RU2827712C1 - Treatment of hypoparathyroidism - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to treatment of hypoparathyroidism. Disclosed is the use of a PTH compound for the treatment of hypoparathyroidism, treatment includes single daily administrations of the compound to a human patient and avoiding the use of standard therapy for four weeks from the moment of administration of the first dose of the compound, compound PTH is a compound of formula (IIf-i):

where the unmarked dotted line shows the attachment to the N-terminal amine functional group of the PTH fragment having the sequence SEQ ID NO: 51; dotted line marked with an asterisk shows attachment to fragment

,

where m and p are independently integer of 400–500, where the single daily dose is selected from 15 mcg/day, 18 mcg/day, 21 mcg/day, the daily dose of the compound can be adjusted depending on the serum calcium level.

EFFECT: invention provides treating hypoparathyroidism with reduced side effects.

9 cl, 2 tbl, 3 ex

Description

The present invention relates to a PTH compound for use in the treatment of hypoparathyroidism, wherein the treatment comprises single daily administrations of the PTH compound to a patient and avoidance of standard therapy by the patient for four weeks from the time of administration of the first dose of the PTH compound.

PTH regulates extracellular calcium levels in the body within very narrow limits, as well as phosphate homeostasis and bone metabolism. Hypoparathyroidism (HP) is a rare disorder associated with impaired PTH production. Most cases (75-78%) are acquired, secondary to anterior neck surgeries (usually thyroidectomy), in which the parathyroid glands are accidentally damaged or removed. Among patients with chronic HP after total thyroidectomy, the risk of death during an approximately 4-year follow-up is 2-fold higher compared to patients without HP (Almquist, M., et al., Mortality in patients with permanent hypoparathyroidism after total thyroidectomy. Br J Surg, 2018. 105 (10): p. 1313-1318). When serum calcium (sCa) levels fall without compensatory PTH secretion, renal calcium reabsorption and phosphate excretion are reduced. In addition, renal conversion of 25-hydroxyvitamin D to active vitamin D is reduced. Deficiency of active vitamin D results in decreased small intestinal absorption of calcium and phosphate, and deficiency of parathyroid hormone results in decreased bone turnover. The end result is that patients with untreated HP develop hypocalcemia, hyperphosphatemia, and increased urinary calcium excretion along with over-mineralized bone.

The standard of care (SOC) for chronic HP, specifically high-dose active vitamin D and calcium, only corrects hypocalcemia, targeting sCa just below or at the lower end of the normal range to avoid worsening hypercalciuria and is often associated with hypocalcemia until the next dose. Doses of active vitamin D and calcium often exceed 3.0 mcg calcitriol and 3000 mg calcium, the former typically taken 2 to 3 times daily and the latter 4 to 6 times daily. Long-term high-dose active vitamin D and calcium may cause adverse effects beyond the initial problems associated with HP, including increases in urinary calcium-phosphate product and calcium (uCa), which together can lead to nephrocalcinosis, nephrolithiasis, and renal failure, as well as ectopic calcifications. Thus, it would be of great benefit to patients if calcium homeostasis could be maintained in the absence of SOC, for example by providing a continuous physiological level of PTH and maintaining daily food intake with or without calcium supplementation to achieve the recommended daily intake of 1000 to 1200 mg/day for the healthy population. This level of supplementation is necessary to maintain overall calcium homeostasis and balance in the body so that skeletal calcium stores are not depleted over a long period to subsidize serum calcium. This recommended daily intake is necessary to replenish calcium excreted daily via the kidneys and gastrointestinal tract. Some healthy individuals can obtain the recommended intake through diet, i.e. from food sources only, while others - due to dietary preference or individual tolerance, such as dairy intolerance - must rely on calcium supplements in addition to food sources to approach or achieve 1000 to 1200 mg/day. In North America, it is estimated that for adult men and women, the ^25th and ^50th percentiles for dietary calcium intake are 600-800 mg/day from food and thus require an additional 400-600 mg/day when taking calcium tablets. 600 mg is suggested as the threshold because calcium carbonate tablets are commonly available and sold in 600 mg strengths. Thus, 600 mg of calcium per day corresponds to one calcium tablet per day.

Based on published data from the US and Europe, 600 mg is considered an insufficient dose for the treatment of moderate to severe biochemical hypoparathyroidism. Instead, the typical calcium dose for the treatment of hypoparathyroidism is 1500 to 2000 mg per day. Therefore, to ensure the recommended dietary intake of calcium, calcium supplements at a dose of ≤600 mg/day as a dietary supplement to meet the recommended dietary intake are not considered treatment-related.

Achieving the goal of calcium homeostasis in the absence of SOC has been attempted by administering short-acting parathyroid hormone molecules. Both PTH(1-34) and PTH(1-84) are approved for the treatment of osteoporosis and hypoparathyroidism, respectively. Both have been used clinically for the treatment of hypoparathyroidism but have failed to adequately control the disease, in part due to inadequate PTH activity throughout the day. In a double-blind, placebo-controlled, randomized phase 3 study in patients with hypoparathyroidism, patients were randomized to receive 50 mcg/day of PTH(1-84), with a half-life of ~3 hours, or placebo for 24 weeks. Active vitamin D and calcium were gradually decreased, while rhPTH(1-84) could be titrated from 50 mcg to 75 mcg and then to 100 mcg over a 5-week titration period. The primary endpoint was the proportion of patients at week 24 who had a 50% or greater reduction in their daily oral calcium and active vitamin D intake from baseline while maintaining serum calcium at or just below the lower limit of normal (ClinicalTrials.gov number NCT00732615). In this study, only 53% of patients in the rhPTH(1-84) group met the primary endpoint. However, there was no significant difference in urinary calcium excretion or clinical episodes of hypocalcemia, while clinical episodes of hypercalcemia showed a numerical increase with treatment.

Thus, there is a need for a more convenient and safe treatment for hypoparathyroidism with reduced side effects.

Thus, the aim of the present invention is to partially eliminate the disadvantages described above.

This objective is achieved using the PTH compound for the treatment of hypoparathyroidism, wherein the treatment comprises single daily administrations of the PTH compound to the patient and the patient being off standard treatment for four weeks from the time of the first dose of the PTH compound.

According to another aspect, the present invention relates to a method of treating or monitoring a patient, wherein the patient is in need of treatment for hypoparathyroidism, wherein the method comprises the step of administering to said patient single daily doses of a PTH compound and excluding the patient from using standard treatment for four weeks from the time of administration of the first dose of the PTH compound.

It was unexpectedly found that daily administration of the PTH compound, particularly the extended-release PTH formulation, could restore serum calcium levels to normal (8.3-10.6 mg/dL or 2.075-2.65 mmol/L) and provide SOC reversal within only 28 days of starting PTH therapy.

Within the framework of the present invention, terms having the following meaning are used.

As used herein, the term “standard of care” or “SOC” refers to oral administration of calcium and active vitamin D.

As used herein, the phrase "withdrawal of standard treatment" refers to discontinuation of oral calcium and active vitamin D in the case of a daily dietary calcium intake of >750 mg/day, and in the case of a daily dietary calcium intake of ≤750 mg/day, means discontinuation of oral active vitamin D and a reduction in the calcium dose to ≤1000 mg/day, in certain embodiments to ≤630 mg/day, in certain embodiments to ≤500 mg/day while maintaining normal serum calcium levels (from 8.3 to 10.6 mg/dL or from 2.075 to 2.65 mmol/L).

As used herein, the terms "within normal limits" and "within normal range" with respect to serum calcium levels refer to the level of calcium typically found in a subject of a given species, sex, and age, with the range defined by a lower limit of normal and an upper limit of normal. In certain embodiments, in humans, a normal level is a serum calcium level greater than 8.5 mg/dL (albumin-corrected). In humans, the upper limit of normal is 10.5 mg/dL.

As used in this document, the term "serum calcium greater than 8.5 mg/dL" refers to albumin-corrected calcium concentrations.

As used herein, the term "albumin-corrected" in relation to calcium levels means that the measured serum calcium level is corrected for albumin-bound calcium according to the following formula:

albumin-corrected serum calcium (mg/dL) = measured total calcium (mg/dL) + 0.8 (4.0 - serum albumin [g/dL]).

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 fragment that releases at least one PTH molecule or PTH fragment with a half-life of at least 12 hours. In certain embodiments, the half-life is no more than 1 month. In certain embodiments, the half-life is no more than three weeks. In a preferred embodiment, the half-life is no more than two weeks. In your embodiment, the half-life is no more than one week.

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

As used herein, the term "PTH" refers to all PTH polypeptides, in certain embodiments in mammalian species, in certain embodiments in humans and mammalian species, in certain embodiments in humans and mouse species, as well as variants, analogs, orthologs, homologs and derivatives and fragments thereof, which are characterized by increasing serum calcium excretion and renal phosphorus excretion and decreasing serum phosphorus excretion and renal calcium excretion. The term "PTH" also refers to all PTHrPs, such as the polypeptide of SEQ ID NO: 121, which binds to and activates the general PTH/PTHrP1 receptor. Preferably, the term "PTH" refers to the PTH polypeptide of SEQ ID NO: 51, as well as variants, homologs and derivatives thereof that exhibit substantially the same biological activity, i.e. increasing serum calcium and renal phosphorus excretion, and decreasing serum phosphorus and renal calcium excretion.

According to certain embodiments, the term "PTN" refers to the following sequences:

SEQ ID NO: 1 (PTN 1-84)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ

SEQ ID NO:2 (PTH 1-83)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS

SEQIDNO: 3 (PTH 1-82)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK

SEQ ID NO: 4 (PTH 1-81)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA

SEQ ID NO:5 (PTH 1-80)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK

SEQ ID NO: 6 (PTN 1-79)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT

SEQ ID NO:7 (PTH 1-78)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL

SEQ ID NO:8 (PTH 1-77)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV

SEQ ID NO:9 (PTH 1-76)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN

SEQ ID NO:10 (PTH 1-75)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV

SEQ ID NO:11 (PTH 1-74)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD

SEQ ID NO:12 (PTH 1-73)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA

SEQ ID NO:13(PTH1-72)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK

SEQ ID NO:14 (PTH 1-71)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD

SEQ ID NO:15 (PTH 1-70)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA

SEQ ID NO:16 (PTH 1-69)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE

SEQ ID NO:17(PTH1-68)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG

SEQ ID NO:18 (PTH 1-67)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL

SEQ ID NO:19 (PTH 1-66)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS

SEQ ID NO:20 (PTH 1-65)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK

SEQ ID NO:21 (PTH 1-64)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE

SEQ ID NO:22 (PTH 1-63)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH

SEQ ID NO:23(PTH1-62)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES

SEQ ID NO:24(PTH1-61)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE

SEQ ID NO:25 (PTH 1-60)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV

SEQ ID NO:26 (PTH 1-59)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL

SEQ ID NO:27(PTH1-58)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV

SEQ ID NO:28(PTH1-57)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN

SEQ ID NO:29 (PTN 1-56)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED

SEQ ID NO: 30 (PTN 1-55)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE

SEQ ID NO:31 (PTH 1-54)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK

SEQ ID NO:32 (PTH 1-53)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK

SEQ ID NO:33(PTH1-52)

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(PTH1-48)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS

SEQ ID NO:38 (PTH 1-47)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG

SEQ ID NO:39(PTH1-46)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA

SEQ ID NO:40 (PTH 1-45)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD

SEQ ID NO:41 (PTH 1-44)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR

SEQ ID NO:42(PTH1-43)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP

SEQ ID NO:43(PTH1-42)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA

SEQ ID NO:44(PTH1-41)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL

SEQ ID NO:45 (PTH 1-40)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP

SEQ ID NO:46 (PTH 1-39)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA

SEQ ID NO:47(PTH1-38)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG

SEQ ID NO:48 (PTH 1-37)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL

SEQ ID NO:49(PTH1-36)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA

SEQ ID NO:50 (PTH 1-35)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV

SEQ ID NO:51 (PTH 1-34)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF

SEQ ID NO:52(PTH1-33)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN

SEQ ID NO:53(PTH1-32)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH

SEQ ID NO:54(PTH1-31)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV

SEQ ID NO:55 (PTH 1-30)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQD

SEQ ID NO:56 (PTH 1-29)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQ

SEQ ID NO:57(PTH1-28)

SVSEIQLMHNLGKHLNSMERVEWLRKKL

SEQ ID NO:58(PTH1-27)

SVSEIQLMHNLGKHLNSMERVEWLRKK

SEQ ID NO:59(PTH1-26)

SVSEIQLMHNLGKHLNSMERVEWLRK

SEQ ID NO:60 (PTH 1-25)

SVSEIQLMHNLGKHLNSMERVEWLR

SEQ ID NO:61 (amidated PTH 1-84)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ, where the C-terminus is amidated

SEQ ID NO:62 (amidated PTH 1-83)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS, where the C-terminus is amidated

SEQ ID NO:63 (amidated PTH 1-82)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK, where the C-terminus is amidated

SEQ ID NO:64 (amidated PTH 1-81)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA, where the C-terminus is amidated

SEQ ID NO: 65 (amidated PTH 1-80)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK, where the C-terminus is amidated

SEQ ID NO:66 (amidated PTH 1-79)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT, where the C-terminus is amidated

SEQ ID NO:67 (amidated PTH 1-78)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL, where the C-terminus is amidated

SEQ ID NO:68 (amidated PTH 1-77)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV, where the C-terminus is amidated

SEQ ID NO:69 (amidated PTH 1-76)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN, where the C-terminus is amidated

SEQ ID NO: 70 (amidated PTH 1-75)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV, where the C-terminus is amidated

SEQ ID NO: 71 (amidated PTH 1-74)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD, where the C-terminus is amidated

SEQ ID NO: 72 (amidated PTH 1-73)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA, where the C-terminus is amidated

SEQ ID NO: 73 (amidated PTH 1-72)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK, where the C-terminus is amidated

SEQ ID NO: 74 (amidated PTH 1-71)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD, where the C-terminus is amidated

SEQ ID NO: 75 (amidated PTH 1-70)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA, where the C-terminus is amidated

SEQ ID NO: 76 (amidated PTH 1-69)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE, where the C-terminus is amidated

SEQ ID NO: 77 (amidated PTH 1-68)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG, where the C-terminus is amidated

SEQ ID NO: 78 (amidated PTH 1-67)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL, where the C-terminus is amidated

SEQ ID NO: 79 (amidated PTH 1-66)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS, where the C-terminus is amidated

SEQ ID NO: 80 (amidated PTH 1-65)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK, where the C-terminus is amidated

SEQ ID NO: 81 (amidated PTH 1-64)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE, where the C-terminus is amidated

SEQ ID NO: 82 (amidated PTH 1-63)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH, where the C-terminus is amidated

SEQ ID NO: 83 (amidated PTH 1-62)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES, where the C-terminus is amidated

SEQ ID NO: 84 (amidated PTH 1-61)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE, where the C-terminus is amidated

SEQ ID NO: 85 (amidated PTH 1-60)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV, where the C-terminus is amidated

SEQ ID NO: 86 (amidated PTH 1-59)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL, where the C-terminus is amidated

SEQ ID NO: 87 (amidated PTH 1-58)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV, where the C-terminus is amidated

SEQ ID NO: 88 (amidated PTH 1-57)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN, where the C-terminus is amidated

SEQ ID NO:89 (amidated PTH 1-56)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED, where the C-terminus is amidated

SEQ ID NO: 90 (amidated PTH 1-55)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE, where the C-terminus is amidated

SEQ ID NO: 91 (amidated PTH 1-54)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK, where the C-terminus is amidated

SEQ ID NO: 92 (amidated PTH 1-53)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK, where the C-terminus is amidated

SEQ ID NO: 93 (amidated PTH 1-52)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR, where the C-terminus is amidated

SEQ ID NO: 94 (amidated PTH 1-51)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP, where the C-terminus is amidated

SEQ ID NO: 95 (amidated PTH 1-50)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR, where the C-terminus is amidated

SEQ ID NO: 96 (amidated PTH 1-49)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ, where the C-terminus is amidated

SEQ ID NO: 97 (amidated PTH 1-48)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS, where the C-terminus is amidated

SEQ ID NO: 98 (amidated PTH 1-47)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG, where the C-terminus is amidated

SEQ ID NO: 99 (amidated PTH 1-46)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD A, where the C-terminus is amidated

SEQ ID NO: 100 (amidated PTH 1-45)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD, where the C-terminus is amidated

SEQ ID NO: 101 (amidated PTH 1-44)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR, where the C-terminus is amidated

SEQ ID NO: 102 (amidated PTH 1-43)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP, where the C-terminus is amidated

SEQ ID NO: 103 (amidated PTH 1-42)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA, where the C-terminus is amidated

SEQ ID NO: 104 (amidated PTH 1-41)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL, where the C-terminus is amidated

SEQ ID NO: 105 (amidated PTH 1-40)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG AP, where the C-terminus is amidated

SEQ ID NO: 106 (amidated PTH 1-39)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG A, where the C-terminus is amidated

SEQ ID NO: 107 (amidated PTH 1-38)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG, where the C-terminus is amidated

SEQ ID NO: 108 (amidated PTH 1-37)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL, where the C-terminus is amidated

SEQ ID NO: 109 (amidated PTH 1-36)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA, where the C-terminus is amidated

SEQ ID NO: 110 (amidated PTH 1-35)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV, where the C-terminus is amidated

SEQ ID NO: 111 (amidated PTH 1-34)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF, where the C-terminus is amidated

SEQ ID NO: 112 (amidated PTH 1-33)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN, where the C-terminus is amidated

SEQ ID NO: 113 (amidated PTH 1-32)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH, where the C-terminus is amidated

SEQ ID NO: 114 (amidated PTH 1-31)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV, where the C-terminus is amidated

SEQ ID NO: 115 (amidated PTH 1-30)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQD, where the C-terminus is amidated

SEQ ID NO: 116 (amidated PTH 1-29)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQ, where the C-terminus is amidated

SEQ ID NO: 117 (amidated PTH 1-28)

SVSEIQLMHNLGKHLNSMERVEWLRKKL, where the C-terminus is amidated

SEQ ID NO: 118 (amidated PTH 1-27)

SVSEIQLMHNLGKHLNSMERVEWLRKK, where the C-terminus is amidated

SEQ ID NO: 119 (amidated PTH 1-26)

SVSEIQLMHNLGKHLNSMERVEWLRK, where the C-terminus is amidated

SEQ ID NO: 120 (amidated PTH 1-25)

SVSEIQLMHNLGKHLNSMERVEWLR, where the C-terminus is amidated

SEQ ID NO: 121 (PTHrP)

AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEIRATSEVSPNSKPSPNTKNHPVRFGSDDEGRYLTQETNKVETYKEQPLKTPGKKKKGKPGKRKEQEKKKRRTRSAWLDSGVTGSGLEGDHLSDTSTTSLELDSRRH

In certain embodiments, the term "PTH" refers to the sequence of SEQ ID NO: 47, 48, 49, 50, 51, 52, 53, 54, 55, 107, 108, 109, 110, 111, 112, 113, 114, and 115. In certain embodiments, the term "PTH" refers to the sequence of SEQ ID NO: 50, 51, 52, 110, 111, and 112. In certain embodiments, the term "PTH" refers to the sequence of SEQ ID NO: 51.

As used herein, the term "variant of a PTH polypeptide" refers to a sequence from the same species that differs from a reference sequence of PTH or PTHrP. In certain embodiments, such a reference sequence is the PTH sequence of SEQ ID NO: 51. In general, the differences are limited such that the amino acid sequences of the reference sequence and the variant are generally very similar and, in many areas, identical. In certain embodiments, the PTH variants are at least 70%, 80%, 90%, or 95% identical to a reference PTH or PTHrP, in certain embodiments the PTH of SEQ ID NO: 51. By a PTH or PTHrP having an amino acid sequence that is at least, for example, 95% "identical" to a reference amino acid sequence, it is meant that the amino acid sequence is identical to the reference sequence, except that the sequence may include up to five amino acid changes for every 100 amino acids of the reference amino acid sequence. These substitutions in the reference sequence may occur at the amino (N-terminal) or carboxy terminal (C-terminal) positions of the reference amino acid sequence or at any location between these terminal positions, and may be distributed either individually among residues in the reference sequence or as one or more contiguous groups in the reference sequence. The sequence of interest may be either the entire amino acid sequence of the reference sequence or any fragment refined as described herein. According to certain embodiments, the sequence of interest is the sequence of SEQ ID NO: 51.

Such PTH variants may be naturally occurring variants, such as naturally occurring allelic variants encoded by one of several alternative forms of PTH or PTHrP occupying a given locus on a chromosome or organism, or isoforms encoded by naturally occurring splice variants derived from a single primary transcript. Alternatively, a PTH variant may be a variant that is not known to occur in nature and that can be produced by mutagenesis techniques known in the art.

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 protein or peptide without significant loss of biological function. Such N- and/or C-terminal deletions are also encompassed by the term PTH variant.

It is also known to those skilled in the art that certain amino acid sequences of PTH or PTHrP can be altered without significantly affecting the structure or function of PTH or PTHrP. Such mutants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art to have little effect on activity. For example, guidance on how to make phenotypically silent amino acid substitutions is provided in Bowie et al. (1990), SC1ence 247: 1306-1310, which is incorporated herein by reference in its entirety, where the authors indicate that there are two general approaches to studying the tolerance of an amino acid sequence to alteration.

The term PTH also encompasses all PTH and PTHrP sequences encoded by PTH and PTHrP analogs, orthologs, and/or species homologs. Those skilled in the art will also recognize that PTHrP and PTHrP analogs are associated with activation of a common PTH/PTHrP1 receptor, so the term PTH sequence also encompasses all PTHrP analogs. As used herein, the term "PTH analog" refers to PTH and PTHrP from different and unrelated organisms that perform the same functions in each organism, but that are not derived from a generic structure that the organisms' ancestors had. Instead, the analogous PTH and PTHrP arose separately and then evolved to perform the same or similar functions. In other words, the similar sequences PTH and PTHrP are proteins or peptides with completely different amino acid sequences, but which have the same biological activity, namely, increasing serum calcium and renal phosphorus excretion, and decreasing serum phosphorus and renal calcium excretion.

As used herein, the term "PTH homologue" refers to PTH and PTHrP from different organisms that perform the same function in each organism and that are derived from an ancestral structure that the organisms' ancestors had in common. In other words, PTH homologues are proteins or peptides with completely similar amino acid sequences that have the same biological activity, namely, increasing serum calcium and renal phosphorus excretion, and decreasing serum phosphorus and renal calcium excretion. According to certain embodiments, PTH homologues can be defined as proteins or peptides that have at least 40%, 50%, 60%, 70%, 80%, 90%, or 95% identity to a PTH or PTHrP reference protein or peptide, according to certain embodiments, the PTH has the sequence of SEQ ID NO: 51.

Thus, the PTH according to the present invention can be, for example: (i) a PTH in which at least one of the amino acid residues has as a substitute a conserved or non-conserved amino acid residue, preferably a conserved amino acid residue, and such substituted amino acid residue may or may not be encoded by the genetic code; and/or (ii) a PTH in which at least one of the amino acid residues comprises a substituent group; and/or (iii) a PTH in which the PTH sequence is fused to another compound, such as a compound for increasing the half-life of a polypeptide (e.g. polyethylene glycol); and/or (iv) a PTH in which additional amino acids are fused to the PTH sequence, such as a peptide or protein, or a leader or secretory sequence, or a sequence that is used to purify the above-mentioned form of a protein or peptide, or a precursor protein sequence.

As used herein, the term "PTH fragment" refers to any protein or peptide comprising a consecutive span of a portion of the amino acid sequence of PTH or PTHrP, according to certain embodiments of the sequence of SEQ ID NO: 51.

More particularly, a fragment of a PTH polypeptide comprises at least 6, such as at least 8, at least 10 or at least 17 consecutive amino acids of a PTH or PTHrP sequence, according to certain embodiments of the sequence of SEQ ID NO: 51. A fragment of PTH can be further described as a subspecies of PTH or PTHrP sequences comprising at least 6 amino acids, where "at least 6" is defined as an integer between 6 and an integer denoting the C-terminal amino acid of a PTH or PTHrP sequence, preferably the sequence of SEQ ID No: 51. Also included are species of PTH or PTHrP fragments of at least 6 amino acids in length, as described above, which are further specified in terms of their N-terminal and C-terminal positions. Also encompassed by the term "PTH fragment" as a separate species are all fragments of PTH or PTHrP of at least 6 amino acids in length, as described above, which may be particularly specified by their N-terminal and C-terminal position. That is, each combination of N-terminal and C-terminal position that a component of at least 6 consecutive amino acid residues in length may occupy, on any given amino acid sequence of PTH or PTHrP, according to certain embodiments of the PTH polypeptide of the sequence SEQ ID: NO 51, is included in the present invention.

The term "PTH" also includes poly(amino acid) conjugates that have a sequence as described above, but have a backbone that contains both amide and non-amide linkages, such as ester linkages, such as depsipeptides. Depsipeptides are chains of amino acid residues in which the backbone contains both amide (peptide) and ester linkages. Accordingly, the term "side chain" as used herein refers to either a moiety attached to the alpha carbon atom of an amino acid moiety if the amino acid moiety is linked via amine linkages, such as in polypeptides, or to any carbon atom-containing moiety attached to the backbone of a poly(amino acid) conjugate, such as in the case of depsipeptides. In certain embodiments, Preferably, the term "PTH" refers to sequences having a backbone formed via amide (peptide) linkages.

Since the term PTH includes the above-described variants, analogs, orthologs, homologs, derivatives and fragments of PTH and PTHrP, all references to specific positions in the reference sequence also include equivalent positions in variants, analogs, orthologs, homologs, derivatives and fragments of the PTH or PTHrP molecule or fragment, even if not specifically stated.

As used herein, the term "peptide" refers to a chain of at least 2 and up to and including 50 monomeric amino acid units, which may also be referred to as "amino acid residues", linked by peptide (amide) bonds. The amino acid monomers may be selected from the group consisting of proteinogenic amino acids and non-proteinogenic amino acids and may be D- or L-amino acids. The term "peptide" also includes peptidomimetics such as peptoids, beta-peptides, cyclic peptides and depsipeptides, and encompasses such peptidomimetic chains containing up to and including 50 monomeric units.

As used herein, the term "protein" refers to a chain of more than 50 amino acid monomer units, which may also be referred to as "amino acid residues", linked by peptide bonds, in which preferably no more than 12,000 amino acid monomer units are linked by peptide bonds, such as no more than 10,000 amino acid monomer units, no more than 8,000 amino acid monomer units, no more than 5,000 amino acid monomer units, or no more than 2,000 amino acid monomer units.

As used herein, the term “physiological conditions” refers to an aqueous buffer with a pH of 7.4, 37°C.

The term "pharmaceutical composition" as used herein refers to a composition comprising one or more active ingredients, such as, for example, at least one PTH compound and one or more excipients, as well as any product that directly or indirectly results from the combination, complexation or aggregation of any two or more ingredients of the composition, or the dissociation of one or more ingredients, or other types of reactions or interactions of one or more ingredients. Accordingly, a pharmaceutical composition for use according to the present invention includes any composition obtained by mixing one or more PTH compounds and a pharmaceutically acceptable excipient.

As used herein, the term "excipient" refers to a diluent, adjuvant, or vehicle with which a therapeutic agent such as a drug or prodrug is administered. Such a pharmaceutical excipient may be a sterile liquid such as water and oils, including liquids of petroleum, animal, vegetable, or synthetic origin, including, but not limited to, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is a preferred excipient when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are preferred vehicles when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably used as liquid excipients for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dry milk, glycerin, propylene glycol, water, ethanol, and the like. The pharmaceutical composition may optionally also contain small amounts of wetting or emulsifying agents, pH buffering agents such as, for example, acetate, succinate, tris, carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, MES (2-(N-morpholine)ethanesulfonic acid) or may contain detergents such as Tween, poloxamers, poloxamines, CHAPS, Igepal, or amino acids such as, for example, glycine, lysine or histidine. Such pharmaceutical formulations may be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release preparations and the like. The pharmaceutical composition may be in the form of a suppository, with conventional binders and excipients such as triglycerides. The oral formulation may contain standard excipients such as pharmaceutical grades mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such compositions contain a therapeutically effective amount of the drug or biologically active fragment, together with a suitable amount of excipient, so as to obtain a form suitable for administration to a patient. The composition must be appropriate for the route of administration.

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

The term "suspension composition" refers to a mixture comprising at least one PTH compound and one or more solvents, such as water.

As used in the present application, the term "dry composition" means that the pharmaceutical composition is provided in dry form. Suitable drying methods are spray drying and lyophilization, i.e. freeze drying. Such a dry prodrug composition has a residual water content of maximum 10%, preferably less than 5% and more preferably less than 2%, as determined by the Karl Fischer method. According to certain embodiments, such a dry pharmaceutical composition according to the present invention is dried by lyophilization.

The term "drug" as used in this application refers to a substance used to treat, alleviate, prevent or diagnose a disease or otherwise improve physical or mental health. If a drug is conjugated to another moiety, the moiety of the resulting product that is derived from the drug is referred to as a "biologically active moiety".

As used herein, the term "prodrug" refers to a covalent conjugate in which a drug moiety is reversibly and covalently linked to a specialized protecting group through a reversible linker moiety, also referred to as a "reversible linker moiety of a prodrug" or "reversible linker moiety", which is reversibly linked to a biologically active moiety, and where the specialized protecting group modifies or eliminates undesirable properties of the parent molecule. This includes enhancing the desired properties of the drug and suppressing undesirable properties. The specialized non-toxic protecting group is referred to as a "carrier". The prodrug releases the reversibly and covalently linked drug moiety in the form of its corresponding drug. In other words, a prodrug is a conjugate comprising a drug moiety that is covalently and reversibly conjugated to a carrier moiety via a reversible linker moiety, wherein the covalent and reversible conjugation of the carrier to the reversible linker moiety occurs either directly or via a spacer. Such a conjugate releases the previously conjugated drug moiety as free, unmodified drug.

The terms "biodegradable linkage" or "reversible linkage" mean a linkage that is hydrolytically degradable, i.e. cleavable, in the absence of enzymes under physiological conditions (aqueous buffer at pH 7.4, 37°C) with a half-life in the range of from one hour to three months, in certain embodiments from one hour to two months, in certain embodiments from one hour to one month, in certain embodiments from one hour to three weeks, in certain embodiments from one hour to two weeks, in certain embodiments from 12 hours to two weeks, in certain embodiments from 12 hours to one week. Accordingly, a stable linkage is a linkage that has a half-life under physiological conditions (aqueous buffer at pH 7.4, 37°C) of greater than two months.

As used in this application, the term "traceless prodrug linker" means a reversible prodrug linker that, when cleaved, releases the drug in its free form. As used in this application, the term "free form" of a drug means the drug in its unmodified, pharmacologically active form.

As used in this application, the term "reagent" means a chemical compound that contains at least one functional group for reaction with a functional group of another chemical compound or a drug. It is understood that a drug containing a functional group (such as a primary or secondary amine or a hydroxyl functional group) is also a reagent.

As used in this application, the term "moiety" means a portion of a molecule that is missing one or more atoms compared to the corresponding reactant. If, for example, a reactant of the formula "H-X-H" reacts with another reactant and becomes part of a reaction product, the corresponding moiety of the reaction product has the structure "H-X-" or "-X-", where each "-" denotes attachment to another moiety. Accordingly, the biologically active moiety is released from the prodrug as a drug.

It is understood that if a sequence or chemical structure of a group of atoms is provided where the group of atoms is attached to two constituents or interrupts a constituent, said sequence or structure may be attached to the two constituents in any orientation unless otherwise specified. For example, the moiety "-C(O)N(R ¹² )-" may be attached to two constituents or interrupts a moiety as either "-C(O)N(R)-" or "-N(R)C(O)-". Similarly, the moiety

can be attached to two fragments or can interrupt a fragment either

or like this

As used in this application, the term "functional group" means a group of atoms that can react with other groups of atoms. Functional groups include, but are not limited to, the following groups: carboxylic acid (-(C=O)OH), primary and secondary amine (-NH2, -NH-), maleimide, thiol (-SH), sulfonic acid (-(O=S=O)OH), carbonate, carbamate (-O(C=O)N<), hydroxyl (-OH), aldehyde (-(C=O)H), ketone (-(C=O)-), hydrazine (>N-N<), isocyanate, isothiocyanate, phosphoric acid (O(P=O)OHOH), phosphonic acid (-O(P=O)OHH), haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, disulfide, sulfonamides, sulfuric acid, vinyl sulfone, vinyl ketone, diazoalkane, oxirane, and aziridine.

In case the PTH compound contains one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically acceptable salts. Thus, the PTH compound for use according to the present invention containing acidic groups can be present and used in the form of alkali metal salts, alkaline earth metal salts or ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, amino acids and other salts or amines known to those skilled in the art. The PTH compound containing one or more basic groups, i.e. groups that can be protonated, can be present and used according to the present invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivaloic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids known to those skilled in the art. Those skilled in the art are familiar with the transformation of a basic group into a cation, such as alkylation of an amine group to produce a positively charged ammonium group and the corresponding counterion of the salt. If the PTH compound simultaneously contains acidic and basic groups, the present invention also includes, in addition to the mentioned salt forms, internal salts or betaines (zwitterions). The corresponding salts can be prepared by conventional methods that are known to those skilled in the art, for example by contacting these prodrugs with an organic or inorganic acid or base in a solvent or dispersant, or by anion or cation exchange with other salts. The present invention also covers all salts of the compounds for use according to the present invention, which, due to low physiological compatibility, are not suitable for direct use in pharmaceutical preparations, but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

As used in this document, the term “pharmaceutically acceptable” means a substance that does not cause harm when administered to a patient and, of course, means approved by a regulatory authority such as the EMA (Europe) and/or FDA (USA) and/or any other national regulatory agency for use in animals, preferably in humans.

As used in this application, the term "about" in combination with a numerical value is used to indicate a range of between and including the numerical value plus or minus no more than 10% of the stated numerical value, in certain embodiments no more than 8% of the stated numerical value, in certain embodiments no more than 5% of the stated numerical value, and in certain embodiments no more than 2% of the stated numerical value. For example, the phrase "about 200" is used to indicate a range of between and including 200 +/- 10%, i.e., between and including 180-220, in certain embodiments 200 +/- 8%, i.e., between and including 184-216, in certain embodiments, between and including 200 +/- 5%, i.e., in the range and including 190-210, and according to certain embodiments 200 +/- 2%, i.e. in the range and including 196-204. It is understood that a percentage given as "about 20%" does not mean "20% +/- 10%", i.e. in the range and including 10-30%, but "about 20%" means in the range and including 18-22%, i.e. plus and minus 10% of the numerical value, which is 20.

As used in the present application, the term "polymer" means a molecule comprising repeating structural units, i.e. monomers linked by chemical bonds in a linear, ring, branched, cross-linked or dendrimeric manner or a combination thereof, which may be of synthetic or biological origin or a combination of both. It is understood that the polymer may also comprise one or more other chemical groups and/or moieties, such as, for example, one or more functional groups. Preferably, the soluble polymer has a molecular weight of at least 0.5 kDa, such as a molecular weight of at least 1 kDa, a molecular weight of at least 2 kDa, a molecular weight of at least 3 kDa, or a molecular weight of at least 5 kDa. If the polymer is soluble, it has, according to certain embodiments, a molecular weight of at most 1000 kDa, such as at most 750 kDa, such as at most 500 kDa, such as at most 300 kDa, such as at most 200 kDa, such as at most 100 kDa. It is understood that for water-insoluble polymers, such as hydrogels, meaningful molecular weight ranges cannot be provided. It is understood that a peptide or protein is also a polymer in which amino acids are repeating structural units, although the side chains of each amino acid may be different.

As used herein, the term "polymeric" or "polymer moiety" means a reactant or moiety comprising one or more polymers or polymer moieties. The polymeric reactant or moiety may optionally also comprise one or more other moieties that, according to certain embodiments, are selected from the group consisting of:

• C _1-50 alkyl, C _2-50 alkenyl, C _2-50 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and

• links selected from a group containing

Where

dotted lines show attachment to the rest of the fragment or reagent, and

-R and ^-Ra are independently selected from the group consisting of -H, 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.

One skilled in the art understands that the polymerization products obtained from a polymerization reaction do not all have the same molecular weight, but rather have a molecular weight distribution. Therefore, molecular weight ranges, molecular weights, ranges of the number of monomers in a polymer, and the number of monomers in a polymer, as used in this application, refer to the number average molecular weight and the average number of monomers, i.e., the arithmetic mean of the molecular weight of the polymer or polymer fragment and the arithmetic mean of the number of monomers of the polymer or polymer fragment.

Accordingly, in a polymer moiety comprising "x" monomer units, any integer given for "x" therefore corresponds to the arithmetic average number of monomers. Any range of integers given for "x" provides the range of integers in which the arithmetic average number of monomers lies. An integer given for "x" as "about x" means that the arithmetic average numbers of monomers lie in the integer range of x +/- 10%, preferably x +/- 8%, in certain embodiments lie in the integer range of x +/- 5%, and in certain embodiments lie in the integer range of x +/- 2%.

As used in this application, the term "number average molecular weight" means the simple arithmetic mean of the molecular weights of the individual polymers.

As used in this application, the term "water-soluble" with reference to a carrier means that when such carrier is part of a PTH compound for use in the present invention, at least 1 g of the PTH compound containing such water-soluble carrier can be dissolved in one liter of water at 20°C to form a homogeneous solution. Accordingly, the term "water-insoluble" with reference to a carrier means that when such carrier is part of a PTH compound for use in the present invention, less than 1 g of the PTH compound containing such water-soluble carrier can be dissolved in one liter of water at 20°C to form a homogeneous solution.

As used in this application, the term "water-soluble" with reference to a carrier means that at least 1 g of the PTH compound can be dissolved in one liter of water at 20°C to form a homogeneous solution. Accordingly, the term "water-insoluble" with reference to the PTH compound means that less than 1 g of the PTH compound can be dissolved in one liter of water at 20°C to form a homogeneous solution.

As used herein, the term "PEG-based" with respect to a moiety or reagent means that said moiety or reagent comprises PEG. According to certain embodiments, the PEG-based reagent comprises at least 10% (w/w) PEG, such as at least 20% (w/w) PEG, such as at least 30% (w/w) PEG, such as at least 40% (w/w) PEG, such as at least 50% (w/w), such as at least 60% (w/w) PEG, such as at least 70% (w/w) PEG, such as at least 80% (w/w) PEG, such as at least 90% (w/w) PEG, such as at least 95% (w/w) PEG. The remaining weight percent of the PEG-based moiety or reactant is other moieties, in certain embodiments selected from the following moieties and linkages:

• C _1-50 alkyl, C _2-50 alkenyl, C _2-50 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and

• links selected from a group containing

Where

dotted lines show attachment to the rest of the fragment or reagent, and

-R and ^-Ra are independently selected from the group consisting of -H, 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.

As used herein, the term "PEG-based comprising at least X% PEG" with respect to a moiety or reactant means that said moiety or reactant comprises at least X% (w/ _{w) ethylene glycol units (-CH2CH2O- )} , wherein the ethylene glycol units may be arranged in a block, alternating, or random fashion in the moiety or reactant, and preferably all of the ethylene glycol units of said moiety or reactant are present in a single block, the remaining weight percent of the PEG-based moiety or reactant being other moieties, in certain embodiments selected from the following moieties and linkages:

• C _1-50 alkyl, C _2-50 alkenyl, C _2-50 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and

• links selected from a group containing

Where

dotted lines show attachment to the rest of the fragment or reagent, and

-R and ^-Ra are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.

The term "hyaluronic acid based, containing at least X% hyaluronic acid" is used accordingly.

As used herein, the term "substituted" means that one or more hydrogen atoms in a molecule or moiety are replaced by another atom or group of atoms, which are called "substituents."

According to certain embodiments, one or more additional optional substituents are independently selected from the group consisting of 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, wherein -T ⁰ , C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally substituted by one or more -R ^x2 , which are the same or different, and wherein the C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally interrupted by 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 )-,

-R ^x1 , -R ^x1a , -R ^x1b are independently selected from the group consisting of -H, -T ⁰ , C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl, wherein -T ⁰ , C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally substituted with one or more -R ^x2 , which are the same or different, and wherein the C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally interrupted by 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 )-,

each T ⁰ is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl, wherein each T ⁰ is independently optionally substituted with one or more -R ^x2 that are the same or different,

each -R ^x2 is independently selected from the group consisting of 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, wherein C _1-6 alkyl is optionally substituted with one or more halogens which are the same or different,

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 C _1-6 alkyl is optionally substituted with one or more halogens that are the same or different.

According to certain embodiments, one or more additional optional substituents are independently selected from the group consisting of 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 _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, wherein -T ⁰ , C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl are optionally substituted by one or more -R ^x2 , which are the same or different, and wherein the C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl are optionally interrupted by 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 )-,

each -R ^x1 , -R ^x1a , -R ^x1b , -R ^x3 , -R ^x3a is independently selected from the group consisting of -H, halogen, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl,

each T ⁰ is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl, wherein each T ⁰ is independently optionally substituted with one or more -R ^x2 that are the same or different,

each -R ^x2 is independently selected from the group consisting of 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)2R ^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, wherein C _1-6 alkyl is optionally substituted with one or more halogens which are the same or different,

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,

According to certain embodiments, one or more additional optional substituents are independently selected from the group consisting of 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)2R ^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 _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, wherein -T°, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted by one or more -R ^x2 , which are the same or different, and wherein the C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally interrupted by 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)r, -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 )- ,

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, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl, wherein each T ⁰ is independently optionally substituted with one or more -R ^x2 that are the same or different.

According to certain embodiments, up to 6 -H atoms of the optionally substituted molecule are independently substituted with a substituent, such as 5 -H atoms are independently substituted with a substituent, 4 -H atoms are independently substituted with a substituent, 3 -H atoms are independently substituted with a substituent, 2 -H atoms are independently substituted with a substituent, or 1 -H atom is substituted with a substituent.

As used herein, the term "interrupted" means that the moiety is inserted between two carbon atoms or, if the insertion is at one end of the moiety, between a carbon or heteroatom and a hydrogen atom, in certain embodiments between a carbon atom and a hydrogen atom.

As used herein, the term "C _1-4 alkyl" by itself or in combination means a straight or branched alkyl moiety having from 1 to 4 carbon atoms. When present at the end of a molecule, examples of straight or branched C _1-4 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. When two moieties of a molecule are linked 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 a C _1-4 alkyl carbon may optionally be substituted with a substituent as defined above. Optionally, the C _1-4 alkyl may be interrupted by one or more moieties as defined below.

As used herein, the term "C _1-6 alkyl" by itself or in combination means a straight or branched alkyl moiety having from 1 to 4 carbon atoms. When present at the end of a molecule, examples of straight or branched C _1-6 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylpropyl. When two moieties of the molecule are linked 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 on a C _1-6 carbon atom may optionally be substituted with a substituent as defined above. Optionally, the C _1-6 alkyl may be interrupted by one or more moieties as defined below.

Accordingly, "C _1-10 alkyl", "C _1-20 alkyl" or "C _1-50 alkyl" means an alkyl chain having from 1 to 10, from 1 to 20 or from 1 to 50 carbon atoms, respectively, wherein each hydrogen atom on a C _1-10 , C _1-20 or C _1-50 carbon atom may optionally be substituted with a substituent as defined above. Optionally, C _1-10 or C _1-50 alkyl may be interrupted by one or more moieties as defined below.

As used herein, the term "C _2-6 alkenyl" by itself or in combination means a straight or branched hydrocarbon moiety containing at least one carbon-carbon double bond having from 2 to 6 carbon atoms. 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 moieties of the molecule are linked by a C _2-6 alkenyl group, then an example of such a C _2-6 alkenyl is -CH=CH-. Each hydrogen atom of the C _2-6 alkenyl moiety may optionally be substituted with a substituent as defined above. Optionally, the C _2-6 alkenyl may be interrupted by one or more moieties as defined below.

Accordingly, the term " _C2-10 alkenyl,"" _C2-20 alkenyl," or " _C2-50 alkenyl" by itself or in combination means a straight or branched hydrocarbon moiety containing at least one carbon-carbon double bond, having from 2 to 10, from 2 to 20, or from 2 to 50 carbon atoms. Each hydrogen atom of a _C2-50 alkenyl, _C2-20 alkenyl, or _C2-50 alkenyl group may optionally be substituted with a substituent as defined above. Optionally, a _C2-10 alkenyl, _C2-20 alkenyl, or _C2-50 alkenyl may be interrupted by one or more moieties as defined below.

As used herein, the term "C _2-6 alkynyl" by itself or in combination means a straight or branched hydrocarbon moiety containing at least one carbon-carbon triple bond having from 2 to 6 carbon atoms. 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 . When two moieties of the molecule are linked by an alkynyl group, then an example is -C≡C-. Each hydrogen atom of the C _2-6 alkynyl group may optionally be substituted with a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, the C _2-6 alkynyl may be interrupted by one or more moieties as defined below.

Accordingly, as used herein, the term " _C2-10 alkynyl", " _C2-20 alkynyl" and " _C2-50 alkynyl" by itself or in combination means a straight or branched hydrocarbon moiety containing at least one carbon-carbon triple bond having from 2 to 10, from 2 to 20 or from 2 to 50 carbon atoms, respectively. Each hydrogen atom of a _C2-10 alkynyl, _C2-20 alkynyl or _C2-50 alkynyl group may optionally be substituted with a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, a _C2-10 alkynyl, _C2-20 alkynyl or _C2-50 alkynyl may be interrupted by one or more moieties as defined below.

As indicated 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 _2-30 alkenyl, C _2-6 alkynyl, C _2-10 alkynyl, C _2-20 alkenyl or C _2-50 alkynyl may optionally be interrupted by one or more moieties which are preferably selected from the group consisting of

Where

dotted lines show attachment to the rest of the fragment or reagent, and

-R and ^{-Ra are} independently selected from the group consisting of -H, 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.

As used herein, the term " _C3-10 cycloalkyl" means a cyclic alkyl chain having from 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 _C3-10 cycloalkyl carbon may be substituted with a substituent as defined above. The term " _C3-10 cycloalkyl" also includes bridged bicycles such as norbornane or norbornene.

The term "8-30 membered carbopolycyclyl" or "8-30 membered carbopolycycle" means a cyclic moiety of two or more rings with 8-30 ring atoms, wherein two adjacent rings share at least one ring atom, and which may contain up to a maximum number of double bonds (aromatic or non-aromatic ring that is fully saturated, partially unsaturated or unsaturated). According to certain embodiments, an 8-30 membered carbopolycyclyl means a cyclic moiety of two, three, four or five rings, more preferably two, three or four rings.

As used in this application, the term "3- to 10-membered heterocyclyl" or "3- to 10-membered heterocycle" means a ring with 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms that may contain up to the maximum number of double bonds (an aromatic or non-aromatic ring that is fully saturated, partially unsaturated or unsaturated), wherein at least one ring atom to four ring atoms are substituted with a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O) _2- ), oxygen and nitrogen (including =N(O)-), and wherein the ring is bonded to the remainder of the molecule through a carbon or nitrogen atom. Examples of 3-10 membered heterocycles include, but are not limited to, aziridine, oxirane, thirane, 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, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine. Each hydrogen atom of a 3- to 10-membered heterocyclyl or 3- to 10-membered heterocyclic group may be substituted with a substituent as defined below.

As used herein, the term "8-11 membered heterobicyclyl" or "8-11 membered heterobicycle" means a heterocyclic moiety of two rings with 8-11 ring atoms, wherein at least one ring atom is shared between the two rings and which contains up to the maximum number of double bonds (an aromatic or non-aromatic ring that is fully saturated, partially unsaturated or unsaturated), wherein at least one ring atom up to six ring atoms are substituted with a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O) _2- ), oxygen and nitrogen (including =N(O)-), and wherein the ring is bonded to the remainder of the molecule through a carbon or nitrogen atom. Examples of 8-11 membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term 8-11 membered heterobicycle also includes spiro structures of two rings such as 1,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles such as 8-azabicyclo[3.2.1]octane. Each hydrogen atom of an 8- to 11-membered heterobicyclyl or 8- to 11-membered heterobicycle may be substituted with a substituent as defined below.

Similarly, the term "8- to 30-membered heteropolycyclyl" or "8- to 30-membered heteropolycycle" means a heterocyclic moiety of more than two rings with 8-30 ring atoms, preferably three, four or five rings, wherein two adjacent rings share at least one ring atom, and which may contain up to a maximum number of double bonds (an aromatic or non-aromatic ring that is fully saturated, partially unsaturated or unsaturated), wherein at least one ring atom up to 10 ring atoms are substituted with a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O) _2- ), oxygen and nitrogen (including =N(O)-), and wherein the ring is bonded to the remainder of the molecule through a carbon or nitrogen atom.

It is understood that the phrase "the pair R ^x /R ^y combines with the atom to which they are attached to form a C3-10 cycloalkyl or a 3-10-membered heterocyclyl" in relation to a fragment of the structure

means that R ^x and R ^y form the following structure:

where R is C _3-10 cycloalkyl or 3-10 membered heterocyclyl.

It is also clear that the phrase "the pair R ^x /R ^y " joins together with the atom to which they are attached to form a ring A" in relation to the fragment of the structure

means that R ^x and R ^y form the following structure:

As used in this application, "halogen" means fluorine, chlorine, bromine, or iodine. In certain embodiments, a halogen is fluorine or chlorine.

In general, the term "comprise" or "comprising" also includes "consists of" or "consisting of."

In certain embodiments, the withdrawal of standard therapy by the patient occurs within four weeks of the first dose of the PTH compound being administered. In certain embodiments, the withdrawal of standard therapy by the patient occurs within three weeks of the first dose of the PTH compound being administered. In certain embodiments, the withdrawal of standard therapy by the patient occurs within two weeks of the first dose of the PTH compound being administered. In certain embodiments, the withdrawal of standard therapy by the patient occurs within two weeks of the first dose of the PTH compound being administered. In certain embodiments, the withdrawal of standard therapy by the patient occurs within 12 days of the first dose of the PTH compound being administered. In certain embodiments, the withdrawal of standard therapy by the patient occurs within 10 days of the first dose of the PTH compound being administered.

In certain embodiments, the administration of the PTH compound is by injection, such as intramuscular, intravenous, or subcutaneous injection. In certain embodiments, the administration is an intramuscular injection. In certain embodiments, the administration is an intravenous injection. In certain embodiments, the administration is a subcutaneous injection.

According to certain embodiments, the administration is performed by means of a syringe. According to certain embodiments, the administration is performed by means of a syringe pen. According to certain embodiments, the administration is performed by means of an automatic injector.

In certain embodiments, the patient, such as a mammal, is selected from a mouse, a rat, a non-human primate, and a human. In certain embodiments, the patient is a human. In certain embodiments, the patient is a child. In certain embodiments, the patient is an adult.

In certain embodiments, a single dose of the PTH compound administered to the patient is less than 31 mcg/day. In certain embodiments, a single dose of the PTH compound administered to the patient is 30 mcg/day. In certain embodiments, a single dose of the PTH compound administered to the patient is 27 mcg/day. In certain embodiments, a single dose of the PTH compound administered to the patient is 24 mcg/day. In certain embodiments, a single dose of the PTH compound administered to the patient is 18 mcg/day. In certain embodiments, a single dose of the PTH compound administered to the patient is 15 mcg/day. In certain embodiments, a single dose of the PTH compound administered to the patient is 12 mcg/day. In certain embodiments, a single dose of the PTH compound administered to a patient is 9 mcg/day. In certain embodiments, a single dose of the PTH compound administered to a patient is 6 mcg/day. All doses are presented as PTH equivalents. It is understood that the amount of the PTH compound administered to a patient depends on the patient and the severity of the disease.

In certain embodiments, the daily dose of the PTH compound administered to the patient is adjusted based on serum calcium levels, such as to avoid hypocalcemia. If serum calcium levels are adequate, the daily dose of the PTH compound may not need to be adjusted.

According to certain embodiments, a patient treated for hypoparathyroidism according to the present invention achieves a statistically significant change in the Short Form Physical Health Score-36 (SF-36 PCS), the Mental Health Score (MCS), or both the SF-36 PCS and the SF-36 MCS 4 weeks after administration of the first dose of a PTH compound. Such a change is measured from the corresponding baseline (BL). As used herein, the term "baseline" refers to the SF-36 PCS or SF-36 MCS numerical scores of the corresponding patient or group of patients before the start of treatment. A change is considered statistically significant if the p-value is equal to or lower than 0.05. According to certain embodiments, such a statistically significant change compared to the BL is a change of at least 3, in particular at least 4. Both the SF-36 PCS and the SF-36 MCS score are generated using a normative scoring system with a score of 50 as the population norm. Unless otherwise stated, figures are not adjusted for placebo, i.e. the change in the corresponding SF-36 component achieved in the placebo group over the same time period is not subtracted.

In certain embodiments, the SF-36 PCS is improved by at least 4 (not placebo adjusted) or at least 5 (placebo adjusted). In certain embodiments, the SF-36 MCS is improved by at least 5 (not placebo adjusted) or at least 6 (placebo adjusted), such as at least 7 or at least 8.

According to certain embodiments, the PTH compound comprises a PTH fragment 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 fragment 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. In certain embodiments, the PTH fragment has the sequence of SEQ ID NO: 50. In certain embodiments, the PTH fragment has the sequence of SEQ ID NO: 52. In certain embodiments, the PTH fragment has the sequence of SEQ ID NO: 110. In certain embodiments, the PTH fragment has the sequence of SEQ ID NO: 111. In certain embodiments, the PTH fragment has the sequence of SEQ ID NO: 112. In certain embodiments, the PTH fragment has the sequence of SEQ ID NO: 51.

According to certain embodiments, the PTH compound is water soluble.

According to a particular embodiment, the PTH compound is a conjugate or a pharmaceutically acceptable salt thereof comprising at least one -D moiety conjugated via at least one ^-L1 - ^L2- moiety to at least one Z moiety, wherein the bond between -D and ^-L1- is reversible and wherein the ^-L2- moiety is conjugated to Z, wherein each -D is independently a PTH moiety, each ^-L1- is independently a reversible linker moiety, each ^-L2- is independently a single chemical bond or a spacer moiety, and each Z is independently a polymeric moiety or a _C8-24 alkyl moiety.

In certain embodiments, the PTH compound is a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

Where

-D is a fragment of PTH,

-L ¹ - is a linker fragment reversibly or covalently linked to the PTH -D fragment via the PTH functional group,

-L ² - is a simple chemical bond or spacer fragment,

-Z represents a polymeric moiety or a C _8-24 alkyl 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, and

y is an integer selected from the group consisting of 2, 3, 4, and 5.

It is understood that the compounds of formula (Ia) and (Ib) are prodrugs of PTH. Such prodrugs of PTH are controlled-release compounds of PTH.

In certain embodiments, the PTH compound is a compound of formula (Ia). In certain embodiments, the PTH compound is a compound of formula (Ib).

In certain embodiments, -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. In certain embodiments, -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. According to certain embodiments, -D has the sequence of SEQ ID NO: 50. According to certain embodiments, -D has the sequence of SEQ ID NO: 52. According to certain embodiments, -D has the sequence of SEQ ID NO: 110. According to certain embodiments, -D has the sequence of SEQ ID NO: 111. According to certain embodiments, -D has the sequence of SEQ ID NO: 112. According to certain embodiments, -D has the sequence of SEQ ID NO: 51.

The -L ¹ - moiety is either conjugated to a side chain functional group of an amino acid residue -D, to an N-terminal amine functional group or to a C-terminal carboxyl functional group of -D, or to a nitrogen atom of the polypeptide backbone -D. Attachment to either the N-terminus or the C-terminus can be either directly via the corresponding amine or carboxyl functional group, respectively, or indirectly, when the spacer moiety is first conjugated to the amine or carboxyl functional group to which the spacer moiety -L ¹ - is conjugated. In certain embodiments, -L ¹ - is conjugated to a side chain functional group of an amino acid residue -D. In certain embodiments, -L ¹ - is conjugated to an N-terminal amine functional group. In certain embodiments, -L ¹ - is conjugated to a C-terminal carboxyl functional group. According to certain embodiments, -L ¹ - is conjugated to a nitrogen atom in the polypeptide backbone of -D.

According to certain embodiments, the amino acid residue of PTH to which -L ¹ - is conjugated comprises a functional group selected from the group consisting of a carboxylic acid, a primary and secondary amine, a maleimide, a thiol, a sulfonic acid, a carbonate, a carbamate, a hydroxyl, an aldehyde, a ketone, a hydrazine, an isocyanate, an isothiocyanate, a phosphoric acid, a phosphonic acid, a haloacetyl, an alkyl halide, an acryloyl, an aryl fluoride, a hydroxyl amine, a sulfate, a disulfide, a vinyl sulfone, a vinyl ketone, a diazoalkane, an oxirane, a guanidine, and an aziridine. According to certain embodiments, the amino acid residue of PTH to which -L ¹ - is conjugated comprises a functional group selected from the group consisting of a hydroxyl, a primary and secondary amine, and a guanidine. In certain embodiments, the amino acid residue of PTH to which -L ¹ - is conjugated comprises a primary or secondary amine functional group. In certain embodiments, the amino acid residue of PTH to which -L ¹ - is conjugated comprises a primary amine functional group.

If the -L ¹ - moiety is conjugated to a side chain functional group of an amino acid residue of PTH, said amino acid residue is selected from the group consisting of proteogenic amino acid residues and non-proteogenic amino acid residues. According to certain embodiments, -L ¹ - is conjugated to a side chain functional group of a non-proteogenic amino acid residue of PTH. It is understood that such a non-proteogenic amino acid is not found in the sequence of natural PTH or fragments thereof and that it can only be present in PTH variants and analogs. According to certain embodiments, -L ¹ - is conjugated to a side chain functional group of a proteogenic amino acid residue in PTH, such as an amino acid selected from the group consisting of histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid and arginine. According to certain embodiments, said amino acid is selected from the group consisting of lysine, aspartic acid, arginine, and serine. According to certain embodiments, said amino acid is selected from the group consisting of lysine, arginine, and serine. According to certain embodiments, -L ¹ - is conjugated to a histidine side chain functional group of PTH. According to certain embodiments, -L ¹ - is conjugated to a lysine side chain functional group of PTH. According to certain embodiments, -L ¹ - is conjugated to a tryptophan side chain functional group of PTH. According to certain embodiments, -L ¹ - is conjugated to a serine side chain functional group of PTH. According to certain embodiments, -L ¹ - is conjugated to a threonine side chain functional group of PTH. According to certain embodiments, -L ¹ - is conjugated to a tyrosine side chain functional group of PTH. In certain embodiments, -L ¹ - is conjugated to an aspartic acid side chain functional group of PTH. In certain embodiments, -L ¹ - is conjugated to a glutamic acid side chain functional group of PTH. In certain embodiments, -L ¹ - is conjugated to an arginine side chain functional group of PTH. It is understood that not every PTH moiety may contain all of these amino acid residues.

In certain embodiments, -L ¹ - is conjugated to the N-terminal amine functional group of PTH, either directly via the corresponding amine functional group, or indirectly, where the spacer moiety is first conjugated to the amine functional group to which the spacer moiety -L ¹ - is conjugated. In certain embodiments, -L ¹ - is directly conjugated to the N-terminal amine functional group of PTH.

In certain embodiments, -L ¹ - is conjugated to the C-terminal functional group of PTH, either directly via the corresponding carboxyl functional group, or indirectly, where the spacer moiety is first conjugated to the carboxyl functional group to which the spacer moiety -L ¹ - is conjugated.

In certain embodiments, -L ¹ - is directly conjugated to the N-terminal amine functional group of PTH.

The -L ¹ - moiety may be connected to -D via any type of linkage, so long as it is reversible. In certain embodiments, -L ¹ - is conjugated to -D via a linkage selected from the group consisting of an amide, an ester, a carbamate, an acetal, an aminal, an imine, an oxime, a hydrazone, a disulfide, and an acyl guanidine. In certain embodiments, -L ¹ - is conjugated to -D via a linkage selected from the group consisting of an amide, an ester, a carbamate, and an acyl guanidine. It is understood that some of these linkages are irreversible in themselves, but that adjacent groups contained in -L ¹ - make these linkages reversible.

In certain embodiments, -L ¹ - is conjugated to -D via an ester linkage. In certain embodiments, -L ¹ - is conjugated to -D via a carbamate linkage. In certain embodiments, -L ¹ - is conjugated to -D via an acyl guanidine. In certain embodiments, -L ¹ - is conjugated to -D via an amide linkage.

The -L ¹ - moiety is a reversible linker from which the drug, i.e. PTH, is released in its free form, meaning that -L ¹ - is a traceless linker. Suitable reversible linkers are known in the art, such as the reversible linker moieties disclosed in WO 2005/099768 A2, WO 2006/136586 A2, WO 2011/089216 A1 and WO 2013/024053 A1, which are incorporated herein by reference.

In certain embodiments, -L ¹ - is a reversible 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.

According to certain embodiments, -L ¹ - is disclosed in WO 2009/095479 A2. Accordingly, according to certain embodiments, -L ¹ - is a compound of formula (II):

where the dotted line shows the attachment to the nitrogen, hydroxyl or thiol of the -D fragment, which is the PTH fragment,

-X- is selected from the group consisting of -C(R ⁴ R ^4a )-, -N(R ⁴ )-, -O-, -C(R ⁴ R ^4a )-C(R ⁵ R ^5a )-, - C(R ⁵ R ^5a )-C(R ⁴ R ^4a )-, -C(R ⁴ R ^4a )-N(R ⁶ )-, -N(R ⁶ )-C(R ⁴ R ^4a )-, - C(R ⁴ R ^4a )-O-, -OC(R ⁴ R ^4a )-, and -C(R ⁷ R ^7a )-,

X ¹ is selected from the group consisting of C, and S(O),

-X ² - is selected from the group consisting of -C(R ⁸ R ^8a )-, and -C(R ⁸ R ^8a )-C(R ⁹ R ^9a )-,

=X ³ is selected from the group consisting of =O, =S, and =N-CN,

-R ¹ , -R ^1a , -R ² , -R ^2a , -R ⁴ , -R ^4a , -R ⁵ , -R ^5a , -R ⁶ , -R ⁸ , -R ^8a , -R ⁹ and -R ^9a are independently selected from the group consisting of -H and C _1-6 alkyl,

-R ³ and -R ^3a are independently selected from the group consisting of -H, and C _1-6 alkyl, with the proviso that when one or both of -R ³ and -R ^3a are not -H, they are bonded to the N to which they are attached through an sp ³ -hybridized carbon atom,

-R ⁷ is selected from the group consisting of -N(R ¹⁰ R ^10a ), and -NR ¹⁰ -(C=O)-R ¹¹ ,

-R ^7a , -R ¹⁰ , -R ^10a and -R ¹¹ are independently selected from the group consisting of -H and C _1-6 alkyl,

optionally, one or more of the pairs -R ^1a / -R ^4a , -R ^1a / -R ^5a , -R ^1a / -R ^7a , -R ^4a / -R ^5a and -R ^8a / -R ^9a form a chemical bond,

optionally, one or more of the pairs -R ¹ /-R ^1a , -R ² /-R ^2a , -R ⁴ /-R ^4a , -R ⁵ /-R ^5a , -R ⁸ /-R ^8a and -R ⁹ /-R ^9a are joined together with the atom to which it is attached to form a C _3-10 cycloalkyl, or a 3-10 membered heterocyclyl,

optionally, one or more of the pairs -R ¹ /-R ⁴ , -R ¹ /-R ⁵ , -R ¹ /-R ⁶ , -R ¹ /-R ^7a , -R ⁴ /-R ⁵ , -R ⁴ /-R ⁶ , -R ⁸ /-R ⁹ and -R ² /-R ³ are joined together with the atom to which they are attached to form a ring A,

optionally, R ³ /R ^3a are joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycle,

A is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3-10-membered heterocyclyl, and 8-11-membered heterobicyclyl, and

where -L ¹ is substituted by -L ² -Z, and where -L ¹ is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (II) is not substituted by -L ² -Z or a substituent,

Where

-L ² - represents a simple chemical bond or spacer, and

-Z is a water-soluble carrier.

According to certain embodiments, -L ¹ - of formula (II) is substituted with one -L ² -Z moiety.

According to certain embodiments, -L ¹ - of formula (II) is not further substituted.

It is clear that if -R ³ /-R ^3a of formula (II) are joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycle, only such 3- to 10-membered heterocycles can be formed in which the atoms directly attached to the nitrogen atom are sp ³ - hybridized carbon atoms. In other words, such a 3- to 10-membered heterocycle formed by -R ³ /-R ^3a together with the nitrogen atom to which they are attached has the following structure:

Where

the dotted line shows the connection to the rest of -L ¹ -,

the ring contains from 3 to 10 atoms, including at least one nitrogen atom, and R ^# and R ^## represent an ^sp3 -hybridized carbon atom.

It is also clear that the 3-10 membered heterocycle can be further substituted.

Exemplary embodiments of suitable 3- to 10-membered heterocycles formed by -R ³ /-R ^3a of formula (II) together with the nitrogen atom to which they are attached are the following:

Where

the dotted line represents attachment to the remainder of the molecule, and

-R is selected from the group consisting of -H and C _1-6 alkyl.

-L1- of formula (II) may optionally be further substituted. In general, any substituent may be used as long as the cleavage principle is not affected, i.e. the hydrogen marked with an asterisk in formula (II) is not replaced and the nitrogen of the fragment

formula (II) remains part of a primary, secondary or tertiary amine, i.e. -R ³ and R ^3a independently of each other represent -H or are linked to -N< through an sp3-hybridized carbon atom

In certain embodiments, -R ¹ or -R ^1a of formula (II) is substituted with -L ² -Z. In certain embodiments, -R ² or -R ^2a of formula (II) is substituted with -L ² -Z. In certain embodiments, -R ³ or -R ^3a of formula (II) is substituted with -L ² -Z. In certain embodiments, -R ⁴ of formula (II) is substituted with -L ² -Z. In certain embodiments, -R ⁵ or -R ^5a of formula (II) is substituted with -L ² -Z. In certain embodiments, -R ⁶ of formula (II) is substituted with -L ² -Z. In certain embodiments, -R ⁷ or -R ^7a of formula (II) is substituted with -L ² -Z. In certain embodiments, -R ⁸ or -R ^8a of formula (II) is substituted with -L ² -Z. In certain embodiments, -R ⁹ or -R ^9a of formula (II) is substituted with -L ² -Z. In certain embodiments, -R ¹⁰ is substituted with -L ² -Z. In certain embodiments, -R ¹¹ is substituted with -L ² -Z.

In certain embodiments, -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 )-. In certain embodiments, -X- of formula (II) is -C(R ⁴ R ^4a )-. In certain embodiments, -X- of formula (II) is -C(R ⁷ R ^7a )-.

According to certain embodiments, -R ⁷ of formula (II) is -NR ¹⁰ -(C=O)-R ¹¹ .

In certain embodiments, -R ^7a of formula (II) is selected from -H, methyl, and ethyl. In certain embodiments, -R ^7a of formula (II) is -H.

In certain embodiments, -R ¹⁰ is selected from -H, methyl, and ethyl. In certain embodiments, -R ¹⁰ is methyl.

In certain embodiments, -R ¹¹ is selected from -H, methyl, and ethyl. In certain embodiments, -R ¹¹ is -H.

In certain embodiments, -R ¹¹ is substituted with -L ² -Z.

According to certain embodiments, -X- of formula (II) is -N(R ⁴ )-.

In certain embodiments, -R ⁴ is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R ⁴ is -H.

According to certain embodiments, X ¹ of formula (II) is C.

According to certain embodiments, =X ³ of formula (II) is =O.

According to certain embodiments, -X ² - of formula (II) is -C(R ⁸ R ^8a )-.

In certain embodiments, -R ⁸ and -R ^8a of formula (II) are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, at least one of -R ⁸ and -R ^8a of formula (II) is -H. In certain embodiments, both -R ⁸ and -R ^8a of formula (II) are -H.

According to certain embodiments, -R ¹ and -R ^1a of formula (II) are independently selected from the group consisting of -H, methyl, and ethyl.

According to certain embodiments, at least one of -R ¹ and -R ^1a of formula (II) is -H, more preferably both -R ¹ and -R ^1a of formula (II) are -H.

According to certain embodiments, at least one of -R ¹ and -R ^1a of formula (II) is methyl. According to certain embodiments, both -R ¹ and -R ^1a of formula (II) are methyl.

In certain embodiments, -R ² and -R ^2a of formula (II) are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, at least one of -R ² and -R ^2a of formula (II) is -H. In certain embodiments, both -R ² and -R ^2a of formula (II) are H.

According to certain embodiments, -R ³ and -R ^3a of formula (II) are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl.

According to certain embodiments, at least one of -R ³ and -R ^3a of formula (II) is methyl, According to certain embodiments, -R ³ of formula (II) is methyl and -R ^3a of formula (II) is -H.

According to certain embodiments, -R ³ and -R ^3a of formula (II) are both -H.

In certain embodiments, D is linked to -L1 via nitrogen by forming an amide bond.

According to certain embodiments, the L1 fragment has formula (IIa-i):

Where

the dotted line shows the addition to the -D nitrogen, which is a PTH fragment, through the formation of an amide bond,

-R ¹ , -R ^1a , -R ² , -R ^2a , -R ³ , -R ^3a , -R ⁴ and -X ² - have the meanings as defined for formula (II), and

where -L ¹ - is substituted by -L ² -Z and where -L ¹ - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIa-i) is not substituted by L ² -Z or a substituent.

It is clear that when one of -R ³ , -R ^3a of formula (IIa-i), or both, is not -H, they are bonded to the N to which they are attached through an sp ³ -hybridized carbon atom.

According to certain embodiments, -L ¹ - of formula (IIa-i) is substituted with one -L ² -Z moiety.

According to certain embodiments, the -L ¹ - moiety of formula (IIa-i) is not further substituted.

In certain embodiments, -R ¹ and -R ^1a of formula (IIa-i) are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, at least one of -R ¹ and -R ^1a of formula (IIa-i) is methyl. In certain embodiments, both -R ¹ and -R ^1a of formula (IIa-i) are methyl.

In certain embodiments, -R ⁴ of formula (IIa-i) is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R ⁴ of formula (IIa-i) is -H.

According to certain embodiments, -X ² - of formula (IIa-i) is -C(R ⁸ R ^8a )-.

In certain embodiments, -R ⁸ and -R ^8a of formula (IIa-i) are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, at least one of -R ⁸ and -R ^8a of formula (IIa-i) is -H. In certain embodiments, both -R ⁸ and -R ^8a of formula (IIa-i) are -H.

In certain embodiments, -R ² and -R ^2a of formula (IIa-i) are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, at least one of -R ² and -R ^2a of formula (IIa-i) is -H. In certain embodiments, both -R ² and -R ^2a of formula (IIa-i) are H.

In certain embodiments, -R ³ and -R ^3a of formula (IIa-i) are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, at least one of -R ³ and -R ^3a of formula (IIa-i) is -H. In certain embodiments, both -R ³ and -R ^3a of formula (IIa-i) are -H.

According to certain embodiments, the -L ¹ - moiety is a compound of formula (IIa-ii):

provided that the hydrogen marked with an asterisk in formula (IIa-i) is not replaced by L2-Z or a substituent,

-R ² , -R ^2a , -R ³ , -R ^3a and -X ² - have the meanings as defined for formula (II), and

where -L ¹ is substituted by -L ² -Z and where -L ¹ is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIa-ii) is not substituted by -L ² -Z or a substituent.

It is understood that when one of -R ³ , -R ^3a of formula (IIa-ii), or both, is not -H, they are bonded to the N to which they are attached through an sp ³ -hybridized carbon atom.

According to certain embodiments, -L ¹ - of formula (IIa-ii) is substituted with one -L ² -Z moiety.

According to certain embodiments, the -L ¹ - moiety of formula (IIa-ii) is not further substituted.

According to certain embodiments, -X ² - of formula (IIa-ii) is -C(R ⁸ R ^8a )-.

In certain embodiments, -R ⁸ and -R ^8a of formula (IIa-ii) are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, at least one of -R ⁸ and -R ^8a of formula (IIa-ii) is -H. In certain embodiments, both -R ⁸ and -R ^8a of formula (IIa-ii) are -H.

In certain embodiments, -R ² and -R ^2a of formula (IIa-ii) are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, at least one of -R ² and -R ^2a of formula (IIa-ii) is -H. In certain embodiments, both -R ² and -R ^2a of formula (IIa-ii) are H.

In certain embodiments, -R ³ and -R ^3a of formula (IIa-ii) are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, at least one of -R ³ and -R ^3a of formula (IIa-ii) is -H. In certain embodiments, both -R ³ and -R ^3a of formula (IIa-ii) are -H.

According to certain embodiments, the -L ¹ - moiety is a compound of formula (IIa-ii'):

Where

where the dotted line represents the addition to the -D nitrogen, which is a PTH fragment, through the formation of an amide bond,

-R ² , -R ^2a , -R ^3a and -X ² - have the meanings as defined for formula (II), and

where -L ¹ is substituted by -L ² -Z, and where -L ¹ is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIa-ii') is not substituted by -L ² -Z or a substituent.

It is clear that when -R ^3a of formula (IIa-ii') is other than -H, it is bonded to the N to which it is attached through an sp ³ -hybridized carbon atom.

According to certain embodiments, the -L ¹ - moiety of formula (IIa-ii') is not further substituted.

According to certain embodiments, -X ² - of formula (IIa-ii') is -C(R ⁸ R ^8a )-.

In certain embodiments, -R ⁸ and -R ^8a of formula (IIa-ii') are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, at least one of -R ⁸ and -R ^8a of formula (IIa-ii') is -H. In certain embodiments, both -R ⁸ and -R ^8a of formula (IIa-ii') are -H.

In certain embodiments, -R ² and -R ^2a of formula (IIa-ii') are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, at least one of -R ² and -R ^2a of formula (IIa-ii') is -H. In certain embodiments, both -R ² and -R ^2a of formula (IIa-ii') are H.

In certain embodiments, -R ^3a of formula (IIa-ii') is selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -R ^3a of formula (IIa-ii') is -H.

According to certain embodiments, the -L ¹ - moiety is a compound of formula (IIa-iii):

Where

the dotted line shows the addition to the nitrogen atom -D, which is a fragment of PTH, through the formation of an amide bond, and

where -L ¹ - is substituted by -L ² -Z and where -L ¹ - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIa-iii) is not substituted by -L ² -Z or a substituent.

It is understood that when one of -R ³ , -R ^3a of formula (IIa-iii), or both, is not -H, they are bonded to the N to which they are attached through an sp ³ -hybridized carbon atom.

According to certain embodiments, -L ¹ - of formula (IIa-iii) is substituted with one -L ² -Z moiety.

According to certain embodiments, the -L ¹ - moiety of formula (IIa-iii) is not further substituted.

According to certain embodiments, the -L ¹ - moiety is a compound of formula (IIa-iii'):

Where

the dotted line shows the addition to the nitrogen atom -D, which is a fragment of PTH, through the formation of an amide bond,

the dotted line marked with an asterisk shows the attachment to -L ² -, and

where -L ¹ is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIa-iii') is not substituted by -L ² -Z or a substituent.

It is clear that the nitrogen adjacent to the dotted line marked with an asterisk in formula (IIa-iii') is attached to -L ² - via an sp ³ -hybridized carbon atom.

According to certain embodiments, the -L ¹ - moiety of formula (IIa-iii') is not further substituted.

According to certain embodiments, the -L ¹ - moiety is disclosed in WO 2016/020373 A1. Accordingly, according to certain embodiments, the -L ¹ - moiety is a compound of formula (III):

Where

the dotted line shows the addition to a primary or secondary amine or hydroxyl -D, which is the PTH moiety, through the formation of an amide or ester bond, respectively,

-R ¹ , -R ^1a , -R ² , -R ^2a , -R ³ and -R ^3a are independently selected from the group consisting of -H, -C(R ⁸ R ^8a R ⁸ b), -C(=O)R ⁸ , -C≡N, -C(=NR ⁸ )R ^8a , -CR ⁸ (=CR ^8a R ⁸ b), -C≡CR ⁸ and -T,

-R ⁴ , -R ⁵ and -R ^5a are independently selected from the group consisting of -H, -C(R ⁹ R ^9a R ^9b ) and -T,

a1 and a2 independently represent 0 or 1,

each -R ⁶ , -R ^6a , -R ⁷ , -R ^7a , -R ⁸ , -R ^8a , -R ^8b , -R ⁹ , -R ^9a , -R ^9b are independently selected from the group consisting of -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, wherein -T, C _1-20 alkyl, C _2-20 alkenyl and C _2-20 alkynyl are optionally substituted with one or more -R ¹¹ , which are the same or different, and where C _1-20 alkyl, C _2-20 alkenyl and C _2-20 alkynyl are optionally 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 -T, C _1-20 alkyl, C _2-20 alkenyl and C _2-20 alkynyl are optionally substituted with one or more -R ¹¹ , which are the same or different, and wherein the C _1-20 alkyl, C _2-20 alkenyl and C _2-20 alkynyl are optionally 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 T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl and 8-11 membered heterobicyclyl, wherein each T is independently optionally substituted with one or more -R ¹¹ , which are the same or different,

each -R ¹¹ is independently selected from 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 alkyl, wherein C _1-6 alkyl is optionally substituted with one or more halogens which are the same or different,

each -R ¹² , -R ^12a , -R ¹³ , -R ^13a , -R ^13b is independently selected from the group consisting of -H and C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with one or more halogens that are the same or different,

optionally, one or more of the pairs -R ¹ /-R ^1a , -R ² /-R ^2a , -R ³ /-R ^3a , -R ⁶ /-R ^6a , -R ⁷ /-R ^7a are joined together with the atom to which it is attached to form a C _3-10 cycloalkyl or a 3-10 membered heterocyclyl,

optionally, one or more of the pairs -R ¹ / -R ² , -R ¹ / -R ³ , -R ¹ / -R ⁴ , -R ¹ / -R ⁵ , -R ¹ / -R ⁶ , -R ¹ / -R ⁷ , -R ² / -R ³ , -R ² / -R ⁴ , -R ² / -R ⁵ , -R ² / -R ⁶ , -R ² / -R ⁷ , -R ³ / -R ⁴ , -R ³ / -R ⁵ , -R ³ / -R ⁶ , -R ³ / -R ⁷ , -R ⁴ / -R ⁵ , -R ⁴ / -R ⁶ , -R ⁴ / -R ⁷ , -R ⁵ / -R ⁶ , -R ⁵ / -R ⁷ , -R ⁶ / -R ⁷ are connected to atoms, to which they are attached, forming ring A,

A is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3-10-membered heterocyclyl, and 8-11-membered heterobicyclic,

where -L ¹ is substituted by -L ² -Z and where -L ¹ is optionally further substituted,

Where

-L ² - represents a simple chemical bond or spacer, and

-Z is a water-soluble carrier.

The optional additional substituents -L ¹ - of formula (III) are preferably as described above.

According to certain embodiments, -L ¹ - of formula (III) is substituted with one -L ² -Z moiety.

According to certain embodiments, -L ¹ - of formula (III) is not further substituted.

Further embodiments for -L ¹ - are disclosed in EP 1 536 334 B1, WO 2009/009712 A1, WO 2008/034122 A1, WO 2009/143412 A2, WO 2011/082368 A2 and US 8,618,124 B2, which are incorporated herein by reference in their entirety.

Additional embodiments for -L ¹ - are disclosed in US 8,946,405 B2 and US 8,754,190 B2, which are incorporated herein by reference in their entireties. Accordingly, in certain embodiments, the -L ¹ - moiety is a compound of formula (IV):

Where

the dotted line shows the attachment to -D, which is a PTH moiety, and where the attachment occurs via a functional group -D selected from the group consisting of -OH, -SH and -NH ₂ ,

m represents 0 or 1,

at least one or both of -R ¹ and -R ² is/are independently selected from the group consisting of -CN, -NO ₂ , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, -C(O)R ³ , -S(O)R ³ , -S(O) ₂ R ³ and -SR ⁴ ,

one and only one of -R ¹ and -R ² is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl,

-R ³ is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR ⁹ and -N(R ⁹ ) ₂ ,

-R ⁴ is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl,

each -R ⁵ is independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl,

-R ⁹ is selected from the group consisting of -H and optionally substituted alkyl,

-Y- is absent and -X- is -O- or -S-, or

-Y- is -N(Q)CH ₂ - and -X- is -O-,

Q is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl,

optionally, -R ¹ and -R ² can be joined to form a 3-8 membered ring, and

optionally, both -R ⁹ together with the nitrogen atom to which they are attached form a heterocyclyl ring,

where -L ¹ is substituted by -L ² -Z and where -L ¹ is optionally further substituted,

Where

-L ² - represents a simple chemical bond or spacer, and

-Z is a water-soluble carrier.

Only in the context of formula (IV) the terms used have the following meanings:

The term "alkyl" as used herein includes linear, branched or cyclic saturated hydrocarbon groups having from 1 to 8 carbon atoms, or in some embodiments from 1 to 6 or from 1 to 4 carbon atoms.

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

The term "alkenyl" includes non-aromatic unsaturated hydrocarbons with carbon-carbon double bonds.

The term "alkynyl" includes non-aromatic unsaturated hydrocarbons with carbon-carbon triple bonds.

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

In certain embodiments, alkenyl, alkynyl, aryl, or heteroaryl moieties may be attached to the remainder of the molecule through an alkylene bond. Under these circumstances, the substituent will be referred to as alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that the alkylene moiety is between the alkenyl, alkynyl, aryl, or heteroaryl and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is bonded.

The term "halogen" includes bromine, fluorine, chlorine and iodine.

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, as well as the exemplary groups listed above for the term "heteroaryl."

When the ring system is optionally substituted, suitable substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or an additional ring, wherein each is optionally further substituted. Optional substituents in any group, including those above, include halo, nitro, cyano, OR, -SR, ^-NR2 , -OCOR _, -NRCOR, -COOR, _-CONR2 , -SOR, _-SO2R , _-SONR2 , _-SO2NR2 , wherein each R is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or two R groups taken together with the atoms to which they are attached form a ring.

According to certain embodiments, -L ¹ - of formula (IV) is substituted with one -L ² -Z moiety.

A further embodiment for -L ¹ - is disclosed in WO 2013/036857 A1, which is incorporated herein by reference in its entirety. Accordingly, in certain embodiments, the -L ¹ - moiety has formula (V):

Where

the dotted line shows the attachment to -D, which is a PTH moiety, and where the attachment occurs through the amine functional group of -D,

-R ¹ is selected from the group consisting of optionally substituted C ₁ -C ₆ linear, branched or cyclic alkyl, optionally substituted aryl, optionally substituted heteroaryl, alkoxy, and -NR ⁵ ₂ ,

-R ² is selected from the group consisting of -H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, and optionally substituted heteroaryl,

-R ³ is selected from the group consisting of -H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, and optionally substituted heteroaryl,

-R ⁴ is selected from the group consisting of -H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, and optionally substituted heteroaryl,

each -R ⁵ is independently selected from the group consisting of -H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, and optionally substituted heteroaryl, or together with two -R ⁵ may be cycloalkyl or cycloheteroalkyl,

where -L ¹ is substituted by -L ² -Z, and where -L ¹ is optionally further substituted,

Where

-L ₂ - represents a simple chemical bond or spacer, and

-Z is a water-soluble carrier.

Only in the context of formula (V) the terms used have the following meanings:

"Alkyl", "alkenyl" and "alkynyl" include linear, branched or cyclic hydrocarbon groups having from 1 to 8 carbon atoms or 1 to 6 carbon atoms or 1 to 4 carbon atoms, wherein alkyl is a saturated hydrocarbon, alkenyl includes one or more carbon-carbon double bonds and alkynyl includes one or more carbon-carbon triple bonds. Unless otherwise specified, they contain 1 to 6 carbon atoms.

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

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

According to certain embodiments, -L ¹ - of formula (V) is substituted with one -L ² -Z moiety.

Another preferred embodiment -L ¹ - is disclosed in US 7,585,837 B2, which is incorporated herein by reference in its entirety. Accordingly, in certain embodiments, -L ¹ - is a compound of formula (VI):

Where

the dotted line shows the attachment to -D, which is a PTH moiety, and where the attachment occurs through the amine functional group of -D,

R ¹ and R ² are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkaryl, ahaloalkyl, halogen, nitro, -SO ₃ H, -SO ₂ NHR ⁵ , amino, ammonium, carboxyl, PO ₃ H ₂ and OPO ₃ H ₂ ,

R ³ , R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen, alkyl and aryl,

where -L ¹ is substituted by -L ² -Z and where -L ¹ is optionally further substituted,

Where

-L ² - represents a simple chemical bond or spacer, and

-Z is a water-soluble carrier.

Suitable substituents for formula (VI) are alkyl (such as C _1-6 alkyl), alkenyl (such as C _2-6 alkenyl), alkynyl (such as C _2-6 alkynyl), aryl (such as phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (such as an aromatic 4-7 membered heterocycle) or halogen moieties.

Only in the context of formula (VI) the terms used have the following meanings:

The terms "alkyl", "alkoxy", "alkoxyalkyl", "aryl", "alkaryl" and "aralkyl" mean alkyl radicals containing 1-8, preferably 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl, and aryl radicals containing 6-10 carbon atoms, such as phenyl and naphthyl. The term "halogen" includes bromine, fluorine, chlorine and iodine.

According to certain embodiments, -L ¹ - of formula (VI) is substituted with one -L ² -Z moiety.

A further embodiment for -L ¹ - is disclosed in WO 2002/089789 A1, which is incorporated herein by reference in its entirety. Accordingly, in certain embodiments, -L ¹ - is a compound of formula (VII):

Where

the dotted line shows the attachment to -D, which is a PTH moiety, and where the attachment occurs through the amine functional group of -D,

L ₁ is a bifunctional linking group,

Y ₁ and Y ₂ independently represent O, S or NR ⁷ ,

^R2 , ^R3 , ^R4 , ^R5 , ^R6 and ^R7 are independently selected from the group consisting of hydrogen, _C1-6alkyl , _{C3-12branchedalkyl} , _{C3-8cycloalkyl, C1-6substitutedalkyl , C3-8substitutedcycloalkyl} , aryl _, substituted aryl, aralkyl, _{C1-6heteroalkyl} , substitutedC1-6heteroalkyl, _C1-6alkoxy , phenoxy and _{C1-6heteroalkoxy} ,

Ar is a moiety which, when included in formula (VII), forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group,

X represents a chemical bond or moiety that is actively transferred into the target cell, a hydrophobic moiety, or a combination of both,

y is equal to 0 or 1.

where -L ¹ is substituted by -L ² -Z and where -L ¹ is optionally further substituted,

Where

-L ² - represents a simple chemical bond or spacer, and

-Z is a water-soluble carrier.

The term "alkyl" should be understood to include, for example, straight-chain, branched, substituted C _1-12 alkyls including alkoxy, C _3-8 cycloalkyls or substituted cycloalkyls, etc.

The term "substitution" is to be understood to include the addition or replacement of one or more atoms contained in a functional group, or the combination with one or more different atoms.

Substituted alkyls include carboxyalkyls, aminoalkyls, dialkylamines, hydroxyalkyls, and mercaptoalkyls; substituted cycloalkyls include moieties such as 4-chlorocyclohexyl; aryls include moieties such as naphthyl; substituted aryls include moieties such as 3-bromophenyl; aralkyls include moieties such as toluyl; heteroalkyls include moieties such as ethylthiophene; substituted heteroalkyls include moieties such as 3-methoxythiophene; alkoxy includes moieties such as methoxy; and phenoxy includes moieties such as 3-nitrophenoxy. Halo should be understood to include fluorine, chlorine, iodine, and bromine.

According to certain embodiments, -L ¹ - of formula (VII) is substituted with one -L ² -Z moiety.

According to certain embodiments, -L ¹ - comprises a structure of formula (VIII)

Where

the dotted line marked with an asterisk shows the addition to the nitrogen atom -D, which is a fragment of PTH, through the formation of an amide bond,

the unmarked dotted line shows the attachment to the remaining part of -L ¹ -, and

where -L ¹ is substituted by -L ² -Z, and where -L ¹ is optionally further substituted,

Where

-L ² - represents a simple chemical bond or spacer, and

-Z is a water-soluble carrier.

According to certain embodiments, -L ¹ - of formula (VIII) is substituted with one -L ² -Z moiety.

According to certain embodiments, -L ¹ - of formula (VIII) is not further substituted.

According to certain embodiments, -L ¹ - comprises a structure of formula (IX)

Where

the dotted line marked with an asterisk shows the addition to the nitrogen of the -D fragment, which is a PTH fragment, through the formation of a carbamate bond,

the unmarked dotted line shows the attachment to the remaining part of -L ¹ -, and

where -L ¹ is substituted by -L ² -Z and where -L ¹ is optionally further substituted,

Where

-L ² - represents a simple chemical bond or spacer, and

-Z is a water-soluble carrier.

According to certain embodiments, -L ¹ - of formula (IX) is substituted with one -L ² -Z moiety.

According to certain embodiments, -L ¹ - of formula (IX) is not further substituted.

In certain embodiments, -L ¹ - has the structure disclosed in WO 2020/206358 A1. Accordingly, in certain embodiments, the moiety -L ¹ - is a compound of formula (X):

Where

The unmarked dotted line shows the attachment to -D,

the dotted line marked with an asterisk shows the attachment to -L ² -Z,

n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6,

-R ¹ and -R ² independently represent an electron-withdrawing group, alkyl, or H, and wherein at least one of -R ¹ or -R ² represents an electron-withdrawing group,

each -R ⁴ is independently C ₁ -C ₃ alkyl or two -R ⁴ together with the carbon atom to which they are attached form a 3- to 6-membered ring, and

-Y- is absent when -D is a drug moiety linked through an amine, or -Y- is -N(R ⁶ )CH ₂ - when -D is a drug moiety linked through a phenol, alcohol, thiol, thiophenol, imidazole, or non-basic amine, where -R ⁶ is optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

In certain embodiments, n of formula (X) is an integer selected from 1, 2, 3, 4, 5, and 6. In certain embodiments, n of formula (X) is an integer selected from 1, 2, and 3. In certain embodiments, n of formula (X) is an integer from 0, 1, 2, and 3. In certain embodiments, n of formula (X) is 1. In certain embodiments, n of formula (X) is 2. In certain embodiments, n of formula (X) is 3.

According to certain embodiments, the electron withdrawing group -R ¹ and -R ² of formula (X) is selected from the group consisting of -CN, -NO ₂ , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, -COR ³ , -SOR ³ , or -SO ₂ R, wherein -R ³ is -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR ⁸ , or -NR ⁸ ₂ , wherein each -R ⁸ is independently -H or optionally substituted alkyl, or both -R ⁸ groups, together with the nitrogen to which they are attached, form a heterocyclic ring, or -SR ⁹ , wherein -R ⁹ is optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl.

In certain embodiments, the electron withdrawing group -R ¹ and -R ² of formula (X) is -CN. In certain embodiments, the electron withdrawing group -R ¹ and -R ² of formula (X) is -NO _2. In certain embodiments, the electron withdrawing group -R ¹ and -R ² of formula (X) is an optionally substituted aryl having 6 to 10 carbon atoms. In certain embodiments, the electron withdrawing group -R ¹ and -R ² of formula (X) is an optionally substituted phenyl, naphthyl, or anthracenyl. In certain embodiments, the electron withdrawing group -R ¹ and -R ² of formula (X) is an optionally substituted heteroaryl having 3 to 7 carbon atoms and having at least one of N, O, or S. In certain embodiments, the electron withdrawing group -R ¹ and -R ² of formula (X) is an optionally substituted pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, or indenyl. In certain embodiments, the electron withdrawing group -R ¹ and -R ² of formula (X) is an optionally substituted alkenyl having 2 to 20 carbon atoms. In certain embodiments, the electron withdrawing group -R ¹ and -R ² of formula (X) is an optionally substituted alkynyl having 2 to 20 carbon atoms. According to certain embodiments, the electron withdrawing group -R ¹ and -R ² of formula (X) is -COR ³ , -SOR ³ , or -SO ₂ R, wherein -R ³ is -H, optionally substituted alkyl of 2 to 20 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR ⁸ , or -NR ⁸ ₂ , wherein each -R ⁸ is independently -H or optionally substituted alkyl of 2 to 20 carbon atoms, or both -R ⁸ groups, together with the nitrogen to which they are attached, form a heterocyclic ring. According to certain embodiments, the electron withdrawing group -R ¹ and -R ² of formula (X) is -SR ⁹ , wherein -R ⁹ is optionally substituted alkyl of 2 to 20 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl.

In certain embodiments, at least one of -R ¹ or -R ² of formula (X) is -CN, -SOR ^3, or -SO ₂ R ^3. In certain embodiments, at least one of -R ¹ and -R ² of formula (X) is -CN or -SO ₂ R ^3. In certain embodiments, at least one of -R ¹ and -R ² of formula (X) is -CN or -SO ₂ R ³ , wherein -R ³ is optionally substituted alkyl, optionally substituted aryl, or -NR ⁸ ₂ . According to certain embodiments, at least one of -R ¹ and -R ² of formula (X) is -CN, -SO ₂ N(CH ₃ ) ₂ , -SO ₂ CH ₃ , phenyl substituted with -SO ₂ , phenyl substituted with -SO ₂ and -Cl, -SO ₂ N(CH ₂ CH ₂ ) ₂ O, -SO ₂ CH(CH ₃ ) ₂ , -SO ₂ N(CH ₃ )(CH ₂ CH ₃ ) or -SO ₂ N(CH ₂ CH ₂ OCH ₃ ) ₂ .

In certain embodiments, each -R ⁴ of formula (X) is independently C ₁ -C ₃ alkyl. In certain embodiments, both -R ⁴ are methyl.

In certain embodiments, -Y- of formula (X) is absent. In certain embodiments, -Y- of formula (X) is -N(R ⁶ )CH ₂ -.

In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 1, -R ¹ is -CN, -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 1, -R ¹ is -SO ₂ N(CH ₃ ) ₂ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 1, -R ¹ is SO ₂ CH ₃ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 1, -R ¹ is -SO ₂ N(CH ₂ CH ₂ ) ₂ CHCH ₃ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 1, -R ¹ is phenyl substituted with -SO ₂ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 1, -R ¹ is phenyl substituted with -SO ₂ and -Cl, -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 1, -R ¹ is -SO ₂ N(CH ₂ CH ₂ ) ₂ O, -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 1, -R ¹ is -SO ₂ CH(CH ₃ ) ₂ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 1, -R ¹ is -SO ₂ N(CH ₃ )(CH ₂ CH ₃ ), -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 1, -R ¹ is -SO ₂ N(CH ₂ CH ₂ OCH ₃ ) ₂ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 1, -R ¹ is phenyl substituted with -SO ₂ and -CH ₃ , -R ² is -H, and -R ⁴ is -CH ₃ .

In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 2, -R ¹ is -CN, -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 2, -R ¹ is -SO ₂ N(CH ₃ ) ₂ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 2, -R ¹ is SO ₂ CH ₃ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 2, -R ¹ is -SO ₂ N(CH ₂ CH ₂ ) ₂ CHCH ₃ , -R ² is -H and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 2, -R ¹ is phenyl substituted with -SO ₂ , -R ² is -H and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 2, -R ¹ is phenyl substituted with -SO ₂ and -Cl, -R ² is -H and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 2, -R ¹ is -SO ₂ N(CH ₂ CH ₂ ) ₂ O, -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 2, -R ¹ is -SO ₂ CH(CH ₃ ) ₂ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 2, -R ¹ is -SO ₂ N(CH ₃ )(CH ₂ CH ₃ ), -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 2, -R ¹ is -SO ₂ N(CH ₂ CH ₂ OCH ₃ ) 2, -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 2, -R ¹ is phenyl substituted with -SO ₂ and -CH ₃ , -R ² is -H, and -R ⁴ is -CH ₃ .

In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 3, -R ¹ is -CN, -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 3, -R ¹ is -SO ₂ N(CH ₃ ) 2, -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 3, -R ¹ is SO ₂ CH ₃ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 3, -R ¹ is -SO ₂ N(CH ₂ CH ₂ ) ₂ CHCH ₃ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 3, -R ¹ is phenyl substituted with -SO ₂ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 3, -R ¹ is phenyl substituted with -SO ₂ and -Cl, -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 3, -R ¹ is -SO ₂ N(CH ₂ CH ₂ ) ₂ O, -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 3, -R ¹ is -SO ₂ CH(CH ₃ ) ₂ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 3, -R ¹ is -SO ₂ N(CH ₃ )(CH ₂ CH ₃ ), -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 3, -R ¹ is -SO ₂ N(CH ₂ CH ₂ OCH ₃ ) ₂ , -R ² is -H, and -R ⁴ is -CH ₃ . In certain embodiments, -L ¹ - is a compound of formula (X) wherein n is 3, -R ¹ is phenyl substituted with -SO ₂ and -CH ₃ , -R ² is -H, and -R ⁴ is -CH ₃ .

Only in the context of formula (X) the terms used have the following meanings:

The term "alkyl" refers to linear, branched, or cyclic saturated hydrocarbon groups containing from 1 to 20, from 1 to 12, from 1 to 8, from 1 to 6, or from 1 to 4 carbon atoms. In certain embodiments, the alkyl is linear or branched. Examples of linear or branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In a desired embodiment, the alkyl is cyclic. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.

The term "alkoxy" refers to alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, and cyclobutoxy.

The term "alkenyl" refers to non-aromatic unsaturated hydrocarbons with carbon-carbon double bonds and 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

The term "alkynyl" refers to non-aromatic unsaturated hydrocarbons with carbon-carbon triple bonds and 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

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

In certain embodiments, the alkenyl, alkynyl, aryl, or heteroaryl moieties may be bonded to the remainder of the molecule through an alkyl bond. In these circumstances, the substituent will be referred to as alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that the alkylene moiety is between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is bonded.

The term "halogen" or "halo" refers to bromine, fluorine, chlorine, and iodine.

The term "heterocyclic ring" or "heterocyclyl" refers to a 3- to 15-membered aromatic or non-aromatic ring containing at least one N, O, or S atom. Examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided for the term "heteroaryl" above. In certain embodiments, the heterocyclic ring or heterocyclyl is non-aromatic. In certain embodiments, the heterocyclic ring or heterocyclyl is aromatic.

The term "optionally substituted" refers to a group that may be unsubstituted or substituted by one or more (e.g. 1, 2, 3, 4 or 5) substituents, which may be the same or different. Examples of substituents include alkyl, alkenyl, alkynyl, halogen, -CN, -OR ^aa , -SR ^aa , -NR ^aa R ^bb , -NO ₂ , -C=NH(OR ^aa ), -C(O)R ^aa , -OC(O)R ^aa , -C(O)OR ^aa , -C(O)NR ^aa R ^bb , -OC(O)NR ^aa R ^bb , -NR ^aa C(O)R ^bb , -NR ^aa C(O)OR ^bb , -S(O)R ^aa , -S(O) ₂ R ^aa , -NR ^aa S(O)R ^bb , -C(O)NR ^aa S(O)R ^bb , -NR ^aa S(O) ₂ R ^bb , -C(O)NR ^aa S(O) ₂ R ^bb , -S(O)NR ^aa R ^bb , -S(O ₎ ^2NRaaRbb , -P(O)( ^ORaa )( ^ORbb ), heterocyclyl, heteroaryl or aryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, ^heterocyclyl , heteroaryl and aryl are each independently optionally substituted ^{with -Rcc} , wherein ^-Raa and ^-Rbb are each independently substituted with -H, alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl or aryl, or ^-Raa and ^-Rbb , together with the nitrogen atom to which they are attached, form a heterocyclyl that is optionally substituted with alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy or -CN, and wherein each ^-Rcc is independently alkyl, alkenyl, alkynyl, halogen, heterocyclyl, heteroaryl, aryl, -CN or _-NO2 .

-L ² - represents a chemical bond or spacer fragment.

In certain embodiments, -L ² - is a chemical bond.

According to certain embodiments, -L ² - is a spacer moiety, such as a spacer moiety selected from the group consisting of -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, wherein -T-, C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally substituted with one or more -R ^y2 , which are the same or different, and wherein the C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally 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(О)N(R ^y3a )- and -OC(О)N(R ^y3 )-,

-R ^y1 and -R ^y1a are independently selected from the group consisting of -H, -T, C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl, wherein -T, C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally substituted by one or more -R ^y2 , which are the same or different, and wherein the C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally 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(О) ₂ N(R ^y4a )-, -S-, -N(R ^y4 )-, -OC(OR ^y4 )(R ^y4a )-, -N(R ^y4 )C(О)N(R ^y4a )- and -OC(О)N(R ^y4 )-,

each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, _C3-10 cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, wherein each T is independently optionally substituted with one or more ^-Ry2 that are the same or different,

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 )S(O) ₂ N(R ^y5a R ^y5b ), -SR ^y5 , -N(R ^y5 R ^y5a ), -NO ₂ , -OC(O)R ^y5 , -N(R ^y5 )C(O)R ^y5a , -N(R ^y5 )S(O) ₂ R ^y5a , -N(R ^y5 )S(O)R ^y5a , -N(R ^y5 )C(O)OR ^y5a , -N(R ^y5 )C(O)N(R ^y5a R ^y5b ), -OC(O)N(R ^y5 R ^y5a ) and C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with one or more halogens which are the same or different, and

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, wherein C _1-6 alkyl is optionally substituted with one or more halogens that are the same or different.

According to certain embodiments, -L ² - is selected from -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, wherein -T-, C _1-20 alkyl, C _2-20 alkenyl and C _2-20 alkynyl are optionally substituted with one or more -R ^y2 , which are the same or different, and wherein the C _1-20 alkyl, C _2-20 alkenyl and C _2-20 alkynyl are optionally 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 )-,

-R ^y1 and -R ^y1a are independently selected from the group consisting of -H, -T, C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, wherein -T, C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl are optionally substituted by one or more -R ^y2 , which are the same or different, and wherein the C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl are optionally 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(О) ₂ N(R ^y4a )-, -S-, -N(R ^y4 )-, -OC(OR ^y4 )(R ^y4a )-, -N(R ^y4 )C(О)N(R ^y4a )- and -OC(О)N(R ^y4 )-,

each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, _C3-10 cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, wherein each T is independently optionally substituted with one or more ^-Ry2 that are the same or different,

-R ^y2 is 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 )S(O) ₂ N(R ^y5a R ^y5b ), -SR ^y5 , -N(R ^y5 R ^y5a ), -NO ₂ , -OC(O)R ^y5 , -N(R ^y5 )C(O)R ^y5a , -N(R ^y5 )S(O) ₂ R ^y5a , -N(R ^y5 )S(O)R ^y5a , -N(R ^y5 )C(O)OR ^y5a , -N(R ^y5 )C(O)N(R ^y5a R ^y5b ), -OC(O)N(R ^y5 R ^y5a ) and C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with one or more halogens which are the same or different, and

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, wherein C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different.

According to certain embodiments, -L ² - is selected from the group consisting of -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, wherein -T-, C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally substituted with one or more -R ^y2 , which are the same or different, and wherein the C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally 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 )-,

-R ^y1 and -R ^y1a are independently selected from the group consisting of -H, -T, C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl,

each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, _C3-10 cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl,

each -R ^y2 is independently selected from the group consisting of halogen and C _1-6 alkyl, and

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, wherein C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different.

According to certain embodiments, ^-L2- is a _C1-20 alkyl chain that is optionally substituted with one or more groups independently selected from -O-, -T-, and -C(O)N( ^Ry1 )-, and ^wherein the _C1-20 alkyl group is optionally substituted with one or more groups independently selected from -OH, -T, and -C(O)N( ^Ry6Ry6a ), wherein ^-Ry1 , ^-Ry6 , ^-Ry6a are independently selected from the group consisting of -H and _C1-4 alkyl, and wherein T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, _C3-10 cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl.

According to certain embodiments, -L ² - has a molecular weight in the range of from 14 g/mol to 750 g/mol.

According to certain embodiments, -L ² - comprises a fragment selected from

Where

the dotted line shows the attachment to the rest of -L ² -, -L ¹ - and/or -Z, respectively, and

-R and ^-Ra are independently selected from the group consisting of -H, 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.

According to certain embodiments, -L ² - has a chain length of from 1 to 20 atoms.

As used herein, the term "chain length" in relation to a -L ² - moiety refers to the number of -L ² - atoms present in the shortest link between -L ¹ - and -Z.

According to certain embodiments, -L ² - is a compound of formula (i)

Where

the dotted line marked with an asterisk shows the attachment to -L ¹ -,

The unmarked dotted line shows the attachment to -Z,

n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18, and

wherein the fragment of formula (i) is optionally further substituted.

In certain embodiments, n of formula (i) is selected from the group consisting of 3, 4, 5, 6, 7, 8, and 9. In certain embodiments, n of formula (i) is 4, 5, 6, or 7. In certain embodiments, n of formula (i) is 4. In certain embodiments, n of formula (i) is 5. In certain embodiments, n of formula (i) is 6.

According to certain embodiments, the fragment -L ¹ -L ² - is selected from the group consisting of

Where

the unmarked dotted line shows the addition to the -D nitrogen, which is a PTH fragment, through the formation of an amide bond, and

The dotted line marked with an asterisk shows the attachment to -Z.

In certain embodiments, the -L ¹ -L ² - moiety is a compound of formula (IIca-i). In certain embodiments, the -L ¹ -L ² - moiety is a compound of formula (IIca-ii). In certain embodiments, the -L ¹ -L ² - moiety is a compound of formula (IIcb-iii).

According to certain embodiments, the PTH compound is a compound of formula (Ia) with x=1.

-Z contains C _8-24 alkyl or polymeric moiety. According to certain embodiments, -Z comprises a polymer moiety, such as a polymer selected from the group consisting of 2-methacryloyloxyethyl phosphoylcholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyl oxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl oxazolines), poly(hydroxymethacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acid copolymers), poly(methacrylamides), poly(methacrylates), poly(methyl oxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinylamines), poly(vinyl methyl ethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethylcelluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other polymers based on carbohydrates, xylans and their copolymers.

In certain embodiments, -Z has a molecular weight in the range of 5 to 200 kDa. In certain embodiments, -Z has a molecular weight in the range of 8 to 100 kDa, such as about 10 to 80 kDa, such as about 12 to 60 kDa, such as about 15 to 40 kDa. In certain embodiments, -Z has a molecular weight of about 20 kDa. In certain embodiments, -Z has a molecular weight of about 40 kDa.

According to certain embodiments, -Z comprises a protein. Preferred proteins are selected from the group consisting of human chorionic gonadotropin carboxyl-terminal peptide as described in US 2012/0035101 A1, which are incorporated herein by reference, albumin, XTEN as described in WO 2011123813 A2, which is incorporated herein by reference, proline/alanine random coil sequences as described in WO 2011/144756 A1, which is incorporated herein by reference, proline/alanine/serine sequences as described in WO 2008/155134 A1 and WO 2013/024049 A1, which are incorporated herein by reference, Fc fusion proteins.

According to one embodiment, -Z is polysarcosine. According to another embodiment, -Z comprises poly(N-methylglycine). According to a particularly preferred embodiment, -Z comprises a random coil protein moiety. According to a preferred embodiment, -Z comprises at least one random coil protein moiety.

In certain embodiments, -Z comprises a fatty acid derivative. In certain embodiments, the fatty acid derivatives are as disclosed in WO 2005/027978 A2 and WO 2014/060512 A1, which are incorporated herein by reference.

According to certain embodiments, -Z is a hyaluronic acid-based polymer.

In certain embodiments, -Z is a carrier as disclosed in WO 2012/02047 A1, which is incorporated herein by reference.

In certain embodiments, -Z is a carrier as disclosed in WO 2013/024048 A1, which is incorporated herein by reference.

In certain embodiments, -Z is a linear PEG-based polymer, such as a linear, branched PES-based polymer, or a multi-arm PES-based polymer. In certain embodiments, -Z is a linear PEG-based polymer. In certain embodiments, -Z is a multi-arm PES-based polymer. In certain embodiments, -Z is a multi-arm PES-based polymer having at least 4 PEG-based arms.

According to certain embodiments, such a PES-based polymer with multiple -Z arms is conjugated to a plurality of -L ² -L ¹ -D units, wherein each -L ² L ¹ -D unit is, according to certain embodiments, connected to the end of an arm. According to certain embodiments, such a PES-based polymer with multiple -Z arms is conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 -L ² -L ¹ -D units. According to certain embodiments, such a PES-based polymer with multiple -Z arms is conjugated to 2, 3, 4, 6, or 8 -L ² -L ¹ -D units. In certain embodiments, such a PES-based polymer with multiple -Z arms is conjugated to 2, 4, or 6 -L ² -L ¹ -D units, in certain embodiments, such a PES-based polymer with multiple -Z arms is conjugated to 4 or 6 -L ² -L ¹ -D units, and in certain embodiments, such a PES-based polymer with multiple -Z arms is conjugated to 4 -L ² -L ¹ -D units.

In certain embodiments, such a multi-armed PES-Z-based polymer is a multi-armed PEG derivative, such as those described in detail in the products listed by JenKem Technology, USA (available for download at http://www.jenkemusa.com/Pages/PEGProducts.aspx on Dec 18, 2014), such as a 4-armed PEG derivative, in particular a 4-armed PEG derivative comprising a pentaerythritol core, an 8-armed PEG derivative comprising a hexaglycerol core, and an 8-armed PEG comprising a tripentaerythritol core. In certain embodiments, the water-soluble PEG-Z-based carrier comprises a moiety selected from:

A 4-armed PEG amine containing a pentaerythritol core:

with n in the range from 20 to 500,

PEG amine with 8 arms containing a hexaglycerol core:

with n in the range from 20 to 500, and

R = hexaglycerol or tripentaerythritol core structure, and

6-armed PEG amine containing a dipentaerythritol core:

with n in the range from 20 to 500, and

R = containing sorbitol or dipentaerythritol core,

and where the dotted lines show the attachment to the PTH conjugate residue.

In certain embodiments, -Z is a branched PEG-based polymer. In certain embodiments, -Z is a branched PEG-based polymer having one, two, three, four, five, or six branch points. In certain embodiments, -Z is a branched PEG-based polymer having one, two, or three branch points. In certain embodiments, -Z is a branched PEG-based polymer having one branch point. In certain embodiments, -Z is a branched PEG-based polymer having two branch points. In certain embodiments, -Z is a branched PEG-based polymer having three branch points.

According to certain embodiments, the branching point is selected from the group consisting of -N<, -CH<, and >C<.

According to certain embodiments, such a branched PEG-Z-based moiety has a molecular weight of at least 10 kDa.

According to certain embodiments, such a branched fragment -Z has a molecular weight in the range of and including 10 kDa to 500 kDa. According to certain embodiments, such a branched fragment -Z has a molecular weight in the range of and including 10 kDa to 250 kDa. According to certain embodiments, such a branched fragment -Z has a molecular weight in the range of and including 10 kDa to 150 kDa. According to certain embodiments, such a branched fragment -Z has a molecular weight in the range of and including 12 kDa to 100 kDa. According to certain embodiments, such a branched fragment -Z has a molecular weight in the range of and including 15 kDa to 80 kDa.

According to certain embodiments, such a branched fragment -Z has a molecular weight in the range and including 10 kDa - 80 kDa. According to certain embodiments, the molecular weight is about 10 kDa. According to certain embodiments, the molecular weight of such a branched fragment -Z is about 20 kDa. According to certain embodiments, the molecular weight of such a branched fragment -Z is about 30 kDa. According to certain embodiments, the molecular weight of such a branched fragment -Z is about 40 kDa. According to certain embodiments, the molecular weight of such a branched fragment -Z is about 50 kDa. According to certain embodiments, the molecular weight of such a branched fragment -Z is about 60 kDa. According to certain embodiments, the molecular weight of such a branched fragment -Z is about 70 kDa. According to certain embodiments, the molecular weight of such a branched fragment -Z is about 80 kDa. According to certain embodiments, such a branched -Z fragment has a molecular mass of about 40 kDa.

According to certain embodiments, -Z comprises a fragment

In certain embodiments, -Z comprises an amide bond.

According to certain embodiments, -Z comprises a fragment of formula (a)

Where

the dotted line shows the attachment to -L - or to the remaining part of -Z,

BP ^a represents a branch point selected from the group consisting of -N<, -CR< and >C<,

-R is selected from the group consisting of -H and C _1-6 alkyl,

a represents failure 0 if BP ^a represents -N< or -CR< and n represents failure 1 if BP ^a represents >C<,

-S ^a -, -S ^a' -, -S ^a'' - and -S ^a''' - independently of one another represent a chemical bond or are selected from the group consisting of C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl, wherein the C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally substituted by one or more -R ¹ , which are the same or different, and wherein the C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R ² )-, -S(O) ₂ N(R ² )-, -S(O)N(R ² )-, -S(O) ₂ -, -S(O)-, -N(R ² )S(O) ₂ N(R ^2a )-, -S-, -N(R ² )-, -OC(OR ² )(R ^2a )-, -N(R ² )C(O)N(R ^2a )- and -OC(O)N(R ² )-,

each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, _C3-10 cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, wherein each -T- is independently optionally substituted with one or more ^-R1 that are the same or different,

each -R ¹ is independently selected from the group consisting of halogen, -CN, oxo (=O), -COOR ³ , -OR ³ , -C(O)R ³ , -C(O)N(R ³ R ^3a ), -S(O) ₂ N(R ³ R ^3a ), -S(O)N(R ³ R ^3a ), -S(O) ₂ R ³ , -S(O)R ³ , -N(R ³ )S(O) ₂ N(R ^3a R ^3b ), -SR ³ , -N(R ³ R ^3a ), -NO ₂ , -OC(O)R ³ , -N(R ³ )C(O)R ^3a , -N(R ³ )S(O) ₂ R ^3a , -N(R ³ )S(O)R ^3a , -N(R ³ )C(O)OR ^3a , -N(R ³ )C(O)N(R ^3a R ^3b ), -OC(O)N(R ³ R ^3a ) and C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with one or more halogens that are the same or different,

each -R ² , -R ^2a , -R ³ , -R ^3a and -R ^3b is independently selected from the group consisting of -H and C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with one or more halogens that are the same or different, and

-P ^a' , -P ^a'' and -P ^a''' independently represent a polymeric moiety.

According to certain embodiments, BP ^a of formula (a) is -N<.

According to certain embodiments, BP ^a of formula (a) is >C<.

In certain embodiments, BP ^a of formula (a) is -CR<. In certain embodiments, -R is -H. Accordingly, formula (a) is 0.

According to certain embodiments, -S ^a - of formula (a) represents a chemical bond.

According to certain embodiments, -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, wherein the C _1-10 alkyl, C _2-10 alkenyl, and C _2-10 alkynyl are optionally interrupted by one or more chemical groups selected from the group consisting of -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 )-, where -T- is 3-10 membered heterocyclyl, and -R ⁴ and -R ^4a are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl.

According to certain embodiments, -S ^a - of formula (a) is selected from the group consisting of C _1-10 alkyl that is interrupted by one or more chemical groups selected from the group consisting of -T-, -C(O)N(R ⁴ )-, and -O-.

According to certain embodiments, -S ^a' - of formula (a) represents a chemical bond.

According to certain embodiments, -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, wherein the C _1-10 alkyl, C _2-10 alkenyl, and C _2-10 alkynyl are optionally 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 )-, where -R ⁴ and -R ^4a are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. Preferably -S ^a' - of formula (a) is selected from the group consisting of methyl, ethyl, propyl, butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)- and -C(O)N(R ⁴ )-.

According to certain embodiments, -S ^a'' - of formula (a) represents a chemical bond.

According to certain embodiments, -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, wherein the C _1-10 alkyl, C _2-10 alkenyl, and C _2-10 alkynyl are optionally 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 )-, wherein -R ⁴ and -R ^4a are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. According to certain embodiments, -S ^a'' of formula (a) is selected from the group consisting of methyl, ethyl, propyl, butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)-, and -C(O)N(R ⁴ )-.

According to certain embodiments, -S ^a''' - of formula (a) represents a chemical bond.

According to certain embodiments, -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, wherein the C _1-10 alkyl, C _2-10 alkenyl, and C _2-10 alkynyl are optionally 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 )-, wherein -R ⁴ and -R ^4a are independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. According to certain embodiments, -S ^a''' - of formula (a) is selected from the group consisting of methyl, ethyl, propyl, butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)-, and -C(O)N(R ⁴ )-.

According to certain embodiments, -Pa ^' , -Pa ^'', and -Pa ^''' of formula (a) independently comprise a polymer selected from the group consisting of 2-methacryloyloxyethylphosphoylcholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyl oxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl oxazolines), poly(hydroxymethacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acid copolymers), poly(methacrylamides), poly(methacrylates), poly(methyl oxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinylamines), poly(vinyl methyl ethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans and their copolymers.

In certain embodiments, -P ^a' , -P ^a'' and -P ^a''' of formula (a) independently comprise a PEG-based moiety. In certain embodiments, -P ^a' , -P ^a'' and -P ^a''' of formula (a) independently comprise a PEG-based moiety, comprising at least 20% PEG, in certain embodiments comprising at least 30%, in certain embodiments comprising at least 40% PEG, in certain embodiments comprising at least 50% PEG, in certain embodiments comprising at least 60% PEG, in certain embodiments comprising at least 70% PEG, in certain embodiments comprising at least 80% PEG, and in certain embodiments comprising at least 90% PEG.

In certain embodiments, -P ^a' , -P ^a'' and -P ^a''' of formula (a) independently have a molecular weight in the range of and including 5 kDa-50 kDa, in certain embodiments have a molecular weight in the range of and including 5 kDa-40 kDa, in certain embodiments in the range of and including 7.5 kDa-35 kDa, in certain embodiments in the range of and including 7.5-30 kDa, in certain embodiments in the range of and including 10-30 kDa.

According to certain embodiments, -P ^a' , -P ^a'', and -P ^a''' of formula (a) have a molecular weight of about 5 kDa.

According to certain embodiments, -P ^a' , -P ^a'', and -P ^a''' of formula (a) have a molecular weight of about 7.5 kDa.

According to certain embodiments, -P ^a' , -P ^a'', and -P ^a''' of formula (a) have a molecular weight of about 10 kDa.

According to certain embodiments, -P ^a' , -P ^a'', and -P ^a''' of formula (a) have a molecular weight of about 12.5 kDa.

According to certain embodiments, -P ^a' , -P ^a'', and -P ^a''' of formula (a) have a molecular weight of about 15 kDa.

According to certain embodiments, -P ^a' , -P ^a'', and -P ^a''' of formula (a) have a molecular weight of about 20 kDa.

In certain embodiments, -Z comprises one fragment of formula (a).

According to certain embodiments, -Z comprises two fragments of formula (a).

According to certain embodiments, -Z comprises three fragments of formula (a).

In certain embodiments, -Z is a fragment of formula (a).

In certain embodiments, -Z comprises a fragment of formula (b)

Where

the dotted line shows the attachment to -L ² - or to the rest of -Z, and

m and p independently of one another are an integer in the range and including 150-1000, in certain embodiments an integer in the range and including 150-500, in certain embodiments an integer in the range and including 200-500, and in certain embodiments an integer in the range and including 400-500.

According to certain embodiments, both formulas (b) represent the same integer.

According to certain embodiments, the formula (b) tier is about 450.

In certain embodiments, -Z is a fragment of formula (b).

According to certain embodiments, the total mass of the PTH conjugate is 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. According to certain embodiments, the total mass of the PTH conjugate is at most 250 kDa, such as at most 200 kDa, 180 kDa, 150 kDa, or 100 kDa. It is understood that no meaningful upper limit on molecular mass can be specified if the PTH compound is water-insoluble.

According to certain embodiments, the PTH compound is a compound of formula (IIf-i):

Where

the unmarked dotted line shows the addition to the -D nitrogen, which is a PTH fragment, through the formation of an amide bond, and

the dotted line marked with an asterisk shows the attachment to the fragment

Where

m and p independently represent an integer in the range from and including 400 to 500.

According to certain embodiments, the formula (IIf-i) tiers are the same integer. According to certain embodiments, the formula (IIf-i) tiers are in the range and include 420-480. According to certain embodiments, the formula (IIf-i) tiers are in the range and include 430-470. According to certain embodiments, the formula (IIf-i) tiers are in the range and include 440-460.

In certain embodiments, -D is attached to the PTH prodrug of formula (IIf-i) via a functional group of the N-terminal amine of the PTH moiety.

According to certain embodiments, -D of formula (IIf-i) is PTH 1-34, i.e., has the sequence SEQ ID NO. 51.

In certain embodiments, the residual activity of the PTH compound is less than 10%, such as less than 1%, such as less than 0.1%, such as less than 0.01%, such as less than 0.001%, and in certain embodiments less than 0.0001%.

As used herein, the term "residual activity" refers to the activity exhibited by a PTH compound with a PTH fragment bound to a carrier, compared to the activity exhibited by the corresponding free PTH. In this context, the term "activity" refers to binding to activate the PTH/PTHrP1 receptor, resulting in activation of adenylate cyclase to form cAMP, phospholipase C to form intracellular calcium, or osteoblastic expression of RANKL (which binds to RANK (receptor activator of nuclear factor kB) on osteoclasts. It is understood that measurement of residual activity of a PTH prodrug for use in the present invention requires a period of time during which a certain amount of PTH will be released from the PTH compound, and that such released PTH may distort the results measured for the PTH compound. It is therefore conventional to test the residual activity of such a compound with a conjugate in which the drug molecule, in the case of PTH, is irreversibly, i.e. stably, bound to a carrier which resembles as closely as possible the structure of the PTH compound for which the residual activity is to be measured.

It is understood that the measurement of residual activity of a PTH prodrug for use in accordance with the present invention requires a period of time during which a certain amount of PTH will be released from the PTH compound, and that such released PTH may distort the results measured for the PTH compound. It is therefore conventional to test the residual activity of such a compound with a conjugate in which the drug molecule, in the case of PTH, is irreversibly, i.e. stably, bound to a carrier which resembles as closely as possible the structure of the PTH compound for which the residual activity is to be measured.

In certain embodiments, the PTH compound is administered in the form of a pharmaceutical composition comprising at least one PTH compound as disclosed herein. In certain embodiments, such a pharmaceutical composition has a pH in the range and including pH 3 to pH 8. In certain embodiments, the pharmaceutical composition has a pH in the range and including pH 4 to pH 6. In certain embodiments, the pharmaceutical composition has a pH in the range and including pH 4 to pH 5.

According to certain embodiments, the pharmaceutical composition is a liquid or suspension composition. It is understood that the pharmaceutical composition is a liquid composition if the PTH compound is soluble in water, and a suspension composition if the PTH compound is insoluble in water. According to certain embodiments, the pharmaceutical composition is a dry formulation that is reconstituted prior to administration to a patient.

Such a liquid, suspension, dry or reconstituted pharmaceutical composition comprises at least one excipient. Excipients used in parenteral compositions can be categorized as follows, for example, buffering agents, isotonicity modifiers, preservatives, stabilizers, anti-adsorption agents, anti-oxidation agents, thickeners/viscosity increasing agents, or other auxiliary agents. However, in some cases, one excipient can have dual or triple functions. According to certain embodiments, the at least one excipient is selected from the group consisting of

(i) Buffering agents: Physiologically acceptable buffers to maintain the pH value in the desired range such as sodium phosphate, bicarbonate, succinate, histidine, citrate and acetate, sulfate, nitrate, chloride, pyruvate; acid neutralizers such as Mg(OH) ₂ or _ZnCO3 may also be used;

(ii) Isotonicity modifiers: to minimise pain that may result from cell damage due to osmotic pressure differences when injecting slow-release agents; glycerol and sodium chloride are examples; effective concentrations can be determined by osmometry using a predetermined osmotic concentration of 285-315 mOsmol/kg for serum;

(iii) Preservatives and/or antimicrobials: Multidose parenteral formulations require the addition of preservatives at sufficient concentration to minimize the risk of contamination of the patient upon injection, and appropriate regulatory requirements should be established; typical preservatives include m-cresol, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenylmercuric nitrate, thimerosol, sorbic acid, potassium sorbate, benzoic acid, chlorocresol, and benzalkonium chloride;

(iv) Stabilizers: Stabilization is achieved by enhancing protein stabilizing forces, destabilizing the denatured state or directly binding excipients to the protein; stabilizers can be amino acids such as alanine, arginine, aspartic acid, glycine, histidine, lysine, proline, sugars such as glucose, sucrose, trehalose, polyols such as glycerol, mannitol, sorbitol, salts such as potassium phosphate, sodium sulfate, chelating agents such as EDTA, hexaphosphate, ligands such as divalent metal ions (zinc, calcium, etc.), other salts or organic molecules such as phenolic derivatives; in addition, oligomers or polymers such as cyclodextrins, dextran, dendrimers, PEG or PVP or protamine or HSA can be used;

(v) Anti-adsorption agents: Generally ionic or non-ionic surfactants or other proteins or soluble polymers are used to coat or competitively adsorb onto the inner surface of the composition container. For example, poloxamer (Pluronic F-68), PEG dodecyl ether (Brij 35), polysorbate 20 and 80, dextran, polyethylene glycol, PEG-polyhistidine, BSA and HSA and gelatins; the concentration and type of excipient selected depends on the effect to be avoided, but typically a monolayer of surfactant is formed at the interface just above the CMC value;

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

(vii) Thickening agents or viscosity increasing agents: in the case of a suspension, these slow down the settling of the particles in the vial and syringe and are used to facilitate mixing and resuspension of the particles and to facilitate injection of the suspension (i.e. with low force on the syringe plunger); Suitable thickeners or viscosity enhancers are, for example, carbomer thickeners such as Carbopol 940, Carbopol Ultrez 10, cellulose derivatives such as hydroxypropyl methyl cellulose (hypromellose, HPMC) or diethylaminoethyl cellulose (DEAE or DEAE-C), colloidal magnesium silicate (Veegum) or sodium silicate, hydroxyapatite gel, tricalcium phosphate gel, xanthans, carrageenans such as Satia gum UTC 30, aliphatic poly(hydroxy acids) such as poly(E, L- or L-lactic acid) (PLA) and poly(glycolic acid) (PGA) and their copolymers (PLGA), terpolymers of D, L-lactide, glycolide and caprolactone, poloxamers, hydrophilic poly(oxyethylene) blocks and hydrophobic poly(oxypropylene) blocks to form a poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) triblock (e.g. Pluronic®), polyether-polyester copolymer such as polyethyleneglycol terephthalate/polybutylene terephthalate copolymer, sucrose acetate isobutyrate (SAIB), dextran or its derivatives, combinations of dextrans and PEG, polydimethylsiloxane, collagen, chitosan, polyvinyl alcohol (PVA) and derivatives, polyalkylimides, poly(acrylamide-co-diallyldimethylammonium (DADMA)), polyvinylpyrrolidone (PVP), glycosaminoglycans (GAGs) such as dermatan sulfate, chondroitin sulfate, keratan sulfate, heparin, heparan sulfate, hyaluronan, ABA triblock or AB block copolymers, consisting of hydrophobic A-blocks, such as polylactide (PLA) or poly(lactide-co-glycolide) (PLGA) and hydrophilic B-blocks, such as polyethyleneglycol (PEG) or polyvinylpyrrolidone; such block copolymers, like the above-mentioned poloxamers, can exhibit reversible thermal gelation (a liquid state at room temperature for ease of administration and a gel state above the sol-gel transition temperature at body temperature after injection);

(viii) A lyophilizing or diffusing agent: modifies the permeability of connective tissue by hydrolyzing extracellular matrix components in the interstitial space, such as, but not limited to, hyaluronic acid, a polysaccharide found in the intercellular space of connective tissue; a lyophilizing agent, such as, but not limited to, hyaluronidase, temporarily reduces the viscosity of the extracellular matrix and promotes diffusion of injected drugs; and

(ix) Other auxiliaries: such as wetting agents, viscosity modifiers, antibiotics, hyaluronidase; acids and bases such as hydrochloric acid and sodium hydroxide are auxiliaries necessary for adjusting the pH value during production.

Treatment of hyperparathyroidism requires withdrawal of the patient's standard therapy for four weeks from the time of the first dose of the PTH compound. Various withdrawal schedules are suitable. In certain embodiments, withdrawal of the patient's standard therapy includes a stepwise reduction and then complete withdrawal of orally administered active vitamin D, followed by a stepwise reduction and then complete withdrawal of orally administered calcium. It is understood that some patients' diets do not provide sufficient absorption of dietary calcium (calcium is generally considered to be ≤750 mg per day), as may be the case, for example, in patients with lactose intolerance. These patients continue to take oral calcium supplements, for example, in the form of a once-daily oral calcium administration, such as a calcium tablet. However, calcium supplementation is not associated with the treatment of hyperparathyroidism and is common practice in healthy individuals.

In certain embodiments, the exclusion regimen is as follows (assuming normal serum calcium levels are maintained and there are no symptoms of hypocalcemia):

(i) Visit 1: decrease the active vitamin D dose by 33-50% (e.g. skip ^{the 2nd} dose per day if taking twice daily, skip the last dose per day if taking three times daily, or decrease the once daily dose of alfacalcidol ≥1.0 mcg by ≥0.5 mcg),

(ii) Day 3-4: discontinuation of active vitamin D,

(iii) Day 6-7: reduce calcium supplement intake by 50%,

(iv) Day 9-10: If the daily dietary calcium intake exceeds 750 mg/day, calcium supplementation should be discontinued; if the daily dietary calcium intake is <750 mg/day, calcium supplementation may be continued to achieve the recommended daily intake at the discretion of the physician.

In certain embodiments, the exclusion regimen is as follows (assuming normal serum calcium levels are maintained and there are no symptoms of hypocalcemia):

(i) Visit 1: decrease the active vitamin D dose by 33-50% (e.g. skip ^{the 2nd} dose per day if taking twice daily, skip the last dose per day if taking three times daily, or decrease the once daily dose of alfacalcidol ≥1.0 mcg by ≥0.5 mcg),

(ii) Day 3-4: Stop taking active vitamin D,

(iii) Day 6-7: if calcium intake ≤2000 mg/day, decrease calcium by ≥50% (≥400 mg/day), if calcium >2000 mg/day, decrease calcium by ≥800 mg/day,

(iv) Day 9-10: If calcium is ≤2000 mg/day, discontinue* or reduce calcium to ≤500 mg/day (*if dietary calcium is <750 mg/day, maintain calcium at 400 or 500 mg/day), if calcium is >2000 mg/day, reduce calcium to ≥800 mg/day.

The dose of the PTH compound for single daily administration is as disclosed elsewhere herein. It is understood that some steps of the elimination regimen may have to be repeated at a different dose if the initial dose was too high or too low.

Materials

Compound 1 has the following structure:

wherein the PTH(1-34) moiety has the sequence SEQ ID NO: 51 and is attached to the remainder of the PTH compound via the nitrogen atom of the N-terminal amine by forming an amide bond. It is understood that the nitrogen immediately to the left of "PTH(1-34) corresponds to the nitrogen of the N-terminal amine.

Compound 1 can be prepared by the method described in WO 2018/060312 A1 for compound 18. Compound 1 is also known as “TransCon PTH”.

Example 1

Human participants were randomly assigned to one of four groups: three groups received fixed doses of Compound 1 and one group received a placebo. Compound 1 or placebo was administered as a subcutaneous injection using a prefilled pen. Neither the study participants nor their doctors knew who was assigned to which group. After four weeks, participants were eligible to continue in the study as part of a long-term extension study. During the extension, all participants received Compound 1 at a dose tailored to their individual needs.

The double-blind, placebo-controlled, parallel-group treatment period of this study was designed to enroll approximately 55 adult men and women with postoperative GP, autoimmune, genetic, or idiopathic GP, for at least 26 weeks at approximately 40 sites worldwide. ClinicalTrials.gov Identifier: NCT04009291.

Subjects were randomized into 4 treatment groups (1:1:1:1):

- Compound 1 15 mcg/day*

- Compound 1 18 mcg/day*

- Compound 121 mcg/day*

- Placebo for compound 1 (excipient solution)

(*The dose of compound 1 refers to the dose of administered PTH(1-34), measured in PTH equivalents)

To maintain blinding, the placebo group was subrandomized into 3 groups (1:1:1) to sham doses of 15, 18, and 21 mcg/day.

Subjects remained on the same dose of study drug for a 4-week blinded treatment period. After successful completion of the blinded treatment period, subjects entered an open-label extension period during which all subjects received compound 1.

The entire study was designed so that each subject's participation could last up to 58 weeks plus a screening period of approximately 4 weeks.

- Screening period (optimization of the supplement): up to approximately 4 weeks

- Blinded treatment period (stable dose of compound 1 with SOC optimization): 4 weeks

- Extension period (open-label treatment with Compound 1): 54 weeks, with an initial 14 weeks of Compound 1 titration and SOC optimization, followed by approximately 40 weeks of stable dosing.

Exclusion regimen (subject to maintaining normal serum calcium levels)

• Visit 1: Reduce active vitamin D dose by 33-50% (eg, skip ^2nd dose per day if taking twice daily, skip last dose per day if taking three times daily, or reduce single daily dose of alfacalcidol ≥1.0 mcg by ≥0.5 mcg),

• Day 3-4: Stop taking active vitamin D,

• Day 6-7: If taking active vitamin D, stop taking active vitamin D, if stopping active vitamin D and taking calcium ≤2000 mg/day, reduce calcium by ≥50% (≥400 mg/day), and if taking calcium >2000 mg/day, reduce calcium by ≥800 mg/day,

• Day 9-10: If taking active vitamin D, stop taking active vitamin D; if stopping active vitamin D and calcium intake ≤2000 mg/day, stop* or reduce calcium intake to ≤500 mg/day (*if dietary calcium <750 mg/day) day, maintain calcium at 400 or 500 mg/day), if calcium >2000 mg/day, reduce calcium by ≥800 mg/day.

Results

Preliminary data from the first 8 subjects who completed 4 weeks of follow-up in the open-label extension study showed that all subjects had completely eliminated standard treatment, with 8/8 subjects no longer requiring active vitamin D. 7/8 subjects no longer required calcium supplements. One subject continued to take a daily calcium supplement at <500 mg to meet the recommended daily intake of calcium.

Full data, 4-week fixed-dose period: All 59 study subjects completed the 4-week initial fixed-dose period, during which dose optimization was not allowed. Patients randomized to receive Compound 1 were able to discontinue oral active vitamin D. Similarly, these patients were able to discontinue therapeutic doses of oral calcium, and oral calcium intake was reduced from a mean of 2213 mg/day at baseline to a mean of 560 mg/day after 4 weeks of Compound 1. In contrast, patients receiving placebo were unable to discontinue standard treatment and had a reduction in oral active vitamin D from 1.1 mcg/day at baseline to 0.9 mcg/day at week 4 and a reduction in oral calcium supplements from 1685 mg/day at baseline to 1368 mg/day at week 4.

Full data, 26 weeks: All 59 subjects completed the initial 4-week period and continued in the open-label extension (OLE), 58 subjects continued in the OLE beyond 6 months (1 withdrew from the study unrelated to safety or efficacy). Compound 1-treated patients continued to taper their oral calcium intake, which decreased to a mean of 294 mg/day at week 26 (n=44) while maintaining normal sCa and decreasing sP and CachP. Importantly, no subjects experienced PTH treatment-related adverse events related to hyper- or hypocalcemia leading to emergency department/urgent care visits and/or hospitalizations.

Example 2

Administration of Compound 1 to the human participants described in Example 1 resulted in statistically significant improvements compared with placebo in a double-blind SF-36 study. The SF-36 survey consists of 36 questions and the results are summarized into a Physical Health Score (PCS) and a Mental Health Score (MCS). At baseline, all subjects had below-average SF-36 scores. Statistically significant and clinically meaningful improvements in PCS and MCS were noted in the 4-week, double-blind, controlled portion of the Phase 2 study. For the PCS score, using a normative scoring system with a score of 50 as the general population norm and an ANCOVA model, subjects receiving Compound 1 demonstrated an average increase of 4.5 points compared with an average decrease of -0.69 points for placebo. The placebo-adjusted mean difference is 5.2 points with a p-value of 0.013. The minimum important difference for PCS is 2 points.

For the mental component summary score, subjects receiving compound 1 demonstrated a mean increase of 6.0 points compared to a mean decrease of -3.8 points for placebo. The placebo-adjusted difference was a mean of 9.8 points with a p-value of 0.0003. The minimally important difference for the MCS is 3 points.

Full data, 26 weeks: All 59 subjects completed the initial 4-week period and continued in the open-label extension (OLE), 58 subjects continued in the OLE beyond 6 months (1 withdrew from the study unrelated to safety or efficacy). Mean scores for all SF-36 summary and domains increased from below normal at baseline to within the normal range by week 26. HPES symptom and impact scores improved steadily over 26 weeks for patients receiving Compound 1 and placebo subjects who crossed over to Compound 1. Details are presented in Table 1. Compound 1 continued to be well tolerated with no treatment-related serious or severe adverse events.

Example 3

All 59 subjects completed the initial 4-week period and continued in the open-label extension (OLE), with 58 subjects continuing in the OLE beyond 6 months (1 withdrew from the study for reasons unrelated to safety or efficacy). At baseline, mean BMD Z-scores at the lumbar spine, femoral neck, and total hip were elevated due to a lack of bone remodeling. With compound 1 treatment, mean BMD Z-scores tended to normalize at week 26, as shown in Table 2.

Abbreviations

BID twice a day, i.e. twice a day

GP hypoparathyroidism

PTH parathyroid hormone

RDA Recommended Daily Allowance/Dietary Allowance

sCA serum calcium

SOC standard of care

TID three times a day, i.e. three times a day.

--->

SEQUENCE LIST

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<120> TREATMENT OF Hypoparathyroidism

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Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

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Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

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Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

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Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys

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Ala Lys Ser Gln

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Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

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Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

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Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

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Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

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Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys

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Ala Lys Ser

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<212> PRT

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<223> human PTH 1-82

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Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

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Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

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Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

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Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

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Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys

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Ala Lys

<210> 4

<211> 81

<212> PRT

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<223> human PTH 1-81

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Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

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Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

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Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys

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Ala

<210> 5

<211> 80

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-80

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Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

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Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

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Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys

65 70 75 80

<210> 6

<211> 79

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-79

<400> 6

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr

65 70 75

<210> 7

<211> 78

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-78

<400> 7

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu

65 70 75

<210> 8

<211> 77

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-77

<400> 8

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val

65 70 75

<210> 9

<211> 76

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-76

<400> 9

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn

65 70 75

<210> 10

<211> 75

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-75

<400> 10

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val

65 70 75

<210> 11

<211> 74

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-74

<400> 11

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp

65 70

<210> 12

<211> 73

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-73

<400> 12

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala

65 70

<210> 13

<211> 72

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-72

<400> 13

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys

65 70

<210> 14

<211> 71

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-71

<400> 14

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp

65 70

<210> 15

<211> 70

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-70

<400> 15

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala

65 70

<210> 16

<211> 69

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-69

<400> 16

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu

65

<210> 17

<211> 68

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-68

<400> 17

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly

65

<210> 18

<211> 67

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-67

<400> 18

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu

65

<210> 19

<211> 66

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-66

<400> 19

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser

65

<210> 20

<211> 65

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-65

<400> 20

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys

65

<210> 21

<211> 64

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-64

<400> 21

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

<210> 22

<211> 63

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-63

<400> 22

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His

50 55 60

<210> 23

<211> 62

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-62

<400> 23

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser

50 55 60

<210> 24

<211> 61

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-61

<400> 24

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu

50 55 60

<210> 25

<211> 60

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-60

<400> 25

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val

50 55 60

<210> 26

<211> 59

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-59

<400> 26

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu

50 55

<210> 27

<211> 58

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-58

<400> 27

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val

50 55

<210> 28

<211> 57

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-57

<400> 28

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn

50 55

<210> 29

<211> 56

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-56

<400> 29

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp

50 55

<210> 30

<211> 55

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-55

<400> 30

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu

50 55

<210> 31

<211> 54

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-54

<400> 31

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys

50

<210> 32

<211> 53

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-53

<400> 32

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys

50

<210> 33

<211> 52

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-52

<400> 33

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg

50

<210> 34

<211> 51

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-51

<400> 34

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro

50

<210> 35

<211> 50

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-50

<400> 35

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg

50

<210> 36

<211> 49

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-49

<400> 36

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln

<210> 37

<211> 48

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-48

<400> 37

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

<210> 38

<211> 47

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-47

<400> 38

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly

35 40 45

<210> 39

<211> 46

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-46

<400> 39

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala

35 40 45

<210> 40

<211> 45

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-45

<400> 40

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp

35 40 45

<210> 41

<211> 44

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-44

<400> 41

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg

35 40

<210> 42

<211> 43

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-43

<400> 42

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro

35 40

<210> 43

<211> 42

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-42

<400> 43

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala

35 40

<210> 44

<211> 41

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH-41

<400> 44

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu

35 40

<210> 45

<211> 40

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-40

<400> 45

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro

35 40

<210> 46

<211> 39

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-39

<400> 46

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala

35

<210> 47

<211> 38

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-38

<400> 47

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly

35

<210> 48

<211> 37

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-37

<400> 48

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu

35

<210> 49

<211> 36

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-36

<400> 49

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala

35

<210> 50

<211> 35

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-35

<400> 50

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val

35

<210> 51

<211> 34

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-34

<400> 51

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe

<210> 52

<211> 33

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-33

<400> 52

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn

<210> 53

<211> 32

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-32

<400> 53

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

<210> 54

<211> 31

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-31

<400> 54

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val

20 25 30

<210> 55

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-30

<400> 55

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp

20 25 30

<210> 56

<211> 29

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-29

<400> 56

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln

20 25

<210> 57

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-28

<400> 57

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu

20 25

<210> 58

<211> 27

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-27

<400> 58

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys

20 25

<210> 59

<211> 26

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-26

<400> 59

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys

20 25

<210> 60

<211> 25

<212> PRT

<213> Artificial sequence

<220>

<223> human PTH 1-25

<400> 60

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg

20 25

<210> 61

<211> 84

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-84

<220>

<221>MOD_RES

<222> (84)..(84)

<223> AMIDATION

<400> 61

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys

65 70 75 80

Ala Lys Ser Gln

<210> 62

<211> 83

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-83

<220>

<221>MOD_RES

<222> (83)..(83)

<223> AMIDATION

<400> 62

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys

65 70 75 80

Ala Lys Ser

<210> 63

<211> 82

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-82

<220>

<221>MOD_RES

<222> (82)..(82)

<223> AMIDATION

<400> 63

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys

65 70 75 80

Ala Lys

<210> 64

<211> 81

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-81

<220>

<221>MOD_RES

<222> (81)..(81)

<223> AMIDATION

<400> 64

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys

65 70 75 80

Ala

<210> 65

<211> 80

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-80

<220>

<221>MOD_RES

<222> (80)..(80)

<223> AMIDATION

<400> 65

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys

65 70 75 80

<210> 66

<211> 79

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-79

<220>

<221>MOD_RES

<222> (79)..(79)

<223> AMIDATION

<400> 66

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr

65 70 75

<210> 67

<211> 78

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-78

<220>

<221>MOD_RES

<222> (78)..(78)

<223> AMIDATION

<400> 67

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu

65 70 75

<210> 68

<211> 77

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-77

<220>

<221>MOD_RES

<222> (77)..(77)

<223> AMIDATION

<400> 68

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val

65 70 75

<210> 69

<211> 76

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-76

<220>

<221>MOD_RES

<222> (76)..(76)

<223> AMIDATION

<400> 69

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn

65 70 75

<210> 70

<211> 75

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-75

<220>

<221>MOD_RES

<222> (75)..(75)

<223> AMIDATION

<400> 70

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val

65 70 75

<210> 71

<211> 74

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-74

<220>

<221>MOD_RES

<222> (74)..(74)

<223> AMIDATION

<400> 71

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp

65 70

<210> 72

<211> 73

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-73

<220>

<221>MOD_RES

<222> (73)..(73)

<223> AMIDATION

<400> 72

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys Ala

65 70

<210> 73

<211> 72

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-72

<220>

<221>MOD_RES

<222> (72)..(72)

<223> AMIDATION

<400> 73

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp Lys

65 70

<210> 74

<211> 71

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-71

<220>

<221>MOD_RES

<222> (71)..(71)

<223> AMIDATION

<400> 74

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala Asp

65 70

<210> 75

<211> 70

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-70

<220>

<221>MOD_RES

<222> (70)..(70)

<223> AMIDATION

<400> 75

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu Ala

65 70

<210> 76

<211> 69

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-69

<220>

<221>MOD_RES

<222> (69)..(69)

<223> AMIDATION

<400> 76

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly Glu

65

<210> 77

<211> 68

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-68

<220>

<221>MOD_RES

<222> (68)..(68)

<223> AMIDATION

<400> 77

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu Gly

65

<210> 78

<211> 67

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-67

<220>

<221>MOD_RES

<222> (67)..(67)

<223> AMIDATION

<400> 78

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser Leu

65

<210> 79

<211> 66

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-66

<220>

<221>MOD_RES

<222> (66)..(66)

<223> AMIDATION

<400> 79

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys Ser

65

<210> 80

<211> 65

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-65

<220>

<221>MOD_RES

<222> (65)..(65)

<223> AMIDATION

<400> 80

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

Lys

65

<210> 81

<211> 64

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-64

<220>

<221>MOD_RES

<222> (64)..(64)

<223> AMIDATION

<400> 81

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu

50 55 60

<210> 82

<211> 63

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-63

<220>

<221>MOD_RES

<222> (63)..(63)

<223> AMIDATION

<400> 82

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His

50 55 60

<210> 83

<211> 62

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-62

<220>

<221>MOD_RES

<222> (62)..(62)

<223> AMIDATION

<400> 83

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser

50 55 60

<210> 84

<211> 61

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-61

<220>

<221>MOD_RES

<222> (61)..(61)

<223> AMIDATION

<400> 84

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu

50 55 60

<210> 85

<211> 60

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-60

<220>

<221>MOD_RES

<222> (60)..(60)

<223> ACETYLATION

<400> 85

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val

50 55 60

<210> 86

<211> 59

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-59

<220>

<221>MOD_RES

<222> (59)..(59)

<223> AMIDATION

<400> 86

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu

50 55

<210> 87

<211> 58

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-58

<220>

<221>MOD_RES

<222> (58)..(58)

<223> AMIDATION

<400> 87

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn Val

50 55

<210> 88

<211> 57

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-57

<220>

<221>MOD_RES

<222> (57)..(57)

<223> AMIDATION

<400> 88

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp Asn

50 55

<210> 89

<211> 56

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-56

<220>

<221>MOD_RES

<222> (56)..(56)

<223> AMIDATION

<400> 89

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu Asp

50 55

<210> 90

<211> 55

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-55

<220>

<221>MOD_RES

<222> (55)..(55)

<223> AMIDATION

<400> 90

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys Glu

50 55

<210> 91

<211> 54

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-54

<220>

<221>MOD_RES

<222> (54)..(54)

<223> AMIDATION

<400> 91

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys Lys

50

<210> 92

<211> 53

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-53

<220>

<221>MOD_RES

<222> (53)..(53)

<223> AMIDATION

<400> 92

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg Lys

50

<210> 93

<211> 52

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-52

<220>

<221>MOD_RES

<222> (52)..(52)

<223> AMIDATION

<400> 93

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro Arg

50

<210> 94

<211> 51

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-51

<220>

<221>MOD_RES

<222> (51)..(51)

<223> AMIDATION

<400> 94

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg Pro

50

<210> 95

<211> 50

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-50

<220>

<221>MOD_RES

<222> (50)..(50)

<223> AMIDATION

<400> 95

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln Arg

50

<210> 96

<211> 49

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-49

<220>

<221>MOD_RES

<222> (49)..(49)

<223> AMIDATION

<400> 96

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

Gln

<210> 97

<211> 48

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-48

<220>

<221>MOD_RES

<222> (48)..(48)

<223> AMIDATION

<400> 97

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser

35 40 45

<210> 98

<211> 47

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-47

<220>

<221>MOD_RES

<222> (47)..(47)

<223> AMIDATION

<400> 98

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly

35 40 45

<210> 99

<211> 46

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-46

<220>

<221>MOD_RES

<222> (46)..(46)

<223> AMIDATION

<400> 99

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala

35 40 45

<210> 100

<211> 45

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-45

<220>

<221>MOD_RES

<222> (45)..(45)

<223> AMIDATION

<400> 100

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp

35 40 45

<210> 101

<211> 44

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-44

<220>

<221>MOD_RES

<222> (44)..(44)

<223> AMIDATION

<400> 101

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg

35 40

<210> 102

<211> 43

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-43

<220>

<221>MOD_RES

<222> (43)..(43)

<223> AMIDATION

<400> 102

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro

35 40

<210> 103

<211> 42

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-42

<220>

<221>MOD_RES

<222> (42)..(42)

<223> AMIDATION

<400> 103

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu Ala

35 40

<210> 104

<211> 41

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-41

<220>

<221>MOD_RES

<222> (41)..(41)

<223> AMIDATION

<400> 104

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro Leu

35 40

<210> 105

<211> 40

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-40

<220>

<221>MOD_RES

<222> (40)..(40)

<223> AMIDATION

<400> 105

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala Pro

35 40

<210> 106

<211> 39

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-39

<220>

<221>MOD_RES

<222> (39)..(39)

<223> AMIDATION

<400> 106

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly Ala

35

<210> 107

<211> 38

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-38

<220>

<221>MOD_RES

<222> (38)..(38)

<223> AMIDATION

<400> 107

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu Gly

35

<210> 108

<211> 37

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-37

<220>

<221>MOD_RES

<222> (37)..(37)

<223> AMIDATION

<400> 108

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala Leu

35

<210> 109

<211> 36

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-36

<220>

<221>MOD_RES

<222> (36)..(36)

<223> AMIDATION

<400> 109

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val Ala

35

<210> 110

<211> 35

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-35

<220>

<221>MOD_RES

<222> (35)..(35)

<223> AMIDATION

<400> 110

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe Val

35

<210> 111

<211> 34

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-34

<220>

<221>MOD_RES

<222> (34)..(34)

<223> AMIDATION

<400> 111

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn Phe

<210> 112

<211> 33

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-33

<220>

<221>MOD_RES

<222> (33)..(33)

<223> AMIDATION

<400> 112

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

Asn

<210> 113

<211> 32

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-32

<220>

<221>MOD_RES

<222> (32)..(32)

<223> AMIDATION

<400> 113

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His

20 25 30

<210> 114

<211> 31

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-31

<220>

<221>MOD_RES

<222> (31)..(31)

<223> AMIDATION

<400> 114

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val

20 25 30

<210> 115

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-30

<220>

<221>MOD_RES

<222> (30)..(30)

<223> AMIDATION

<400> 115

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp

20 25 30

<210> 116

<211> 29

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-29

<220>

<221>MOD_RES

<222> (29)..(29)

<223> AMIDATION

<400> 116

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln

20 25

<210> 117

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-28

<220>

<221>MOD_RES

<222> (28)..(28)

<223> AMIDATION

<400> 117

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu

20 25

<210> 118

<211> 27

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-27

<220>

<221>MOD_RES

<222> (27)..(27)

<223> AMIDATION

<400> 118

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys

20 25

<210> 119

<211> 26

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-26

<220>

<221>MOD_RES

<222> (26)..(26)

<223> AMIDATION

<400> 119

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg Lys

20 25

<210> 120

<211> 25

<212> PRT

<213> Artificial sequence

<220>

<223> amidated human PTH 1-25

<220>

<221>MOD_RES

<222> (25)..(25)

<223> AMIDATION

<400> 120

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn

1 5 10 15

Ser Met Glu Arg Val Glu Trp Leu Arg

20 25

<210> 121

<211> 141

<212> PRT

<213> Homo sapiens

<400> 121

Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln

1 5 10 15

Asp Leu Arg Arg Arg Phe Phe Leu His His Leu Ile Ala Glu Ile His

20 25 30

Thr Ala Glu Ile Arg Ala Thr Ser Glu Val Ser Pro Asn Ser Lys Pro

35 40 45

Ser Pro Asn Thr Lys Asn His Pro Val Arg Phe Gly Ser Asp Asp Glu

50 55 60

Gly Arg Tyr Leu Thr Gln Glu Thr Asn Lys Val Glu Thr Tyr Lys Glu

65 70 75 80

Gln Pro Leu Lys Thr Pro Gly Lys Lys Lys Lys Gly Lys Pro Gly Lys

85 90 95

Arg Lys Glu Gln Glu Lys Lys Lys Arg Arg Thr Arg Ser Ala Trp Leu

100 105 110

Asp Ser Gly Val Thr Gly Ser Gly Leu Glu Gly Asp His Leu Ser Asp

115 120 125

Thr Ser Thr Thr Ser Leu Glu Leu Asp Ser Arg Arg His

130 135 140

<---

Claims (25)

1. The use of a PTH compound for the treatment of hypoparathyroidism, wherein the treatment comprises single daily administrations to a human patient of a PTH compound and the patient's exclusion of standard therapy for four weeks from the time of the first dose of the PTH compound, wherein the PTH compound is a compound of formula (IIf-i): Where the unmarked dotted line shows the attachment to the N-terminal amine functional group of the PTH fragment having the sequence SEQ ID NO:51; and the dotted line marked with an asterisk shows the attachment to the fragment Where m and p independently represent an integer in the range and including 400 – 500, wherein the single daily dose of the PTH compound is selected from 15 mcg/day, 18 mcg/day and 21 mcg/day, and wherein the daily dose of the administered PTH compound can be adjusted depending on the serum calcium level. 2. Use according to paragraph 1, where the patient's use of standard therapy is excluded within three weeks from the moment of administration of the first dose of the PTH compound. 3. Use according to paragraph 1, where the exclusion of the patient's use of standard therapy occurs within two weeks from the moment of administration of the first dose of the PTH compound. 4. Use according to claim 1, wherein the administration is by subcutaneous injection. 5. Use according to paragraph 1, where the administration is carried out using a syringe pen. 6. Use according to paragraph 1, where the exclusion of the use of standard therapy by patients includes a stepwise reduction followed by a complete refusal of orally administered active vitamin D. 7. Use according to item 6, where the withdrawal of orally administered active vitamin D is followed by a gradual reduction and then complete withdrawal of oral calcium intake, with the exception of additional calcium with food in an amount of ≤750 mg calcium per day, necessary due to insufficient absorption of calcium with food. 8. Use according to paragraph 1, where the exclusion of the patient’s use of standard therapy is carried out according to the following exclusion scheme: (i) Visit 1: reduction of active vitamin D dose by 33-50%, (ii) Day 3-4: discontinuation of active vitamin D, (iii) Day 6-7: reduce calcium supplement intake by 50%, (iv) Day 9-10: If daily dietary calcium intake exceeds 750 mg/day, calcium supplementation should be discontinued; if daily dietary calcium intake is <750 mg/day, calcium supplementation may be continued to achieve the recommended daily allowance at the discretion of the physician. 9. Use according to one of paragraphs 1 - 8, where the exclusion of the patient's use of standard therapy is carried out according to the following exclusion scheme: (i) Visit 1: reduction of active vitamin D dose by 33-50%, (ii) Day 3-4: discontinuation of active vitamin D, (iii) Day 6-7: if calcium intake ≤2000 mg/day, decrease calcium by ≥50% (≥400 mg/day), if calcium >2000 mg/day, decrease calcium by ≥800 mg/day, (iv) Day 9-10: If calcium is ≤2000 mg/day, discontinue; if dietary calcium is <750 mg/day, maintain calcium at 400 or 500 mg/day or reduce calcium to 500 mg/day; if calcium is >2000 mg/day, reduce calcium by ≥800 mg/day.