of crystals, nanoparticles, microparticles, nanospheres, and microspheres.

12. The pharmaceutical composition according to claim 10 or 11, wherein the water-insoluble release-controlled PTH compound comprises at least one PTH molecule or substructure incorporated non-covalently into poly(lactic acid-coglycolic acid) (PLGA).

13. The pharmaceutical composition according to any one of claims 1 to 9, wherein the release-controlled PTH compound is water-soluble.

14. The release-controlled PTH compound is a compound of formula (Ia) or (Ib). 【Chemistry 1】 (In the formula, -D is a PTH substructure, -L 1 - is a reversible prodrug linker substructure linked to the PTH substructure-D via the functional group of PTH, -L 2 - is a single chemical bond or spacer substructure. -Z is a water-soluble carrier substructure, 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.) A pharmaceutical composition according to any one of claims 1 to 9 or 13, or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the conditions that can be treated, managed, delayed, or prevented by 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, fractures, alopecia, chemotherapy-induced alopecia, and thrombocytopenia.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the condition that can be treated, managed, delayed, or prevented with PTH is hypoparathyroidism.

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