RU2806753C2 - Method of treating or control of hypoparathyroidus using parathrooid hormone (pth) conjugate - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention discloses a method of treating or controlling hypoparathyroidism in a patient, wherein the method includes the step of administering an initial dose of 4.4 ± 0.3 nmol/day of a parathyroid hormone (PTH) conjugate, in which the PTH moiety is reversibly conjugated to a polymer constituent or a pharmaceutically acceptable salt thereof, or the step of administering an initial dose of 4.4 ± 0.3 nmol/day of a pharmaceutical composition containing the said PTH conjugate or a pharmaceutically acceptable salt thereof, and wherein the PTH conjugate has the following formula (IIf-i), where the unlabeled dotted line shows the attachment to the N-terminal amine functionality of a PTH moiety having the following sequence SEQ ID NO: 51, due to the formation of an amide bond; and the dotted line marked with an asterisk shows the addition to the component where m and p independently represent an integer in the interval and including 400–500.

EFFECT: technical result of the invention is the reduction of side effects due to a safe and effective initial dose of a long-acting PTH conjugate.

6 cl, 1 dwg, 1 tbl, 1 ex

Description

The present invention relates to a PTH conjugate in which the PTH moiety is reversibly conjugated to a polymeric or fatty acid moiety, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said PTH conjugate or a pharmaceutically acceptable salt thereof, for use in the treatment, control, delaying or preventing a disease that can be treated, controlled, delayed or prevented by PTH, wherein the initial dose is in the range of 0.8 to 4.9 nmol/day, and to appropriate treatments.

Hypoparathyroidism (HP) is a rare disorder of mineral metabolism. Clinical manifestations may include muscle cramps, spasms or tetany and, in rare cases, life-threatening events such as seizures or laryngospasm. The etiology is often neck surgery in adults or genetic disorders in children.

Conventional therapy with vitamin D analogues and calcium may normalize serum calcium by increasing intestinal absorption but does not restore PTH-dependent renal calcium reabsorption or correct decreased bone turnover. Hypercalciuria and hyperphosphatemia often occur even when serum calcium levels are maintained below normal levels. Chronic hypercalciuria can cause irreversible kidney damage and renal failure, and sustained hyperphosphatemia, resulting in increased CxP product, can cause ectopic calcification in the renal parenchyma, vasculature, lens of the eye, and basal ganglia of the brain, leading to additional potential morbidity and mortality. To reduce this risk, doses of vitamin D and calcium analogues are often reduced to maintain serum calcium levels at the lowest tolerated level. Consequently, many patients with hypoparathyroidism suffer from varying degrees of hypocalcemia to avoid renal damage caused by hypercalciuria. (Clin Endocrinol Metab. 2012 Feb; 97(2): 391-399).

It is well known that overproduction of PTH causes a distinct pathophysiological syndrome, hyperparathyroidism, characterized by hypercalcemia, hypercalciuria, hypophosphatemia, phosphaturia, and increased osteoclastic bone resorption. Continuous exposure to supraphysiological PTH after continuous infusion reproduces many of the symptoms of hyperparathyroidism. In this study, both administered doses of PTH resulted in hypercalcemia, resulting in a marked decrease in endogenous PTH(1-84) secretion, consistent with supraphysiological doses of PTH. Suppression of endogenous PTH(1-84) secretion occurs in response to increased serum calcium levels. The maximum suppression in response to hypercalcemia in healthy volunteers has been shown to be approximately 3-5 pg/ml, regardless of baseline serum calcium values. (Journal of Bone and Mineral Research, Vol. 26, No. 9, September 2011, pp 2287-2297).

Because one of the goals of HP therapy is to normalize serum calcium, supraphysiologic PTH levels should be avoided.

A single or twice daily injection of PTH 1-34 can restore serum and urinary calcium to normal or near-normal levels. Teriparatide has a short half-life of approximately 5 minutes after intravenous administration and 1 hour after subcutaneous administration due to prolonged absorption (Forteo Prescribing Information). The better results with twice daily dosing may be explained by the short half-life of PTH(1-34), whose calcium-normalizing effect does not last a full 24 hours after a single dose.

In 2015, PTH(1-84), Natpara, was approved for subcutaneous injection once daily as a supplement to vitamin D and calcium in patients with hypoparathyroidism. Although this represents an important advance in the treatment of the disease, Natpara has not demonstrated the ability to reduce the incidence of hypercalcemia, hypocalcemia, or hypercalciuria compared with conventional therapy in patients eligible for treatment, likely due to its short half-life (about 5 minutes when administered intravenously; approximately 3 hours for subcutaneous administration).

Thus, there is a high need for improved PTH-based treatments for hypoparathyroidism that can maintain PTH and serum calcium levels within the physiological range. One such approach is to provide continuous exposure to PTH. For example, regarding the provision of physiological levels of PTH, clinical studies have been conducted with PTH(1-34) administered via pump delivery compared to twice daily injections. Pump delivery of PTH(1-34) achieved simultaneous normalization of bone turnover markers, serum calcium, serum phosphate, serum magnesium, and urinary calcium excretion.

However, the requirement to rely on an infusion pump is burdensome for patients, and it would be a significant improvement if continuous PTH infusion could be achieved with a single daily injection.

To address this issue, reversible polymeric PTH conjugates (WO2017/148883A1) have been developed to provide extended, continuous release of PTH through daily injections. Because both hypo- and hypercalcemia are associated with significant morbidity, it is critical that the initial dose of such daily therapy is appropriately selected to ensure that patients receive both clinical benefit and a reduced risk of side effects. There is currently no information available on suitable and safe starting doses of these PTH conjugates.

Thus, there is a need to determine a safe and effective starting dose of long-acting PTH conjugates. This is the object of the present invention.

This object is achieved by a PTH conjugate in which the PTH moiety is reversibly conjugated to a polymeric or fatty acid moiety, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said PTH conjugate or a pharmaceutically acceptable salt thereof, for use in treatment, control , delay or prevention of a disease that can be treated, controlled, delayed or prevented by PTH, where the initial dose is in the range of 0.8 to 4.9 nmol/day. In certain embodiments, the initial dose is in the range of 0.8 to 3.9 nmol/day.

In another aspect, the present invention provides a method of treating, controlling, delaying or preventing a patient suffering from a disease that can be treated, controlled, delaying or preventing with PTH, comprising administering an effective amount of a PTH conjugate in which the PTH moiety is reversibly conjugated to a polymer moiety or a fatty acid moiety, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said PTH conjugate or a pharmaceutically acceptable salt thereof, to a patient at an initial dose ranging from 0.8 to 4.9 nmol/day. In certain embodiments, the initial dose is in the range of 0.8 to 3.9 nmol/day.

Surprisingly, it was found that a dose in the range of 0.8 to 4.9 nmol/day was able to suppress the secretion of endogenous PTH (1-84) but did not cause hypercalcemia, and that a dose in the range of 0.8 to 3.9 nmol /day was able to increase serum calcium levels without completely suppressing the secretion of endogenous PTH (1-84).

In the context of the present invention, the terms used have the following meanings.

In the context of the present invention, the term "initial dose" refers to the dose of the PTH conjugate according to the present invention that is administered to the patient during the first initial therapy with the PTH conjugate, i.e. such patient has not previously received a dose of the indicated PTH conjugate. It is understood that such an initial dosage may be continued for a period of time, such as several weeks or months, to allow the patient to stabilize and adjust other medications, such as oral calcium and active vitamin D.

As used herein, the term “PTH” refers to all PTH polypeptides, preferably mammalian species, more preferably human and primate species, more preferably human, as well as variants, analogues, orthologs, homologs and derivatives and fragments thereof, which are characterized by increasing serum calcium and phosphorus excretion by the kidneys, and a decrease in serum phosphorus and calcium excretion by the kidneys. The term “PTH” also refers to all PTHrP polypeptides, such as the polypeptide of SEQ ID NO: 121, which binds to and activates the common PTH/PTHrP1 receptor. Preferably, the term “PTH” refers to the PTH polypeptide of SEQ ID NO: 51 as well as variants, homologues and derivatives thereof exhibiting substantially the same biological activity, i.e. increasing serum calcium and phosphorus excretion by the kidneys, and decreasing serum phosphorus and calcium excretion by the kidneys.

Preferably, the term “PTH” refers to a polypeptide sequence selected from the group consisting of:

SEQ ID NO: 1 (PTH 1-84)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ

SEQ ID NO: 2 (PTH 1-83)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS

SEQ ID NO: 3 (PTH 1-82)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK

SEQ ID NO: 4 (PTH 1-81)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA

SEQ ID NO: 5 (PTH 1-80)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK

SEQ ID NO: 6 (PTH 1-79)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT

SEQ ID NO: 7 (PTH 1-78)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL

SEQ ID NO: 8 (PTH 1-77)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV

SEQ ID NO: 9 (PTH 1-76)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN

SEQ ID NO: 10 (PTH 1-75)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV

SEQ ID NO: 11 (PTH 1-74)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD

SEQ ID NO: 12 (PTH 1-73)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA

SEQ ID NO: 13 (PTH 1-72)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK

SEQ ID NO: 14 (PTH 1-71)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD

SEQ ID NO: 15 (PTH 1-70)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA

SEQ ID NO: 16 (PTH 1-69)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE

SEQ ID NO: 17 (PTH 1-68)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG

SEQ ID NO: 18 (PTH 1-67)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL

SEQ ID NO: 19 (PTH 1-66)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS

SEQ ID NO: 20 (PTH 1-65)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK

SEQ ID NO: 21 (PTH 1-64)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE

SEQ ID NO: 22 (PTH 1-63)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH

SEQ ID NO: 23 (PTH 1-62)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES

SEQ ID NO: 24 (PTH 1-61)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE

SEQ ID NO: 25 (PTH 1-60)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV

SEQ ID NO: 26 (PTH 1-59)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL

SEQ ID NO: 27 (PTH 1-58)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV

SEQ ID NO: 28 (PTH 1-57)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN

SEQ ID NO: 29 (PTH 1-56)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED

SEQ ID NO: 30 (PTH 1-55)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE

SEQ ID NO: 31 (PTH 1-54)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK

SEQ ID NO: 32 (PTH 1-53)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK

SEQ ID NO: 33 (PTH 1-52)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR

SEQ ID NO: 34 (PTH 1-51)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP

SEQ ID NO: 35 (PTH 1-50)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR

SEQ ID NO: 36 (PTH 1-49)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ

SEQ ID NO: 37 (PTH 1-48)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS

SEQ ID NO: 38 (PTH 1-47)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG

SEQ ID NO: 39 (PTH 1-46)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA

SEQ ID NO: 40 (PTH 1-45)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD

SEQ ID NO: 41 (PTH 1-44)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR

SEQ ID NO: 42 (PTH 1-43)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP

SEQ ID NO: 43 (PTH 1-42)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA

SEQ ID NO: 44 (PTH 1-41)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL

SEQ ID NO: 45 (PTH 1-40)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP

SEQ ID NO: 46 (PTH 1-39)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA

SEQ ID NO: 47 (PTH 1-38)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG

SEQ ID NO: 48 (PTH 1-37)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL

SEQ ID NO: 49 (PTH 1-36)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA

SEQ ID NO: 50 (PTH 1-35)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV

SEQ ID NO: 51 (PTH 1-34)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF

SEQ ID NO: 52 (PTH 1-33)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN

SEQ ID NO: 53 (PTH 1-32)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH

SEQ ID NO: 54 (PTH 1-31)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV

SEQ ID NO: 55 (PTH 1-30)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQD

SEQ ID NO: 56 (PTH 1-29)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQ

SEQ ID NO: 57 (PTH 1-28)

SVSEIQLMHNLGKHLNSMERVEWLRKKL

SEQ ID NO: 58 (PTH 1-27)

SVSEIQLMHNLGKHLNSMERVEWLRKK

SEQ ID NO: 59 (PTH 1-26)

SVSEIQLMHNLGKHLNSMERVEWLRK

SEQ ID NO: 60 (PTH 1-25)

SVSEIQLMHNLGKHLNSMERVEWLR

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

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ; 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)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA; 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)

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP; where the C-terminus is amidated

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

SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA; 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

More preferably, the term “PTH” refers to a sequence selected from the group consisting of SEQ ID:NO 47, 48, 49, 50, 51, 52, 53, 54, 55, 107, 108, 109, 110, 111, 112 , 113, 114 and 115. Even more preferably, the term “PTH” refers to a sequence selected from the group consisting of SEQ ID:NO 50, 51, 52, 110, 111 and 112. In a particularly preferred embodiment of the present invention, the term “ PTH” refers to the sequence SEQ ID NO: 51.

As used herein, the term “variant PTH polypeptide” refers to a polypeptide from the same species that is different from the reference PTH or PTHrP polypeptide. Preferably, such reference polypeptide is the PTH polypeptide sequence of SEQ ID NO: 51. In general, differences are limited such that the amino acid sequences of the reference polypeptide and the variant are generally very similar and, in many areas, identical. Preferably, the PTH polypeptide variants are at least 70%, 80%, 90%, or 95% identical to the reference PTH or PTHrP polypeptide, preferably the PTH polypeptide of SEQ ID NO: 51. By polypeptide having an amino acid sequence of at least e.g. 95% “identical” to the subject amino acid sequence is meant to mean that the amino acid sequence of a given polypeptide is identical to the subject sequence, except that the polypeptide sequence may include up to five amino acid changes for every 100 amino acids of the subject 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, distributed either individually among residues in the reference sequence or as one or more more adjacent groups in the reference sequence. The sequence in question may be either the entire amino acid sequence of the reference sequence or any fragment specified as described herein. Preferably, the sequence in question is the sequence of SEQ ID NO: 51.

Such PTH polypeptide 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 originating from one primary transcript. Alternatively, the PTH polypeptide variant may be a variant that is not known to occur in nature, and which can be generated by mutagenesis techniques known in the art.

It is known in the art that one or more amino acids can be removed from the N-terminus or C-terminus of a bioactive polypeptide without significant loss of biological function. Such N- and/or C-terminal deletions are also included within the term PTH polypeptide variant.

It is also known to those skilled in the art that certain amino acid sequences of PTH or PTHrP polypeptides can be changed without significantly affecting the structure or function of the polypeptide. 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, instructions on how to make phenotypically silent amino acid substitutions are provided in Bowie et al. (1990), Science 247:1306-1310, which is incorporated herein by reference in its entirety, where the authors indicate that there are two main approaches to studying amino acid sequence tolerance to variation.

The term PTH polypeptide also covers all PTH and PTHrP polypeptides encoded by PTH and PTHrP analogues, orthologues and/or species homologs. It will also be understood by those skilled in the art that PTHrP and PTHrP analogs bind to the activation of the common PTH/PTHrP1 receptor, so the term PTH polypeptide also covers all PTHrP analogs. As used herein, the term “PTH analogue” refers to PTH and PTHrP o different and unrelated organisms that perform the same functions in each organism, but that do not originate from the ancestral structure of the organisms. Instead, the analogous PTH and PTHrP arose separately and then evolved to perform the same or similar functions. In other words, the analogous polypeptides PTH and PTHrP are polypeptides 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 “ottolog PTH” refers to PTH and PTHrP of two different species, the sequences of which are related to each other through a common homologous PTH in the ancestral species, but which have become distinct from each other during the course of evolution.

As used herein, the term “PTH homologue” refers to PTHs and PTHrPs of different organisms that perform the same function in each organism and that are derived from the ancestral structure that the organisms' ancestors generally had. In other words, PTH homologous polypeptides are polypeptides with exactly 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. Preferably, PTH polypeptide homologs can be defined as polypeptides having at least 40%, 50%, 60%, 70%, 80%, 90%, or 95% identity with the reference PTH or PTHrP polypeptide, preferably the PTH polypeptide of SEQ ID NO: 51.

Thus, a PTH polypeptide according to the present invention may be, for example: (i) a polypeptide wherein at least one of the amino acid residues is substituted by a conserved or non-conserved amino acid residue, preferably a conserved amino acid residue, and such substituted amino acid residue may or cannot be genetically encoded; and/or (ii) a polypeptide in which at least one of the amino acid residues includes a substituent group; and/or (iii) a polypeptide wherein the PTH polypeptide is fused to another compound, such as a compound to increase the half-life of the polypeptide (eg, polyethylene glycol); and/or (iv) a polypeptide in which additional amino acids are fused to the PTH polypeptide, such as a polypeptide or leader or secretory sequence of an IgG Fc fusion region or a sequence that is used to purify the above form of the polypeptide, or a precursor protein sequence.

As used herein, the term “PTH polypeptide fragment” refers to any peptide containing a contiguous portion of the amino acid sequence of a PTH or PTHrP polypeptide, preferably a polypeptide of the sequence SEQ ID NO: 51.

More specifically, the PTH polypeptide fragment contains at least 6, such as at least 8, at least 10, or at least 17 consecutive amino acids of a PTH or PTHrP polypeptide, more preferably a polypeptide of the sequence SEQ ID NO: 51. The PTH polypeptide fragment may be further described as a subset of PTH or PTHrP polypeptides containing at least 6 amino acids, where “at least 6” is defined as an integer between 6 and an integer indicating the C-terminal amino acid of the PTH or PTHrP polypeptide, preferably a polypeptide of the sequence SEQ ID No: 51. Also included are PTH or PTHrP polypeptide fragment species 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 polypeptide fragment” are all fragments of a PTH or PTHrP polypeptide 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 positions that a component of at least 6 consecutive amino acid residues in length may occupy, on any given amino acid sequence of a PTH or PTHrP polypeptide, preferably a PTH polypeptide of the sequence SEQ ID:NO51, is included in the present invention.

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

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, homologues, derivatives and fragments of the PTH or PTHrP moiety, even unless specifically stated.

In the context of the present invention, the term "random helix" refers to a peptide or protein adopting/having/forming, preferably having, a conformation that is substantially free of defined secondary and tertiary structure, as determined by circular dichroism spectroscopy performed in aqueous buffer at ambient temperature. environment, and pH 7.4. Preferably, the ambient temperature is about 20°C, that is, from 18°C to 22°C, most preferably the ambient temperature is 20°C.

As used herein, the term “pharmaceutical composition” refers to a composition containing one or more active ingredients, such as, for example, at least one drug compound or conjugate, in the context of the present invention in particular a PTH conjugate according to the present invention, and optionally 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, the pharmaceutical composition of the present invention includes any composition prepared by mixing one or more PTH conjugates of the present invention and optionally a pharmaceutically acceptable excipient.

As used herein, the term “liquid composition” refers to a mixture containing a water-soluble PTH conjugate and one or more solvents, such as water.

As used herein, 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 composition, for example the PTH conjugate of the present invention, has a residual water content of at most 10%, preferably less than 5% and more preferably less than 2%, as determined by the Karl Fischer method. Preferably, the pharmaceutical composition according to the present invention is dried by lyophilization.

The term “drug” as used herein refers to a substance used to treat, alleviate, prevent or diagnose a disease or otherwise to 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 the “bioactive moiety.” The PTH conjugate of the present invention contains a PTH moiety which is released from the PTH conjugate in the form of a PTH drug.

It is understood that the PTH conjugates of the present invention are prodrugs of PTH. As used herein, the term “prodrug” refers to a conjugate containing a biologically active moiety reversibly and covalently linked to a specialized protecting group through a reversible linker moiety, also referred to as a “prodrug linker moiety,” which contains a reversible linkage to the biologically active moiety, and wherein the specialized protecting group modifies or reduces undesirable properties in the parent molecule. This also includes enhancing the desired properties of the drug and suppressing undesirable properties. The specialized non-toxic protecting group is designated as a “carrier”. A prodrug releases a reversibly and covalently bound biologically active moiety in the form of its corresponding drug. In other words, a prodrug is a conjugate containing a biologically active moiety that is reversibly and covalently conjugated to a carrier moiety via a reversible linker moiety, wherein the covalent or reversible conjugation of the carrier to the reversible linker moiety is either direct or via a spacer. Such a conjugate releases the previously conjugated biologically active moiety in its free form.

The terms “biodegradable bond” or “reversible bond” mean a bond that is destructible, i.e. degradable, for example by hydrolysis, in the absence of enzymes under physiological conditions (aqueous buffer at pH 7.4, 37°C) with a half-life ranging from one hour to two months, preferably from one hour to one month, even more preferably from 6 hours to two weeks. Accordingly, a stable bond is a bond having a half-life under physiological conditions (aqueous buffer at pH 7.4, 37°C) of more than two months.

Accordingly, a “reversible linker moiety of a prodrug” or a “reversible linker moiety” is a moiety that is covalently conjugated to a biologically active moiety, such as PTH, through a reversible bond, and covalently conjugated to a carrier moiety, such as -Z, wherein covalently conjugated to the specified carrier component is carried out either directly or through a spacer component such as -L ² -. Preferably, the bond between -Z and -L ² - is a stable bond.

As used herein, the term “traceless prodrug linker” means a reversible prodrug linker that, upon cleavage, releases the drug in its free form. As used herein, the term “free form” of a drug means a drug in its unmodified, pharmacologically active form.

As used herein, the term “excipient” refers to a diluent, adjuvant or carrier with which a therapeutic agent, such as a drug or PTH conjugate of the present invention, is administered. Such 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 the preferred excipient when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are the preferred excipients when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous solutions of dextrose and glycerol are preferably used as liquid excipients for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, milk powder, glycerin, propylene glycol, water, ethanol and things like that. The composition may, if desired, 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-piperazine ethane sulfonic 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 compositions may take 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 preparation may contain conventional excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such compositions contain a therapeutically effective amount of a drug or biologically active moiety, together with a suitable amount of excipient, so as to provide a form suitable for administration to a patient. The composition must be appropriate for the route of administration.

As used herein, the term “reagent” means a chemical compound that contains at least one functional group to react with a functional group of another chemical compound or drug. It will be understood that a drug containing a functional group (such as a primary or secondary amine or hydroxyl functional group) is also a reagent.

As used herein, the term “constituent” means a part of a molecule that is missing one or more atoms from the corresponding reactants. If, for example, a reactant of the formula “H X-H” reacts with another reactant and becomes part of the reaction product, the corresponding constituent of the reaction product has the structure “H-X-” or “-X-”, where each “-” denotes addition to the other moiety. Accordingly, the biologically active moiety is released from the conjugates of the present invention as a drug.

It is understood that if a sequence or chemical structure of a group of atoms is provided wherein 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 component “-C(O)N(R)-“ can be attached to two components or interrupt the component as either “-C(O)N(R)-“ or “-N(R)-C( O)-“. Likewise, the component

can be attached to two components or can interrupt a component, either

, or as .

As used herein, 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 (-NH ₂ , -NH-), maleimide, thiol (-SH), sulfonic acid ( -(O=S=O)OH), carbonate, carbamate (-O(C=O)N<), hydroxyl (-OH), aldehyde (-(C=O)H), ketone (-(C=O )-), hydrazine (>NN<), 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 conjugates of the present invention contain 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 conjugates of the present invention containing acid groups can be used in the present invention, for example, 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 ammonium salts or with organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Conjugates according to the present invention containing one or more basic groups, i.e. groups that can be protonated may 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, naphthalene sulfonic 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 qualified specialists in this field. Conversions of a basic group to a cation, such as alkylation of an amine group to produce a positively charged ammonium group and corresponding salt counterion, are known to those skilled in the art. If the Conjugates of the present invention simultaneously contain acidic and basic groups, the present invention also includes, in addition to the salt forms mentioned, internal salts or betaines (zwitterions). The corresponding salts can be prepared by conventional methods known to those skilled in the art, for example, by contacting these conjugates with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the conjugates according to the present invention, which, due to low physiological compatibility, are not suitable for use directly in pharmaceutical products, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

The term "pharmaceutically acceptable" means a substance that is not harmful when administered to a patient and is preferably approved by a regulatory authority such as EMEA (Europe) and/or FDA (USA) and/or any other national regulatory authority for use in animals, preferably humans .

As used herein, the term “about” in combination with a numerical value is used to indicate a range within the interval and including the numerical value plus and minus not more than 20% of the specified numerical value, more preferably not more than 10% of the specified value, even more preferably no more than 5% of the specified value and most preferably no more than 2% of the specified value. For example, the phrase “about 200” is used to indicate a range within and including 200 +/- 20%, i.e. in the range and including 160 - 240; preferably 200 +/- 10%, i.e. in the range and including 180 - 220; even more preferably in the range and including 200 +/-5%, i.e. in the range and including 190 - 210; and most preferably 200 +/- 2%, i.e. in the range and including 196 - 204. It is clear that the 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 herein, the term “polymer” means a molecule containing repeating structural units, i.e. monomers linked by chemical bonds in a linear, circular, branched, cross-linked or dendrimeric manner or a combination thereof, which may be of synthetic or biological origin or a combination of both. It will be understood that the polymer may also contain one or more other chemical groups and/or constituents, such as, for example, one or more functional groups. Preferably, the soluble polymer has a molecular weight of at least 0.5 kDa, for example 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 molecular weight of at least 5 kDa. If the polymer is soluble, it preferably has a molecular weight of at most 1000 kDa, such as at most 750 kDa, such as at most 500 kDa, such as at most 300 kDa, such as at most 200 kDa, such as at most 100 kYes.

As used herein, the term “polymeric” means a reagent or constituent containing one or more polymers or polymeric constituents. The polymeric reactant or component may optionally also contain one or more other components, which are preferably selected from the group consisting of:

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

• connections selected from a group containing

Where

dotted lines indicate addition of a constituent or reactant to the remainder, and

-R and -R ^a are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.

One of ordinary skill 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, number of monomers in a polymer, and number of monomers in a polymer ranges, as used herein, refer to number average molecular weight and average number of monomers, i.e. to the arithmetic average of the molecular weight of the polymer or polymer fragment and the arithmetic average of the number of monomers of the polymer or polymer fragment.

Accordingly, in a polymer moiety containing “x” monomer units, any integer given for “x” therefore corresponds to the arithmetic average of the number of monomers. Any range of integers given for “x” provides a range of integers within which the arithmetic average of the number of monomers lies. An integer for “x” given as “about x” means that the arithmetic average of the monomer numbers is in the integer range x +/- 20%, preferably x +/- 10%, more preferably x +/- 5% and most preferably x +/- 2%.

As used herein, the term “number average molecular weight” means the usual arithmetic average of the molecular weights of individual polymers.

As used herein, the term “water-soluble” with reference to a carrier means that when such carrier is part of the PTH conjugate of the present invention, at least 1 g of the PTH conjugate containing such water-soluble carrier can be dissolved in one liter 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 the PTH conjugate of the present invention, less than 1 g of the PTH conjugate containing such water-soluble carrier can be dissolved in one liter of water at 20° C. formation of a homogeneous solution.

As used herein, the term “PEG-based” in relation to a moiety or reagent means that said moiety or reagent contains PEG. Preferably, the PEG-based component or reagent contains at least 10% (w/w) PEG, such as at least 20% (w/w) PEG, such as at least 30% (w/w) PEG. wt.) PEG, such as at least 40% (wt./wt.) PEG, such as at least 50% (wt./wt.) PEG, such as at least 60 (wt./wt.) 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 for example at least 95%. The remaining percentages by weight of the PEG-based moiety or reactant are other moieties, preferably selected from the following moieties and relationships:

• 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

• connections selected from a group containing

Where

dotted lines indicate addition of a constituent or reactant to the remainder, and

-R and -R ^a are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.

As used herein, the term “PEG-based containing at least X% PEG” with respect to a moiety or reactant means that said moiety or reactant contains at least X% (w/w) ethylene glycol units (-CH ₂ CH ₂ O-), wherein the ethylene glycol units may be arranged in a block, alternating manner, or may be randomly arranged in a component or reactant, and preferably all of the ethylene glycol units of said component or reactant are present in one block; the remaining percentages by weight of the PEG-based moiety or reactant are other moieties, preferably 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

• connections selected from a group containing

Where

dotted lines indicate addition of a constituent or reactant to the remainder, and

-R and -R ^a are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.

The term “hyaluronic acid-based, containing at least X% hyaluronic acid” is applied accordingly.

The term “substituted”, as used herein, means that one or more hydrogen atoms of a molecule or moiety are replaced by another atom or group of atoms, which are referred to as a “substituent”.

Preferably, 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 C _1-50 alkyl, C ₂₅₀ alkenyl and C _2-50 alkynyl 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 ₂₅₀ 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 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 the C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different;

-R ^x3 , -R ^x3a , -R ^x4 , -R ^x4a , -R ^x4b are each independently selected from the group consisting of -H and C _1-6 alkyl; wherein the C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different.

More preferably, 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 C _1-10 alkyl, C ₂₁₀ alkenyl and C _{2 -10} alkynyl groups 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 , -R ^x3 , -R ^x3a are each 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) 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 the C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different;

-R ^x4 , -R ^x4a , -R ^x4b are each independently selected from the group consisting of -H, halogen, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl;

Even more preferably, 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 _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl ; wherein -T ⁰ , C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted by one or more -R ^x2 which are the same or different, and wherein C _1-6 alkyl, C ₂₆ alkenyl and C _2-6 alkynyl 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 , -R ^x2 , -R ^x3 , -R ^x3a are each 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; where each T ⁰ is independently optionally replaced by one or more -R ^x2 that are the same or different.

Preferably, a maximum of 6 -H atoms of an optionally substituted molecule are independently substituted with a substituent, e.g., 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 The -H atom is replaced by a substituent.

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 atom or heteroatom and a hydrogen atom, preferably between a carbon atom and a hydrogen atom.

The term “spacer” refers to any moiety that is suitable for connecting two moieties. Preferably, the spacer 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 by one or more -R ^y2 , which are the same or different, and wherein 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 _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl; where -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 C _1-50 alkyl, C _2-50 alkenyl and The C _2-50 alkynyl groups 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 (O) ₂ N(R ^y4a )-, -S-, -N(R ^y4 )-, -OC(OR ^y4 )(R ^y4a ), -N(R ^y4 )-C(O)N(R ^y4a ) - and -OC(O)N(R ^y4 )-;

each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C _3-10 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 -R ^y2 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 the C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different; And

-R ^y3 , -R ^y3a , -R ^y4 , -R ^y4a , -R ^y5 , -R ^y5a and -R ^y5b are each independently selected from the group consisting of -H and C _1-6 alkyl, wherein C _1-6 alkyl optionally substituted with one or more halogens, which are the same or different.

Even more preferably, the spacer 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 by one or more -R ^y2 , which are the same or different, and wherein C _1-20 alkyl, C ₂₂₀ alkenyl and C _2-20 alkynyl 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; where -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 C _1-10 alkyl, C _2-10 alkenyl and The C _2-10 alkynyl groups 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 (O) ₂ N(R ^y4a )-, -S-, -N(R ^y4 )-, -OC(OR ^y4 )(R ^y4a )-, -N(R ^y4 )-C(O)N(R ^y4a )- and -OC(O)N(R ^y4 )-;

each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C _3-10 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 -R ^y2 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 the C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different; And

-R ^y3 , -R ^y3a , -R ^y4 , -R ^y4a , -R ^y5 , -R ^y5a and -R ^y5b are each independently selected from the group consisting of halogen -H and C _1-6 alkyl; wherein the C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different.

Even more preferably, the spacer 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 by one or more -R ^y2 which are the same or different, and wherein C _1-50 alkyl, C ₂₅₀ alkenyl and C _{2- 50} alkynyls 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, C _3-10 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

-R ^y3 , -R ^y3a , -R ^y4 , -R ^y4a , -R ^y5 , -R ^y5a and -R ^y5b are each independently selected from the group consisting of halogen -H and C _1-6 alkyl; wherein the C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different.

As used herein, the term “C ₁ - ₄ alkyl,” alone or in combination, means a straight-chain or branched alkyl moiety having 1 to 4 carbon atoms. When present at the end of the 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 constituent molecules are linked by a C _1-4 alkyl, examples of such C _1-4 alkyl groups are -CH ₂ -, -CH ₂ CH ₂ -, -CH(CH ₃ )-, -CH ₂ CH ₂ CH ₂ -, - CH(C ₂ H ₅ )-, -C(CH ₃ ) ₂ -. Each hydrogen of the C _1-4 alkyl carbon may optionally be replaced by a substituent as defined above. Optionally, 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,” alone or in combination, means a straight-chain or branched alkyl moiety having from 1 to 6 carbon atoms. If present at the end of the molecule, examples of straight or branched C _1-6 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl. When two constituent molecules 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 at the C _1-6 carbon atom may optionally be replaced by 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, where each the hydrogen atom at the C _1-10 , C _1-20 or C _1-50 carbon atom may optionally be replaced by a substituent as defined above. Optionally, the 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,” alone or in combination, means a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon double bond having from 2 to 6 carbon atoms. If present at the end of the molecule, examples are -CH=CH ₂ , -CH=CHCH ₃ , -CH ₂ CH=CH ₂ , -CH=CHCH ₂ CH ₃ and -CH=CHCH=CH ₂ . When two constituent molecules are linked by a C _2-6 alkenyl group, then an example of such a C _2-6 alkenyl is -CH=CH-. Each C _2-6 hydrogen atom of the alkenyl moiety may optionally be replaced by 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 “C _2-10 alkenyl”, “C _2-20 alkenyl” or “C _2-50 alkenyl”, alone 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 C _2-10 alkenyl, C _2-20 alkenyl or C _2-50 alkenyl group may optionally be replaced by a substituent as defined above. Optionally, _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,” alone or in combination, means a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon triple bond having from 2 to 6 carbon atoms. If present at the end of the molecule, examples are -C≡CH, -CH ₂ C≡CH, -CH ₂ CH ₂ C≡CH and -CH ₂ C≡CCH ₃ . When two constituent molecules 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 replaced by 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 terms “C _2-10 alkynyl,” “C _2-20 alkynyl,” and “C _2-50 alkynyl,” alone or in combination, mean a straight-chain or branched hydrocarbon moiety containing at least one a carbon-carbon triple bond having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, respectively. Each hydrogen atom of a C _2-10 alkynyl, C _2-20 alkynyl or C _2-50 alkynyl group may optionally be replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, _C2-10 alkynyl, _C2-20 alkynyl, or _C2-50 alkynyl may be interrupted by one or more moieties, as defined below.

As stated above, C_1-4 alkyl, C_1-6 alkyl, C_1-10 alkyl, C_1-20 alkyl, C_1-50 alkyl, C_2-6 alkenyl, C_2-10 alkenyl, C_2-20 alkenyl, C_2-50 alkenyl, C_2-6 alkynyl, C_2-10 alkynyl, C_2-20 alkenyl or C_2-50 alkynyl may optionally be interrupted by one or more moieties, which are preferably selected from the group consisting of

Where

dotted lines indicate addition of a constituent or reactant to the remainder; And

-R and -R ^a are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.

As used herein, the term "C _3-10 cycloalkyl" means a cyclic alkyl chain having from 3 to 10 carbon atoms, which may be saturated or unsaturated, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl. Each C _3-10 hydrogen atom of the cycloalkyl carbon may be replaced by a substituent as defined above. The term "C _3-10 cycloalkyl" also includes bridged bicycles such as norbornane or norbornene.

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

As used herein, the term "3-10 membered heterocyclyl" or "3-10 membered heterocycle" means a ring with 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, 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 to four ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O )-, -S(O) ₂ -), oxygen and nitrogen (including =N(O)-), and where the ring is connected 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, tyrane, azirine, oxirene, thiirene, azetidine, oxetane, thietan, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane , pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine. Each hydrogen atom of a 3-10 membered heterocyclyl or 3-10 membered heterocyclyl group may be replaced by a substituent, as defined below.

As used herein, the term "8- to 11-membered heterobicyclyl" or "8- to 11-membered heterobicycle" means a two-ring heterocyclic moiety with 8 to 11 ring atoms, where at least one ring atom is shared between the two rings and which contains 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 to six ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O) ₂ -), oxygen and nitrogen (including =N(O)-), and where the ring is bonded to the remainder of the molecule through a carbon or nitrogen atom. Examples of 8-11 membered heterobicycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, de cahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline , benzazepine, purine or pteridine. The term 8- to 11-membered heterobicycle also includes two-ring spiro structures such as 1,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles such as 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom of an 8-11 membered heterobicyclyl or 8-11 membered heterobicyclyl may be replaced by a substituent, as defined below.

Similarly, the term “8-30 membered heteropolycyclyl” or “8-30 membered heteropolycycle” means a heterocyclic moiety of more than two rings with 8 to 30 ring atoms, preferably three, four or five rings, where two adjacent rings are separated 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 to 10 ring atoms are replaced by a heteroatom selected from the group , consisting of sulfur (including -S(O)-, -S(O) ₂ -), oxygen and nitrogen (including =N(O)-), and where the ring is connected to the remainder of the molecule through a carbon or nitrogen atom.

It is clear that the phrase “the pair R ^x /R ^y combines together with the atom to which they are attached to form a C _3-10 cycloalkyl or 3-10 membered heterocyclyl” in relation to the constituent structure

means that Rx and Ry form the following structure:

,

where R represents 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 ring A” refers to the constituent structure

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

.

As used herein, "halogen" means fluorine, chlorine, bromine or iodine. In general, it is preferred that the halogen is fluorine or chlorine.

In general, the term “comprises” or “comprising” also covers “consists of” or “consisting of”.

In certain embodiments, the initial dose is in the range of 0.8 to 4.9 nmol/day, preferably 1 to 4.8 nmol/day, more preferably 1.2 to 4.7 nmol/day, even more preferably from 1.5 to 4.6 nmol/day, even more preferably 1.8 to 4.5 nmol/day and most preferably 2 to 4.4 nmol/day.

In certain embodiments, the initial dose is in the range of 0.8 to 3.9 nmol/day, preferably 1 to 3.7 nmol/day, even more preferably 1.5 to 3.4 nmol/day, even more preferably from 2 to 3.2 nmol/day and most preferably from 2.5 to 3 nmol/day.

In certain embodiments, the initial dose is at least 0.8 nmol/day. In certain embodiments, the initial dose is at least 1.0 nmol/day. In certain embodiments, the initial dose is at least 1.2 nmol/day. In certain embodiments, the initial dose is at least 1.4 nmol/day. In certain embodiments, the initial dose is at least 1.6 nmol/day. In certain embodiments, the initial dose is at least 1.8 nmol/day. In certain embodiments, the initial dose is at least 1.9 nmol/day. In certain embodiments, the initial dose is at least 2.0 nmol/day. In certain embodiments, the initial dose is at least 2.1 nmol/day. In certain embodiments, the initial dose is at least 2.2 nmol/day. In certain embodiments, the initial dose is at least 2.3 nmol/day. In certain embodiments, the initial dose is at least 2.4 nmol/day. In certain embodiments, the initial dose is at least 2.5 nmol/day. In certain embodiments, the initial dose is at least 2.6 nmol/day. In certain embodiments, the initial dose is at least 2.7 nmol/day. In certain embodiments, the initial dose is at least 2.8 nmol/day. In certain embodiments, the initial dose is at least 2.9 nmol/day. In certain embodiments, the initial dose is at least 3.0 nmol/day. In certain embodiments, the initial dose is at least 3.1 nmol/day. In certain embodiments, the initial dose is at least 3.2 nmol/day. In certain embodiments, the initial dose is at least 3.3 nmol/day. In certain embodiments, the initial dose is at least 3.4 nmol/day. In certain embodiments, the initial dose is at least 3.5 nmol/day. In certain embodiments, the initial dose is at least 3.6 nmol/day. In certain embodiments, the initial dose is at least 3.7 nmol/day. In certain embodiments, the initial dose is at least 3.8 nmol/day. In certain embodiments, the initial dose is at least 3.9 nmol/day. In certain embodiments, the initial dose is at least 4.0 nmol/day.

In certain embodiments, the initial dose is at most 4.9 nmol/day. In certain embodiments, the initial dose is at most 4.8 nmol/day. In certain embodiments, the initial dose is at most 4.7 nmol/day. In certain embodiments, the initial dose is at most 4.6 nmol/day. In certain embodiments, the initial dose is at most 4.5 nmol/day. In certain embodiments, the initial dose is at most 4.4 nmol/day. In certain embodiments, the initial dose is at most 4.3 nmol/day. In certain embodiments, the initial dose is at most 4.2 nmol/day. In certain embodiments, the initial dose is at most 4.1 nmol/day. In certain embodiments, the initial dose is at most 4.0 nmol/day. In certain embodiments, the initial dose is at most 3.9 nmol/day.

In certain embodiments, the initial dose is at least 2.9 nmol/day and at most 4.9 nmol/day. In certain embodiments, the initial dose is at least 2.9 nmol/day and at most 4.5 nmol/day.

In one embodiment, the starting dose is 1.5 ± 0.3 nmol/day, preferably 1.5 ± 0.2 nmol/day, even more preferably 1.5 ± 0.1 nmol/day. According to another embodiment, the initial dose is 1.7 ± 0.3 nmol/day, preferably 1.7 ± 0.2 nmol/day, even more preferably 1.7 ± 0.1 nmol/day. According to another embodiment, the initial dose is 2 ± 0.3 nmol/day, preferably 2 ± 0.2 nmol/day, even more preferably 2 ± 0.1 nmol/day. According to another embodiment, the initial dose is 2.3 ± 0.3 nmol/day, preferably 2.3 ± 0.2 nmol/day, even more preferably 2.3 ± 0.1 nmol/day. According to another embodiment, the starting dose is 2.5 ± 0.3 nmol/day, preferably 2.5 ± 0.2 nmol/day, even more preferably 2.5 ± 0.1 nmol/day. According to another embodiment, the starting dose is 2.7 ± 0.3 nmol/day, preferably 2.7 ± 0.2 nmol/day, even more preferably 2.7 ± 0.1 nmol/day. According to another embodiment, the starting dose is 2.9 ± 0.3 nmol/day, preferably 2.9 ± 0.2 nmol/day, even more preferably 2.9 ± 0.1 nmol/day. According to another embodiment, the starting dose is 3.2 ± 0.3 nmol/day, preferably 3.2 ± 0.2 nmol/day, even more preferably 3.2 ± 0.1 nmol/day. According to another embodiment, the starting dose is 3.5 ± 0.3 nmol/day, preferably 3.5 ± 0.2 nmol/day, even more preferably 3.5 ± 0.1 nmol/day. According to another embodiment, the starting dose is 3.7 ± 0.3 nmol/day, preferably 3.7 ± 0.2 nmol/day, even more preferably 3.7 ± 0.1 nmol/day. According to another embodiment, the starting dose is 3.8 ± 0.3 nmol/day, preferably 3.8 ± 0.2 nmol/day, even more preferably 3.8 ± 0.1 nmol/day. According to another embodiment, the starting dose is 3.9 ± 0.3 nmol/day, preferably 3.9 ± 0.2 nmol/day, even more preferably 3.9 ± 0.1 nmol/day. According to another embodiment, the starting dose is 4.0 ± 0.3 nmol/day, preferably 4.0 ± 0.2 nmol/day, even more preferably 4.0 ± 0.1 nmol/day. According to another embodiment, the starting dose is 4.1 ± 0.3 nmol/day, preferably 4.1 ± 0.2 nmol/day, even more preferably 4.1 ± 0.1 nmol/day. According to another embodiment, the starting dose is 4.2 ± 0.3 nmol/day, preferably 4.2 ± 0.2 nmol/day, even more preferably 4.2 ± 0.1 nmol/day. According to another embodiment, the starting dose is 4.2 ± 0.3 nmol/day, preferably 4.2 ± 0.2 nmol/day, even more preferably 4.2 ± 0.1 nmol/day. According to another embodiment, the starting dose is 4.3 ± 0.3 nmol/day, preferably 4.3 ± 0.2 nmol/day, even more preferably 4.3 ± 0.1 nmol/day. According to another embodiment, the starting dose is 4.4 ± 0.3 nmol/day, preferably 4.4 ± 0.2 nmol/day, even more preferably 4.4 ± 0.1 nmol/day. According to another embodiment, the starting dose is 4.5 ± 0.3 nmol/day, preferably 4.5 ± 0.2 nmol/day, even more preferably 4.5 ± 0.1 nmol/day. According to another embodiment, the starting dose is 4.6 ± 0.3 nmol/day, preferably 4.6 ± 0.2 nmol/day, even more preferably 4.6 ± 0.1 nmol/day.

The disease that can be treated, controlled, delayed or prevented by PTH is preferably selected from the group consisting of hypoparathyroidism, hyperphosphatemia, osteoporosis, fracture healing, osteomalacia, osteomalacia and osteoporosis in patients with hypophosphatasia, steroid-induced osteoporosis, osteoporosis in men, arthritis, osteoarthritis, abnormal bone formation, fibrous dysplasia, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy, osteopenia, periodontal disease, bone fracture, alopecia, chemotherapy-induced alopecia, and thrombocytopenia. Most preferably, said disease is hypoparathyroidism.

Preferably, the disease being treated with a PTH conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one PTH conjugate of the present invention occurs in a mammalian patient, more preferably in a human patient. Likewise, the patient suffering from a disease that can be treated, controlled, delayed or prevented by PTH is preferably a mammalian patient, more preferably a human patient.

Preferably, the PTH conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said PTH conjugate or a pharmaceutically acceptable salt thereof, is administered to the patient daily, that is, once a day. Even more preferably, the PTH conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said PTH conjugate or a pharmaceutically acceptable salt thereof, is administered to the patient once every 24 hours.

Preferably, the PTH conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising said PTH conjugate or a pharmaceutically acceptable salt thereof according to the present invention is for use in treating a disease that can be treated with PTH.

Preferably, the method of the present invention is a method for treating a patient suffering from a disease that can be treated with PTH.

PTH conjugates release PTH under physiological conditions (aqueous buffer, pH 7.4 and 37°C) with a half-life ranging from 6 hours to one week, more preferably from 12 hours to 6 days, even more preferably from one day to 5 days , even more preferably 2 days to 4 days, even more preferably 2 days to 3 days.

Preferably, the total mass of the PTH conjugate according to the present invention 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 kYes. preferably, the total mass of the PTH conjugate according to the present invention is at most 250 kDa, such as at most 200 kDa, at most 180 kDa, at most 150 kDa, at most 100 kDa, at most 80 kDa, or at most 60 kDa.

Preferably, the PTH conjugate has formula (Ia) or (Ib)

Where

-D represents the PTH component;

-L ¹ - represents a linker moiety covalently and reversibly attached to -D;

-L ² - represents a chemical bond or represents a spacer component;

-Z is a polymeric or fatty acid 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.

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

In one embodiment, -D has the sequence SEQ ID NO: 50.

In another embodiment, -D has the sequence SEQ ID NO: 52.

In another embodiment, -D has the sequence SEQ ID NO: 110.

In another embodiment, -D has the sequence SEQ ID NO: 111.

In another embodiment, -D has the sequence SEQ ID NO: 112.

Most preferably, -D has the sequence 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 -D, or to a nitrogen atom of the main polypeptide chain -D. Attachment to either the N-terminus or the C-terminus can be either directly through the appropriate amine or carboxyl functional group, respectively, or indirectly, where the spacer moiety is first conjugated to the amine or carboxyl functional group to which the spacer moiety -L ¹ is conjugated -.

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

If the -L ¹ - moiety is conjugated to a side chain functional group of a PTH amino acid residue, the amino acid residue is selected from the group consisting of proteogenic amino acid residues and non-proteogenic amino acid residues.

In one embodiment of the present invention -L¹- conjugated to the side chain functional group of the non-proteogenic amino acid residue 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 may only be present in variants, orthologues, homolags and derivatives of PTH.

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

In one embodiment of the present invention, -L ¹ - is conjugated to a histidine side chain functional group of PTH.

In another embodiment of the present invention, -L ¹ - is conjugated to a lysine side chain functional group of PTH.

In another embodiment of the present invention, -L ¹ - is conjugated to a tryptophan side chain functional group PTH.

In another embodiment of the present invention, -L ¹ - is conjugated to a serine side chain functional group of PTH.

In another embodiment of the present invention, -L ¹ - is conjugated to a threonine side chain functional group PTH.

In another embodiment of the present invention, -L ¹ - is conjugated to a PTH tyrosine side chain functional group.

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

In another embodiment of the present invention, -L ¹ - is conjugated to a glutamic acid side chain functional group PTH.

In another embodiment of the present invention, -L ¹ - is conjugated to an arginine side chain functional group PTH.

It is clear that not every PTH component can contain all of these amino acid residues.

In a preferred embodiment of the present invention, -L ¹ - is conjugated to the N-terminal amine functional group of PTH, either directly through the corresponding amine functional group, or indirectly, when the spacer moiety is first conjugated to the amine functional group to which the spacer moiety -L ¹ is conjugated -. Even more preferably, -L ¹ - is directly conjugated to the N-terminal amine functionality of PTH, preferably PTH 1-34, i.e. PTH having the sequence SEQ ID NO: 51.

In an equally preferred embodiment of the present invention, -L ^{1 -} is conjugated to the C-terminal PTH functionality, either directly through the corresponding carboxyl functionality, or indirectly when the spacer moiety is first conjugated to the carboxyl functionality to which the spacer moiety -L ¹ - is conjugated. .

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

The -L ¹ - component can be connected to -D through any type of connection, provided that it is reversible. Preferably, -L ¹ - is connected to -D through a bond selected from the group consisting of amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide and acylguanidine. Even more preferably, -L ¹ - is connected to -D through a bond selected from the group consisting of amide, ester, carbamate and acylguanidine. It is understood that some of these bonds are not themselves reversible, but in the present invention the adjacent groups contained in -L ¹ - make these bonds reversible.

In one embodiment of the present invention, -L ¹ - is connected to -D via an ether bond.

In another embodiment of the present invention, -L ¹ - is connected to -D via a carbamate bond.

In another embodiment of the present invention, -L ¹ - is linked to -D via an acylguanidine bond.

In a preferred embodiment of the present invention, -L ¹ - is connected to -D via an amide bond.

The -L ¹ - moiety is a reversible linker from which the drug, i.e. PTH is released in its free form, i.e. 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.

According to another embodiment, -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 application via link.

A particularly preferred component -L ¹ - is described in WO 2009/095479 A2. Accordingly, according to a preferred embodiment, the component -L ¹ - has formula (II):

,

where the dotted line represents the addition of a -D moiety to the amine, hydroxyl or thiol, which is a PTH moiety;

-X- is -C(R ⁴ R ^4a )-; -N(R ⁴ )-; -O-; -C(R ⁴ R ^4a )-C(R ⁵ R ^5a )-; -C(R ⁵ R ^5a )-C(R ⁴ R ^4a )-; -C(R ⁴ R ^4a )-N(R ⁶ )-; -N(R ⁶ )-C(R ⁴ R ^4a )-; -C(R ⁴ R ^4a )-O-; -OC(R ⁴ R ^4a )-; or -C(R ⁷ R ^7a )-;

-X ¹ represents C; or S(O);

-X ² - represents -C(R ⁸ R ^8a )-; or -C(R ⁸ R ^8a )-C(R ⁹ R ^9a )-;

=X ³ represents =O; =S; or =NCN;

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

-R ³ , -R ^3a are independently selected from the group consisting of -H and C _1-6 alkyl, with the proviso that if one or both of -R ³ , -R ^3a are other than hydrogen, they are connected to the N to which they attached via SP ³ -hybridized carbon atom;

-R ⁷ is -N(R ¹⁰ R ^10a ); or -NR ¹⁰ -(C=O)-R ¹¹ ;

-R ^7a , -R ¹⁰ , -R ^10a , -R ¹¹ are independently -H or 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 , -R ^8a /R ^9a forms 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 , -R ⁹ /R ^9a are connected together with the atom to which they are attached to form a C _3-10 cycloalkyl or 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 , -R ² /R ³ are joined together with the atoms to which they are attached to form ring A;

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

A is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl and 8-11 membered heterobicyclyl; And

where -L¹- has -L as a substituent²-Z, and where -L¹- optionally further substituted, provided that the hydrogen indicated by an asterisk in formula (II) is not substituted -L²-Z or substituent;

Where

-L ² - represents a simple chemical bond or spacer;

-Z is a polymeric or fatty acid moiety.

Preferably -L ¹ - of formula (II) is replaced by one component -L ² -Z.

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

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

,

where the dotted line denotes attachment to the residue -L ¹ -;

the ring contains from 3 to 10 atoms, including at least one nitrogen atom; And

R ^# and R ^## represent an SP ³ -hybridized carbon atom.

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

Exemplary embodiments of suitable 3-10 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 indicates attachment to the remainder of the molecule; And

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

-L ¹ - of formula (II) may optionally be further substituted. In general, any substituent can be used as long as the cleavage principle is not affected, i.e. hydrogen, marked with an asterisk in formula (II), is not replaced, and nitrogen is a component

formula (II) remains part of the primary, secondary or tertiary amine, i.e. -R ³ and -R ^3a independently represent -H or are connected to -N< via an SP ³ -hybridized carbon atom.

In one embodiment of the present invention, -R ¹ or -R ^1a of formula (II) has -L ² -Z as a substituent. In another embodiment of the present invention, -R ² or -R ^2a of formula (II) has -L ² -Z as a substituent. In another embodiment of the present invention, -R ³ or -R ^3a of formula (II) has -L ² -Z as a substituent. In another embodiment of the present invention, -R ⁴ of formula (II) has -L ² -Z as a substituent. In another embodiment of the present invention, -R ⁵ or -R ^5a of formula (II) has -L ² -Z as a substituent. In another embodiment of the present invention, -R ⁶ of formula (II) has -L ² -Z as a substituent. In another embodiment of the present invention, -R ⁷ or -R ^7a of formula (II) has -L ² -Z as a substituent. In another embodiment of the present invention, -R ⁸ or -R ^8a of formula (II) has -L ² -Z as a substituent. In another embodiment of the present invention, -R ⁹ or -R ^9a of formula (II) has -L ² -Z as a substituent. In another embodiment of the present invention, -R ¹⁰ has -L ² -Z as a substituent. In another embodiment of the present invention, -R ¹¹ has -L ² -Z as a substituent.

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

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

According to one preferred embodiment, -X- of formula (II) is -C(R ⁷ R ^7a )-.

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

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

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

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

Preferably, -R ¹¹ is substituted with -L ² -Z.

According to another preferred embodiment, -X- of formula (II) is -N(R ⁴ )-.

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

Preferably, X ¹ of formula (II) is C.

Preferably, =X ³ of formula (II) is =O.

Preferably, -X ² - of formula (II) is -C(R ⁸ R ^8a )-.

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

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

According to one preferred embodiment, 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.

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

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

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

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

According to another preferred embodiment, -R ³ and -R ^3a of formula (II) are both -H.

Preferably, -D is connected to -L ¹ - via an amine by forming an amide bond.

According to a preferred embodiment, the component -L ¹ - has the formula (IIb-i)

Where

the dotted line shows the addition of a -D moiety to the amine, which is a PTH moiety due to 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 with -L ² -Z, and where -L ¹ - is optionally further substituted, provided that the hydrogen indicated by an asterisk in formula (IIb-i) is not substituted with -L ² -Z or a substituent.

Preferably -L ¹ - of formula (IIb-i) is replaced by one component -L ² -Z.

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

Preferably, -R ¹ and -R ^1a of formula (IIb-i) are independently selected from the group consisting of -H, methyl and ethyl. More preferably, at least one of -R ¹ and -R ^1a of formula (IIb-i) is methyl.

Even more preferably, both -R ¹ and -R ^1a of formula (IIb-i) are methyl.

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

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

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

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

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

Preferably, -R ³ or -R ^3a of formula (IIb-i) is substituted with -L ² -Z.

More preferably, the component -L ¹ - has the formula (IIb-ii):

where the dotted line shows the addition of a -D moiety to the amine, which is a PTH moiety due to the formation of an amide bond;

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

Preferably -L ¹ - of formula (IIb-ii) is replaced by one component -L ² -Z.

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

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

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

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

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

Preferably, -R ³ or -R ^3a of formula (IIb-ii) is substituted with -L ² -Z.

Even more preferably, the -L ¹ - component has the formula (IIb-ii'):

Where

the unlabeled dotted line shows attachment to the amine of the -D moiety, which is the PTH moiety due to the formation of an amide bond, and the starred dotted line shows attachment to the -L ² - moiety;

-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 one moiety -L ² -Z, as indicated, and where -L ¹ - is optionally further substituted, provided that the hydrogen indicated by an asterisk in formula (IIb-ii') is not replaced by a substituent.

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

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

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

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

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

Even more preferably, the component -L ¹ - has the formula (IIb-iii):

Where

the dotted line shows the addition of a -D moiety to the amine, which is a PTH moiety due to the formation of an amide bond; And

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

Preferably -L ¹ - of formula (IIb-iii) is replaced by one component -L ² -Z.

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

Preferably, -R ³ or -R ^3a of formula (IIb-iii) is substituted with -L ² -Z.

Most preferably, the component -L ¹ - has the formula (IIb-iii'):

Where

the dotted line shows the addition of the -D moiety to the amine, which is the PTH moiety due to the formation of the amide bond, and the starred dotted line shows the addition of the -L ² - moiety;

-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 with -L ² -Z as indicated, and where -L ¹ - is optionally further substituted, provided that the hydrogen indicated by an asterisk in formula (IIb-iii') is not replaced by a substituent.

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

Another preferred component -L ¹ - is disclosed in WO 2016/020373 A1. Accordingly, according to another preferred embodiment, the component -L ¹ - has formula (III):

Where

the dotted line shows the addition of a -D moiety to the primary or secondary amine or hydroxyl, which is a PTH moiety due to 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 ^8b ), -C( =O)R ⁸ , -C≡N, -C(=NR ⁸ )R ^8a , -CR ⁸ (=CR ^8a R ^8b ), -C≡CR ⁸ and -T;

-R ⁴ , -R ⁵ and -R ^5a are independently 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; where -T, C _1-20 alkyl, C _2-20 alkenyl and C _2-20 alkynyl are optionally substituted by one or more -R ¹¹ which are the same or different, and wherein C _1-20 alkyl, C _2-20 alkenyl and The C _2-20 alkynyl groups 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 )-;

-R ¹⁰ , -R ^10a , -R ^10b are each independently selected from the group consisting of -H, -T, C _1-20 alkyl, C _2-20 alkenyl, and C _2-20 alkynyl; where -T, C _1-20 alkyl, C _2-20 alkenyl and C _2-20 alkynyl are optionally substituted by one or more -R ¹¹ which are the same or different, and wherein C _1-20 alkyl, C _2-20 alkenyl and The C _2-20 alkynyl groups 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 halogen, 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 each 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 the C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different;

-R ¹² , -R ^12a , -R ¹³ , -R ^13a , -R ^13b are each independently selected from the group consisting of -H and C _1-6 alkyl; wherein the C _1-6 alkyl is optionally substituted with one or more halogens, which 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 they are attached, with the formation of C _3-10 cycloalkyl or 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} joined together with the atoms to which they are attached to form ring A;

A is selected from the group consisting of phenyl; naphthyl; indenyl; indanila; tetralinyl; C _3-10 cycloalkyl; 3-10 membered heterocyclyl; and 8-11 membered heterobicyclyl;

where -L ¹ is substituted with -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 polymeric or fatty acid moiety.

the optional additional substituents -L ¹ - of formula (III) preferably have the meaning as described above.

Preferably -L ¹ - of formula (III) is replaced by one component -L ² -Z.

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

Additional preferred embodiments for -L ¹ - are disclosed in EP 1536334 B1, WO 2009/009712 A1, WO 2008/034122 A1, WO 2009/143412 A2, WO 2011/082368 A2 and US 8618124 B2, which are incorporated herein by reference in full.

Additional preferred embodiments for -L ¹ - are disclosed in US 8946405 B2 and US 8754190 B2, which are incorporated herein by reference in their entirety. Accordingly, a preferred moiety -L ¹ - has formula (IV):

Where

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

m is 0 or 1;

at least one or both of -R ¹ and -R ² is selected/independently of each other 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 join to form a 3-8 membered ring; And

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

where -L ¹ - has -L ² -Z as a substituent, and where -L ¹ - is optionally further substituted;

Where

-L ² - represents a simple chemical bond or spacer; And

-Z is a polymeric or fatty acid moiety.

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 of the present invention from 1 to 6 or 1 to 4 carbon atoms.

The term “alkoxy” includes alkyl groups attached 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 anthracene. 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 some cases, alkenyl, alkynyl, aryl or heteroaryl moieties may be linked to the remainder of the molecule via 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 from 3 to 7 carbon atoms and at least one N, O, or S atom. Examples are piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine and tetrahydrofuranyl, as well as exemplary groups given 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, where each is optionally further substituted. Optional substituents in any group, including those above, include halo, nitro, cyano, -OR, -SR, -NR ₂ , -OCOR, -NRCOR, -COOR, CONR ₂ , -SOR, -SO ₂ R, -SONR ₂ . -SO ₂ NR ₂ 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.

Preferably -L ¹ - of formula (IV) has one component -L ² -Z as a substituent.

A further preferred embodiment -L ¹ - is disclosed in WO2013/036857A1, which is incorporated herein by reference in its entirety. Accordingly, a preferred moiety -L ¹ - has formula (V):

Where

the dotted line shows the attachment to -D, which represents

PTH moiety, and where the attachment is through the amine functional group of the -D moiety;

-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 two -R ⁵ taken together may represent cycloalkyl or cycloheteroalkyl;

where -L ¹ - has -L ² -Z as a substituent, and where -L ¹ - is optionally further substituted;

Where

-L ² - represents a simple chemical bond or spacer;

-Z is a polymeric or fatty acid moiety.

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 1-6 carbon atoms or 1-4 carbon atoms, where alkyl is a saturated hydrocarbon, alkenyl includes one or more than carbon-carbon double bonds, and alkynyl includes one or more carbon-carbon triple bonds. Unless otherwise stated, they contain 1-6 carbon atoms.

“Aryl” includes aromatic hydrocarbon groups having from 6 to 18 carbon atoms, preferably 6 to 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 containing one or more substituent groups in place of one or more hydrogen atoms. Substituents can generally 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; HE; 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 anthracene; heteroaryls, 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.

Preferably -L ¹ - of formula (V) has one component -L ² -Z as a substituent.

Preferably -L ¹ - of formula (V) has as a substituent one component -L ² -Z or -L ² -Z'.

Another preferred embodiment -L ¹ - is disclosed in US 7585837 B2, which is incorporated herein by reference in its entirety. Accordingly, a preferred moiety -L ¹ - has formula (VI):

Where

the dotted line shows attachment to -D, which is the PTH moiety, and where the attachment is via the amine functionality of the -D moiety;

-R ¹ and -R ² are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkaryl, aralkyl, 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 - has -L ² -Z as a substituent, and where -L ¹ - is optionally further substituted;

Where

-L ² - represents a simple chemical bond or spacer; And

-Z is a polymeric or fatty acid moiety.

Suitable substituents for formula (VI) include the constituents 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.

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, for example methyl, ethyl, propyl, isopropyl and butyl, and aryl radicals containing 6-10 carbon atoms, for example, phenyl and naphthyl. The term “halogen” includes bromine, fluorine, chlorine and iodine.

Preferably -L ¹ - of formula (VI) has one component -L ² -Z as a substituent.

Another preferred embodiment -L ¹ - is disclosed in WO 2002/089789 A1, which is incorporated herein by reference in its entirety. Accordingly, a preferred moiety -L ¹ - has formula (VII):

Where

the dotted line shows attachment to -D, which is the PTH moiety, and where the attachment is via the amine functionality of the -D moiety;

-L ₁ - represents a bifunctional linking group,

Y ₁ and Y ₂ are independently O, S or NR ⁷ ;

-R ² , -R ³ , -R ⁴ , -R ⁵ , -R ⁶ and -R ⁷ are independently selected from the group consisting of hydrogen, C _1-6 alkyls, C _3-12 branched alkyls, C _3-8 cycloalkyls , C _1-6 substituted alkyls, C _3-8 substituted cycloalkyl, aryls, substituted aryls, aralkyl, C _1-6 heteroalkyl, substituted C _1-6 heteroalkyl, C _1-6 alkoxy, phenoxy and C _1-6 heteroalkoxy;

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 thereof,

y is 0 or 1;

where -L ¹ - has -L ² -Z as a substituent, and where -L ¹ - is optionally further substituted;

Where

-L ² - represents a simple chemical bond or spacer; And

-Z is a polymeric or fatty acid moiety.

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

The term “alkyl” is to be understood to include, for example, straight-chain, branched, substituted C _1-12 alkyls, including alkoxy, C _3-8 cycloalkyl or substituted cycloalkyl, etc.

The term “substitution” is to be understood to include the addition or substitution of one or more atoms contained in a functional group, or compounds 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 constituents 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 constituents such as methoxy; and phenoxy includes constituents such as 3-nitrophenoxy. halo-, as must be understood, includes fluorine, chlorine, iodine and bromine.

Preferably -L ¹ - of formula (VII) has one component -L ² -Z as a substituent.

In another preferred embodiment of the present invention -L ¹ - contains a substructure of formula (VIII)

Where

the dotted line marked with an asterisk represents the addition of a -D moiety, which is a PTH moiety, to the nitrogen atom by forming an amide bond;

unlabeled dotted lines indicate attachment to the remainder of -L ¹ -; And

where -L ¹ - has -L ² -Z as a substituent, and where -L ^1- is optionally further substituted;

Where

-L ² - represents a simple chemical bond or spacer; And

-Z is a polymeric or fatty acid moiety.

Preferably -L ¹ - of formula (VIII) is replaced by one component -L ² -Z.

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

According to another preferred embodiment -L ¹ - contains structural formula (IX)

Where

the dotted line marked with an asterisk indicates the addition of a -D moiety, which is a PTH moiety, to the nitrogen atom by forming a carbamate bond;

unlabeled dotted lines indicate attachment to the remainder of -L ¹ -; And

where -L ¹ is substituted with -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 polymeric or fatty acid moiety.

Preferably -L ¹ - of formula (IX) is replaced by one component -L ² -Z.

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

In the conjugates of the present invention, -L ² - represents a chemical bond or spacer moiety

According to one embodiment, -L ² - represents a chemical bond.

According to another embodiment, -L ² - is a spacer moiety.

When -L ² - is other than a simple chemical bond, -L ² - is preferably 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 by one or more -R ^y2 , which are the same or different, and wherein 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 _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl; where -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 C _1-50 alkyl, C _2-50 alkenyl and The C _2-50 alkynyl groups 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 (O) ₂ N(R ^y4a )-, -S-, -N(R ^y4 )-, -OC(OR ^y4 )(R ^y4a )-, -N(R ^y4 )-C(O)N(R ^y4a )-, and -OC(O)N(R ^y4 )-;

each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C _3-10 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 by one or more R ^y2 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 the C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different; And

-R ^y3 , -R ^y3a , -R ^y4 , -R ^y4a , -R ^y5 , -R ^y5a and -R ^y5b are each independently selected from the group consisting of -H and C _1-6 alkyl, wherein C _1-6 alkyl optionally substituted with one or more halogens, which are the same or different.

When -L ² - is other than a simple chemical bond, -L ² - is even more preferably 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-, _C1-20 alkyl, _C2-20 alkenyl, and _C2-20 alkynyl are optionally substituted by one or more ^-Ry2 , which are the same or different, and wherein _C1-20 alkyl, _C2-20 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; where -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 C _1-10 alkyl, C _2-10 alkenyl and The C _2-10 alkynyl groups 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 (O) ₂ N(R ^y4a )-, -S-, -N(R ^y4 )-, -OC(OR ^y4 )(R ^y4a )-, -N(R ^y4 )-C(O)N(R ^y4a )-, and -OC(O)N(R ^y4 )-;

each -T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C _3-10 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 -R ^y2 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 the C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different; And

-R ^y3 , -R ^y3a , -R ^y4 , -R ^y4a , -R ^y5 , -R ^y5a and -R ^y5b are each independently selected from the group consisting of halogen -H and C _1-6 alkyl; wherein the C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different.

When -L ² - is other than a simple chemical bond, -L ² - is even more preferably 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 by one or more -R ^y2 , which are the same or different, and wherein 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, C _3-10 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

-R ^y3 , -R ^y3a , -R ^y4 , -R ^y4a , -R ^y5 , -R ^y5a and -R ^y5b are each independently selected from the group consisting of -H and C _1-6 alkyl; wherein the C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different.

Even more preferably, -L ² - represents a C _1-20 alkyl chain, which is optionally interrupted by one or more groups independently selected from -O-, -T- and C(O)N(R ^y1 )-; and wherein the C _1-20 alkyl chain is optionally substituted with one or more groups independently selected from -OH, -T and -C(O)N(R ^y6 R ^y6a ); where -R ^y1 , -R ^y6 , -R ^y6a are independently selected from the group consisting of -H and C _1-4 alkyl, and where -T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C _{3 -10} cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl.

Preferably, -L ² - has a molecular weight in the range from 14 g/mol to 750 g/mol.

Preferably, -L ² - contains a component selected from

Where

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

-R and -R ^a are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.

In one preferred embodiment of the present invention, -L ² - has a chain length of from 1 to 20 atoms.

As used herein, the term “chain length” with respect to the -L ² - moiety refers to the number of -L ² - atoms present in the shortest compound between -L ¹ - and -Z.

Preferably, -L ² - has formula (i)

Where

the dotted line marked with an asterisk indicates attachment to -L ¹ -;

unlabeled dotted line represents 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 a moiety of formula (i) is optionally further substituted.

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

According to one preferred embodiment, the component -L ¹ -L ² is selected from the group consisting of

Where

the unlabeled dotted line shows the addition of a -D moiety to the nitrogen, which is the PTH moiety due to the formation of an amide bond; And

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

According to one embodiment, the component -L ¹ -L ² has the formula (IIcb-i).

According to another embodiment, the component -L ¹ -L ² has the formula (IIcb-ii).

According to another embodiment, the component -L ¹ -L ² has the formula (IIcb-iii).

-Z is a polymeric or fatty acid moiety. In one embodiment, -Z is a fatty acid moiety. In another embodiment, -Z is a polymer moiety, preferably a polymer moiety, preferably containing a polymer selected from the group consisting of 2-methacryloyl-oxyethyl 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 and glycolic copolymers acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly (vinyl alcohols), poly(vinylamines), poly(vinylmethyl 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.

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

In one embodiment of the present invention, such -Z contains a protein. Preferred proteins are selected from the group consisting of carboxyl-terminal human chorionic gonadotropin polypeptide 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 helix 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; with Fc fusion proteins.

In one embodiment of the present invention, -Z is polysarcosine.

In another embodiment, -Z contains poly(N-methylglycine).

In another embodiment, -Z comprises a random helix protein moiety.

According to one embodiment, such a random helix protein component contains at least 25 amino acid residues and at most 2000 amino acids. Preferably, such a random helix protein component contains at least 30 amino acid residues and at most 1500 amino acid residues. Even more preferably, such a random helix protein component contains at least 50 amino acid residues and at most 500 amino acid residues.

In one embodiment, -Z comprises a random helix protein moiety, wherein at least 80%, preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, even more preferably at least 98% and most preferably at least 99% of the total amino acids forming said protein component of the random helix are selected from alanine and proline. Even more preferably, at least 10%, but less than 75%, preferably less than 65%, of the total amino acid residues of such a random helix protein component are proline residues. Preferably, such a random helix protein moiety is as described in WO 2011/144756 A1, which is incorporated herein by reference in its entirety. Even more preferably, -Z contains at least one moiety selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 51 and SEQ ID NO: 61, as disclosed in WO 2011/144756, which is incorporated herein by reference.

In another embodiment, -Z comprises a random helix protein component of at least 80%, preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, even more preferably at least at least 98% and most preferably at least 99% of the total amino acids forming said random helix protein component are selected from alanine, serine and proline. Even more preferably, at least 4%, but less than 40% of the total amino acid residues of the random-coil component of the protein are proline residues. Preferably, the protein component with a random helix structure is described in WO 2008/155134 A1, which is incorporated herein by reference in its entirety. Even more preferably, -Z contains at least one moiety selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54 and SEQ ID NO: 56, as described in WO 2008/155134 A1, which is incorporated herein by reference.

In another embodiment, -Z comprises a random helix protein component of at least 80%, preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, even more preferably at least at least 98% and most preferably at least 99% of the total number of amino acids forming said reverse helix protein is selected from alanine, glycine, serine, threonine, glutamate and proline. Preferably, the protein component with a random helix structure is as described in WO 2010/091122 A1, which is incorporated herein by reference. Even more preferably, -Z contains at least one moiety selected from the group consisting of SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184; SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, SEQ ID NO: 193, SEQ ID NO: 194, SEQ ID NO: 195, SEQ ID NO: 196, SEQ ID NO: 197, SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 200, SEQ ID NO: 201, SEQ ID NO: 202, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 205, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 210, SEQ ID NO: 211, SEQ ID NO: 212, SEQ ID NO: 213, SEQ ID NO: 214, SEQ ID NO: 215, SEQ ID NO: 216, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 220, SEQ ID NO: 221, SEQ ID NO: 759, SEQ ID NO: 760, SEQ ID NO: 761, SEQ ID NO: 762, SEQ ID NO: 763, SEQ ID NO: 764, SEQ ID NO: 765, SEQ ID NO: 766, SEQ ID NO: 767, SEQ ID NO: 768, SEQ ID NO: 769, SEQ ID NO: 770, SEQ ID NO: 771, SEQ ID NO: 772, SEQ ID NO: 773, SEQ ID NO: 774, SEQ ID NO: 775, SEQ ID NO: 776, SEQ ID NO: 777, SEQ ID NO: 778, SEQ ID NO: 779, SEQ ID NO: 1715, SEQ ID NO: 1716, SEQ ID NO: 1718, SEQ ID NO: 1719, SEQ ID NO: 1720, SEQ ID NO: 1721 and SEQ ID NO: 1722, as described in WO2010/091122A1, which is included in this application by reference.

In another embodiment, -Z is a fatty acid moiety. Preferred fatty acid constituents are those described in WO 2005/027978 A2 and WO 2014/060512 A1, which are incorporated herein by reference.

In another embodiment, -Z is a hyaluronic acid-based polymer.

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

According to another embodiment, -Z is a carrier as disclosed in WO 2013/024048 A1, which is incorporated herein by reference.

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

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

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

Preferably, such a multi-arm PEG polymer -Z is connected to a plurality of -L ² -L ¹ -D moieties, wherein each -L ² -L ¹ -D moiety is preferably connected to an end of a leg, preferably to an end of a leg. Preferably, such multi-arm PEG polymer -Z is coupled to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 -L ² -L ¹ - moieties D. Even more preferably, such a multi-arm PEG polymer -Z is coupled to 2, 3, 4, 6 or 8 -L ² -L ¹ - D moieties. Even more preferably, such a multi-arm PEG polymer is coupled to 2 , 4 or 6 -L ² -L ¹ -D units, even more preferably such a PEG-based polymer with multiple branches -Z is connected to 4 or 6 -L ² -L ¹ -D units, and most preferably such a PEG-based polymer with many branches -Z is connected to 4 components -L ² -L ¹ -D.

Preferably, such multi-arm PEG-based polymer -Z is a multi-arm PEG derivative, such as is, for example, described in detail for the products listed in JenKem Technology, USA (available at http://www.jenkemusa.com/Pages/PEGProducts.aspx as of December 18, 2014), such as a 4-arm PEG derivative, in particular a 4-arm PEG derivative containing a pentaerythritol core, an 8-arm PEG derivative containing a hexaglycerol core, and an 8-arm PEG derivative containing tripentaerythritol core. More preferably, the water-soluble PEG-based carrier -Z contains a constituent selected from:

PEG-amine with 4 branches containing a pentaerythritol core:

with n in the range from 20 to 500;

An eight-arm PEG amine containing a hexaglycerol core:

with n in the range from 20 to 500; And

R = hexaglycerol or tripentaerythritol core structure; And

A six-arm PEG amine containing a sorbitol or dipentaerythritol core:

with n in the range from 20 to 500; And

R = containing a core of sorbitol or dipentaerythritol;

and where the dotted lines indicate attachment to the rest of the PTH conjugate.

In a preferred embodiment of the present invention, -Z is a branched PEG-based polymer. In one embodiment of the present invention, -Z is a branched PEG-based polymer having one, two, three, four, five or six branch points. Preferably, -Z is a branched PEG-based polymer having one, two or three branch points. In one embodiment of the present invention, -Z is a branched PEG-based polymer having a single branch point. In another embodiment of the present invention, -Z is a branched PEG-based polymer having two branch points. In another embodiment of the present invention, -Z is a branched PEG-based polymer having three branch points.

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

Preferably, such a branched -Z moiety has a molecular weight of at least 10 kDa.

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

Preferably, such branched -Z moiety has a molecular weight in the range and including 10 kDa - 80 kDa. In one embodiment of the present invention, the molecular weight is about 10 kDa. In another embodiment of the present invention, the molecular weight of such a branched -Z moiety is about 20 kDa. In another embodiment of the present invention, the molecular weight of such a branched -Z moiety is about 30 kDa. In another embodiment of the present invention, the molecular weight of such a branched -Z moiety is about 40 kDa. In another embodiment of the present invention, the molecular weight of such a branched -Z moiety is about 50 kDa. In another embodiment of the present invention, the molecular weight of such a branched -Z moiety is about 60 kDa. In another embodiment of the present invention, the molecular weight of such a branched -Z moiety is about 70 kDa. In another embodiment of the present invention, the molecular weight of such a branched -Z moiety is about 80 kDa. Most preferably, such a branched -Z moiety has a molecular weight of about 40 kDa.

Preferably -Z contains the component

.

In an equally preferred embodiment, -Z contains an amide bond.

Preferably -Z contains a component of formula (a)

Where

the dotted line indicates attachment to -L ² - or to the remainder of -Z;

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

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

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

-S ^a -, -S ^a '-, -S ^a ''- and -S ^a ''' independently 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 C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally substituted with one or more -R ¹ substituents that are the same or different, and wherein C _1-50 alkyl, C _2-50 alkenyl and C _{2 -50} alkynyl 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, C _3-10 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 -R ¹ substituents 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 the C _1-6 alkyl is optionally substituted with one or more halogen substituents, which are the same or different;

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

-P ^a ', -P ^a '' and -P ^a ''' independently represent the polymer moiety.

In one embodiment of the present invention, BP ^{a of} formula (a) is -N<.

In another embodiment of the present invention, BP ^a of formula (a) is >C<.

In a preferred embodiment of the present invention, BP ^a of formula (a) is -CR<. Preferably, -R is -H. Accordingly, a of formula (a) is equal to 0.

In one embodiment of the present invention, -S ^a - of formula (a) is a chemical bond.

In another embodiment of the present invention, -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 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- represents a 3-10 membered heterocyclyl; and -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 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-.

In one embodiment of the present invention, -S ^a '- of formula (a) is a chemical bond.

In another embodiment of the present invention, -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 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 )-.

In one embodiment of the present invention -S ^a ''- of formula (a) is a chemical bond.

In another embodiment of the present invention, -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 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 )-.

In one embodiment of the present invention, -S ^a '''- of formula (a) is a chemical bond.

In another embodiment of the present invention, -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 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 )-.

Preferably, -P ^a ', -P ^a '' and -P ^a ''' of formula (a) independently contain a polymer selected from the group consisting of 2-methacryloyl-oxyethylphosphoylcholines, 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(ethyloxazolines) , poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl oxazolines), poly(hydroxymethacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids) , poly(copolymers of lactic and glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes) , poly(urethanes), poly(vinyl alcohols), poly(vinylamines), poly(vinylmethyl ethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other polymers based on carbohydrates, xylans and their copolymers.

More preferably, -P ^a ', -P ^a '' and -P ^a ''' of formula (a) independently contain a PEG-based moiety. Even more preferably, -P ^a ', -P ^a '' and -P ^a ''' of formula (a) independently contain a PEG-based moiety containing at least 20% PEG, even more preferably at least 30%, even more preferably at least 40% PEG, even more preferably at least 50% PEG, even more preferably at least 60% PEG, even more preferably at least 70% PEG, even more preferably at least 80% PEG and most preferably at least 90% PEG.

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

In one embodiment of the present invention, -P ^a ', -P ^a '' and -P ^a ''' of formula (a) have a molecular weight of about 5 kDa.

In another embodiment of the present invention, -P ^a ', -P ^a '' and -P ^a ''' of formula (a) have a molecular weight of about 7.5 kDa.

In another embodiment of the present invention, -P ^a ', -P ^a '' and -P ^a ''' of formula (a) have a molecular weight of about 10 kDa.

In another embodiment of the present invention, -P ^a ', -P ^a '' and -P ^a ''' of formula (a) have a molecular weight of about 12.5 kDa.

In another embodiment of the present invention, -P ^a ', -P ^a '' and -P ^a ''' of formula (a) have a molecular weight of about 15 kDa.

In another embodiment of the present invention, -P ^a ', -P ^a '' and -P ^a ''' of formula (a) have a molecular weight of about 20 kDa.

In one embodiment of the present invention, -Z contains one component of formula (a).

In another embodiment of the present invention, -Z contains two components of formula (a).

In another embodiment of the present invention, -Z contains three components of formula (a).

Preferably, -Z is a component of formula (a).

More preferably, -Z contains a component of formula (b) (b),

Where

the dotted line indicates attachment to -L ² - or to the remainder of -Z; And

m and p independently of each other represent an integer in the range and inclusive of 150 to 1000; preferably an integer in the range and inclusive of 150 to 500; more preferably an integer in the range and inclusive of 200 to 500; and most preferably an integer in the range and inclusive of 400 to 500.

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

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

Preferably, -Z is a component of formula (b).

According to a preferred embodiment, the PTH conjugate of the present invention has formula (IIe-i):

Where

the unlabeled dotted line shows the addition of a -D moiety to the nitrogen, which is the PTH moiety due to the formation of an amide bond; And

The dotted line marked with an asterisk shows the connection to the component

Where

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

Preferably, -D is attached to the PTH conjugate of formula (IIe-i) via the N-terminal amine functionality of the PTH moiety.

According to another preferred embodiment, the PTH conjugate of the present invention has the formula (IIf-i):

Where

the unlabeled dotted line shows the addition of a -D moiety to the nitrogen, which is the PTH moiety due to the formation of an amide bond; And

The dotted line marked with an asterisk shows the connection to the component

Where

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

Preferably, -D is attached to the PTH conjugate of formula (IIf-i) via the N-terminal amine functionality of the PTH moiety.

If a PTH conjugate is present in a pharmaceutical composition, the pharmaceutical composition contains at least one PTH conjugate according to the present invention and at least one excipient.

In another embodiment of the present invention, the pharmaceutical composition is a dry composition. It is understood that such dry compositions require reconstitution before administration to a patient. According to another embodiment, the pharmaceutical composition is a liquid composition.

Such a liquid or dry pharmaceutical composition contains 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, oxidation protectants, thickeners/viscosity-increasing agents, or other adjuvant agents. However, in some cases, a single excipient may have dual or triple functions. Preferably, at least one excipient contained in the pharmaceutical composition according to the present invention is selected from the group consisting of the following:

(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 ZnCO ₃ can also be used;

(ii) Isotonicity modifiers: to minimize pain that may result from cellular damage due to osmotic pressure differences when injecting slow-absorbing substances; glycerin and sodium chloride are examples; effective concentrations can be determined by osmometry, using the permissible osmotic concentration of the solution equal to 285-315 mOsmol/kg for serum;

(iii) Preservatives and/or antimicrobials: Multi-dose parenteral formulations require the addition of preservatives at sufficient concentrations to minimize the risk of patient infection upon injection, and appropriate regulatory requirements must 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 may 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, sulfate sodium, 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 applied 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 chosen depends on the effect to be avoided, but typically a monolayer of surfactant will form at the interface just above the CMC value;

(vi) Anti-oxidation agents: antioxidants such as ascorbic acid, ectoine, methionine, glutathione, monothioglycerol, morin, polyethylenimine (PEI), propyl gallate and vitamin E; chelating agents such as citric acid, EDTA, hexaphosphate and thioglycolic acid may also be used;

(vii) Thickeners or viscosity-increasing agents: in the case of a suspension, retard the sedimentation of particles in the vial and syringe and are used to facilitate mixing and resuspension of 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 methylcellulose (hypromellose, HPMC) or diethylaminoethylcellulose (DEAE or DEAEC), colloidal magnesium silicate (Veegum) or sodium silicate, hydroxyapatite gel, tricalcium phosphate gel, xanthans, carrageenans such as Satia UTC 30 gum, aliphatic poly(hydroxy acids) such as poly(D-, L- or L-lactic acid) (PLA) and poly(glycolic acid) (PGA) and their copolymers (PLGA), terpolymers of D, L-lactide, glycolide and caprolactone, poloxamers, hydrophilic poly(oxyethylene) blocks and hydrophobic poly(oxypropylene) blocks to create triblock poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) (e.g. Pluronic®), polyether-polyester copolymer, such as polyethylene glycol 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 (GAG) 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 polyethylene glycol (PEG) or polyvinylpyrrolidone; such block copolymers, like the aforementioned poloxamers, can exhibit reversible thermal gelation (a liquid state at room temperature to facilitate administration and a gel state above the sol-gel transition temperature at body temperature after injection);

(viii) Lyophilizing or diffusing agent: modifies the permeability of connective tissue by hydrolyzing components of the extracellular matrix 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 auxiliary agents: such as wetting agents, viscosity modifiers, antibiotics, hyaluronidase; acids and bases such as hydrochloric acid and sodium hydroxide are auxiliary agents necessary to establish the pH value during preparation.

A pharmaceutical composition containing at least one PTH conjugate can be administered to a patient by various routes of administration, such as by topical, enteral or parenteral administration and by topical, injection or infusion methods, including intra-articular, periarticular, intradermal, subcutaneous, intramuscular, intravenous , intraosseous, intraperitoneal, intrathecal, intracapsular, intraocular, intravitreal, intratympanic, intravesical, intrastracheal, transcutaneous, subcuticular, subcapsular, subarachnoid, intraspinal, intraventricular administration, intrasternal injection and infusion, direct delivery to the brain through an implanted device that allows delivery of the invention or that the like into brain tissue or brain fluids (eg, Ommaya reservoir), direct intracerebroventricular injection or infusion, injection or infusion into the brain or brain-related areas, injection into the subchoroidal space, retroorbital injection, and ocular instillation. Preferably, the pharmaceutical composition containing at least one PTH prodrug is administered by subcutaneous injection.

Preferably, the entire initial dose is administered to the patient in one step, preferably as a single subcutaneous injection.

Subcutaneous injection is preferably performed with a syringe and needle or a pen, even more preferably a pen.

According to another aspect, the present invention relates to the use of a PTH conjugate, in which the PTH moiety is reversibly conjugated to a polymeric moiety or a fatty acid moiety, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said PTH conjugate or a pharmaceutically acceptable salt thereof, to produce a medicinal product. agents for the treatment, control, delay or prevention of a disease that can be treated, controlled, delayed or prevented by PTH, where the initial dose of the specified drug is in the range from 0.8 to 4.9 nmol/day. In certain embodiments, the initial dose of said drug is in the range of 0.8 to 3.9 nmol/day.

In FIG. Figure 1 shows the average maximum PTH suppression (1-84) plotted for each dose level tested.

Materials and methods

Compound 1 is shown below and can be synthesized as described for compound 18 of example 18 in WO 2017/148883 A1:

.

Examples

Example 1

To determine a safe starting dose for the treatment of patients suffering from hypoparathyroidism, the pharmacodynamic effects of single and multiple daily dosing of the long-acting PTH molecule were studied.

The safety, efficacy and pharmacokinetics of compound 1 were tested in a phase 1 study in healthy volunteers. A randomized and placebo-controlled study examined the effects after single and multiple escalating doses. Each group consisted of 10 subjects (8 active, 2 placebo) who were administered either a single dose or 10 daily doses of TransCon PTH. Single-dose groups received a single dose ranging from 0.8-30.1 nmol, while multiple-dose groups received one dose per day for 10 days ranging from 0.8-5.8 nmol.

Compound 1 was generally well tolerated without serious or severe drug-related side effects. Primary efficacy endpoints included serum calcium adjusted for albumin and endogenously secreted intact PTH(1-84).

The maximum tolerated dose (MTD) was 4.9 nmol/day of compound 1; 5 of 8 participants in the multiple escalating dose group (all women) who received compound 1 at a dose of 5.8 nmol/day, and both female participants in the placebo group, had orthostatic hypotension, palpitations and/or tachycardia, and 1 there were fainting spells. Two of the three men had asymptomatic hypercalcemia. The observed side effects leading to MTD reflect the known pharmacology of PTH.

Total calcium was measured in serum by chelation with 2,2'-[1,8-dihydroxy-3,6-disulfonaphthylene-2,7-bisazo]bisbenzolarsonic acid (Arsenazo III, Beckman Coulter, Inc., USA) and determination by bichromatic absorption at 600/700 nm. Albumin was measured by the dye binding method using 5,5-dibromo-o-cresol sulfonephthalein (Bromocresol Purple, -Randox Laboratories, UK) and detection by bichromatic absorbance at 600/700 nm. Albumin-corrected serum calcium levels were calculated as total calcium (mg/dL) + 0.8 (4 - albumin in g/dL). Intact PTH (184) was measured using the “Architect Intact PTH” assay from Abbott Laboratories; in vitro chemiluminescent microparticle immunoassay (CMIA) for the quantification of intact parathyroid hormone (PTH) in human serum and plasma. All analytical methods were essentially performed as described by the manufacturer.

In the multiple-dose groups, serum calcium levels corrected for albumin levels were measured daily for two days before the first dose and daily for two weeks after the first dose. Intact PTH (1-84) was measured the day before administration, before the first dose, and 1, 2, 3, 4, 9, 11, and 13 days after the first dose.

The effect of Compound 1 was demonstrated by dose-dependent responses on efficacy parameters as shown in FIG. 1 and in the table below.

Maximum PTH suppression (1–84) was calculated for individual subjects as the ratio (percentage) of the largest deviation from baseline during the sampling period and the difference between the subject's baseline level and the lower limit of quantitation of the assay (3 pg/mL). Baseline was defined as the PTH measurement (1–84) before the first dose. The mean maximum PTH suppression (1-84) for each dose level was then plotted (Figure 1). Daily doses from 0.8 to 3.9 nmol induced linear suppression of PTH(1-84) secretion, with endogenous PTH(1-84) secretion achieving maximum suppression at doses above 3.9 nmol.

The maximum increase from baseline in albumin-adjusted serum calcium level was calculated for individual subjects as the largest deviation from baseline during the sampling period for that subject. Baseline was calculated as the mean (n = 3) of samples collected before dosing. The mean maximum increase was calculated for each dose level and is presented in the table below.

Dose level
(daily for 10 days) serum calcium level corrected for albumin level (mg/dL)
Mean maximum increase relative to baseline (n=8) 0.8 nmol 0.44 1.7 nmol 0.35 2.9 nmol 0.66 3.9 nmol 0.82 4.9 nmol 1.21 5.8 nmol 1.42

Surprisingly, it has been found that the initial dose of a PTH conjugate for patients with hypoparathyroidism can be determined by gradually increasing the dose in healthy subjects. The range for the initial dose would be the lowest dose to increase serum calcium by about 0.3-0.4 mg/dL from baseline in healthy subjects, and the upper dose range would be the highest dose that suppresses endogenous PTH secretion (1-84) and does not cause hypercalcemia in healthy people.

Abbreviations

HP - hypoparathyroidism

PTH - parathyroid hormone.

Claims (11)

1. A method of treating or controlling hypoparathyroidism in a patient, wherein the method includes the step of administering an initial dose of 4.4 ± 0.3 nmol/day of a parathyroid hormone (PTH) conjugate, in which the PTH moiety is reversibly conjugated to a polymer moiety or a pharmaceutically acceptable salt thereof or the step of administering an initial dose of 4.4±0.3 nmol/day of a pharmaceutical composition containing said PTH conjugate or a pharmaceutically acceptable salt thereof, and wherein the PTH conjugate has the formula (IIf-i) wherein the unlabeled dotted line shows the attachment to the N-terminal amine functionality of the PTH moiety having the sequence of SEQ ID NO: 51 due to the formation of an amide bond; And The dotted line marked with an asterisk shows the connection to the component where m and p independently represent an integer in the range and including 400-500. 2. The method according to claim 1, where the initial dose is 4.4 ± 0.2 nmol/day. 3. The method according to claim 1, where the initial dose is 4.4 ± 0.1 nmol/day. 4. The method according to claim 1, where the initial dose is administered to the patient by subcutaneous injection. 5. The method according to claim 4, where the initial dose is administered to the patient in the form of a single subcutaneous injection. 6. The method according to claim 4, where the subcutaneous injection is performed with a pen syringe.