PTH prodrugs
The present invention relates to PTH prodrugs, pharmaceutical compositions comprising such PTH prodrugs and their uses.
1. A compound according to formula 31, or a pharmaceutically acceptable salt thereof, wherein PTH(1-34) is parathyroid hormone of the amino acid sequence SEQ ID NO:51, N αs1 is the alpha amino group of the N-terminal serine of SEQ ID NO:51 and 2×10 kDa PEG comprises a branched polyethylene glycol polymer of two arms in which each arm has a molecular weight of about 10 kDa:
2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein each 2×10 kDa PEG is a moiety of formula (b):
wherein the dashed line indicates attachment to —S— in compound 31, and each of m and p of each moiety is independently an integer.
3. The compound of claim 1 or the pharmaceutically acceptable salt thereof, formed by reaction of the compound of formula 30:
with PEG 2×10 kDa maleimide.
4. A pharmaceutical composition comprising the compound of claim 1 or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
5. A pharmaceutical composition comprising the compound of claim 2 or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
6. A pharmaceutical composition comprising the compound of claim 3 or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
7. The pharmaceutical composition of claim 6 suitable for subcutaneous administration to a human.
8. A syringe and needle or pen injector comprising the compound or the pharmaceutically acceptable salt thereof of claim 1 .
9. A method of treating a patient having hypoparathyroidism comprising administering to the patient a therapeutically effective amount of the compound of claim 1 or the pharmaceutically acceptable salt thereof thereby treating hypoparathyroidism in the patient.
10. The method of claim 9 , wherein the compound or the pharmaceutically acceptable salt thereof is administered to the patient by subcutaneous administration.
11. The method of claim 10 , wherein the subcutaneous administration is with a pen injector.
12. The method of claim 10 , wherein the subcutaneous administration is with a syringe and needle.
13. The method of claim 9 , wherein the compound or the pharmaceutically acceptable salt thereof is administered at intervals of at least 24 hours.
14. The method of claim 9 , wherein the compound or the pharmaceutically acceptable salt thereof is administered at interval of one week.
15. A method of parathyroid hormone replacement therapy, comprising administering the compound of claim 1 or the pharmaceutically acceptable salt thereof to a patient in need of the therapy, thereby alleviating symptoms relating to hypocalcemia, hypercalciuria, and hyperphosphatemia, without causing hypercalcemia.