CNP prodrugs with large carrier moieties
The present invention relates to a CNP prodrug or a pharmaceutically acceptable salt thereof comprising a CNP moiety -D; and a carrier moiety —Z that is conjugated through a moiety -L 2 - to a reversible prodrug linker moiety -L 1 -, which reversible prodrug linker moiety -L 1 - is covalently and reversibly conjugated to -D; wherein -L 2 - is a chemical bond or a spacer; and —Z is a polymer having a molecular weight of at least 10 kDa. It further relates to pharmaceutical compositions comprising the CNP prodrug or a pharmaceutically acceptable salt thereof, their use as a medicament and to methods of treatment.
1. A compound of formula (IIf)
or a pharmaceutically acceptable salt thereof;
wherein
the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of a CNP moiety of SEQ ID NO:24 by forming an amide bond; and
the dashed line marked with the asterisk indicates attachment to —Z having the structure
wherein
each —Z a is
wherein
each c1 is an integer independently ranging from 200 to 250.
2. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein each c1 is about 225.
3. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of formula (IIf′)
wherein
the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; and
the dashed line marked with the asterisk indicates attachment to —Z having the structure
wherein
each —Z a is
wherein
each c1 is an integer independently ranging from 200 to 250.
4. The compound or pharmaceutically acceptable salt thereof of claim 3 , wherein each c1 is about 225.
5. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein the CNP prodrug is of the following formula:
wherein
the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; and
the dashed line marked with the asterisk indicates attachment to —Z having the structure
wherein
each —Z a is
wherein each c1 is an integer independently ranging from 200 to 250.
6. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 5 , wherein each c1 is about 225.
7. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 1 and at least one excipient.
8. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 2 and at least one excipient.
9. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 3 and at least one excipient.
10. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 4 and at least one excipient.
11. The pharmaceutical composition of claim 9 consisting of the compound or pharmaceutically acceptable salt thereof and the at least one excipient.
12. The pharmaceutical composition of claim 10 consisting of the compound or pharmaceutically acceptable salt thereof and the at least one excipient.
13. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 5 and at least one excipient.
14. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 6 and at least one excipient.
15. The pharmaceutical composition of claim 13 consisting of the compound or pharmaceutically acceptable salt thereof and the at least one excipient.
16. The pharmaceutical composition of claim 14 consisting of the compound or pharmaceutically acceptable salt thereof and the at least one excipient.
17. A method of treating a patient suffering from achondroplasia, hypochondroplasia, short stature, Noonan syndrome or SHOX deficiency, the method comprising the step of administering an effective dose of the compound or pharmaceutically acceptable salt thereof of claim 1 to the patient.
18. The method of claim 17 , wherein the disease is achondroplasia.
19. The method of claim 17 , wherein the patient is a pediatric patient.
20. The method of claim 17 , wherein each c1 is about 225.
21. The method of claim 17 , wherein the compound is of formula (IIf′)
wherein
the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; and
the dashed line marked with the asterisk indicates attachment to —Z having the structure
wherein
each —Z a is
wherein
each c1 is an integer independently ranging from 200 to 250.
22. The method of claim 21 , wherein each c1 of the compound is about 225.
23. A method of treating a patient suffering from achondroplasia, hypochondroplasia, short stature, Noonan syndrome or SHOX deficiency, the method comprising the step of administering an effective dose of the compound or pharmaceutically acceptable salt thereof of claim 5 to the patient.
24. The method of claim 23 , wherein the disease is achondroplasia.
25. The method of claim 23 , wherein the patient is a pediatric patient.
26. A method of treating a patient suffering from achondroplasia, hypochondroplasia, short stature, Noonan syndrome or SHOX deficiency, the method comprising the step of administering an effective dose of the compound or pharmaceutically acceptable salt thereof of claim 6 to the patient.
27. The method of claim 26 , wherein the disease is achondroplasia.
28. The method of claim 26 , wherein the patient is a pediatric patient.