Dosage regimen for controlled-release PTH compound

Abstract

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

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition comprising at least one controlled release PTH compound or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment, management, delay or prevention of conditions that can be treated, managed, delayed or prevented with PTH, wherein the dosage of the controlled release PTH compound corresponds to 70% or less of the molar equivalent dosage necessary to maintain serum calcium within normal levels over said 24 hours in humans for PTH 1-84 administered once every 24 hours, and is administered at a frequency of no more than once every 24 hours, and to a method of treating, managing, delaying or preventing said condition.

Background Art

[0002] Hypoparathyroidism is a rare endocrine disorder of calcium and phosphate metabolism, and most often occurs as a result of parathyroid injury or removal during thyroid surgery. Hypoparathyroidism is rare among endocrine disorders and until recently has not been treated by replacement of the deficient hormone, parathyroid hormone, i.e., PTH. Conventional treatments for hypoparathyroidism include high doses of vitamin D and oral calcium supplementation, which are often effective but result in significant fluctuations in blood Ca 2+ levels, excessive urinary calcium excretion, nephrocalcinosis, and ectopic calcification including those of blood vessels, basal ganglia, and the lens of the eye.

[0003] Calcium is the most abundant inorganic substance 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. It is particularly important to maintain the calcium concentration as stable as possible. This is because various cell lines or organs, including the central nervous system, muscles, and external / endocrine glands, react strongly even to small fluctuations in Ca 2+ levels. PTH is the main regulator of calcium homeostasis.

[0004] Ca in serum 2+Inappropriately low PTH levels in relation to concentration are characteristic of hypoparathyroidism and lead to decreased renal tubular reabsorption of Ca 2+ and, concomitantly, increased renal tubular reabsorption of phosphate. Therefore, the main biochemical abnormalities in hypoparathyroidism are hypocalcemia and hyperphosphatemia. The clinical features of this disease include symptoms of hypocalcemia such as circumoral numbness, paresthesia, and carpal / pedal muscle spasms. Laryngeal spasm, tetany, and seizure attacks are severe, life-threatening complications. Hyperphosphatemia and increased calcium×phosphate product contribute to ectopic deposition of insoluble calcium phosphate complexes in soft tissues, including the vasculature, brain, kidneys, and other organs.

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

[0006] Some concerns arise regarding the long-term use of high doses of calcium and active vitamin D, particularly with respect to hypercalciuria, kidney stones, nephrocalcinosis, and ectopic soft tissue calcification. In addition, conventional therapies with calcium and active vitamin D do not relieve quality-of-life complaints and do not improve the bone remodeling abnormalities specific to this disease. In short, an improved therapy for hypoparathyroidism is highly needed.

[0007] In 2015, Natpara, PTH(1-84), was approved for once-daily subcutaneous injection as an adjunct to vitamin D and calcium in patients with hypoparathyroidism. Natpara, PTH(1-84), was approved for the management of hypocalcemia based on pivotal trials demonstrating that 42 percent of trial participants treated with PTH(1-84) achieved normal serum calcium levels with reduced doses of calcium supplements and active-form vitamin D, compared with 3 percent of trial participants treated with placebo. Following time-course monitoring of serum calcium after injection, 71 percent of patients treated with PTH(1-84) developed hypercalcemia in one or more measurements over 24 hours. PTH(1-84) reduced urinary calcium excretion 2 to 8 hours after injection, but urinary calcium excretion did not change after 24 hours. Similarly, urinary phosphate excretion increased only during the first 8 hours after PTH(1-84) injection.

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

[0009] Therefore, an improved PTH-based therapy for hypoparathyroidism is highly needed.

[0010] PTH(1-34), i.e., teriparatide, was approved by the FDA for the treatment of osteoporosis in 2002. Although PTH(1-34) has not been approved for this indication for the treatment of hypoparathyroidism, it has been used for a long time and patients have been administered injections twice or three times a day. Clinical studies have been conducted using PTH(1-34) administered by pump delivery compared to twice-daily injections to promote more physiological PTH levels. Over six months, pump delivery produced normal steady-state calcium levels with minimal variation and avoided the increase in serum and urinary calcium levels that appears immediately after PTH injection. A marked 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 the calcium-sparing effect of the kidney. 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 the twice-daily PTH(1-34) injection regimen.

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

[0012] Long-term daily administration of PTH is associated with progressive cortical bone loss due to increased bone metabolism. In a six-year follow-up study of patients treated with PTH(1-84) (Rubin, JCEM 2016), bone turnover markers maintained values greater than pre-treatment values, peaked in the first few years after the start of PTH(1-84), and then decreased, but remained significantly higher than baseline values until the sixth year. Bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) was consistent with the known site-specific effects of PTH, i.e., an increase in the lumbar spine and a decrease in the distal 1 / 3 of the radius. The decrease observed at the distal 1 / 3 site is consistent with the effect of intermittent PTH, which is known to increase cortical porosity and endosteal resorption.

Prior Art Documents

Non-Patent Documents

[0013]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0014] A method of intermittently administering PTH, which provides improved management of serum and urinary calcium and serum phosphorus compared to currently available PTH therapies and results in less increase in bone turnover markers, is an object of the present invention. Preferably, intermittent means daily, or more preferably, at weekly intervals.

[0015] In the preclinical development programs of both Forteo, PTH(1-34), and Natpara, PTH(1-84), a dose-dependent increase in osteosarcoma incidence was observed in rats treated with daily injections of the PTH compound. In the Natpara study, administration to high-dose rats was discontinued due to an excessive number of deaths mainly due to metastatic osteosarcoma in this group. This is thought to be due to the rat's sensitivity to the anabolic action of intermittent PTH. In contrast, it is known that continuous exposure to PTH has no significant bone 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 with lower doses administered to improve symptom control. Preferably, intermittent means daily, or more preferably or alternatively, at weekly intervals.

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

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

Means for Solving the Problems

[0018] This object is achieved by a pharmaceutical composition comprising at least one controlled-release PTH compound or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment, management, delay or prevention of a condition that can be treated, managed, delayed or prevented with PTH, wherein the dosage of the controlled-release PTH compound corresponds to 70% or less of the molar equivalent dosage necessary to maintain serum calcium within normal levels over said 24 hours in humans for PTH 1-84 administered once every 24 hours, and the pharmaceutical composition is administered at a frequency of once or less per 24 hours.

Mode for Carrying Out the Invention

[0019] Surprisingly, such controlled-release PTH compounds have higher potency than PTH 1-84, and thus require a lower molar equivalent to achieve a beneficial serum calcium level in a patient for at least 24 hours upon single administration, which has been found to improve efficacy and reduce the risk of side effects.

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

[0021] In the present invention, terms having the following meanings are used.

[0022] As used herein, the terms "a frequency of once or less per 24 hours" and "once or more per at least 24 hours" are used synonymously and mean that the time between two consecutive administrations is 24 hours or more, which means that, for example, there may be 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, or one week between two consecutive administrations.

[0023] As used herein, the terms "within normal levels" and "within normal range" with respect to serum calcium levels refer to calcium levels commonly found in a given species, sex, and age of subject, provided as a range given by a normal lower limit and a normal upper limit. In the case of humans, normal levels preferably correspond to a serum calcium level (corrected for albumin) that is higher than 8.5 mg / dL. In the case of humans, the normal upper limit is less than 10.5 mg / dL.

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

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

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

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

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

[0029] As used herein, the terms "release half-life" and "half-life" refer to the time required for half of all the PTH or PTH substructures contained in a 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).

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

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

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

[0033] As used herein, the term "PTH polypeptide variant" refers to a polypeptide from the same species that is different from a reference PTH or PTHrP polypeptide. Preferably, such a reference is a PTH polypeptide sequence and has the sequence of SEQ ID NO: 51. Generally, the differences are limited, and thus the amino acid sequences of the reference and the variant are generally similar throughout and identical in many regions. Preferably, a PTH polypeptide variant is at least 70%, 80%, 90% or 95% identical to a reference PTH or PTHrP polypeptide, preferably the PTH polypeptide of SEQ ID NO: 51. A polypeptide having an amino acid sequence that is at least, for example, 95% "identical" to a query amino acid sequence means that the amino acid sequence of the subject polypeptide is identical to the query sequence, except that it may contain up to 5 amino acid changes per 100 amino acids of the query amino acid sequence. These changes in the reference sequence may be present at the amino-terminal (N-terminal) or carboxy-terminal (C-terminal) positions of the reference amino acid sequence, or may be scattered individually among the residues within the reference sequence, or among one or more adjacent groups within the reference sequence, and may be present at any position between these terminal positions. The query sequence may be the entire amino acid sequence of the reference sequence or any fragment specified as described herein. Preferably, the query sequence is the sequence of SEQ ID NO: 51.

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

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

[0036] Those skilled in the art also recognize that the amino acid sequence of a part of the PTH or PTHrP polypeptide can be changed 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 hereby incorporated by reference in its entirety, and the authors of this reference show that there are two main approaches for studying the tolerance of amino acid sequences to change.

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

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

[0039] As used herein, the term "PTH homolog" refers to PTH or PTHrP in different organisms that perform the same function and originate from an ancestral structure that their organisms' ancestors had in common. In other words, homologous PTH polypeptides are polypeptides having substantially the same amino acid sequences that perform the same biological activity, i.e., increase serum calcium and renal phosphorus excretion and decrease serum phosphorus and renal calcium excretion. Preferably, a PTH polypeptide homolog can be defined as a polypeptide having at least 40%, 50%, 60%, 70%, 80%, 90% or 95% identity to a reference PTH or PTHrP polypeptide, preferably the PTH polypeptide of SEQ ID NO: 51.

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

[0041] As used herein, the term "PTH polypeptide fragment" refers to any polypeptide that includes 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.

[0042] More specifically, a PTH polypeptide fragment includes at least 6, such as at least 8, at least 10, or at least 17 contiguous amino acids of a PTH or PTHrP polypeptide, more preferably the polypeptide of SEQ ID NO: 51. Further, a PTH polypeptide fragment may be described as a subclass of PTH or PTHrP polypeptides that include at least 6 amino acids, where "at least 6" in this case is defined as any integer between 6 and the integer representing the C-terminal amino acid of the PTH or PTHrP polypeptide, preferably SEQ ID NO: 51. Also included are species of PTH or PTHrP polypeptide fragments of at least 6 amino acids in length as described above, further specified with respect to N-terminal and C-terminal positions. All PTH or PTHrP polypeptide fragments of at least 6 amino acids in length as described above, which may be specifically specified by N-terminal and C-terminal positions, are also included within the term "PTH polypeptide fragment" as individual species. That is, all combinations of N-terminal and C-terminal positions that a fragment of at least 6 amino acids in length, contiguous on any given amino acid sequence of a PTH or PTHrP polypeptide, preferably the PTH polypeptide of SEQ ID NO: 51, can occupy are included in the present invention.

[0043] The term "PTH" includes poly(amino acid) conjugates having the above-described sequences and having a backbone that includes both amide and non-amide linkages, such as ester linkages, for example, like depsipeptides. A depsipeptide is a chain of amino acid residues in which the backbone includes both amide (peptide) and ester linkages. Thus, as used herein, the term "side chain" refers to the substructure attached to the alpha-carbon of an amino acid substructure when the amino acid substructures are linked by amine linkages, for example, in the case of polypeptides, or to any carbon atom-containing substructure attached to the backbone of a poly(amino acid) conjugate, such as in the case of a depsipeptide. Preferably, the term "PTH" refers to polypeptides having a backbone formed by amide (peptide) linkages.

[0044] Since the term PTH includes the above variants, analogs, orthologs, homologs, derivatives and fragments of PTH or PTHrP, all references to specific positions within the reference sequence include, even if not specifically stated, equivalent positions within variants, analogs, orthologs, homologs, derivatives and fragments of the PTH or PTHrP substructure.

[0045] As used herein, the term "micelle" means an aggregate of amphiphilic molecules dispersed in a liquid colloid. In an aqueous solution, a typical micelle forms an aggregate, also called a "normal-phase micelle", in which the hydrophilic substructure of the surfactant molecules faces the surrounding solvent and the hydrophobic substructure of the surfactant faces inward. An "inverse micelle" has a hydrophilic substructure facing inward and a hydrophobic substructure facing the surrounding solvent.

[0046] As used herein, the term "liposome" refers to vesicles having at least one lipid bilayer, preferably spherical vesicles. Preferably, liposomes contain phospholipids, more preferably phosphatidylcholine. The term "liposome" refers to various structures and sizes, for example, multilamellar liposome vesicles (MLV) having more than one concentric lipid bilayer and an average diameter of 100-1000 nm, small unilamellar liposome vesicles (SUV) having one lipid bilayer and an average diameter of 25-100 nm, large unilamellar liposome vesicles (LUV) having one lipid bilayer and an average diameter of about 1000 μm, and giant unilamellar vesicles (GUV) having one lipid bilayer and an average diameter of 1-100 μm. The term "liposome" also includes elastic vesicles such as transferosomes and ethosomes.

[0047] As used herein, the term "aquasome" refers to spherical nanoparticles having a diameter of 60-300 nm, comprising at least three layers of self-assembled structures, i.e., a solid-phase nanocrystal core covered with an oligomeric film to which drug molecules, modified or unmodified drugs, are adsorbed.

[0048] As used herein, the term "ethosome" refers to lipid vesicles containing phospholipids, as well as relatively high concentrations of ethanol and / or isopropanol, and water, and having a size in the range of tens of nanometers to micrometers.

[0049] As used herein, the term "LeciPlex" refers to a positively charged phospholipid-based vesicle system containing 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.

[0050] As used herein, the term "niosomes" refers to unilamellar or multilamellar vesicles containing nonionic surfactants.

[0051] As used herein, the term "pharmacosome" refers to ultrafine vesicles, micelles or hexagonal aggregates derived from lipids covalently bound to a bioactive moiety.

[0052] As used herein, the term "proniosome" refers to a dry preparation of a surfactant-coated carrier that forms niosomes when rehydrated and gently agitated.

[0053] As used herein, the term "polymersome" refers to an artificial spherical vesicle containing a membrane formed from an amphiphilic synthetic block copolymer, which may optionally contain an aqueous solution in its core. Polymersomes have a wide range of diameters from 50 nm to 5 μm and larger. This term also includes syntosomes, which are polymersomes designed to contain channels that allow a particular chemical substance to enter or exit the vesicle through the membrane.

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

[0055] As used herein, the term "transferosome" refers to an ultra-flexible lipid vesicle containing an aqueous core, which is formed from a mixture of suitable terminally activated lipids having a common polarity. Having a common polarity promotes the formation of a highly curved bilayer, and this curved bilayer makes the transferosome highly deformable.

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

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

[0058] As used herein, the term "protein" refers to a peptide containing more than 50 amino acid residues. Preferably, the protein contains up to 20,000 amino acid residues, such as up to 15,000 amino acid residues, such as up to 10,000 amino acid residues, such as up to 5,000 amino acid residues, such as up to 4,000 amino acid residues, such as up to 3,000 amino acid residues, such as up to 2,000 amino acid residues, such as up to 1,000 amino acid residues.

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

[0060] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more active ingredients, such as at least one controlled-release PTH compound, etc., and one or more excipients, and any product directly or indirectly obtained from the combination, complexation or aggregation of any two or more of the 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. Thus, the pharmaceutical compositions for use in the present invention include any composition produced by mixing one or more controlled-release PTH compounds with a pharmaceutically acceptable excipient.

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

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

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

[0064] As used herein, the term "drug" refers to a substance used in the treatment, cure, prevention or diagnosis of a disease, or used to otherwise improve physical or mental well-being, such as PTH. When a drug is conjugated with another substructure, the substructure of the resulting product that is derived from that drug is referred to as the "bioactive substructure".

[0065] 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 with the bioactive substructure. The reversible linker substructure is also referred to as the "reversible prodrug linker substructure", and the special protecting group changes or removes an undesirable property of the parent molecule. This also includes enhancing the desirable properties of the drug and suppressing the undesirable properties. The special non-toxic protecting group is referred to as a "carrier". The prodrug releases the bioactive substructure that is reversibly covalently bound in the form of its corresponding drug. In other words, the prodrug is a conjugate that includes a bioactive substructure reversibly covalently conjugated to a carrier substructure via a reversible prodrug linker substructure, and the reversible covalent bond of the carrier to the reversible linker substructure is either direct or via a spacer. Such a conjugate releases the bioactive substructure that was previously conjugated in the form of a free unmodified drug.

[0066] "Biodegradable bond" or "reversible bond" is a bond that can be decomposed, i.e., cleaved, by hydrolysis in the absence of enzymes under physiological conditions (aqueous buffer at pH 7.4, 37 °C), with a half-life in the range of 1 hour to 3 months, preferably 1 hour to 2 months, 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 having a half-life longer than 3 months under physiological conditions (aqueous buffer at pH 7.4, 37 °C).

[0067] As used herein, the term "trace-free prodrug linker" means a reversible prodrug linker that releases the drug in its free form upon cleavage, i.e., a linker substructure that reversibly covalently links a bioactive moiety to a carrier. The term "drug in free form" as used herein means the drug in its unmodified pharmacologically active form.

[0068] As used herein, the term "excipient" refers to something useful for treatment, such as a diluent, adjuvant or vehicle used for administering a drug or prodrug. Such pharmaceutical excipients can be sterile liquids, such as water and oils (including but not limited to peanut oil, soybean oil, mineral oil, sesame oil, etc., including those derived from petroleum, animal, plant or synthetic sources). Water is a preferred excipient when the pharmaceutical composition is administered orally. When the pharmaceutical composition is administered intravenously, saline and aqueous dextrose solutions are preferred excipients. Saline solutions, as well as aqueous solutions of dextrose and glycerol, 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, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerol, propylene, glycol, water, ethanol, etc. The pharmaceutical composition may optionally also contain a small amount of wetting or emulsifying agent, pH buffer, such as acetate, succinate, tris, carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), etc., or a surfactant, such as Tween, poloxamer, poloxamine, CHAPS, Igepal, or an amino acid, such as glycine, lysine or histidine, etc. These pharmaceutical compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. The pharmaceutical composition may also be formulated as a suppository using conventional binders and excipients, such as triglycerides. Oral formulations can include standard excipients, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such compositions will contain a therapeutically effective amount of a drug or bioactive moiety together with a suitable amount of excipient to produce a dosage form suitable for proper administration to a patient. The formulation should be suitable for the method of administration.

[0069] As used herein, the term "reagent" means a compound that contains at least one functional group for reaction with a functional group of another compound or drug. It is understood that drugs containing functional groups (e.g., primary or secondary amines or hydroxyl functional groups) are also reagents.

[0070] As used herein, the term "substructure" means a part of a molecule that has one or more atoms less compared to the corresponding reagent. For example, when a reagent of the formula "H-X-H" reacts with another reagent and becomes part of the reaction product, the corresponding substructure of the reaction product has the structure "H-X-" or "-X-", where each "-" represents a bond to another substructure. Thus, a bioactive substructure is released from a prodrug as a drug.

[0071] When an atomic group is provided with an arrangement or chemical structure of an atomic group that is bonded to two substructures or inserted into one substructure, unless otherwise clearly described, it is understood that the said arrangement or chemical structure may be bonded to the two substructures in any orientation. For example, the substructure "-C(O)N(R 1 )-" may be bonded to two substructures as "-C(O)N(R 1 )-" or as "-N(R 1 )C(O)-", or may be inserted into one substructure. Similarly, the substructure

Chem.

Chem.

[0072] As used herein, the term "functional group" means an atomic group that can react with other atomic groups. Functional groups include, but are not limited to, the following groups: carboxylic acid (-(C=O)OH), primary or secondary amine (-NH 2, -NH-), maleimide, thiol (-SH), sulfonic acid (-(O=S=O)OH), carbonate, carbamate (-O(C=O)N<), hydroxyl (-OH), aldehyde (-(C=O)H), ketone (-(C=O)-), hydrazine (>N-N<), isocyanate, isothiocyanate, phosphoric acid (-O(P=O)OHOH), phosphonic acid (-O(P=O)OHH), haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, disulfide, sulfonamide, sulfonic acid, vinyl sulfone, vinyl ketone, diazoalkane, oxirane and aziridine.

[0073] If the controlled release PTH compounds for use in the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, particularly their pharmaceutically available salts. Thus, a controlled release PTH compound for use in the present invention containing an acidic group can be used according to the present invention, for example, as an alkali metal salt, an alkaline earth metal salt or an ammonium salt. More detailed examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine, etc.) or amino acids. There may also be present a controlled release PTH compound for use in the present invention containing one or more basic groups, i.e., groups that can be protonated, and such prodrugs can be used according to 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 appropriate counterions for positively charged ammonium groups and their salts, are known to those skilled in the art. If the controlled release PTH compounds for use in the present invention contain both acidic and basic groups simultaneously, the present invention also includes inner salts or betaines (zwitterions) in addition to the salt forms mentioned. Each salt can be obtained, for example, by conventional methods known to those skilled in the art, such as by contacting these compounds with an organic or inorganic acid or base 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 for use in the present invention that, due to 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.

[0074] The term "pharmaceutically acceptable" means a substance that does not cause harm when administered to a patient, and preferably means that it has been approved for use in animals, preferably for use in humans, by a regulatory agency, such as EMA (Europe) and / or FDA (USA) and / or any other national regulatory agency.

[0075] The term "about", as used in combination with a numerical value herein, is used to indicate a range that includes the numerical value itself plus / minus up to 10% of the numerical value, more preferably up to 8% of the numerical value, even more preferably up to 5% of the numerical value, and most preferably up to 2% of the numerical value. For example, the phrase "about 200" means a range of 200+ / -10%, i.e., a range of 180 to 220, preferably a range of 200+ / -8%, i.e., a range of 184 to 216, even more preferably a range of 200+ / -5%, i.e., a range of 190 to 210, and most preferably a range of 200+ / -2%, i.e., a range of 196 to 204. It is understood that the percentage indicated as "about 20%" does not mean a range of "20%+ / -10%", i.e., 10 to 30%, but rather "about 20%" means a range of 18 to 22%, i.e., plus / minus 10% of the numerical value of 20.

[0076] 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 fashion or a combination 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, no meaningful molecular weight range can be provided. Proteins are also understood to be polymers in which the amino acids are the repeating structural units, even if the side chains of each amino acid may be different.

[0077] 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 heterobicyclic, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and · bonds selected from the group comprising:

Chemical formula

[0078] Those skilled in the art will understand that the polymerization products obtained from the polymerization reaction do not all have the same molecular weight, but rather exhibit a molecular weight distribution. Therefore, the molecular weight ranges, molecular weights, monomer number ranges in the polymer, and monomer numbers in the polymer used herein refer to the number average molecular weight and the average number of monomers, that is, the arithmetic mean of the molecular weights of the polymer or the polymer partial structure, and the arithmetic mean of the number of monomers in the polymer or the polymer partial structure.

[0079] Therefore, in the case of a polymer partial structure containing "x" monomer units, any integer applied to "x" corresponds to the arithmetic mean of the monomers. Any range of integers applied to "x" provides an integer range in which the arithmetic mean of the monomers exists. The integer "x" indicated as "about x" means that the arithmetic mean of the monomers exists within an integer range of x + / - 10%, preferably x + / - 8%, more preferably x + / - 5%, and most preferably x + / - 2%.

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

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

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

[0083] As used herein, the term "hydrogel" means a hydrophilic or amphiphilic polymer network composed of a homopolymer or copolymer that is insoluble due to the presence of covalent chemical bonds. The cross-linking agent provides the network structure and physical integrity.

[0084] As used herein, the term "thermogelation" means a compound that is a liquid or low-viscosity solution having a viscosity of less than 500 cps at 25 °C at a shear rate of about 0.1 / sec at a low temperature in the range of about 0 °C to about 10 °C, but is a compound having a higher viscosity of less than 10,000 cps at 25 °C at a shear rate of about 0.1 / sec at a higher temperature in the range of about 30 °C to about 40 °C, for example about 37 °C.

[0085] As used herein, the term "PEG-based" with respect to a partial structure or reagent means that the partial structure or reagent contains PEG. Preferably, the PEG-based partial structure or reagent contains at least 10% (w / w) PEG, such as at least 20% (w / w) PEG, such as at least 30% (w / w) PEG, such as at least 40% (w / w) PEG, such as at least 50% (w / w), such as at least 60 (w / w) PEG, such as at least 70% (w / w) PEG, such as at least 80% (w / w) PEG, such as at least 90% (w / w) PEG, such as at least 95%. The remaining weight percentage of the PEG-based partial structure or reagent is preferably another partial structure selected from the following partial structures and bonds: ·C 1-50 alkyl, C 2-50 alkenyl, C 2-50 alkynyl, C 3-10Cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and ·A bond selected from the group consisting of: [Chemical formula] (wherein, The dashed line indicates a bond to the remainder of the partial structure or reagent, -R and -R a are each independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl).

[0086] The term "PEG-based containing at least X% PEG" as used herein with respect to a partial structure or reagent means that the partial structure or reagent contains at least X% (w / w) ethylene glycol units (-CH 2 CH 2 O-), and the ethylene glycol units may be arranged in an alternating block pattern or may be randomly distributed within the partial structure or reagent. Preferably, all of the ethylene glycol units of the partial structure or reagent are present within one block, and the remaining weight percentage of the PEG-based partial structure or reagent is preferably another partial structure selected from the following partial structures and bonds: ·C 1-50 alkyl, C 2-50 alkenyl, C 2-50 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and ·A bond selected from the group consisting of: [Chemical formula] (wherein, The dashed line indicates a bond to the remainder of the partial structure or reagent, -R and -R aare, independently of each other, selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl).

[0087] The term "hyaluronic acid-based containing at least X% hyaluronic acid" is used as appropriate.

[0088] As used herein, the term "substituted" means that one or more -H atoms of a molecule or substructure are replaced by another atom or atomic group, and said another atom or atomic group is referred to as a "substituent".

[0089] Preferably, one or more further optional substituents are, independently of each other, halogen, -CN, -COOR x1 , -OR x1 , -C(O)R x1 , -C(O)N(R x1 R x1a ), -S(O) 2 N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O) 2 R x1 , -S(O)R x1 , -N(R x1 ), S(O) 2 N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO 2 , -OC(O)R x1 , -N(R x1 ), C(O)R x1a , -N(R x1 ), S(O) 2 R x1a , -N(R x1 ), S(O)R x1a , -N(R x1 ), C(O)OR x1a , -N(R x1 ), C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl selected from the group consisting of, where -T 0 , C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl are optionally substituted with one or more -R x2 , and C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl may optionally have inserted therein one or more groups selected from the group consisting of -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 ), -, -S(O) 2 N(R x3 ), -, -S(O)N(R x3 ), -, -S(O) 2 -, -S(O)-, -N(R x3 ), S(O) 2 N(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 ), and -R x1 , -R x1a , -R x1b are each independently selected from the group consisting of -H, -T 0 , C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl, and 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 said C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl may optionally have inserted therein -T 0-, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-, -S(O) 2 N(R x3 )-, -S(O)N(R x3 )-; -S(O) 2 -, -S(O)-, -N(R x3 )S(O) 2 N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-, -N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )- may optionally be interrupted by one or more groups selected from the group consisting of, Each T 0 is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic, and each T 0 is independently optionally substituted with one or more of the same or different -R x2 s, Each R x2 is independently halogen, -CN, oxo (=O), -COOR x4 , -OR x4 , -C(O)R x4 , -C(O)N(R x4 R x4a ), -S(O) 2 N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O) 2 R x4 ), -S(O)R x4 , -N(R x4 )S(O) 2 N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO 2 , -OC(O)R x4 , -N(R x4)C(O)R x4a 、 -N(R x4 )S(O) 2 R 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, wherein said C 1-6 alkyl is optionally substituted with one or more of the same or different halogens, each -R x3 、 -R x3a 、 -R x4 、 -R x4a 、 -R x4b is independently selected from the group consisting of -H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more of the same or different halogens.

[0090] More preferably, one or more additional optional substituents are, independently of each other, halogen, -CN, -COOR x1 、 -OR x1 、 -C(O)R x1 、 -C(O)N(R x1 R x1a )、 -S(O) 2 N(R x1 R x1a )、 -S(O)N(R x1 R x1a )、 -S(O) 2 R x1 、 -S(O)R x1 、 -N(R x1 )S(O) 2 N(R x1a R x1b )、 -SR x1 、 -N(R x1 R x1a )、 -NO 2 、 -OC(O)R x1 、 -N(R x1 )C(O)Rx1a ,-N(R x1 )S(O) 2 R x1a ,-N(R x1 )S(O)R x1a ,-N(R x1 )C(O)OR x1a ,-N(R x1 )C(O)N(R x1a R x1b ),-OC(O)N(R x1 R x1a ),-T 0 ,C 1-10 alkyl,C 2-10 alkenyl,and C 2-10 alkynyl selected from the group consisting of, where -T 0 ,C 1-10 alkyl,C 2-10 alkenyl and C 2-10 alkynyl may be optionally substituted with one or more -R x2 s, and C 1-10 alkyl,C 2-10 alkenyl and C 2-10 alkynyl may contain -T 0 -,-C(O)O-,-O-,-C(O)-,-C(O)N(R x3 )-,-S(O) 2 N(R x3 )-,-S(O)N(R x3 )-,-S(O) 2 -,-S(O)-,-N(R x3 )S(O) 2 N(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 )- selected from the group consisting of one or more groups inserted, each -R x1 ,-R x1a ,-R x1b ,-R x3 ,-R x3a is independently -H, halogen, C 1-6 alkyl,C2-6 Alkenyl and C 2-6 alkynyl, Each T 0 are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; 0 may independently be one or more of the same or different -R x2 and optionally substituted with Each R x2 are independently halogen, -CN, oxo (=O), -COOR x4 , -OR x4 , -C(O)R x4 , -C(O)N(R x4 R x4a ), -S(O) 2 N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O) 2 R x4 , -S(O)R x4 , -N(R x4 )S(O) 2 N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO 2 , -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O) 2 R x4a , -N(R x4 )S(O)R x4a , -N(R x4 )C(O)OR x4a , -N(R x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ), and C 1-6 alkyl, 1-6The alkyl is optionally substituted with one or more identical or different halogens, each -R x4 , -R x4a , -R x4b is independently selected from the group consisting of -H, halogen, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl.

[0091] More preferably, one or more additional optional substituents are, independently of one another, halogen, -CN, -COOR x1 , -OR x1 , -C(O)R x1 , -C(O)N(R x1 R x1a ), -S(O) 2 N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O) 2 R x1 , -S(O)R x1 , -N(R x1 ), -N(R 2 )S(O) x1a N(R x1b ), -SR x1 , -N(R x1 R x1a ), -NO 2 , -OC(O)R x1 , -N(R x1 ), -N(R x1a ), -N(R x1 ), -N(R 2 R x1a , -N(R x1 ), -N(R x1a ), -N(R x1 ), -N(R x1a ), -N(R x1 ), -N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 , C 1-6 alkyl, C 2-6 alkenyl, and C 2-6Selected from the group consisting of alkynyl, where -T 0 , C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl is optionally substituted with one or more -R x2 , and said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl contains one or more groups selected from the group consisting of -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-, -S(O) 2 N(R x3 )-, -S(O)N(R x3 )-, -S(O) 2 -, -S(O)-, -N(R x3 )S(O) 2 N(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 )- inserted, each -R x1 , -R x1a , -R x1b , -R x2 , -R x3 , -R x3a is independently selected from the group consisting of -H, halogen, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each T 0 is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic, and each said T 0 is optionally substituted with one or more -R x2 .

[0092] 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 replaced by a substituent.

[0093] The term "interrupted" means that the 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.

[0094] The term "C 1-4 alkyl" as used herein alone or in combination means a straight or branched alkyl substructure having 1 to 4 carbon atoms. When present at the end of a molecule, the straight or branched C 1-4 alkyl examples are methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, sec - butyl and tert - butyl. When two substructures of a molecule are joined by C 1-4 alkyl, examples of such C 1-4 alkyl groups are -CH 2 -, -CH 2 -CH 2 -,-CH(CH 3 )-,-CH 2 -CH 2 -CH 2 -,-CH(C 2 H 5 )-,-C(CH 3 ) 2 -. Each hydrogen of the C 1-4 alkyl carbon may optionally be replaced by a substituent as defined above. Optionally, one or more substructures as defined below may interrupt the C 1-4 alkyl.

[0095] The term "C 1-6 alkyl", used alone or in combination herein, means a straight-chain or branched alkyl substructure having 1 to 6 carbon atoms. When present at the end of a molecule, straight-chain and branched C 1-6 alkyl groups examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl. When two substructures of a molecule are joined by a C 1-6 alkyl group, examples of such C 1-6 alkyl groups are -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(C 2 H 5 )- and -C(CH 3 ) 2 -. Each hydrogen atom of C 1-6 carbon may optionally be replaced by a substituent as defined above. Optionally, one or more substructures as defined below may interrupt the C 1-6 alkyl.

[0096] Thus, "C 1-10 alkyl", "C 1-20 alkyl" or "C 1-50 alkyl" each mean an alkyl chain having 1 to 10, 1 to 20, or 1 to 50 carbon atoms, and each hydrogen atom of C 1-10 -, C 1-20 - or C 1-50 -carbon may optionally be replaced by a substituent as defined above. Optionally, one or more substructures as defined below may interrupt C 1-10 - or C 1-50 alkyl.

[0097] The term "C 2-6 alkenyl", used alone or in combination herein, means a straight-chain or branched hydrocarbon substructure having from 2 to 6 carbon atoms and containing at least one carbon-carbon double bond. When present at the end of a molecule, examples are -CH=CH 2 , -CH=CH-CH 3 , -CH 2 -CH=CH 2 , -CH=CHCH 2 -CH 3 and -CH=CH-CH=CH 2 . When two substructures of a molecule are joined by C 2-6 alkenyl, an example of such C 2-6 alkenyl is -CH=CH-. Each hydrogen atom of the C 2-6 alkenyl substructure may optionally be replaced by a substituent as defined above. Optionally, one or more substructures as defined below may be inserted into the C 2-6 alkenyl.

[0098] Thus, the term "C 2-10 alkenyl", "C 2-20 alkenyl" or "C 2-50 alkenyl", used alone or in combination, means a straight-chain or branched hydrocarbon substructure having from 2 to 10, from 2 to 20, or from 2 to 50 carbon atoms and containing at least one carbon-carbon double bond. Each hydrogen atom of the C 2-10 alkenyl, C 2-20 alkenyl or C 2-50 alkenyl group may optionally be replaced by a substituent as defined above. Optionally, one or more substructures as defined below may be inserted into the C 2-10 alkenyl, C 2-20 alkenyl or C 2-50 alkenyl.

[0099] The term "C 2-6"Alkynyl" means a straight-chain 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 are -C≡CH, -CH 2 -C≡CH, CH 2 -CH 2 -C≡CH and CH 2 -C≡C-CH 3 and so on. When two substructures of a molecule are joined by an alkynyl group, an example is -C≡C-. 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, one or more substructures as defined below may interrupt the C 2-6 alkynyl. 2-6

[0100] Accordingly, the term "C 2-10 alkynyl", "C 2-20 alkynyl" or "C 2-50 alkynyl" as used herein alone or in combination each means a straight-chain or branched hydrocarbon substructure having 2 to 10, 2 to 20, or 2 to 50 carbon atoms and containing at least one carbon-carbon triple bond. Each hydrogen atom of the C 2-10 alkynyl, C 2-20 alkynyl or C 2-50 alkynyl group may optionally be replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, one or more substructures as defined below may interrupt the C 2-10 alkynyl, C 2-20 alkynyl or C 2-50 alkynyl.

[0101] As described above, C 1-4 alkyl, C 1-6 alkyl, C 1-10 alkyl, C 1-20 alkyl, C 1-50 alkyl, C 2-6 alkenyl, C 2-10 alkenyl, C 2-20 ​Alkenyl, C 2-50 Alkenyl, C 2-6 Alkynyl, C 2-10 Alkynyl, C 2-20 Alkenyl or C 2-50 One or more substructures may optionally be interposed in the alkenyl or alkynyl, and the one or more substructures are preferably [Chemical formula] (wherein The dashed line indicates a bond to the remainder of the substructure or reagent, -R and -R a are each independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl) selected from the group consisting of

[0102] As used herein, the term "C 3-10 cycloalkyl" means a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl. Each hydrogen atom of the C 3-10 cycloalkyl carbon may be replaced by a substituent as defined above. The term "C 3-10 cycloalkyl" also includes bridged bicyclics such as norbornane or norbornene.

[0103] The term "8- to 30-membered carbopolycyclic" or "8- to 30-membered carbopolycycle" means a cyclic substructure having 8 to 30 ring atoms, in which two adjacent rings share at least one ring atom, and which can contain a maximum number of double bonds (fully saturated, partially saturated or unsaturated, aromatic or non-aromatic rings). Preferably, 8- to 30-membered carbopolycyclic means a cyclic substructure of 2, 3, 4 or 5 rings, more preferably 2, 3 or 4 rings.

[0104] As used herein, the term "3- to 10-membered heterocyclyl" or "3- to 10-membered heterocyclic ring" has 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, with at least 1 and up to a maximum of 4 ring atoms being replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O) 2 -), oxygen, and nitrogen (including =N(O)-), and may contain a maximum number of double bonds (a fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic ring), and means a ring attached to the remainder of the molecule by a carbon or nitrogen atom. Examples of 3- to 10-membered heterocyclic rings include, but are not limited to, aziridine, oxirane, thiirane, azirine, oxirene, thiirene, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine, and homopiperazine. Each hydrogen atom of a 3- to 10-membered heterocyclyl or 3- to 10-membered heterocyclic group may optionally be replaced by a substituent as defined below.

[0105] As used herein, the term "8- to 11-membered heterobicyclic" or "8- to 11-membered heterocyclic ring" refers to a bicyclic heterocyclic substructure having 8 to 11 ring atoms and capable of containing up to the maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings), wherein at least one ring atom is shared by both rings, and at least one ring atom, up to a maximum of 6 ring atoms, is replaced by a heteroatom selected from the group consisting of sulfur (-S(O)-, -S(O) 2 -), oxygen, and nitrogen (=N(O)-), and the ring is attached to the remainder of the molecule by a carbon or nitrogen atom. Examples of 8- to 11-membered heterocyclic rings include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, and pteridine. The term 8- to 11-membered heterocyclic ring also includes bicyclic spiro structures such as 1,4-dioxa-8-azaspiro[4.5]decane, or bridged heterocycles such as 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom of an 8- to 11-membered heterobicyclic or 8- to 11-membered heterocyclic ring carbon may optionally be replaced by a substituent as defined below.

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

[0107] Structure:

Chem.

Chem.

[0108] Structure:

Chem.

Chem.

[0109] As used herein, "halogen" means fluoro, chloro, bromo or iodo. Halogen is generally preferably fluoro or chloro.

[0110] Generally, the term "comprising" or "comprises" also encompasses "consisting of" or "consists of".

[0111] It is understood that experiments in humans are subject to strict rules. Therefore, in order to determine the dosage of PTH 1-84 necessary to maintain serum calcium within normal levels in hypocalcemic subjects without doing so, a more readily available test system in the form of an animal model may be required, where the normal levels preferably refer to a serum albumin-corrected calcium level higher than 8.5 mg / dL and less than 10.5 mg / dL, with 9.5 mg / dL being the optimal level in humans, and the serum albumin-corrected calcium level corresponds to a range of 2.125 - 2.625 nmol / L, with 2.375 nmol / L being optimal. One such animal model is the thyroparathyroidectomized (TPTX) rat. Rats that have undergone thyroparathyroidectomy are unable to produce parathyroid hormone, PTH, which is a major regulator of calcium homeostasis, and as a result, they develop hypocalcemia.

[0112] However, it is also understood that serum calcium levels can vary between species, for example, between humans and rats, and it is necessary to correct the values to account for these interspecies differences in order to achieve equivalent results. Therefore, when using such an animal model, it is necessary to first determine the normal serum calcium level for that species for a given sex and age. For example, Watchorn (Biochem J. 1933; 27(6): 1875-1878) provides the normal range of serum calcium (uncorrected) for male rats as 10.29 - 13.16 mg / dL and for female rats as 9.61 - 14.04 mg / dL. Preferably, the normal serum calcium range is determined as a serum calcium concentration higher than the lower limit of the normal range, for example, higher than 9.6 mg / dL (uncorrected), more preferably for female rats, and even more preferably for female rats aged 13 - 22 weeks. Preferably, the normal serum calcium range is determined as a serum calcium concentration lower than the upper limit of the normal range, for example, less than 14 mg / dL (uncorrected), more preferably for female rats, and even more preferably for female rats aged 13 - 22 weeks.

[0113] Thus, when performing thyroidectomy on female rats to obtain TPTX rats, the normal range targeted for treatment would be higher than 9.6 mg / dL (uncorrected), preferably less than 14 mg / dL (uncorrected) for such animals at 13 - 22 weeks of age.

[0114] Preferably, the pharmaceutical composition of the present invention is for use in the treatment of conditions that can be treated by PTH.

[0115] The pharmaceutical composition for use of the present invention is administered at a frequency of once or less per 24 hours, for example, once every 24 hours, once every 48 hours, once every 72 hours, once every 96 hours, once every 120 hours, once every 144 hours, once a week, once every two weeks. Preferably, the administration of the pharmaceutical composition of the present invention is carried out in units that are multiples of 24 hours, that is, N times in 24 hours, where N is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.

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

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

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

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

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

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

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

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

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

[0125] It is understood that the method of administration of the controlled-release PTH compound is the same as the method of administration of PTH 1-84, that is, when PTH 1-84 is administered by subcutaneous injection, the controlled-release PTH compound is also administered by subcutaneous injection. When PTH 1-84 is administered by intramuscular injection, the controlled-release PTH compound is also administered by intramuscular injection.

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

[0127] In the present invention, the pharmaceutical composition for use of the present invention is administered at a dosage of a controlled release PTH compound corresponding to 70% or less of the molar equivalent dosage of PTH 1-84 required to maintain serum calcium within the normal range, preferably above 8.5 mg / dL, in humans over 24 hours, at the following frequency every 24 hours. Preferably, the pharmaceutical composition for use of the present invention is at a dosage of a controlled release PTH compound corresponding to 65% or less of the molar equivalent dosage of PTH 1-84 required to maintain serum calcium within the normal range, preferably above 8.5 mg / dL, in humans over 24 hours, more preferably at a dosage of a controlled release PTH compound corresponding to 60% or less, even more preferably at a dosage of a controlled release PTH compound corresponding to 55% or less, even more preferably at a dosage of a controlled release PTH compound corresponding to 50% or less, even more preferably at a dosage of a controlled release PTH compound corresponding to 45% or less, even more preferably at a dosage of a controlled release PTH compound corresponding to 40% or less, even more preferably at a dosage of a controlled release PTH compound corresponding to 35% or less, and most preferably at a dosage of a controlled release PTH compound corresponding to 30% or less.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0144] In another embodiment, the water-insoluble controlled release PTH compound is a liposome that contains at least one PTH molecule or PTH substructure. Preferably, such liposomes are selected from the group consisting of aquasomes, nonionic surfactant vesicles such as niosomes and proniosomes, cationic liposomes such as LeciPlex, transferrosomes, ethosomes, ufasomes, sphingosomes, and pharmacosomes.

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

[0146] In another embodiment, the water-insoluble controlled release PTH compound comprises at least one PTH molecule non-covalently incorporated into a water-insoluble polymer. Preferably, such water-insoluble polymers include polymers selected from the group consisting of 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy) polymers, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartoamide), 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(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate), 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(vinyl pyrrolidone), silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, ramnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and copolymers thereof.

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

[0148] In another embodiment, the water-insoluble controlled release PTH compound comprises at least one PTH molecule reversibly conjugated by a covalent bond to a water-insoluble polymer. Preferably, such a water-insoluble polymer is 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy) polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartoamide), 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(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxy methacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate), 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(vinyl pyrrolidone), silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and polymers selected from the group consisting of copolymers thereof.

[0149] In one embodiment, such a water-insoluble controlled release PTH compound is conjugate D-L (wherein, -D is a PTH substructure, -L is a reversible prodrug linker substructure -L 1 - containing the substructure -L 1 - is linked to the PTH substructure -D via a functional group of PTH, said -L 1 - is -L 2 - substituted with -Z' and optionally further substituted, -L 2 - is a single chemical bond or a spacer substructure, -Z' is a water-insoluble carrier substructure) is a compound comprising.

[0150] A number of substructures -L 2 -L 1 -D being linked to the 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, is understood.

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

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

[0153] In a preferred embodiment, such a water-soluble controlled-release PTH compound is a compound of formula (Ia) or (Ib)

Chemical formula

[0154] It is understood that the compounds of formulas (Ia) and (Ib) are PTH prodrugs, more specifically water-soluble PTH prodrugs.

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

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

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

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

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

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

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

[0162] 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 the C-terminal carboxyl functional group of -D, or to the nitrogen atom in the backbone polypeptide chain of -D. The bond to either the N-terminus or the C-terminus may be direct or indirect by the corresponding amine or carboxyl functional group respectively, in which case a spacer sub-structure is first conjugated to the amine or carboxyl functional group, and the spacer sub-structure -L 1 - is conjugated.

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

[0164] Sub-structure -L 1 - When - is conjugated to the functional group of the side chain of the amino acid residue of PTH, the amino acid residue is selected from the group consisting of protein constituent amino acid residues and non-protein constituent amino acid residues.

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

[0166] 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.

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

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

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

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

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

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

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

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

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

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

[0177] In a preferred embodiment, -L 1 - is directly conjugated to the N-terminal amine functional group of PTH by the corresponding amine functional group or indirectly conjugated, in which case the spacer substructure is first conjugated to the amine functional group and the spacer substructure -L 1 - is conjugated to that functional group. Even more preferably, -L 1 - is directly conjugated to the N-terminal amine functional group of PTH.

[0178] In a similarly preferred embodiment, -L 1 - is directly conjugated to the C-terminal amine functional group of PTH by the corresponding carboxyl functional group or indirectly conjugated, in which case the spacer substructure is first conjugated to the carboxyl functional group and the spacer substructure -L 1 - is conjugated to that functional group.

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

[0180] Substructure -L 1- 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, aminals, imine, oxime, hydrazone, disulfide and acylguanidine. Even more preferably, -L 1 - is linked to -D by a bond selected from the group consisting of amide, ester, carbamate and acylguanidine. Some of these bonds are not reversible per se, however, in the present invention -L 1 - it is understood that the adjacent groups contained in - cause these bonds to be reversible.

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

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

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

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

[0185] The substructure -L 1 - is a drug, i.e., a reversible prodrug linker from which PTH is released in its free form, i.e., a prodrug linker that leaves no trace. Suitable prodrug linkers, for example, 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.

[0186] In another embodiment, -L 1 - is a reversible prodrug linker as described in WO 2011 / 012722 A1, WO 2011 / 089214 A1, WO 2011 / 089215 A1, WO 2013 / 024052 A1 and WO 2013 / 160340 A1, which are incorporated herein by reference.

[0187] A particularly preferred substructure -L 1 - is disclosed in WO 2009 / 095479 A2. Thus, in a preferred embodiment, the substructure -L 1 - is of formula (II):

Chemical formula

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

[0189] In one embodiment, -L of formula (II) 1 - is further unsubstituted.

[0190] -R of formula (II) 3 / -R 3a When they together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring, it is understood that only such 3- to 10-membered heterocyclic rings in which the atom directly bonded to nitrogen is an sp 3 hybridized carbon atom can be formed. In other words, -R 3 / -R 3a such 3- to 10-membered heterocyclic rings formed by -R / -R and the nitrogen atom to which they are attached have the following structure:

Chemical formula

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

[0192] -R of formula (II) 3 / -R 3a Exemplary embodiments of suitable 3- to 10-membered heterocyclic rings formed by -R / -R and the nitrogen atom to which they are attached are as follows: [Chemical formula] (wherein, the dashed line indicates the bond to the remainder of the molecule, -R is selected from the group consisting of -H and C 1-6 alkyl).

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

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

[0195] Preferably, -X- of formula (II) is selected from the group consisting of -C(R 4 R 4a )-, -N(R 4 )- and -C(R 7 R 7a ).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0211] In another preferred embodiment, at least one of -R of formula (II) 1 and -R 1a is methyl, and more preferably, both -R of formula (II) 1 and -R 1a are methyl.

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

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

[0214] In one preferred embodiment, -R of formula (II) 3 and -R 3a at least one of which is methyl, more preferably, -R of formula (II) 3 is methyl and -R of formula (II) 3a is -H.

[0215] In another preferred embodiment, both -R of formula (II) 3 and -R 3a are -H.

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

[0217] In one preferred embodiment, the substructure -L 1 - is of formula (IIa-i):

Chemical formula

[0218] -R of formula (IIa-i)3 , -R 3a If one or both of them are other than -H, they are understood to be linked to the N to which they are attached by sp 3 hybridized carbon atoms.

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

[0220] Preferably, the substructure -L of formula (IIa-i) 1 - is further unsubstituted.

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

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

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

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

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

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

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

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

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

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

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

[0232] More preferably, the substructure -L 1 - is of formula (IIa-ii):

Chemical formula

[0233] When one or both of -R 3 , -R 3a in formula (IIa-ii) are other than -H, it is understood that they are linked to the N to which they are attached by an sp 3 hybridized carbon atom.

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

[0235] Preferably, the substructure -L 1 - in formula (IIa-ii) is not further substituted.

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

[0237] Preferably, -R in formula (IIa-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 (IIa-ii) is -H. Even more preferably, both -R 8 and -R 8a in formula (IIa-ii) are -H.

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

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

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

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

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

[0243] In a more preferred embodiment, the substructure -L 1 - is of the formula (IIa-ii'):

Chemical formula

[0244] When one or both of -R 3 and -R 3a in formula (IIa-ii') are other than -H, it is understood that they are linked to the N to which they are attached by an sp 3 hybridized carbon atom.

[0245] Preferably, the substructure -L 1 - in formula (IIa-ii') is not further substituted.

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

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

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

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

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

[0251] Even more preferably, the substructure -L 1 - has the formula (IIa-iii):

Chemical formula

[0252] -R of formula (IIa-iii) 3 , -R 3a If one or both of them are other than -H, it is understood that they are linked to the N to which they are attached by sp 3 hybrid carbon atoms.

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

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

[0255] Most preferably, the substructure -L 1 - is of formula (IIa-iii'):

Chemical formula

[0256] -R of formula (IIa-iii') 3 , -R 3aIf one or both of them are other than -H, they are understood to be linked to the N to which they are attached by sp 3 hybridized carbon atoms.

[0257] Preferably, the substructure -L 1 - of formula (IIa-iii') is further unsubstituted.

[0258] In another preferred embodiment, the substructure -L 1 - is of formula (IIb-i):

Chemical formula

[0259] If one or both of -R 3 , -R 3a in formula (IIb-i) are other than -H, they are understood to be linked to the N to which they are attached by sp 3 hybridized carbon atoms.

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

[0261] Preferably, the substructure -L of formula (IIb-i) 1 - is further unsubstituted.

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

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

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

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

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

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

[0268] More preferably, the substructure -L 1 - is of formula (IIb-ii):

Chemical formula

[0269] -R of formula (IIb-ii) 3 , -R 3aIf one or both of them are other than -H, they are understood to be linked to the N to which they are attached by sp 3 hybridized carbon atoms.

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

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

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

[0273] Preferably, -R of 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 of formula (IIb-ii) 8 and -R 8a is -H. Even more preferably, both -R of formula (IIb-ii) 8 and -R 8a are -H.

[0274] Preferably, -R of 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 of formula (IIb-ii) 2 and -R 2a is -H. Even more preferably, both -R of formula (IIb-ii) 2 and -R 2a are H.

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

[0276] Even more preferably, the substructure -L 1 - is of formula (IIb-ii'):

Chemical formula

[0277] When -R 3a of formula (IIb-ii') is other than -H, it is understood that it is linked to the N to which it is attached by an sp 3 hybridized carbon atom.

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

[0279] Preferably, -X 2- is -C(R 8 R 8a )-.

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

[0281] Preferably, -R 2 and -R 2a in formula (IIb-ii') 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.

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

[0283] Even more preferably, the substructure -L 1 - is of formula (IIb-iii):

Chemical formula

[0284] -R in formula (IIb-iii) 3 , -R 3a If one or both of them are other than -H, it is understood that they are linked to the N to which they are attached by an sp 3 hybridized carbon atom.

[0285] Preferably, -L in formula (IIb-iii) 1 - is a single substructure -L 2 -Z or -L 2 -Z' substituted.

[0286] Preferably, the substructure -L in formula (IIb-iii) 1 - is not further substituted.

[0287] Most preferably, the substructure -L 1 - has the formula (IIb-iii'):

Chemical formula

[0288] The nitrogen adjacent to the dashed line marked with an asterisk in formula (IIb-iii') is sp3 -L is linked by hybrid carbon atoms 2 and is understood to be linked to -

[0289] Preferably, the partial structure -L of formula (IIb-iii') 1 - is further unsubstituted

[0290] Another preferred partial structure -L 1 - is disclosed in WO2016 / 020373A1. Therefore, in another preferred embodiment, the partial structure -L 1 - has the formula (III): [Chemical formula] (wherein the dashed lines each represent a bond formed by forming an amide or ester bond to a primary or secondary amine or hydroxyl of -D which is a PTH partial structure -R 1 , -R 1a , -R 2 , -R 2a , -R 3 and -R 3a are each independently selected from the group consisting of -H, -C(R 8 R 8a R 8b ), -C(=O)R 8 , -C≡N, -C(=NR 8 )R 8a , -CR 8 (=CR 8a R 8b ), -C≡CR 8 and -T, -R 4 , -R 5 and -R 5a are each independently selected from the group consisting of -H, -C(R 9 R 9a R 9b ) and -T, a1 and a2 are each independently 0 or 1, each -R 6 , -R 6a , -R 7 , -R7a ,-R 8 ,-R 8a ,-R 8b ,-R 9 ,-R 9a ,-R 9b is, independently of one another, -H, halogen, -CN, -COOR 10 , -OR 10 , -C(O)R 10 , -C(O)N(R 10 R 10a ), -S(O) 2 N(R 10 R 10a ), -S(O)N(R 10 R 10a ), -S(O) 2 R 10 , -S(O)R 10 , -N(R 10 ),S(O) 2 N(R 10a R 10b ), -SR 10 , -N(R 10 R 10a ), -NO 2 , -OC(O)R 10 , -N(R 10 ),C(O)R 10a , -N(R 10 ),S(O) 2 R 10a , -N(R 10 ),S(O)R 10a , -N(R 10 ),C(O)OR 10a , -N(R 10 ),C(O)N(R 10a R 10b ), -OC(O)N(R 10 R 10a ), -T, C 1-20 alkyl, C 2-20 alkenyl, and C 2-20 alkynyl selected from the group consisting of, wherein said -T, C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl are optionally substituted with one or more of the same or different -R 11 and C 1-20 alkyl, C 2-20 alkenyl and C2-20 The alkynyl may optionally be interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 12 ), -S(O) 2 N(R 12 ), -S(O)N(R 12 ), -S(O) 2 -, -S(O)-, -N(R 12 )S(O) 2 N(R 12a ), -S-, -N(R 12 ), -OC(OR 12 )(R 12a ), -N(R 12 )C(O)N(R 12a ), and -OC(O)N(R 12 ); Each -R 10 , -R 10a , -R 10b is independently selected from the group consisting of -H, -T, C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl, wherein said -T, C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl may optionally be substituted with one or more identical or different -R 11 ; and said C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl may optionally be interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 12 ), -S(O) 2 N(R 12 ), -S(O)N(R 12 ), -S(O) 2 -, -S(O)-, -N(R 12 )S(O) 2 N(R 12a ), -S-, -N(R 12 ), -OC(OR 12 )(R 12a ), -N(R 12 )C(O)N(R 12a ), and -OC(O)N(R 12)-consisting of one or more groups selected from the group may optionally intervene, Each T, independently of one another, is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic, each of said Ts is independently one or more -R 11 Optionally substituted with Each -R 11 Independently of one another, is halogen, -CN, oxo(=O), -COOR 13 , -OR 13 , -C(O)R 13 , -C(O)N(R 13 R 13a ), -S(O) 2 N(R 13 R 13a ), -S(O)N(R 13 R 13a ), -S(O) 2 R 13 , -S(O)R 13 , -N(R 13 )S(O) 2 N(R 13a R 13b ), -SR 13 , -N(R 13 R 13a ), -NO 2 , -OC(O)R 13 , -N(R 13 )C(O)R 13a , -N(R 13 )S(O) 2 R 13a , -N(R 13 )S(O)R 13a , -N(R 13 )C(O)OR 13a , -N(R 13 )C(O)N(R 13a R 13b ), -OC(O)N(R 13 R 13a ), and C 1-6 Selected from alkyl, said C 1-6 Alkyl is optionally substituted with one or more of the same or different halogens, Each -R12 , -R 12a , -R 13 , -R 13a , -R 13b , -R is independently selected from the group consisting of -H and C 1-6 alkyl, and said C 1-6 alkyl may be optionally substituted with one or more identical or different halogens, optionally, the pair -R 1 / -R 1a , -R 2 / -R 2a , -R 3 / -R 3a , -R 6 / -R 6a , -R 7 / -R 7a one or more of which, together with the atom to which they are attached, form a C 3-10 cycloalkyl or 3- to 10-membered heterocyclyl, optionally, the pair -R 1 / -R 2 , -R 1 / -R 3 , -R 1 / -R 4 , -R 1 / -R 5 , -R 1 / -R 6 , -R 1 / -R 7 , -R 2 / -R 3 , -R 2 / -R 4 , -R 2 / -R 5 , -R 2 / -R 6 , -R 2 / -R 7 , -R 3 / -R 4 , -R 3 / -R 5 , -R 3 / -R 6 , -R 3 / -R 7 , -R 4 / -R 5 , -R 4 / -R 6 , -R 4 / -R7 、 -R 5 / -R 6 、 -R 5 / -R 7 、 -R 6 / -R 7 One or more of them, together with the atoms to which they are attached, form ring A, A is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic ()) having said -L 1 - is -L 2 -Z or -L 2 -Z', and optionally, said -L 1 - is further substituted, -L 2 - is a single chemical bond or a spacer, -Z is a water-soluble carrier, -Z' is a water-insoluble carrier.

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

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

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

[0294] -L 1- Further preferred embodiments are disclosed in European Patent No. 1536334 B1, WO2009 / 009712 A1, WO2008 / 034122 A1, WO2009 / 143412 A2, WO2011 / 082368 A2, and US Patent No. 8,618,124 B2, and the entire disclosures of said patent documents are incorporated herein by reference.

[0295] -L 1 - Further preferred embodiments are disclosed in US Patent No. 8,946,405 B2 and US Patent No. 8,754,190 B2, and the entire disclosures of said patent documents are incorporated herein by reference. Accordingly, the preferred substructure -L 1 - is of formula (IV):

Chemical formula

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

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

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

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

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

[0301] In some cases, the alkenyl, alkynyl, aryl or heteroaryl substructures may be coupled to the rest of the molecule by an alkylene bond. The substituents in these situations are referred to as alkenylalkyl, alkynylalkyl, arylalkyl or heteroarylalkyl, which indicate that the alkylene substructure is between the alkenyl, alkynyl, aryl or heteroaryl substructure and the molecule to which the alkenyl, alkynyl, aryl or heteroaryl is coupled.

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

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

[0304] When the ring system is optionally substituted, suitable substituents are selected from the group consisting of alkyl, alkenyl, alkynyl or an additional ring, each of which is optionally further substituted. Optional substituents for any of the groups including the above are halo, nitro, cyano, -OR, -SR, -NR 2 、-OCOR, -NRCOR, -COOR, -CONR 2 、-SOR, -SO 2 R, -SONR 2 、-SO 2 NR 2 where each R is independently alkyl, alkenyl, alkynyl, aryl or heteroaryl, or two R groups together with the atoms to which they are attached form a ring.

[0305] Preferably, -L 1 - of formula (IV) is substituted with one substructure -L 2 -Z or -L 2 -Z'.

[0306] -L 1 - Further preferred embodiments of - are disclosed in WO2013 / 036857A1, which patent document is hereby incorporated by reference in its entirety. Accordingly, the preferred partial structure -L 1 - is of formula (V):

Chemical formula

[0307] Terms used exclusively in connection with formula (V) have the following meanings: "Alkyl", "alkenyl" and "alkynyl" include straight-chain, branched or cyclic hydrocarbon groups of 1 to 8, or 1 to 6, or 1 to 4 carbon atoms, where alkyl is a saturated hydrocarbon, alkenyl contains one or more carbon-carbon double bonds, and alkynyl contains one or more carbon-carbon triple bonds. Unless otherwise specified, these contain 1 to 6 C

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

[0309] The term "substituted" means an alkyl, alkenyl, alkynyl, aryl or heteroaryl group containing one or more substituents in place of one or more hydrogen atoms. Substituents generally include halogen (including F, Cl, Br and I), lower alkyl (including straight-chain, branched and cyclic), lower haloalkyl (including fluoroalkyl, chloroalkyl, bromoalkyl and iodoalkyl), OH, lower alkoxy (including straight-chain, branched and cyclic), SH, lower alkylthio (including straight-chain, branched and cyclic), amino, alkylamino, dialkylamino, silyl (including alkylsilyl, alkoxysilyl and arylsilyl), nitro, cyano, carbonyl, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aminocarbonyl, aminoacyl, carbamate, urea, thiocarbamate, thiourea, ketene, sulfone, sulfonamide, aryl (including phenyl, naphthyl and anthracenyl), heteroaryl (including 5-membered heteroaryl such as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole and tetrazole, 6-membered heteroaryl such as pyridine, pyrimidine and pyrazine, and fused heteroaryl such as benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzisoxazole and benzisothiazole) and may be selected from.

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

[0311] -L 1 A further preferred embodiment for - is disclosed in U.S. Patent No. 7,585,837 B2, which patent document is incorporated herein by reference in its entirety. Accordingly, the preferred substructure -L 1 - is of formula (VI):

Chemical formula

[0312] Preferred substituents of formula (VI) are alkyl (e.g., C 1-6 alkyl), alkenyl (e.g., C 2-6 alkenyl), alkynyl (e.g., C 2-6 alkynyl), aryl (e.g., phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (e.g., aromatic 4- to 7-membered heterocycle) or halogen partial structure.

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

[0314] Preferably, -L of formula (VI) 1 - is a single substructure -L 2 -Z or -L 2 - is substituted with -Z'.

[0315] -L 1 Further preferred embodiments for -L are disclosed in WO2002 / 089789A1, which patent document is hereby incorporated by reference in its entirety. Accordingly, the preferred substructure -L 1 - is of formula (VII):

Chemical formula

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

[0317] The term "substituted" is understood to include adding one or more atoms contained in a functional group or compound and replacing one or more different atoms.

[0318] The substituted alkyl includes carboxyalkyl, aminoalkyl, dialkylamino, hydroxyalkyl and mercaptoalkyl, the substituted cycloalkyl includes partial structures such as 4-chlorocyclohexyl, the aryl includes partial structures such as naphthyl, the substituted aryl includes partial structures such as 3-bromo-phenyl, the aralkyl includes partial structures such as toluyl, the heteroalkyl includes partial structures such as ethylthiophene, the substituted heteroalkyl includes partial structures such as 3-methoxythiophene, the alkoxy includes partial structures such as methoxy, and the phenoxy includes partial structures such as 3-nitrophenoxy. Halo- is understood to include fluoro, chloro, iodo and bromo.

[0319] Preferably, -L of formula (VII) 1 - is a single partial structure -L 2 -Z or -L 2 - is substituted with -Z'.

[0320] In another preferred embodiment, -L 1 - is a substructure of formula (VIII)

Chemical formula

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

[0322] In one embodiment, -L of formula (VIII) 1 - is further unsubstituted.

[0323] In another preferred embodiment, -L 1 - is a substructure of formula (IX)

Chemical formula

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

[0325] In one embodiment, -L of formula (IX) 1 - is further unsubstituted.

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

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

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

[0329] -L 2 When -L is other than a single chemical bond, -L 2 - is preferably -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-, -S(O) 2 N(R y1 )-, -S(O)N(R y1 )-, -S(O) 2 -, -S(O)-, -N(R y1 )S(O) 2 N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-, -N(R y1 )C(O)N(R y1a )-, -OC(O)N(R y1 )-, C 1-50 alkyl, C 2~50 alkenyl, and C 2~50 alkynyl, and is selected from the group consisting of, where -T-, C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl may be optionally substituted with one or more of the same or different -R y2 and C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl include -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-, -S(O) 2 N(R y3 )-, -S(O)N(R y3 )-, -S(O) 2 -, -S(O)-, -N(R y3 )S(O) 2 N(R y3a)-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-, -N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- may optionally interrupt, -R y1 and -R y1a are, independently of each other, -H, -T, C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl selected from the group consisting of, said -T, C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl may optionally be substituted with one or more -Ry 2 wherein said C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl may optionally contain -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y4 )-, -S(O) 2 N(R y4 )-, -S(O)N(R y4 )-, -S(O) 2 -, -S(O)-, -N(R y4 )S(O) 2 N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-, -N(R y4 )C(O)N(R y4a )-, and -OC(O)N(R y4 )- may optionally interrupt, each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, 8- to 30-membered carbopolycyclic, and 8- to 30-membered heteropolycyclic, and each said T is independently optionally substituted with one or more -R y2and is optionally substituted, each R y2 is independently selected from the group consisting of halogen, -CN, oxo (=O), -COOR y5 , -OR y5 , -C(O)R y5 , -C(O)N(R y5 R y5a ), -S(O) 2 N(R y5 R y5a ), -S(O)N(R y5 R y5a ), -S(O) 2 R y5 , -S(O)R y5 , -N(R y5 ), -N(R 2 ), -SR y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO 2 , -OC(O)R y5 , -N(R y5 ), -N(R y5a ), -N(R y5 ), -N(R 2 R y5a ), -N(R y5 ), -N(R y5a ), -N(R y5 ), -N(R y5a ), -N(R y5 ), -N(R y5a R y5b ), -OC(O)N(R y5 R y5a ), and C 1-6 alkyl, and said C 1-6 alkyl is optionally substituted with 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 is independently selected from the group consisting of -H and C 1-6 alkyl, and said C 1-6The alkyl is optionally substituted with one or more halogens which may be the same or different.

[0330] -L 2 When - is other than a single chemical bond, -L 2 - is more preferably -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-, -S(O) 2 N(R y1 )-, -S(O)N(R y1 )-, -S(O) 2 -,-S(O)-, -N(R y1 )S(O) 2 N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-, -N(R y1 )C(O)N(R y1a )-, -OC(O)N(R y1 )-, C 1-50 alkyl, C 2~50 alkenyl, and C 2~50 alkynyl, where -T, C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl are optionally substituted with one or more -R y2 and C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl include -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-, -S(O) 2 N(R y3 )-, -S(O)N(R y3 )-, -S(O) 2 -,-S(O)-, -N(R y3 )S(O) 2 N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-, -N(R y3 )C(O)N(R y3a )-, and -OC(O)N(Ry3 )-selected from the group consisting of may optionally be interrupted by one or more groups, -R y1 and -R y1a are, independently of each other, -H, -T, C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl selected from the group consisting of, said -T, C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl may optionally be substituted with one or more of the same or different -R y2 and said C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl may optionally be interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y4 )-, -S(O) 2 N(R y4 )-, -S(O)N(R y4 )-, -S(O) 2 -, -S(O)-, -N(R y4 )S(O) 2 N(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 )-selected from the group consisting of may optionally be interrupted by one or more groups, each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, 8- to 30-membered carbopolycyclic, and 8- to 30-membered heteropolycyclic, and each said T may optionally be substituted with one or more of the same or different -R y2 and -R y2 is halogen, -CN, oxo(=O), -COOR y5 , -OR y5 , -C(O)R y5, -C(O)N(R y5 R y5a ), -S(O) 2 N(R y5 R y5a ), -S(O)N(R y5 R y5a ), -S(O) 2 R y5 , -S(O)R y5 , -N(R y5 ), -N(R 2 N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO 2 , -OC(O)R y5 , -N(R y5 ), -N(R y5a ), -N(R y5 ), -N(R 2 R y5a ), -N(R y5 ), -N(R y5a ), -N(R y5 ), -N(R y5a ), -N(R y5 ), -N(R y5a R y5b ), -OC(O)N(R y5 R y5a ), and C 1-6 selected from the group consisting of alkyl, said C 1-6 alkyl is optionally substituted with 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 is independently selected from the group consisting of -H and C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more of the same or different halogens.

[0331] -L 2 - is other than a single chemical bond, -L 2- is more preferably -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-, -S(O) 2 N(R y1 )-, -S(O)N(R y1 )-, -S(O) 2 -, -S(O)-, -N(R y1 )S(O) 2 N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-, -N(R y1 )C(O)N(R y1a )-, -OC(O)N(R y1 )-, C 1-50 alkyl, C 2~50 alkenyl, and C 2~50 alkynyl, and is selected from the group consisting of, where -T-, C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl may optionally be substituted with one or more of the same or different -R y2 , and C 1-50 alkyl, C 2-50 alkenyl and C 2-50 alkynyl may optionally be interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-, -S(O) 2 N(R y3 )-, -S(O)N(R y3 )-, -S(O) 2 -, -S(O)-, -N(R y3 )S(O) 2 N(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 )-, and -R y1 and -R y1a are independently -H, -T, C1-10 alkyl, C 2-10 alkenyl and C 2-10 selected from the group consisting of alkynyl, each T is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic, 8- to 30-membered carbopolycyclic, and 8- to 30-membered heteropolycyclic, -R y2 is independently selected from the group consisting of halogen and C 1-6 alkyl, each -R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b is independently selected from the group consisting of -H and C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted with one or more of the same or different halogens.

[0332] Even more preferably, -L 2 - is a C y1 alkyl chain in which one or more groups independently selected from -O-, -T- and -C(O)N(R 1-20 )- are optionally inserted, and the C 1-20 alkyl chain is optionally substituted with one or more groups independently selected from -OH, -T and -C(O)N(R y6 R y6a )), and the -R y1 , -R y6 , -R y6a are independently selected from the group consisting of H and C 1-4 alkyl, and the T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic, 8- to 30-membered carbopolycyclic, and 8- to 30-membered heteropolycyclic.

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

[0334] Preferably, -L 2 - contains a partial structure selected from the following:

Chemical formula

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

[0336] The term "chain length" as used herein with respect to the partial structure -L 2 - refers to the number of atoms of -L 1 - present in the shortest connecting part between -L 2 - and -Z.

[0337] Preferably, -L 2 - has the formula (i)

Chemical formula

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

[0339] In another preferred embodiment, the substructure -L 1 -L 2 - is selected from the group consisting of:

Chemical formula

[0340] In one preferred embodiment, the substructure -L 1 -L 2 - is

Chemical formula

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

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

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

[0344] Carrier-Z contains C 8-24 alkyl, or a polymer. Preferably, -Z is a polymer, preferably 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy) polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartoamide), 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(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate), 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(vinyl pyrrolidone), silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, ramnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and polymers selected from the group consisting of copolymers thereof.

[0345] Preferably, -Z has a molecular weight in the range of 5 to 200 kDa. Even more preferably, -Z has a molecular weight in the range of 8 to 100 kDa, even more preferably 10 to 80 kDa, even more preferably 12 to 60 kDa, even more preferably 15 to 40 kDa, and most preferably, -Z has a molecular weight of about 20 kDa. In another equally preferred embodiment, -Z has a molecular weight of about 40 kDa.

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

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

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

[0349] In a particularly preferred embodiment, -Z contains a random coil protein substructure.

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

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

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

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

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

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

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

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

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

[0359] In a preferred embodiment, 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 of -Z are selected from alanine and proline, and the random coil protein substructure is included. More preferably, at least 10%, but less than 75%, preferably less than 65% of the total number of amino acid residues of such a random coil protein substructure are proline residues. Preferably, such a random coil protein substructure is as 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 NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:51, and SEQ ID NO:61, which are disclosed in WO 2011 / 144756 incorporated herein by reference. A substructure containing such a random coil protein containing alanine and proline will be referred to as "PA" or "PA substructure".

[0360] Accordingly, -Z includes a PA substructure.

[0361] In a similarly preferred embodiment, 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 of -Z are selected from alanine, serine, and proline, and the random coil protein substructure is included. More preferably, at least 4%, but less than 40% of the total number of amino acid residues of such a random coil protein substructure are proline residues. Preferably, such a random coil protein substructure is as 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 NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, and SEQ ID NO: 56, which are disclosed in WO 2008 / 155134 A1 and incorporated herein by reference. A substructure containing such a random coil protein substructure containing alanine, serine, and proline will be referred to as "PAS" or "PAS substructure".

[0362] Accordingly, -Z includes a PAS substructure.

[0363] In a similarly preferred embodiment, at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, even more preferably at least 98%, and most preferably at least 99% of the total number of amino acids forming the random coil protein substructure of -Z are selected from alanine, glycine, and proline, and the random coil protein substructure is included. A substructure including such a random coil protein substructure containing alanine, glycine, and proline will be referred to as "PAG" or "PAG substructure".

[0364] Therefore, -Z includes a PAG substructure.

[0365] In a similarly preferred embodiment, at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, even more preferably at least 98%, and most preferably at least 99% of the total number of amino acids forming the random coil protein substructure of -Z are selected from proline and glycine, and the random coil protein substructure is included. A substructure including such a random coil protein substructure containing proline and glycine will be referred to as "PG" or "PG substructure".

[0366] Preferably, such a PG substructure includes a substructure of formula (a-0): [(Gly) p -Pro-(Gly) q r (a-0) (wherein p is selected from the group consisting of 0, 1, 2, 3, 4, and 5, q is selected from the group consisting of 0, 1, 2, 3, 4, and 5, r is an integer in the range of 10 to 1000, provided that at least one of p and q is at least 1).

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

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

[0369] More preferably, the PG substructure is the sequence of SEQ ID NO: 122: GGPGGPGPGGPGGPGPGGPG and includes.

[0370] More preferably, the PG substructure is the sequence (GGPGGPGPGGPGGPGPGGPG) of formula (a-0-a) v (a-0-a) and v in this sequence is an integer in the range of 1 to 50.

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

[0372] Therefore, -Z includes the PG substructure.

[0373] In a similarly preferred embodiment, 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 of -Z are selected from alanine, glycine, serine, threonine, glutamate and proline, and it contains the said random coil protein substructure. Preferably, such a random coil protein substructure is as described in WO 2010 / 091122 A1 which is incorporated herein by reference. More preferably, -Z contains at least one substructure selected from the group consisting of SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184; SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, SEQ ID NO: 193, SEQ ID NO: 194, SEQ ID NO: 195, SEQ ID NO: 196, SEQ ID NO: 197, SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 200, SEQ ID NO: 201, SEQ ID NO: 202, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 205, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 210, SEQ ID NO: 211, SEQ ID NO: 212, SEQ ID NO: 213, SEQ ID NO: 214, SEQ ID NO: 215, SEQ ID NO: 216, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 220, SEQ ID NO: 221, SEQ ID NO: 759, SEQ ID NO: 760, SEQ ID NO: 761, SEQ ID NO: 762, SEQ ID NO: 763, SEQ ID NO: 764, SEQ ID NO: 765, SEQ ID NO: 766, SEQ ID NO: 767, SEQ ID NO: 768, SEQ ID NO: 769, SEQ ID NO: 770, SEQ ID NO: 771, SEQ ID NO: 772, SEQ ID NO: 773, SEQ ID NO: 774, SEQ ID NO: 775, SEQ ID NO: 776, SEQ ID NO: 777, SEQ ID NO: 778, SEQ ID NO: 779, SEQ ID NO: 1715, SEQ ID NO: 1716, SEQ ID NO: 1718, SEQ ID NO: 1719, SEQ ID NO: 1720, SEQ ID NO: 1721 and SEQ ID NO: 1722 as disclosed in WO2010 / 091122A1 which is incorporated herein by reference.Such a partial structure containing a random coil protein partial structure containing alanine, glycine, serine, threonine, glutamate and proline shall be referred to as "XTEN" or "XTEN partial structure" according to its name in WO 2010 / 091122 A1.

[0374] Therefore, -Z contains an XTEN partial structure.

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

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

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

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

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

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

[0381] In another embodiment, -Z is a multi-arm PEG-based polymer. Preferably, -Z is a multi-arm PEG-based polymer having at least 4 PEG-based arms.

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

[0383] Preferably, such a multi-arm PEG-based 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, for example, the product list of JenKem Technology, USA (obtained by downloading from http: / / www.jenkemusa.com / Pages / PEGProducts.aspx on December 18, 2014). Even more preferably, the water-soluble PEG-based carrier -Z is 4-arm PEG amine containing a pentaerythritol core: [Chemical formula] (n ranges from 20 to 500), 8-Arm PEG Amine Containing Hexaglycerin Core: [Chemical formula] (n ranges from 20 to 500, R = hexaglycerin or tripentaerythritol core structure), and 6-Arm PEG Amine Containing Sorbitol or Dipentaerythritol Core: [Chemical formula] (n ranges from 20 to 500, R = containing sorbitol or dipentaerythritol core structure) It contains a partial structure selected from, and the dashed lines in these formulas indicate the bonds to the remainder of the PTH prodrug.

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

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

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

[0387] 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.

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

[0389] Preferably, -Z or -Z' includes the following substructure:

Chemical formula

[0390] In a similarly preferred embodiment, -Z contains an amide bond.

[0391] Preferably, -Z includes the substructure of formula (a):

Chemical formula

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

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

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

[0395] In one embodiment, the -S a - in formula (a) is a chemical bond.

[0396] In another embodiment, the -S a - in formula (a) is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl, and said C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl may be substituted with -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 ), -S(O) 2 N(R 4 ), -S(O)N(R 4 ), -S(O) 2 -, -S(O)-, -N(R 4 )S(O) 2 N(R 4a ), -S-, -N(R 4 ), -OC(OR 4 )(R 4a)-, -N(R 4 )C(O)N(R 4a )-, and -OC(O)N(R 4 )- may optionally be interrupted by one or more chemical groups selected from the group consisting of, wherein -T- is a 3- to 10-membered heterocyclyl, -R 4 and -R 4a are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl.

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

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

[0399] In another embodiment, the -S a' - of formula (a) is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, and this C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl may optionally be interrupted by one or more chemical groups selected from the group consisting of -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O) 2 N(R 4 )-, -S(O)N(R 4 )-, -S(O) 2 -, -S(O)-, -N(R 4 )S(O) 2 N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-, -N(R 4 )C(O)N(R 4a )-, and -OC(O)N(R 4 )- may optionally be interrupted by one or more chemical groups selected from the group consisting of, said -R4 and -R 4a is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. Preferably, -S of formula (a) a' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, and one or more chemical groups selected from the group consisting of -O-, -C(O)-, and -C(O)N(R 4 )- may optionally intervene.

[0400] In one embodiment, -S of formula (a) a'' - is a chemical bond.

[0401] In another embodiment, -S of formula (a) a'' - is C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, and this C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl may optionally be interrupted by one or more chemical groups selected from the group consisting of -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O) 2 N(R 4 )-, -S(O)N(R 4 )-, -S(O) 2 -, -S(O)-, -N(R 4 )S(O) 2 N(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 -R 4 and -R 4a is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. Preferably, -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(R4 )- is optionally interrupted by one or more chemical groups selected from the group consisting of

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

[0403] In another embodiment, the -S in formula (a) a''' - is C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl, and this C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl may be interrupted by one or more chemical groups selected from the group consisting of -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O) 2 N(R 4 )-, -S(O)N(R 4 )-, -S(O) 2 -, -S(O)-, -N(R 4 )S(O) 2 N(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 -R 4 and -R 4a are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Preferably, the -S in formula (a) a''' - is selected from the group consisting of methyl, ethyl, propyl, butyl, and these may be interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)- and -C(O)N(R 4 )-.

[0404] Preferably, the -P in formula (a) a' , -P a'' and -P a'''comprises a polymer independently selected from the group consisting of 2-methacryloyloxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy) polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartoamide), 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(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropylmethacrylamide), poly(hydroxypropyl methacrylate), 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(vinyl pyrrolidone), silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and copolymers thereof.

[0405] More preferably, -P of formula (a) a' , -P a'' and -P a''' each independently comprises a PEG-based substructure. Even more preferably, -P of formula (a) a' , -P a'' and -P a'''independently contains at least 20% PEG, more preferably at least 30%, even more preferably at least 40%, even more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% PEG, and includes a PEG-based partial structure.

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

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

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

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

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

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

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

[0413] In one embodiment, -Z contains one substructure of formula (a).

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

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

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

[0417] More preferably, -Z contains a substructure of formula (b):

Chemical formula

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

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

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

[0421] Carrier-Z' is a water-insoluble polymer, more preferably a hydrogel. Preferably, such a hydrogel comprises a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy) polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(acid anhydride), poly(aspartoamide), 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(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropylmethacrylamide), poly(hydroxypropyl methacrylate), 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(vinyl pyrrolidone), silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and copolymers thereof.

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

[0423] 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.

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

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

[0426] In a preferred embodiment, the controlled-release PTH compound has the formula (IIe-i): [Chemical formula] (wherein, The unmarked dashed line indicates the bond to the nitrogen of -D, which is the PTH substructure, by forming an amide bond, The dashed line with an asterisk is the substructure [Chemical formula] represents the bond to, wherein, m and p are independently integers in the range of 400 to 500).

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

[0428] In another preferred embodiment, the PTH prodrug for use in the present invention has formula (IIf-i):

Chemical formula

Chemical formula

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

[0430] In a preferred embodiment, 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%.

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

[0432] Preferably, a pharmaceutical composition comprising at least one controlled-release PTH compound for use in 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.

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

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

[0435] Such liquid, suspension, dry or reconstituted pharmaceutical compositions comprise at least one excipient. Excipients used in parenteral formulations can be classified, for example, as buffers, isotonicity regulators, preservatives, stabilizers, absorption inhibitors, antioxidants, thickeners / viscosity increasing agents, or other auxiliaries. However, in some cases, one excipient may have dual or triple functions. Preferably, at least one excipient comprised in the pharmaceutical composition for use in the present invention is selected from the group consisting of: (i) Buffers: Physiologically acceptable buffers for maintaining the pH within the desired range, such as sodium phosphate, bicarbonate, succinate, histidine, citrate and acetate, sulfate, nitrate, chloride, pyruvate. Antacids, such as Mg(OH) 2 or ZnCO 3 may also be used; (ii) Isotonicity regulators: For minimizing pain that may result as a consequence of cell damage due to osmotic pressure differences in injection depots. Glycerol and sodium chloride are examples. The effective concentration can be determined by osmotic pressure measurement using an assumed molar osmotic concentration of 285 - 315 mOsmol / kg for serum; (iii) Preservatives and / or antibacterial agents: For multiple - dose parenteral formulations, addition of a sufficient concentration of a preservative is required to minimize the risk of infection of patients by injection, and corresponding regulatory requirements are established. Typical preservatives include m - cresol, phenol, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, chlorobutanol, benzyl alcohol, phenylmercuric nitrate, thimerosal, sorbic acid, potassium sorbate, benzoic acid, chlorocresol and benzalkonium chloride; (iv) Stabilizers: Stabilization is achieved by enhancing the protein-stabilizing power, destabilizing the denatured state, or directly binding the excipient to the protein. Stabilizers can be amino acids such as alanine, arginine, aspartic acid, glycine, histidine, lysine, proline; sugars such as glucose, sucrose, trehalose; polyols such as glycerol, mannitol, sorbitol; salts such as potassium phosphate, sodium sulfate; chelating agents such as EDTA, hexaphosphate; ligands such as divalent metal ions (zinc, calcium, etc.); other salts or organic molecules such as phenolic derivatives. Additionally, oligomers or polymers such as cyclodextrin, dextran, dendrimer, PEG or PVP or protamine or HSA may be used; (v) Absorption inhibitors: Mainly ionic or non-ionic surfactants or other proteins or soluble polymers such as poloxamer (Pluronic F-68), PEG dodecyl ether (Brij 35), polysorbates 20 and 80, dextran, polyethylene glycol, PEG-polyhistidine, BSA and HSA, and gelatin are used for coating the inner surface of the formulation container or for competitive adsorption to the inner surface. The excipient concentration and type selected depend on the effect to be avoided, but typically a monolayer of surfactant is formed at the interface just above the CMC value; (vi) Antioxidants: Antioxidants such as ascorbic acid, ectoine, methionine, glutathione, monothioglycerol, molybdenum, polyethyleneimine (PEI), propyl gallate, and vitamin E. Chelating agents such as citric acid, EDTA, hexaphosphate, and thioglycolic acid may also be used; (vii) Thickening agent or viscosity increasing agent: In the case of a suspension, it delays the sedimentation of particles in vials and syringes, promotes the mixing and resuspension of particles, and is used to make it easier to inject the suspending agent (i.e., with a small force against the syringe plunger). Suitable thickening agents or viscosity increasing agents are, for example, carbomer thickeners such as Carbopol 940, Carbopol Ultrez 10; cellulose derivatives such as hydroxypropylmethylcellulose (hypromellose, HPMC) or diethylaminoethylcellulose (DEAE or DEAE-C); colloidal magnesium silicate (Veegum) or sodium silicate; hydroxyapatite gel; tricalcium phosphate gel; xanthan; carrageenan such as Satia gum UTC 30; aliphatic poly(hydroxy acids) such as poly(D,L- or L-lactic acid) (PLA) and poly(glycolic acid) (PGA) and their copolymers (PLGA), a terpolymer of D,L-lactide, glycolide and caprolactone; poloxamer; hydrophilic poly(oxyethylene) blocks and hydrophobic poly(oxypropylene) blocks for forming triblocks of poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) (e.g., Pluronic®); polyether ester copolymers such as polyethylene glycol terephthalate / polybutylene terephthalate copolymer; sucrose acetate isobutyrate (SAIB); dextran or its derivatives; a combination of dextran and PEG; polydimethylsiloxane; collagen; chitosan; polyvinyl alcohol (PVA) and derivatives; polyalkylimide; poly(acrylamide-co-diallyldimethylammonium (DADMA)); polyvinylpyrrolidone (PVP); glycosaminoglycans (GAG) such as dermatan sulfate, chondroitin sulfate, keratan sulfate, heparin, heparan sulfate, hyaluronan; ABA triblock or AB block copolymers composed of a hydrophobic A block such as polylactide (PLA) or poly(lactide-co-glycolide) (PLGA) and a hydrophilic B block such as polyethylene glycol (PEG) or polyvinylpyrrolidone.Such block copolymers and the above-described poloxamers can exhibit inverse thermogelation behavior (fluid at room temperature to facilitate administration and gelled at a temperature higher than the sol-gel transition temperature at body temperature after injection). (viii) Spreading or diffusing agents: Regulate the permeability of connective tissue by hydrolysis of components of the extracellular matrix in the interstitial cavity (e.g., hyaluronic acid, a polysaccharide found in the intercellular spaces of connective tissue, without limitation). Spreading agents, such as, without limitation, hyaluronidase, temporarily reduce the viscosity of the extracellular matrix and promote the diffusion of the injected drug; and (ix) Other adjuvants: Wetting agents, viscosity modifiers, antibiotics, hyaluronidase, etc. Acids and bases such as hyaluronic acid and sodium hydroxide are adjuvants necessary for pH adjustment during manufacture.

[0436] A further aspect of the invention is a method of treating, managing, delaying or preventing one or more conditions that can be treated, managed, delayed or prevented with PTH in a mammalian patient, the method comprising administering a pharmaceutical composition comprising at least one controlled release PTH compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, at a frequency of once or less per 24 hours, in a dosage of the controlled release PTH compound corresponding to 70% or less of the molar equivalent dosage necessary to maintain serum calcium within normal levels over 24 hours for PTH 1-84 administered at the same dosing frequency.

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

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

[0439] Preferably, the conditions that can be treated, managed, delayed or prevented with PTH are 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, the conditions that can be treated, managed, delayed or prevented with PTH are hypoparathyroidism, hyperphosphatemia, fracture repair, arthritis, osteoarthritis, rheumatoid arthritis, osteopenia, periodontal disease, fractures, alopecia, chemotherapy-induced alopecia, and thrombocytopenia.

[0440] Most preferably, the condition is hypoparathyroidism.

Examples

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

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

[0443] PEG 2x20 kDa maleimide, Sunbright GL2-400MA, was purchased from NOF Europe N.V., 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 stated.

[0444] Compound 11a (Examples 11 - 15) was synthesized according to the procedure described in Patent WO29095479A2, Example 1.

[0445] A syringe equipped with a polyethylene frit (MultiSynTech GmbH, Witten, Germany) was used as the reaction vessel or in the washing step of the peptide resin.

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

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

[0448] RP-HPLC purification: For preparative RP-HPLC, a Waters 600 controller and a 2487 Dual Absorbance Detector were used, equipped with the following columns: Waters XBridge™ BEH300 Prep C18 5 μm, 150 × 10 mm, flow rate 6 mL / min, or Waters XBridge™ BEH300 Prep C18 10 μm, 150 × 30 mm, flow rate 40 mL / min. A linear gradient of solvent system A (water containing 0.1% TFA v / v) and solvent system B (acetonitrile containing 0.1% TFA v / v) was used. Unless otherwise stated, HPLC fractions containing the product were pooled and lyophilized.

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

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

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

[0452] Analytical methods Ultra-high performance 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 a LTQ Orbitrap Discovery mass spectrometer from Thermo Scientific or a Waters Micromass ZQ.

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

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

[0455] [Chemical formula] JPEG2025084970000050.jpg52154

[0456] N-Methyl-N-Boc-ethylenediamine (2 g, 11.48 mmol) and NaCNBH in MeOH (20 mL) 3To a solution of [substance with 819 mg, 12.63 mmol], 2,4,6-trimethoxybenzaldehyde (2.08 g, 10.61 mmol) was added portionwise. The mixture was stirred at room temperature for 90 minutes, acidified with 3M HCl (4 mL), and stirred for an additional 15 minutes. The reaction mixture was added to saturated NaHCO 3 solution (200 mL) and extracted 5 times with DCM. The combined organic phases were dried over Na 2 SO 4 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: 3.76 g (11.48 mmol, purity 89%, 1a: double Tmob-protected product = 8:1) MS: m / z 355.22 = [M+H] + , (calculated monoisotopic mass = 354.21).

[0457] To a solution of 1a (2 g, 5.65 mmol) in DCM (24 mL), 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 3 times with 0.1M H 2 SO 4 (100 mL) and 3 times with saturated brine (100 mL). The aqueous phase was re-extracted with DCM (100 mL). The combined organic phases were dried over Na 2 SO 4 and filtered, and the residue was concentrated to a volume of 24 mL. 1b was purified using flash chromatography. Yield: 5.31 g (148%, 6.66 mmol) MS: m / z 796.38 = [M+H] + , (calculated monoisotopic mass = 795.37).

[0458] A solution of 1b (5.31 g, up to 4.52 mmol with respect to N-Fmoc-N-Me-Asp(OBn)-OH) in THF (60 mL) was added with DBU (1.8 mL, 3% v / v). The solution was stirred at room temperature for 12 minutes, diluted with DCM (400 mL), and washed three times with 0.1 M H 2 SO 4 (150 mL) and three times with saturated brine (150 mL). The aqueous phase was re-extracted with DCM (100 mL). The combined organic phases were dried over Na 2 SO 4 and filtered. 1c was isolated by evaporation of the solvent and used in the next reaction without further purification. MS: m / z 574.31 = [M+H] + , (calculated monoisotopic mass = 573.30).

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

[0460] i-PrOH (33 mL) and H 2To a solution of 1d (2.63 g, 2.78 mmol) in O(11 mL) was added LiOH (267 mg, 11.12 mmol), 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 H 2 SO 4 (50 mL) and three times with saturated brine (50 mL). The aqueous phase was re-extracted with DCM (100 mL). The combined organic phases were dried over Na 2 SO 4 and filtered, and 1e was isolated by evaporation of the solvent. 1e was purified using flash chromatography. Yield: 2.1 g (88%) MS: m / z 878.4 = [M+Na] + , (calculated monoisotopic mass = 837.40).

[0461] To a solution of 1e (170 mg, 0.198 mmol) in anhydrous DCM (4 mL) were added DCC (123 mg, 0.59 mmol) and a catalytic amount of DMAP. After 5 minutes, N-hydroxy-succinimide (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 fractions were neutralized with 0.5 M pH 7.4 phosphate buffer and concentrated. The remaining aqueous phase was extracted with DCM, and 1f was isolated by evaporation of the solvent. Yield: 154 mg (81%) MS: m / z 953.4 = [M+H] + , (calculated monoisotopic mass = 952.43).

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

[0463] [Chemical formula]

[0464] 4-Methoxytritylphenylmethyl chloride (3.00 g, 9.71 mmol) was dissolved in DCM (20 mL), and the solution was 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 brine / 0.1 M NaOH 30 / 1 (v / v) and once with saturated brine. The organic phase was dried over Na 2 SO 4 and 2b was isolated by evaporation of the solvent. Yield: 3.18 g (98%)

[0465] The Mmt-protected intermediate 2b (3.18 g, 9.56 mmol) was dissolved in DCM (30 mL). 6-(Tritylthio)-hexanoic acid (4.48 g, 11.5 mmol), PyBOP (5.67 g, 10.9 mmol) and DIPEA (5.0 mL, 28.6 mmol) were added and the mixture was stirred at room temperature for 30 minutes. The solution was diluted with diethyl ether (250 mL) and washed three times with saturated brine / 0.1 M NaOH 30 / 1 (v / v) and once with saturated brine. The organic phase was dried over Na 2 SO 4 and the solvent was removed under vacuum. 2c was purified using flash chromatography. Yield: 5.69 g (85%) MS: m / z 705.4 = [M+H] + , (calculated monoisotopic mass = 704.34).

[0466] Compound 2c (3.19 g, 4.53 mmol) was dissolved in anhydrous THF (50 mL), and a 1 M BH 3 ·THF solution (8.5 mL, 8.5 mmol) in THF was added, and the mixture was stirred at room temperature for 16 hours. An additional 1 M BH 3·Add THF solution (14 mL, 14.0 mmol), and stir the mixture at room temperature for an additional 16 h. Add methanol (8.5 mL) and N,N'-dimethyl-ethylenediamine (3.00 mL, 27.9 mmol), and heat the mixture under reflux for 3 h. Leave the mixture to cool, and add ethyl acetate (300 mL). Wash the solution twice with an aqueous solution of Na 2 CO 3 and twice with an aqueous solution of NaHCO 3 . Dry the organic phase over Na 2 SO 4 , and remove the solvent under vacuum to obtain 2d. Yield: 3.22 g (103%) MS: m / z 691.4 = [M+H] + , (calculated monoisotopic mass = 690.36).

[0467] Dissolve di-tert-butyl dicarbonate (2.32 g, 10.6 mmol) and DIPEA (3.09 mL, 17.7 mmol) in DCM (5 mL), and add to a solution of 2d (2.45 g, 3.55 mmol) in DCM (5 mL). Stir the mixture at room temperature for 30 min. Concentrate the solution under vacuum and purify by flash chromatography to obtain product 2e. Yield: 2.09 g (74%) MS: m / z 791.4 = [M+H] + , (calculated monoisotopic mass = 790.42).

[0468] Dissolve compound 2e (5.01 g, 6.34 mmol) in acetonitrile (80 mL). Add 0.4 M aqueous HCl solution (80 mL), followed by acetonitrile (20 mL), and stir the mixture at room temperature for 1 h. Adjust the pH to pH 5.5 by adding 5 M aqueous NaOH solution. Remove the organic solvent under vacuum, and extract the remaining aqueous solution 4 times with DCM. Dry the combined organic phases over Na 2 SO 4 , and remove the solvent under vacuum to obtain 2f. Yield: 4.77 g (95%) MS: m / z 519.3 = [M+H]+ , (Calculated monoisotopic mass = 518.30).

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

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

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

[0472] [Example 4] Synthesis of Persistent K26 PTH(1 - 34) Conjugate 4

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

[0474] [Example 5] Synthesis of Transient S1 PTH(1 - 34) Conjugate

[0475] [Chemical formula] The Fmoc of side-chain protected PTH(1-34) on TCP resin with 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 h. 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 h. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Cleavage of the peptide from the resin and removal of the protecting groups were effected by adding 7 mL of cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole and stirring the suspension at room temperature for 1 h. The crude 5 was precipitated into pre-cooled diethyl ether (-18 °C). The precipitate was dissolved in ACN / water and purified by RP-HPLC. The product fractions were lyophilized. Yield: 78 mg (24%), 5*9 TFA MS: m / z 1101.59 = [M+4H] 4+ , ([M+4H] 4+ calculated monoisotopic mass for = 1101.57).

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

[0477] [Chemical formula] The Fmoc of side-chain protected PTH(1-34) on TCP resin with 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 carried out as described above. A solution of 2g (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. Peptide cleavage from the resin and removal of protecting groups were effected by adding 3 mL of cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole and stirring the suspension at room temperature for 1 hour. Crude 6 was precipitated into pre-cooled diethyl ether (-18 °C). The precipitate was dissolved in ACN / water and purified by RP-HPLC. The product fractions were lyophilized. Yield: 25 mg (18%), 6*9 TFA MS: m / z 1098.75 = [M+4H] 4+ , ([M+4H] 4+ calculated monoisotopic mass for = 1098.07).

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

[0479] [Chemical formula] The Fmoc of side-chain protected PTH(1-34) on TCP resin with 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 carried out as described above. A solution of 2 g (144 mg, 211 μmol) and DIPEA (53 μL, 305 μmol) in DMF (1.8 mL) was added to the resin. The suspension was shaken at room temperature for 7 hours. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Peptide cleavage from the resin and removal of protecting groups were effected by adding 6 mL of cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole and stirring the suspension at room temperature for 1 hour. Crude 7 was precipitated into pre-cooled diethyl ether (-18 °C). The precipitate was dissolved in ACN / water and purified by RP-HPLC. The product fractions were lyophilized. Yield: 54 mg (20%), 7·9 TFA MS: m / z 1102.08 = [M + 4H] 4+ , ([M + 4H] 4+ calculated monoisotopic mass for = 1102.07).

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

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

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

[0483] [Chemical formula] The Fmoc of the side-chain protected PTH(1-34) on TCP resin with 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 h. The resin was washed 10 times with DMF and 10 times with DCM and dried under vacuum. Peptide cleavage from the resin and removal of the protecting groups were effected by adding 20 mL of cleavage cocktail 100 / 3 / 3 / 2 / 1 (v / w / v / v / v) TFA / DTT / TES / water / thioanisole and stirring the suspension at room temperature for 1 h. Crude 9 was precipitated into pre-cooled diethyl ether (-18 °C). The precipitate was dissolved in ACN / water and purified by RP-HPLC. The product fractions were lyophilized. Yield: 47 mg (8%), 9*9 TFA MS: m / z 1108.58 = [M + 4H] 4+ , ([M + 4H] 4+ calculated monoisotopic mass for = 1108.57).

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

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

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

[0487]

Chem.

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

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

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

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

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

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

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

[0495] [Chem.] JPEG2025084970000066.jpg38144 Conjugate 15 was synthesized as described for 11b by using thiol 10 (5.2 mg, 0.95 μmol) and maleimide 11a (1.23 mg, 1.14 μmol). Yield: 2.1 mg (33%), 15*9 TFA MS: m / z 1102.60 = [M+5H] 5+ , ([M+5H] 5+ Calculated monoisotopic mass for = 1102.59).

[0496] [Example 16] Synthesis of Persistent 2x20 kDa S1 PEG Conjugate 16

[0497] [Chemical formula] 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). 0.5M NaH 2 PO 4 buffer (0.66 mL, 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 1M HCl was added. Conjugate 16 was purified by IEX and then by RP-HPLC using a linear gradient of solvent system A (water containing 0.1% AcOH v / v) and solvent system B (acetonitrile containing 0.1% AcOH v / v). The product-containing fractions were lyophilized. Yield: 97 mg (2.01 μmol, 57%) conjugate 16*8AcOH

[0498] [Example 17] Synthesis of Persistent 2x20 kDa K26 PEG Conjugate 17

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

[0500] [Example 18] Synthesis of temporary 2x20 kDa S1 PEG conjugate 18

[0501] [Chemical formula] Conjugate 18 was prepared as described for 16 by reacting 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 fractions were lyophilized. Yield: 161 mg (3.33 μmol, 40%) conjugate 18*9AcOH

[0502] [Example 19] Synthesis of temporary 2x20 kDa S1 PEG conjugate 19

[0503] [Chemical formula] Conjugate 19 was prepared as described for 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

[0504] [Example 20] Synthesis of temporary 2x20 kDa S1 PEG conjugate 20

[0505] [Chemical formula] Conjugate 20 was prepared as described for 16 by 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 TFA without prior addition of 2-mercaptoethanol. Conjugate 20 was purified by IEX and then by SEC for desalting. The product-containing fractions were lyophilized. Yield: 194 mg (4.01 μmol, 47%) conjugate 20*9AcOH

[0506] [Example 21] Synthesis of transient 2x20 kDa K26 PEG conjugate 21

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

[0508] [Example 22] Pharmacodynamic effects in thyroparathyroidectomized (TPTx) rats during a 28-day study with daily subcutaneous injection of conjugate 18 or PTH(1-84) This study was conducted to test and compare the effects of daily subcutaneous injection of compound 18 and the current standard treatment, PTH(1-84), in an animal disease model suitable for studying the treatment of hypoparathyroidism (HP). Rats that underwent thyroparathyroidectomy (TPTx) by blunt dissection are unable to produce parathyroid hormone, PTH, a major regulator of calcium homeostasis. Therefore, TPTx rats develop hypocalcemia and hyperphosphatemia, which are characteristic of HP. 17-week-old female SD TPTx rats (n = 9 / group) were administered compound 18 (5 μg PTH equivalent / kg / day; 1.2 nmol / kg / day in 10 mM acetic acid, 46 g / L mannitol, pH 4.0), PTH(1-84) (70 μg PTH equivalent / kg / d; 7.3 nmol / kg / day in 10 mM citric acid, 39.0 g / L mannitol, pH 5.0), or vehicle subcutaneously for 28 days. In addition, one group of rats (n = 9) that underwent sham surgery, corresponding to normal physiological background controls, was also given vehicle. Serum calcium (sCa) and phosphorus (sP) levels in these animals were measured before and after administration on days 1, 6, 12, and 27. Furthermore, bone turnover markers (P1NP and CTx) were measured, and bone mass was evaluated ex vivo by pQCT.

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

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

[0511] Abbreviations: ACN Acetonitrile AcOH Acetic acid Aib 2-Aminoisobutyric acid BMD Bone mineral density Bn Benzyl Boc tert-Butyloxycarbonyl COMU (1-Cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate cAMP Cyclic adenosine monophosphate d Day DBU 1,3-Diazabicyclo[5.4.0]undecene DCC N,N'-Dicyclohexylcarbodiimide DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMAP Dimethylamino-pyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DTT Dithiothreitol EDTA Ethylenediaminetetraacetic acid eq Stoichiometric equivalent ESI-MS Electrospray ionization mass spectrometry Et Ethyl Fmoc 9-Fluorenylmethyloxycarbonyl Glu-C Endoproteinase Glu-C h Hour HATU O(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HP Hypoparathyroidism HPLC High performance liquid chromatography ivDde 4,4-Dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl LC Liquid chromatography LTQ Linear trap quadrupole Lys-C Endoproteinase Lys-C LLOQ Lower limit of quantification Mal 3-Maleimidopropyl Me Methyl MeOH Methanol min Minute Mmt Monomethoxytrityl MS Mass spectrum / mass spectrometry m / z Mass-to-charge ratio OtBu tert-Butyloxy PEG Poly(ethylene glycol) pH Hydrogen ion exponent PK Pharmacokinetics Pr Propyl PTH Parathyroid hormone PyBOP Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate Q-TOF Quadrupole time-of-flight type RP-HPLC Reversed-phase high performance liquid chromatography rt Room temperature sCa Serum calcium SIM Single ion monitoring SEC Size exclusion chromatography sc Subcutaneous sP Serum phosphate t 1 / 2 Half-life TCP Trityl chloride polystyrene TES Triethylsilane TFA Trifluoroacetic acid THF Tetrahydrofuran Tmob 2,4,6-Trimethoxybenzyl TPTx Thyroparathyroidectomy Trt Triphenylmethyl, trityl ULOQ Upper limit of quantification UPLC Ultra performance liquid chromatography UV Ultraviolet ZQ Single quadrupole

Claims

1. A pharmaceutical composition comprising at least one controlled-release PTH compound or a pharma- ceutical acceptable salt, hydrate or solvate thereof, for use in the treatment, management, delay or prevention of a condition that can be treated, managed, delayed or prevented with PTH, the pharmaceutical composition being administered no more than once every 24 hours, at a dosage of the controlled-release PTH compound equivalent to no more than 70% of the molar equivalent dose required to maintain serum calcium within normal levels in a human over said 24 hour period for PTH 1-84 administered every 24 hours.

2. 2. The pharmaceutical composition for use according to claim 1, which is administered once every 24 hours.

3. 2. The pharmaceutical composition for use according to claim 1, which is administered once a week.

4. The pharmaceutical composition for use according to any one of claims 1 to 3, which is administered by injection.

5. The pharmaceutical composition for use according to any one of claims 1 to 4, which is administered by subcutaneous injection.

6. The pharmaceutical composition for use according to any one of claims 1 to 5, which is administered by a pen injection.

7. 7. The pharmaceutical composition for use according to any one of claims 1 to 6, wherein said dosage is no more than 60% of the molar equivalent dose of PTH 1-84 required to maintain serum calcium within normal levels over a 24 hour period in humans.

8. The pharmaceutical composition for use according to any one of claims 1 to 7, wherein said PTH compound comprises a PTH molecule or a PTH substructure having the sequence of SEQ ID NO:

51.

9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein the controlled release PTH compound is water insoluble.

10. 10. The pharmaceutical composition for use according to claim 9, wherein said water insoluble controlled release PTH compound comprises at least one PTH molecule non-covalently incorporated into poly(lactic-co-glycolic acid).

11. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein the controlled release PTH compound is water soluble.

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

13. The pharmaceutical composition for use according to any one of claims 1 to 12, having a pH in the range from pH 3 to pH 8.

14. 14. The pharmaceutical composition for use according to any one of claims 1 to 13, wherein the condition is 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 malignancy, osteopenia, periodontal disease, fractures, alopecia, chemotherapy-induced alopecia, and thrombocytopenia.

15. The pharmaceutical composition for use according to any one of claims 1 to 14, wherein the condition is hypoparathyroidism.

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

17. 17. The method of claim 16, wherein the pharmaceutical composition is administered once every 24 hours.

18. 17. The method of claim 16, wherein the pharmaceutical composition is administered once a week.

19. The method according to any one of claims 16 to 18, wherein the pharmaceutical composition is administered by injection.

20. The method according to any one of claims 16 to 19, wherein the pharmaceutical composition is administered by subcutaneous injection.

21. The method according to any one of claims 16 to 20, wherein the pharmaceutical composition is administered by means of a pen injection device.

22. 22. The method of any one of claims 16-21, wherein the pharmaceutical composition is administered no more than once every 24 hours, at a dosage of the controlled release PTH compound that corresponds to no more than 60% of the molar equivalent dose required to maintain serum calcium within normal levels over a 24 hour period for PTH 1-84 administered at the same dosing frequency.

23. 23. The method of any one of claims 16 to 22, wherein the PTH compound comprises a PTH molecule or PTH substructure having the sequence of SEQ ID NO:

51.

24. The method of any one of claims 16 to 23, wherein the controlled release PTH compound is water insoluble.

25. 25. The method of claim 24, wherein the water-insoluble controlled-release PTH compound comprises at least one PTH molecule non-covalently incorporated into poly(lactic-co-glycolic acid).

26. The method of any one of claims 16 to 23, wherein the controlled release PTH compound is water soluble.

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

28. The method according to any one of claims 16 to 27, wherein the pharmaceutical composition has a pH in the range from pH 3 to pH 8.

29. 29. The method of any one of claims 16 to 28, wherein the condition is 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 malignancy, osteopenia, periodontal disease, bone fractures, alopecia, chemotherapy-induced alopecia, and thrombocytopenia.

30. 30. The method of any one of claims 16 to 29, wherein the condition is hypoparathyroidism.

31. The method of any one of claims 16 to 30, wherein the mammalian patient is a human patient.

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