Calcitonin derivative or a pharmaceutically acceptable salt thereof, polypeptide, pharmaceutical composition, use of the calcitonin derivative or a pharmaceutically acceptable salt thereof, and use of the polypeptide.

Description

1 / 68 A derivative of calcitonin or a pharmaceutically acceptable salt. OF THE SAME, POLYPEPTIDE, PHARMACEUTICAL COMPOSITION, USE OF THE CALCITONIN DERIVATIVE OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME AND USE OF POLYPEPTIDE FIELD OF TECHNIQUE

[0001] This application relates to the field of polypeptide technology, specifically to a calcitonin analogue and a derivative and use thereof. BACKGROUND

[0002] Amylin, a polypeptide hormone consisting of 37 amino acids, is co-secreted with insulin in the β cells of the islets and is deficient in patients with diabetes. It functions in several different organ systems, primarily by virtue of amylin 1-3 receptors (AMYRs 1-3). Amylin can inhibit glucagon secretion, delay gastric emptying, generate a satiety signal, and suppress appetite. Clinical studies have demonstrated that amylin receptor agonists can be used to treat overweight, obesity, type 1 diabetes, and / or type 2 diabetes. An amylin analogue known as Pramlintide (trade name Symlin) can reduce blood glucose levels and be used to treat diabetic patients taking insulin. However, Pramlintide has a half-life of less than one hour and must be administered before meals. Therefore, the patient needs to take this medication several times a day for treatment.Due to its instability and pronounced predisposition to... Petition 870250099872, dated 10 / 31 / 2025, page 7 / 19 2 / 68 fibrillation at neutral pH, which results in its precipitation and therefore ineffectiveness, Pramlintide is supplied in acidic solution.

[0003] Calcitonin is a hormone produced in the thyroid gland that regulates calcium and phosphate levels in the blood, and calcitonin receptors are found in many body tissues and are involved in regulating bone remodeling. Salmon calcitonin, currently marketed under the name Miacalcic, is useful in treating conditions such as hypercalcemia and osteoporosis. Calcitonin is also unstable at neutral pH and is therefore supplied in an acidic solution. Salmon calcitonin has a half-life of less than two hours and needs to be administered to the patient once or more times a day. The calcitonin drugs currently available on the market are salmon calcitonin and elkatonin (eel calcitonin), which require daily administration by injection due to their low molecular weight.Furthermore, exhibiting desirable stability only under acidic conditions, but not under neutral conditions, represents a major barrier to pharmaceutical use and the development of formulations of these molecules.

[0004] The short half-life of natural amylin and calcitonin receptor agonists has made extending the half-life a target in the development of these drugs. In addition, as a result of the low stability and strong tendency to fibrillation of amylin and calcitonin receptor agonists at neutral pH, improving stability at physiological pH has become another target in drug development. SUMMARY OF THE INVENTION

[0005] Consequently, the present request makes Petition 870250089796, dated 02 / 10 / 2025, page 10 / 92 3 / 68 improvements in polypeptides that agonist against amylin receptors in order to obtain pharmaceutically acceptable analogs or derivatives or salts, with increased in vivo efficacy and increased stability.

[0006] Specifically, the present request is directed to the following technical solution: A calcitonin derivative or a pharmaceutically acceptable salt thereof comprising a polypeptide with an amino acid sequence of X0 X1SX3LS TX7VLG RLSX14E LHRLX20 X21X22PRT X26X27GX29X30 S X32-NH2, where: X0 is either D or E, or it is absent; X1 is A, L, V, I, S, E, R or K; X3 is Q, E, or D; X7 is A, L, V, I, S, R, E or D; X14 is Q, D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; X29 is S or A; X30 is G or E;e X32 is P or trans-Hyp.

[0007] In a preferred embodiment, the calcitonin derivative or a pharmaceutically acceptable salt thereof comprises a polypeptide with the following sequence of Petition 870250089796, dated 02 / 10 / 2025, p. 11 / 92 4 / 68 amino acids: Xo X1SX3LS TX7VLG RLSX14E LHRLX20 X21X22PRT X26X27GX29X30 S X32NH2, where: X0 is either D or E or is absent; A combination of Xi and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE, RD, KE, KD, or EE; X3 is Q, E, or D; X14 is Q, D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, Lou F; X26 is D or Q; X27 is V or S; A combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0008] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0009] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is LL, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0010] In a preferred embodiment, X0 is absent, Petition 870250089796, dated 02 / 10 / 2025, page 12 / 92 5 / 68 the combination between Xi and X7 is VV, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination between X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0011] In a preferred embodiment, Xo is absent, the combination of X1 and X7 is II, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0012] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SS, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0013] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AS, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0014] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SA, X3 is Q, E or D; X14 is Q, D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0015] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is ER, X3 is Q, E or D; X14 is Q, D, Petition 870250089796, dated 02 / 10 / 2025, page 13 / 92 6 / 68 E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0016] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is RE, X3 is Q, E or D; X14 is Q,D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0017] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RD, X3 is Q, E or D; X14 is Q,D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0018] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KE, X3 is Q, E or D; X14 is Q,D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0019] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KD, X3 is Q, E or D; X14 is Q,D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0020] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is EE, X3 is Q, E or D; X14 is Q,D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 Petition 870250089796, dated 02 / 10 / 2025, page 14 / 92 7 / 68 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0021] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is AA, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0022] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is LL, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0023] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is VV, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0024] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is II, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0025] In a preferred embodiment, Xo is absent, the combination of X1 and X7 is SS, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from Petition 870250089796, dated 02 / 10 / 2025, page 15 / 92 8 / 68 SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0026] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is AS, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0027] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SA, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0028] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is ER, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0029] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RE, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0030] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RD, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp. Petition 870250089796, dated 02 / 10 / 2025, page 16 / 92 9 / 68

[0031] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is KE, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0032] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KD, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is either True or False; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0033] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is EE, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is either True or False; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0034] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, or LL, or VV, or II, or SS, or AS, or SA, or ER, or RE, or EE, X3 is D; X14 is Q, D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or transHyp.

[0035] In a preferred embodiment, Xo is absent, the combination of X1 and X7 is AA, or LL, or VV, or II, or SS, or AS, or SA, or ER, or RE, or EE, X3 is E; X14 isQ, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; Petition 870250089796, dated 02 / 10 / 2025, page 17 / 92 10 / 68 X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or transHyp.

[0036] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is AA, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0037] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is LL, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0038] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is VV, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q, X27 is V or S, the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0039] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is II, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0040] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SS, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; Petition 870250089796, dated 02 / 10 / 2025, page 18 / 92 11 / 68 X27 is either V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is either P or trans-Hyp.

[0041] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is AS, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0042] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SA, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0043] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is ER, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0044] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RE, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0045] In a preferred embodiment, Xo is absent, the combination of X1 and X7 is RD, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from Petition 870250089796, dated 02 / 10 / 2025, page 19 / 92 12 / 68 SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0046] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is KE, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0047] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KD, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0048] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is EE, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0049] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, or LL, or VV, or II, or SS, or AS, or SA, or ER, or RE, or RD, or KE, or KD or EE, X3 is Q, E or D; X14 is Q; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0050] In a preferred embodiment, Xo is absent, the combination of X1 and X7 is AA, or LL, or VV, or II, or SS, or AS, or SA, or ER, or RE, or RD, or KE, or KD or Petition 870250089796, dated 02 / 10 / 2025, page 20 / 92 13 / 68 EE, X3 is Q, E, or D; X14 is D; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29 and X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0051] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is AA, or LL, or VV, or II, or SS, or AS, or SA, or ER, or RE, or RD, or KE, or KD or EE, X3 is Q, E or D; X14 is E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0052] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, or LL, or VV, or II, or SS, or AS, or SA, or ER, or RE, or RD, or KE, or KD or EE, X3 is Q, E or D; X14 is Aib; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0053] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, or LL, or VV, or II, or SS, or AS, or SA, or ER, or RE, or RD, or KE, or KD or EE, X3 is Q, E or D; X14 is S; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29 and X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0054] In a preferred embodiment, X0 is absent, Petition 870250089796, dated 02 / 10 / 2025, page 21 / 92 14 / 68 the combination between Xi and X7 is AA, or LL, or VV, or II, or SS, or AS, or SA, or ER, or RE, or RD, or KE, or KD, or EE; X3 is Q, E, or D; X14 is T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29 and X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0055] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is AA, or LL, or VV, or II, or SS, or AS, or SA, or ER, or RE, or RD, or KE, or KD or EE, X3 is Q, E, or D; X14 is Q, D, E, Aib, S, or T; X20 is E; X21 is D or E; X22 is Y, L, or F; and the combination of X29-X30 is selected from SG, AG, AE, or SE.

[0056] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, X3 is Q, E or D; X14 is Q, D, E, Aib, S, or T; X20 is Q; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0057] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is LL, X3 is Q, E or D; X14 is Q, D, E, Aib, S, or T; X20 is Q; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0058] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is VV, X3 is Q, E or D; X14 is Q, D, E, Aib, S, or T; X20 is Q; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected. Petition 870250089796, dated 02 / 10 / 2025, page 22 / 92 15 / 68 among SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0059] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is II, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0060] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SS, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0061] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AS, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0062] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SA, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0063] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is ER, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp. Petition 870250089796, dated 02 / 10 / 2025, page 23 / 92 16 / 68

[0064] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is RE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0065] In a preferred embodiment, Xo is absent, the combination of X1 and X7 is RD, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0066] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0067] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KD, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0068] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is EE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0069] In a preferred embodiment, X0 is absent, Petition 870250089796, dated 02 / 10 / 2025, page 24 / 92 17 / 68 the combination between Xi and X7 is AA, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination between X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0070] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is LL, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0071] In a preferred embodiment, X0 is absent, the combination of Xi and X7 is VV, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0072] In a preferred embodiment, X0 is absent, the combination of Xi and X7 is II, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X2i is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0073] In a preferred embodiment, X0 is absent, the combination of Xi and X7 is SS, X3 is Q, E or D; Xi4 is Q, D, E, Aib, S or T; X20 is Q or E; X2i is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0074] In a preferred embodiment, X0 is absent, the combination of Xi and X7 is AS, X3 is Q, E or D; Xi4 is Q, D, Petition 870250089796, dated 02 / 10 / 2025, page 25 / 92 18 / 68 E, Aib, S, or T; X20 is Q or E; X21 is E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0075] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is SA, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0076] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is ER, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0077] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0078] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RD, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0079] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D Petition 870250089796, dated 02 / 10 / 2025, page 26 / 92 19 / 68 or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0080] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is KD, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0081] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is EE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0082] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0083] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is LL, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0084] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is VV, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected Petition 870250089796, dated 02 / 10 / 2025, page 27 / 92 20 / 68 among SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0085] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is II, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0086] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SS, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0087] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AS, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0088] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SA, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0089] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is ER, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp. Petition 870250089796, dated 02 / 10 / 2025, page 28 / 92 21 / 68

[0090] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is RE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0091] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RD, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0092] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0093] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KD, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0094] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is EE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0095] In a preferred embodiment, Xo is absent, Petition 870250089796, dated 02 / 10 / 2025, page 29 / 92 22 / 68 the combination between Xi and X7 is AA, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination between X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0096] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is LL, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0097] In a preferred embodiment, X0 is absent, the combination of Xi and X7 is VV, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0098] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is II, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0099] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SS, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0100] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AS, X3 is Q, E or D; X14 is Q, D, Petition 870250089796, dated 02 / 10 / 2025, page 30 / 92 23 / 68 E, Aib, S or T; X20 is Q or E; X21 is Q; X27 is V or S; the combination among SG, AG, AE or SE; and X32 is P or

[0101] In one embodiment the combination between Xi and X7 is SA, E, Aib, S or T; X20 is Q or E; X21 is Q; X27 is V or S; the combination of SG, AG, AE or SE; and X32 is P or

[0102] In one embodiment the combination of X1 and X7 is ER, E, Aib, S or T; X20 is Q or E; X21 is Q; X27 is V or S; the combination among SG, AG, AE or SE; and X32 is P or

[0103] In one embodiment the combination between X1 and X7 is RE, E, Aib, S or T; X20 is Q or E; X21 is Q; X27 is V or S; the combination among SG, AG, AE or SE; and X32 is P or

[0104] In one embodiment the combination between X1 and X7 is RD, E, Aib, S or T; X20 is Q or E; X21 is Q; X27 is V or S; the combination among SG, AG, AE or SE; and X32 is P or

[0105] In one embodiment the combination between X1 and X7 is KE, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or X29-X30 is selected from trans-Hyp. If preferred, X0 is absent; X3 is Q, E, or D; X14 is Q, D, D, or E; X22 is Y; X26 is D or X29-X30 is selected from trans-Hyp. preferred, X0 is absent, X3 is Q, E or D; X14 is Q, D, D or E; X22 is Y; X26 is D or X29-X30 is selected from trans-Hyp. Preferred, X0 is absent, X3 is Q, E or D; X14 is Q, D, D or E; X22 is Y; X26 is D or X29-X30 is selected from trans-Hyp. preferred, X0 is absent, X3 is Q, E or D; X14 is Q, D, D or E; X22 is Y; X26 is D or X29-X30 is selected from trans-Hyp. preferred, X0 is absent, X3 is Q, E or D; X14 is Q, D, D or E; X22 is Y; X26 is D or Petition 870250089796, dated 02 / 10 / 2025, page 31 / 92 24 / 68 Q; X27 is either True or False; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0106] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is KD, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0107] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is EE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0108] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0109] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is LL, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0110] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is VV, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from Petition 870250089796, dated 02 / 10 / 2025, page 32 / 92 25 / 68 SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0111] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is II, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0112] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SS, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0113] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AS, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0114] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SA, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0115] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is ER, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp. Petition 870250089796, dated 02 / 10 / 2025, page 33 / 92 26 / 68

[0116] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is RE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0117] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RD, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0118] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0119] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KD, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0120] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is EE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0121] In a preferred embodiment, X0 is absent; Petition 870250089796, dated 02 / 10 / 2025, page 34 / 92 27 / 68 the combination between Xi and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE or EE; X3 is Q or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is F; X26 is D or Q; X27 is V or S; the combination between X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0122] In a preferred embodiment, Xo is absent; The combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE, or EE; X3 is Q or D; X14 is Q, D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; a combination of X26-X27 is DV; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or transHyp.

[0123] In a preferred embodiment, X0 is absent; the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE or EE; X3 is Q or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; the combination of X26-X27 is QS; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or transHyp.

[0124] In a preferred embodiment, X0 is absent; the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE or EE; X3 is Q or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; the combination of X26-X27 is QV; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or transHyp. Petition 870250089796, dated 02 / 10 / 2025, page 35 / 92 28 / 68

[0125] In a preferred embodiment, Xo is absent; The combination of Xi and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE, or EE; X3 is Q or D; X14 is Q. D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; The combination of X26-X27 is DS; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or transHyp.

[0126] In a preferred embodiment, Xo is absent, the combination of X1 and X7 is AA, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SG; and X32 is P or trans-Hyp.

[0127] In a preferred embodiment, Xo is absent, the combination of X1 and X7 is LL, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SG; and X32 is P or trans-Hyp.

[0128] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is VV, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SG; and X32 is P or trans-Hyp.

[0129] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is II, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SG; and X32 Petition 870250089796, dated 02 / 10 / 2025, page 36 / 92 29 / 68 is P or trans-Hyp.

[0130] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is SS, X3 is Q, E or D; X14 is Q,D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SG; and X32 is P or trans-Hyp.

[0131] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AS, X3 is Q, E or D; X14 is Q,D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SG; and X32 is P or trans-Hyp.

[0132] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SA, X3 is Q, E or D; X14 is Q,D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SG; and X32 is P or trans-Hyp.

[0133] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is ER, X3 is Q, E or D; X14 is Q,D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SG; and X32 is P or trans-Hyp.

[0134] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RE, X3 is Q, E or D; X14 is Q,D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SG; and X32 is P or trans-Hyp. Petition 870250089796, dated 02 / 10 / 2025, page 37 / 92 30 / 68

[0135] In a preferred embodiment, Xo is absent, the combination of Xi and X7 is RD, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SG; and X32 is P or trans-Hyp.

[0136] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is DE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SG; and X32 is P or trans-Hyp.

[0137] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KD, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SG; and X32 is P or trans-Hyp.

[0138] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is EE, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SG; and X32 is P or trans-Hyp.

[0139] In a preferred embodiment, X0 is absent; the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE, or EE; X3 is Q or D; X14 is Q, D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is AG; and X32 is P or trans-Hyp. Petition 870250089796, dated 02 / 10 / 2025, page 38 / 92 31 / 68

[0140] In a preferred embodiment, Xo is absent; The combination of Xi and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE, or EE; X3 is Q or D; X14 is Q. D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is AE; and X32 is P or trans-Hyp.

[0141] In a preferred embodiment, X0 is absent; The combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE, or EE; X3 is Q or D; X14 is Q. D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is SE; and X32 is P or trans-Hyp.

[0142] In a preferred embodiment, X0 is absent; The combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE, or EE; X3 is Q or D; X14 is Q. D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P.

[0143] In a preferred embodiment, X0 is absent; The combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE, or EE; X3 is Q or D; X14 is Q. D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is trans-Hyp.

[0144] In a preferred embodiment, X0 is D; the combination of X1 and X7 is selected from AA, LL, VV, Petition 870250089796, dated 02 / 10 / 2025, page 39 / 92 32 / 68 II, SS, AS, SA, ER, RE, or EE; X3 is Q or D; X14 is Q, D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y, L, or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0145] In a preferred embodiment, Xo is E; the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE or EE; X3 is Q or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0146] In a preferred embodiment, X0 is D or E or is absent, the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, RE, RD, KE or KD; X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y or L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0147] In a preferred embodiment, Xo is D or E or is absent, the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, RE, RD, KE or KD; X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; a combination of X20-X21 is EE; X22 is Y or L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0148] In a preferred embodiment, X0 is D or E or is absent, the combination of X1 and X7 is selected from Petition 870250089796, dated 02 / 10 / 2025, page 40 / 92 33 / 68 AA, LL, VV, II, SS, AS, SA, RE, RD, KE or KD, X3 is Q, E or D; a combination of X14-X22 is DL; X20 is Q or E; X21 is D or E; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0149] In a preferred embodiment, Xo is D or E or is absent, the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, RE, RD, KE or KD, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y or L; X26-X27 is QS; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or transHyp.

[0150] In a preferred embodiment, Xo is D or E or is absent, the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, RE, RD, KE or KD, X3X14-X20 is EEE; X21 is D or E; X22 is Y or L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE or SE; and X32 is P or trans-Hyp.

[0151] In a preferred embodiment, X0 is D or E or is absent, the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, or RE; X3 is Q, E, or D; X14 is Q, D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y or L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or transHyp.

[0152] In a preferred embodiment, X0 is D or E Petition 870250089796, dated 02 / 10 / 2025, page 41 / 92 34 / 68 or is absent, the combination of Xi and X7 is selected from AA, LL, VV, II, SS, AS, SA, or RE; X3 is Q, E, or D; X14 is Q, D, E, Aib, S, or T; X20-X21 is EE; X22 is Y or L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0153] In a preferred embodiment, Xo is D or E or is absent, the combination of Xi and X7 is selected from AA, LL, VV, II, SS, AS, SA, or RE; X3 is Q, E, or D; X14X22 is DL; X20 is Q or E; X21 is D or E; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0154] In a preferred embodiment, X0 is D or E or is absent, the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, or RE, X3 is Q, E, or D; X14 is Q, D, E, Aib, S, or T; X20 is Q or E; X21 is D or E; X22 is Y or L; X26-X27 is QS; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0155] In a preferred embodiment, X0 is D or E or is absent, the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, or RE, X3-X14-X20 is EEE; X21 is D or E; X22 is Y or L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from SG, AG, AE, or SE; and X32 is P or trans-Hyp.

[0156] In a preferred embodiment, the derivative or a pharmaceutically acceptable salt thereof comprises a polypeptide with an amino acid sequence of ASQLS TAVLG Petition 870250089796, dated 02 / 10 / 2025, p. 42 / 92 35 / 68 RLSX14E LHRLX20 DX22PRT DVGX29G SP-NH2, where, X14 is Q, D, or E; X20 is either Q or E, preferably Q; X22 is Y or L; and X29 is S or A.

[0157] In a preferred embodiment, the derivative or a pharmaceutically acceptable salt thereof comprises a polypeptide with an amino acid sequence of ASQLS TAVLG RLSX14E LHRLQ DX22PRT DVGSG SP-NH2, wherein X14 is Q, D or E, preferably Q or D; and X22 is Y or L.

[0158] In a preferred embodiment, the calcitonin derivative or a pharmaceutically acceptable salt thereof comprises an amino acid sequence selected from any one of SEQ ID NO. 1–SEQ ID NO. 38 in Table 2.

[0159] In a preferred embodiment, the calcitonin derivative or a pharmaceutically acceptable salt thereof comprises an amino acid sequence selected from any of: ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 (SEQ ID NO.7), ASQLS TAVLG RLSQE LHRLQ DLPRT DVGSG SP-NH2 (SEQ ID NO. 17), ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 (SEQ ID NO.8), ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAG SP-NH2 (SEQ ID NO. 18), ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAE SP-NH2 (SEQ ID NO. 19) or ASQLS TAVLG RLSQE LHRLE DYPRT DVGSG SP-NH2 (SEQ ID NO. 12). Petition 870250089796, dated 02 / 10 / 2025, p. 43 / 92 36 / 68

[0160] In a preferred embodiment, the calcitonin derivative or a pharmaceutically acceptable salt thereof comprises a side chain, preferably a fatty acid-containing side chain, to modify the amino acids.

[0161] In a preferred embodiment, the calcitonin derivative or a pharmaceutically acceptable salt thereof comprises a fatty acid-containing side chain attached to the N-terminal amino acid sequence.

[0162] In a preferred embodiment, the fatty acid-containing side chain is in the form of Z1+Z2+Z3, wherein Z1 is a C16-C22 fatty acid diacid; Z2 is selected from any of yGlu, aGlu, [8Asp, aAsp, Inp, and Trx, or is absent; and Z3 is n AEEA(s), where n ^ 0. Z1, Z2, and Z3 are connected by amide bonds.

[0163] In a preferred modality, n is selected from 0, 1, 2, 3, 4, 5 or 6.

[0164] In a preferred embodiment, n is 6.

[0165] In a preferred embodiment, n is 4.

[0166] In a preferred embodiment, n is 2.

[0167] In a preferred embodiment, n is 0.

[0168] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty acid diacid) + yGlu.

[0169] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 diacid Petition 870250089796, dated 02 / 10 / 2025, p. 44 / 92 37 / 68 fatty) + aGlu.

[0170] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty acid diacid) + pAsp.

[0171] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty acid diacid) + aAsp.

[0172] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty acid diacid) + Inp.

[0173] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty acid diacid) + Trx.

[0174] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty acid diacid).

[0175] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty acid diacid) + yGlu+2 AEEAs.

[0176] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty acid diacid) + yGlu+4 AEEAs.

[0177] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty acid diacid) + yGlu+6 AEEAs.

[0178] In a preferred embodiment, the chain Petition 870250089796, dated 02 / 10 / 2025, p. 45 / 92 38 / 68 lateral containing fatty acid is in the form of (C16-C22 fatty) + αGlu + 2 AEEAs.

[0179] In a preferred embodiment, the fatty acid-containing side is in the form of (C16-C22 fatty) + pAsp+2 AEEAs.

[0180] In a preferred embodiment, the fatty acid-containing side is in the form of (C16-C22 fatty) + αAsp + 2 AEEAs.

[0181] In a preferred embodiment, the fatty acid-containing side is in the form of (C16-C22 fatty) + Inp+2 AEEAs.

[0182] In a preferred embodiment, the fatty acid-containing side is in the form of (C16-C22 fatty) + Trx + 2 AEEAs.

[0183] In a preferred embodiment, the fatty acid-containing side is in the form of (C20 fatty) + yGlu.

[0184] In a preferred embodiment, the fatty acid-containing side is in the form of (C20 fatty) + aGlu.

[0185] In a preferred embodiment, the fatty acid-containing side is in the form of (C20 fatty) + pAsp.

[0186] In a preferred embodiment, the fatty acid-containing side is in the form of (C20 fatty) + aAsp. diacid chain diacid chain diacid chain diacid chain diacid chain diacid chain diacid chain diacid chain diacid chain diacid chain Petition 870250089796, dated 02 / 10 / 2025, p. 46 / 92 39 / 68

[0187] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid diacid) + Inp.

[0188] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid diacid) + Trx.

[0189] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid diacid).

[0190] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid diacid) + yGlu+2 AEEAs.

[0191] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid diacid) + yGlu+4 AEEAs.

[0192] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid diacid) + YGlu+6 AEEAs.

[0193] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid diacid) + aGlu+2 AEEAs.

[0194] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 diacid fatty acid) + pAsp + 2 AEEAs.

[0195] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 diacid. Petition 870250089796, dated 02 / 10 / 2025, p. 47 / 92 40 / 68 fatty) + aAsp + 2 AEEAs.

[0196] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid diacid) + Inp+2 AEEAs.

[0197] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid diacid) + Trx + 2 AEEAs.

[0198] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C22 fatty acid diacid) + yGlu+2 AEEAs.

[0199] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C22 fatty acid diacid) + yGlu+4 AEEAs.

[0200] The present application also provides a polypeptide analogue, which is a polypeptide comprising an amino acid sequence of any of the derivatives described above.

[0201] This application also provides a pharmaceutical composition comprising one or more of the analogues, or derivatives or a pharmaceutically acceptable salt thereof described above. Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, for example, a non-toxic filler, stabilizer, diluent, carrier, solvent or similar.

[0202] This application also provides for the use of an analogue, or derivative or a pharmaceutically available salt. Petition 870250089796, dated 02 / 10 / 2025, page 48 / 92 41 / 68 acceptable of the same as described above in the manufacture of a medicine to prevent and / or treat overweight and / or obesity and / or type I or type II diabetes and / or osteoporosis and / or neuropathic pain.

[0203] This application also provides for the use of an analogue, or derivative or pharmaceutically acceptable salt thereof described above in reducing food intake and / or body weight, for example, use thereof in the manufacture of a health care product, food or medicine to reduce food intake and / or body weight.

[0204] The present application also provides a method for preventing and / or treating overweight and / or obesity and / or type I or type II diabetes and / or osteoporosis and / or neuropathic pain, comprising administering to a subject a prophylactic or therapeutically effective amount of the analogue, derivative or pharmaceutically acceptable salt thereof, or of the pharmaceutical composition described above.

[0205] The present application also provides a method for reducing food intake, comprising administering to a subject an effective amount of the analogue, derivative or pharmaceutically acceptable salt thereof, or of the pharmaceutical composition described above. BRIEF DESCRIPTION OF THE DRAWINGS

[0206] The drawings are intended for better understanding and do not constitute any undue limitation of Petition 870250089796, dated 02 / 10 / 2025, page 49 / 92 42 / 68 present request, in which: Figure 1 is the reversed-phase chromatography spectrum of the D3 (Mimylin) molecule on day 26 of a heat-accelerated assay; Figure 2 is the reversed-phase chromatography spectrum of the calcitonin analog M5 on day 26 of a heat-accelerated assay; Figure 3 is the reversed-phase chromatography spectrum of the M8 molecule alone on day 26 of a heat-accelerated assay under neutral conditions; Figure 4 is the reversed-phase chromatography spectrum of M8 and M51 in a neutral buffer solution without excipients after a one-month heat-accelerated assay; Figure 5 is the reversed-phase chromatography spectrum of M8 and M51 in a neutral buffer solution with excipients after a one-month heat-accelerated assay; Figure 6 is a trend graph showing the effect of the first group of calcitonin analogs or derivatives on weight change in rats in the experiment; Figure 7 is a trend graph showing the effect of the first group of calcitonin analogs or derivatives on the cumulative food intake of rats in the experiment; Figure 8 is a trend graph showing the effect of the second group of calcitonin analogs or derivatives on weight change in rats in the experiment; and Figure 9 is a trend graph that shows the effect. Petition 870250089796, dated 02 / 10 / 2025, pp. 50 / 92 43 / 68 of the second group of calcitonin analogs or derivatives in the cumulative dietary intake of rats in the experiment. DETAILED DESCRIPTION

[0207] An analogue, as described in this document, refers to a compound formed from a specific polypeptide molecule in which at least one amino acid residue has been replaced by another, and / or at least one amino acid residue has been deleted, and / or at least one amino acid residue has been added to the N- or C-terminus, and / or at least one amino acid residue has been inserted between any two amino acids.

[0208] The terms polypeptide and analogue, and the corresponding form thereof, as used in a composition, have the same meaning and are used interchangeably in the present application, unless otherwise specified in the context. In certain cases, the terms calcitonin and calcitonin analogue have the same meaning and are used interchangeably, for example, in a derivative of a calcitonin analogue and a calcitonin derivative.

[0209] A derivative, as described herein, refers to a product resulting from the modification of a functional group (e.g., an amino acid residue) in a biomacromolecule (e.g., a polypeptide or protein) with certain groups or structures (e.g., structures of certain small molecules). The modification includes, Petition 870250089796, dated 02 / 10 / 2025, pp. 51 / 92 44 / 68 but without limitation, acylation, amidation, esterification and thioesterification. Abbreviations

[0210] The corresponding names or structures of some abbreviations used in the examples in this application are as follows: TABLE IA Trx: / —\ 0 H2r / \—f I AEEA: O H2N / K / X XOH Inp: / ---\ 0 ΗΓ·ί' )---- / '----' OH AA: Amino acid; Boc: t-butyloxycarbonyl; DCM: dichloromethane; DMF: N,N-Dimethylformamide; DIEA: N,N-Diisopropylethylamine; EDT: 1,2-Ethanedithiol; Fmoc: 9-fluorenylmethyloxycarbonyl; OtBu: t-butyl ester; Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl chloride; Pip: Piperidine; TBTU: O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; tBu: tertiary butyl; TFA: Trifluoroacetic acid; TIS: Triisopropylsilane; Trt: Triphenylmethyl; aGlu: α-glutamic acid; YGlu: γ-glutamic acid; «Asp: α-aspartic acid; and [3Asp: β-aspartic acid.

[0211] Illustrative examples of the present application are described below, in which various details of the examples in the present application are included for ease of understanding and should be interpreted as illustrative only. Therefore, Petition 870250089796, dated 02 / 10 / 2025, pp. 52 / 92 45 / 68 Those of ordinary skill in the art should be aware that many alterations and modifications can be made to the examples described herein without departing from the scope and spirit of the present application. For clarity and conciseness, the following description also omits the representation of well-known functions and structures. EXAMPLES Example 1: Preparation of Polypeptide Derivatives

[0212] Polypeptides were synthesized by organic solid-phase synthesis, specifically, solid-phase peptide synthesis (SPPS) with Fmoc-protected amino acids, and then cleaved, oxidized, and purified to produce target products. Taking the compound Cagrilintida (designated as “D1”) as an example, the synthesis process was as follows: 1.1 Solid-phase synthesis

[0213] Using MBHA resin with Fmoc-Ligand S=0.32 mmol / ge and Fmoc / tBu processing, amino acids were linked by sequential condensation from the C-terminal to the N-terminal (from right to left), according to the sequence of the aforementioned peptide, as per the method provided in Table 1B. Table 1B. List of synthesis procedures Solvent No. Number of times Duration (min / time) Petition 870250089796, dated 02 / 10 / 2025, page 53 / 92 46 / 68 1 20% Pip / DMF 1 10 2 20% Pip / DMF 1 5 3 DMF 5 1 4 Sampling for colorimetric tests 5 AA / DIEA / TBTU 1 60 6 DMF 4 1 7 Sampling for colorimetric tests Observations 1. Repeat 1-7 until the end of linear peptide synthesis

[0214] The following amino acids were coupled in order: A-01 Fmoc-Pro-OH, A-02 Fmoc-Thr(tBu)-OH, A-03 FmocAsn(Trt)-OH, A-04 Fmoc-Ser(tBu)-OH, A-05 Fmoc-Gly-OH, A-06 Fmoc-Val-OH, A-07 Fmoc-Asn(Trt)-OH, A-08 Fmoc-Thr(tBu)-OH, A09 Fmoc-Pro-OH, A-10 Fmoc-Pro-OH, A-11 Fmoc-Leu-OH, A-12 FmocIle-OH, A-13 Fmoc-Pro-OH, A-14 Fmoc-Gly-OH, A-15 Fmoc-Phe-OH, A-16 Fmoc-Asn(Trt)-OH, A-17 Fmoc-Asn(Trt)-OH, A-18 FmocSer(tBu)-OH, A-19 Fmoc-Ser(tBu)-OH, A-20 Fmoc-His(Trt)-OH, A21 Fmoc-Arg(Pbf)-OH, A-22 Fmoc-Leu-OH, A-23 Fmoc-Phe-OH, A-24 Fmoc-Glu(OtBu)-OH, A-25 Fmoc-Ala-OH, A-26 Fmoc-Leu-OH, A-27 Fmoc-Arg(Pbf)-OH, A-28 Fmoc-Gln(Trt)-OH, A-29 Fmoc-Thr(tBu)OH, A-30 Fmoc-Ala-OH, A-31 Fmoc-Cys(Trt)-OH, A-32 FmocThr(tBu)-OH, A-33 Fmoc-Ala-OH, A-34 Fmoc-Thr(tBu)-OH, A-35 Fmoc-Asn(Trt)-OH, A-36 Fmoc-Cys(Trt)-OH, A-37 Fmoc-Lys(Boc)OH, A-38 Fmoc-Glu-otbu, e A-39 C20 diácido.

[0215] Finalmente, um derivado de polipeptídeo em Petição 870250089796, de 02 / 10 / 2025, pág. 54 / 92 47 / 68 resina foi formado.

[0216] The polypeptide resin derivative was washed, transferred, and dried to a constant weight for cleavage. 1.2 Cleavage

[0217] Formulation of a cleavage reagent: the cleavage reagent was TFA:H2O:EDT:TIS = 95:1:2:2, the amount of which was a volume of 10 ml ± 2 ml per 1 g of peptide on resin. H2O, TFA, EDT and TIS comprising the required cleavage reagent were added sequentially to a cleavage reaction flask and controlled at a temperature of 0-10 °C. The cleavage reagent was added to the resin under stirring and, after the system temperature stabilized, the reagents were stirred for another 2.5 hours under a controlled temperature of 25-30 °C. The cleavage solution was filtered and left to precipitate using glacial diethyl ether of a 5x volume of the liquid. The precipitates were filtered, washed 3 times with glacial diethyl ether using a volume 3 times the liquid, and then dried under reduced pressure at room temperature to produce a crude solid. 1.3 Oxidation

[0218] The crude product was finely ground and added slowly, with stirring, to the purified water, while an aqueous solution of acetonitrile was added dropwise. After the crude product had been added and completely dissolved, a methanolic iodine solution was added and stirred for half an hour. Petition 870250089796, dated 02 / 10 / 2025, pp. 55 / 92 48 / 68 1.4 Purification and freeze-drying

[0219] The oxidized liquid, as described above, was filtered with a 0.45 µm microporous filter membrane. The crude product was separated and purified using a column prepared with C-18 column packing material with a suitable gradient at room temperature, and then the target product was collected, detected, analyzed, and classified. A purity > 90% was required. Substandard target products were collected, separated, and purified again with a suitable gradient to achieve qualified liquid peaks. The qualified liquid samples mentioned above were lyophilized under reduced pressure to produce lyophilized powder of the refined polypeptide.

[0220] Polypeptides and derivatives prepared using a method similar to that described in Example 1 of the present application are shown in Table 2. D2 denotes the natural salmon calcitonin sequence, D1 and D3 represent the calcitonin sequences modified in the prior art, and the remainder are calcitonin analogs or derivatives provided in the present application, wherein the fatty acid diacid chemical portion of the polypeptide derivative is located on the outer side of the fatty acid-containing side chain for modification relative to the amino acid sequence and is therefore positioned at the distal end of the side chain attachment to the amino acid sequence. Table 2. Amino acid sequences and modifications Petition 870250089796, dated 02 / 10 / 2025, pp. 56 / 92 49 / 68 ID SEQ ID NO. Sequência de aminoácidos Sítio de modif icaçã o Cadeia lateral contendo ácido Graxo D1 SEQ ID NO. 1 KCNTATCATQ RLAEFLRHSS NNFGPILPPT NVGSNTP-NH2 N-terminal C20 diácido + YGlu D2 SEQ ID NO. 2 CSNLS TCVLG KLSQE LHKLQ TYPRT NTGSG TP-NH2 Nenhum Nenhum D3 SEQ ID NO. 3 EASEL STAAL GRLSA ELHEL ATLPR TETGP ESP-NH2 Nenhum Nenhum M5 SEQ ID NO. 5 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 Nenhum Nenhum M6 SEQ ID NO. 5 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 N-terminal C20 diácido + YGlu M7 SEQ ID NO. 6 ASDLS TAVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 N-terminal C20 diácido + YGlu M8 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 N-terminal C20 diácido + YGlu M9 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N-terminal C20 diácido + YGlu M10 SEQ ID NO. 9 ASQLS TAVLG RLS-Aib-E LHRLQ DYPRT DVGSG SP- NH2 N-terminal C20 diácido + YGlu Petition 870250089796, on 10 / 02 / 2025, page. 57 / 92 50 / 68 M11 SEQ ID NO. 10 ASQLS TAVLG RLSSE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diacido + yGlu M12 SEQ ID NO. 11 ASQLS TAVLG RLSTE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diacido + yGlu M13 SEQ ID NO. 12 ASQLS TAVLG RLSQE LHRLE DYPRT DVGSG SP-NH2 N- termi nal C20 diacido + yGlu M14 SEQ ID NO. 13 ASQLS TAVLG RLSQE LHRLE EYPRT DVGSG SP-NH2 N- termi nal C20 diacido + yGlu M15 SEQ ID NO. 14 ASQLS TAVLG RLSQE LHRLQ DYPRT QVGSG SP-NH2 N- termi nal C20 diacido + yGlu M16 SEQ ID NO. 15 ASQLS TAVLG RLSQE LHRLQ DYPRT DSGSG SP-NH2 N- termi nal C20 diacido + yGlu M17 SEQ ID NO. 16 ASQLS TAVLG RLSQE LHRLQ DYPRT QSGSG SP-NH2 N- termi nal C20 diacido + yGlu M18 SEQ ID NO. 17 ASQLS TAVLG RLSQE LHRLQ DLPRT DVGSG SP-NH2 N- termi nal C20 diacido + yGlu M19 SEQ ID NO. 18 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAG SP-NH2 N- termi nal C20 diacido + yGlu M2 0 SEQ ID NO. 19 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAE SP-NH2 N- terminus C20 diacido + yGlu Petition 870250089796, of 02 / 10 / 2025, p. 58 / 92 51 / 68 nal M21 SEQ ID NO. 2 0 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGSE SP-NH2 N- termi nal C20 diacido + yGlu M22 SEQ ID NO. 21 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGSG S-transHyp -NH2 N- term nal C20 diacido + yGlu M2 3 SEQ ID NO. 22 D ASQLS TAVLG RLSQE LHRLQ DYPRT DVGSG SP- NH2 N- termi nal C18 diacido M2 4 SEQ ID NO. 2 3 E ASQLS TAVLG RLSQE LHRLQ DYPRT DVGSG SPNH2 N- termi nal C18 diacid M2 5 SEQ ID NO. 2 4 LSQLS TLVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diacido + yGlu M2 6 SEQ ID NO. 2 5 VSQLS TVVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diacido + yGlu M2 7 SEQ ID NO. 2 6 ISQLS TIVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diacido + yGlu M2 8 SEQ ID NO. 2 7 SSQLS TSVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diacido + yGlu M2 9 SEQ ID NO. 2 8 ASQLS TSVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diacid + yGlu M30 SEQ ID SSQLS TAVLG RLSQE LHRLQ N- C20 diacid Petition 870250089796, of 02 / 10 / 2025, p. 59 / 92 52 / 68 NODE. 2 9 DYPRT DVGSG SP-NH2 terminal + yGlu M31 SEQ ID NO. 3 0 ESQLS TRVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 N- terminal C20 diacid + yGlu M32 SEQ ID NO. 31 RSQLS TEVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 N- terminal C20 diacid + yGlu M33 SEQ ID NO. 32 ESQLS TEVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 N- terminal C20 diacid + yGlu M34 SEQ ID NO. 33 ASELS TAVLG RLSEE LHRLE DYPRT DVGSG SP-NH2 N- terminal C20 diacid + yGlu M35 SEQ ID NO. 34 RSQLS TDVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 N- terminal C20 diacid +yGlu M3 6 SEQ ID NO. 35 KSQLS TEVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 N- terminal C20 diacid +yGlu M37 SEQ ID NO. 3 6 KSQLS TDVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 N- terminal C20 diacid +yGlu M38 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 N- terminal C22 diacid + yGlu M39 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 N-terminal C18 diacid + yGlu Petition 870250089796, dated 02 / 10 / 2025, pp. 60 / 92 53 / 68 M4 0 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 N- terminal C16 diacid + yGlu M41 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 N- terminal C20 diacid + aGlu M42 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 N- terminal C18 diacid + aGlu M43 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 N- terminal C20 diacid + pAsp M44 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 N-terminus C18 diacid + aAsp M45 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 N-terminus C20 diacid + Trx M4 6 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 N-terminus C18 diacid + Trx M47 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 N-terminus C20 diacid + Inp M4 8 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 N-terminus C18 diacid + Inp M4 9 SEQ ID NO. 37 ASQLS TAVLG RLSQE LHRLQ DFPRT DVGSG SP-NH2 N-termi C20 diacido +yGlu Petition 870250089796, de 02 / 10 / 2025, pág. 61 / 92 54 / 68 nal M50 SEQ ID NO. 3 8 ASQLS TAVLG RLSDE LHRLQ DLPRT DVGSG SP-NH2 N- termi nal C20 diácido +yGlu M51 SEQ ID NO. 4 HVEGTFTSDVSSYLEEQAAREF IKWLVRGRG-OH 30K C18 diácido +YGlu +2 AEEAs M52 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diácido +aGlu M53 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diácido + pAsp M54 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N-terminal C20 diácido +aAsp M55 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N-terminal C20 diácido + Trx M5 6 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N-terminal C20 diácido + Inp M57 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N-terminal C20 diácido+YGlu +2 AEEAs M58 SEQ ID ASQLS TAVLG RLSEE LHRLQ N- C20 diácido Petition 870250089796, on 10 / 02 / 2025, page. 62 / 92 55 / 68 NO. 8 DYPRT DVGSG SP-NH2 termi nal + aGlu+2 AEEAs M59 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diacido + pAsp+2 AEEAs M60 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diacid + aAsp+2 AEEAs M61 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diacido + Trx+2 AEEAs M62 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diacido + Inp+2 AEEAs M63 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diacido + yGlu+4 AEEAs M64 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C20 diacido + yGlu+6 AEEAs M65 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N- termi nal C22 diacido +YGlu M6 6 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N-termi nal C22 diacido + YGlu+2 AEEAs Petition 870250089796, of 02 / 10 / 2025, p. 63 / 92 56 / 68 M67 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 N- terminal C22 diacid + yGlu+4 AEEAs Example 2: Testing the Activity of Derivatives in Cells

[0221] The aim of this assay is to test the activity or potency of calcitonin analogues or derivatives at human amylin receptors in vitro using a luciferase assay. 2.1 Construction of an amylin / CRE-luc receptor cell line

[0222] Using standard protocol, CHOK1 / Ga15 / AMY3 cells (purchased from GenScript, with calcitonin receptor and receptor activity-modifying peptide (RAMP) already constructed) were transfected with a plasmid containing a luciferase expression cassette driven by multiple copies of cAMP response elements (CREs). The cells were cultured in an F12 medium containing 200 µg / ml zeocin, 2 µg / ml puromycin, 100 µg / ml hygromycin, and 400 µg / ml G418 to provide a stably transfected amylin / CRE-luc receptor cell line. 2.2 Amylin luciferase assay

[0223] The lyophilized powder, obtained according to the method of Example 1, was dissolved in 20 mM phosphate buffer solution with pH 7.0 and diluted in a growth medium (F12 culture medium containing 10% FBS) to provide a derivative sample with an initial concentration of 10 nM, which Petition 870250089796, dated 02 / 10 / 2025, pp. 64 / 92 Sample 57 / 68 was then subjected to a 5-fold serial dilution in growth medium to provide samples of 7 concentrations, including 10 nM, 2 nM, 0.4 nM, etc. 50 μL of the tested sample solution at a respective concentration was added to each well of a 96-well blank plate.

[0224] Stably transfected amylin / CRE-luc receptor CHO cells were resuspended in growth medium at a given density, and 50 μL of the cell suspension were added at a density of approximately 20,000 cells per well to a 96-well blank plate containing the test sample solution. After 24 hours of incubation at 37 °C and 5% CO2, 100 μL of a luciferase substrate were added to each well, incubated for 3 minutes, and finally tested for luminescence on SpectraMax L (Molecular Devices) using SoftMax Pro 7.0.3 GxP software. A standard curve was plotted using the fluorescence intensities to calculate EC50. The results are shown in Table 3 below. Table 3. Results for activity against amylin receptors in cells ID EC50 / nM ID EC50 / nM ID EC50 / nM ID EC50 / nM D1 0.036 M19 0.016 M3 6 0.032 M53 0.017 D4 0.031 M2 0 0.017 M37 0.052 M54 0.017 M5 0.033 M21 0.017 M38 0.022 M55 0.017 M6 0.017 M22 0.017 M39 0.016 M56 0.017 M8 0.017 M2 3 0.010 M4 0 0.002 M57 0.017 M9 0.017 M2 4 0.016 M41 0.069 M58 0.017 M10 0.016 M2 5 0.016 M42 0.016 M59 0.017 Petition 870250089796, on 10 / 02 / 2025, page. 65 / 92 58 / 68 M11 0.017 M2 6 0.079 M43 0.017 M60 0.016 M12 0.017 M2 7 0.016 M44 0.016 M61 0.015 M13 0.017 M2 8 0.017 M4 6 0.119 M62 0.016 M14 0.017 M2 9 0.017 M47 0.082 M63 0.037 M15 0.016 M30 0.017 M4 8 0.063 M64 0.044 M16 0.025 M32 0.030 M4 9 0.075 M65 0.017 M17 0.042 M34 0.058 M50 0.017 M6 6 0.017 M18 0.028 M35 0.037 M52 0.017 M67 0.017

[0225] The data in the table demonstrated that most of the calcitonin analogs or derivatives provided in the present application had strong activity against amylin receptors in cells, and some of the derivatives even had an activity value that was an order of magnitude greater than the calcitonin analogs or derivatives in the prior art. Example 3 Heat-Accelerated Stability Test 3.1 Materials and Devices

[0226] A stability test chamber (BINDER GmbH), a 0.01 mg readability balance (METTLER TOLEDO), a pH meter (METTLER TOLEDO), a biosafety cabinet (ESCO), a small motorized clamping machine T2G- Π (Changsha zhongya pharmaceutical equipment co. LTD), a high-speed refrigerated centrifuge (Eppendorf), a sterilizing cabinet (Shinva Medical), an Agilent 1260 high-performance liquid chromatograph, and a Sepax Bio-C18 4.6*250 mm 3 μm 200 Å reversed-phase column were used. Petition 870250089796, dated 02 / 10 / 2025, pp. 66 / 92 59 / 68

[0227] Reagents and consumables included ultrapure water (18.2 MΩ, own manufacture), acetonitrile (HPLC grade), trifluoroacetic acid (HPLC grade), sodium dihydrogen phosphate (pharmaceutical grade, Hunan Jiudian Hongyang Pharmaceutical Co., Ltd), hydrochloric acid (pharmaceutical grade, Hunan Er-Kang Pharmaceutical Co., Ltd), sodium hydroxide (analytical reagent grade, Hushi®, Sinopharm Chemical Reagent Co., Ltd), bottles, rubber stoppers, disposable syringes and sterile filters. 3.2 Test methods

[0228] The lyophilized powder (1 mg / ml) of calcitonin analogues or derivatives prepared according to the method of Example 1 was mixed with sodium dihydrogen phosphate (1.42 mg / ml) and dissolved in ultrapure water at the indicated mass-volume ratios. After adjusting the pH to approximately 7.4 with hydrochloric acid / sodium hydroxide, the solution was filtered into a sterilized flask on a clean bench using a sterile 0.22 μm filter. The flask was then stoppered and placed in the stability test chamber at 40 °C. Detections were performed on days 7 (7d) and 26 (26d), and during the assay, changes in the characteristics and properties of the polypeptides were observed and recorded. The sample was then centrifuged for 3 min at 10,000 rpm at 4 °C, and the supernatant was transferred to a liquid-phase sample bottle to detect the concentration and purity of the polypeptides using liquid-phase chromatography described below, where the concentration of Petition 870250089796, dated 02 / 10 / 2025, pp. 67 / 92 60 / 68 polypeptide = peak area / injection volume / extinction coefficient / 60 x flow rate, and polypeptide purity = target peak area / total peak area * 100%.

[0229] Reversed-phase chromatography conditions Flow rate: 1.0 ml / min; Autosampler temperature: 15 T; Column temperature: 25 T; Detection wavelengths: 280 nm and 214 nm; Mobile phase A: 100% H2O + 0.05% TFA; Mobile phase B: 100% ACN; and Elution gradient listed in Table 4: Table 4. Listing of the elution gradient in liquid chromatography. Time (min) 0 3 8 13 14 20 % B 25 25 70 70 25 25 3.3 Test results

[0230] The results were shown in Tables 5 and 7 below. A difference of more than 5% in content compared to the initial value was normally considered (e.g., as prescribed by the Chinese Pharmacopeia (2020 Edition)) as a significant change. Within a reasonable margin of error, a decrease of less than 1% from the initial value to the detected content is denoted as “no change” below. Table 5. Changes in characteristics or properties in the accelerated heat stability test. ID 0d 7d ID 0d 7d ID 0d 7d D1 Clear Clear M16 Clear Clear M40 Clear Clear Petition 870250089796, dated 02 / 10 / 2025, pp. 68 / 92 61 / 68 D2 Clear Clear M19 Clear Clear M41 Clear Clear D3 Clear Clear M2 2 Clear Clear M42 Clear Clear M5 Clear Clear M2 4 Clear Clear M43 Clear Clear M7 Clear Clear M2 7 Clear Clear M44 Clear Clear M8 Clear Clear M2 9 Clear Clear M45 Clear Clear M9 Clear Clear M32 Clear Clear M46 Clear Clear M10 Clear Clear M3 4 Clear Clear M47 Clear Clear M11 Clear Clear M3 8 Clear Clear M48 Clear Clear M13 Clear Clear M3 9 Clear Clear

[0231] As shown in Table 5, the calcitonin analogs or derivatives provided in this application did not exhibit any perceptible alteration in characteristics or properties during the accelerated heat stability test under neutral conditions. The solution was still clear on the 7th day of the accelerated test, indicating almost no characteristic or property alteration of the polypeptides. Molecules such as M8, M9, and M13 did not exhibit any significant change in characteristics or properties and remained in a clear solution even on the 26th day of the accelerated test, manifesting considerably stable characteristics and properties. Table 6. Concentration changes in the heat-accelerated stability test. ID Change in concentration (7d-0d) / % ID Change in concentration (7d-0d) / % ID Change in concentration (7d-0d) / % D2 -40.064 M22 No change M41 -3.134 M5 -1.051 M2 4 No change M42 -3.344 M7 No change M2 7 No change M43 No change Petition 870250089796, dated 02 / 10 / 2025, pp. 69 / 92 62 / 68 M8 No change M2 9 No change M44 -2.285 M9 No change M32 No change M45 -2.670 M10 No change M34 -1.618 M4 6 No change M11 No change M4 No change M47 -3.488 M13 No change M38 No change M4 8 -1.678 M16 No change M39 No change M19 No change M4 0 -2.280

[0232] Table 6 showed that there was no obvious change in the concentration of the calcitonin analogs or derivatives provided in the present application during the accelerated heat stability test under neutral conditions. Concentration changes were all below 4% on Day 7 of the accelerated test and were found to be close to 1% (e.g., M5) or even below 1% (denoted as “no change”; e.g., M8 and M13) for some of the calcitonin analogs or derivatives. M8 and M13 had a concentration change of less than 2%, even on Day 26 of the accelerated test, compared to Day 0, exhibiting high concentration stability. Table 7. Changes in purity in the heat-accelerated stability assay (reversed-phase chromatography purity - 214 nm) ID % change: (7d-0d) % change: (26d-0d) ID % change: (7d-0d) % change: (26d-0d) D1 -12.73 / M32 No change / Petition 870250089796, dated 02 / 10 / 2025, pp. 70 / 92 63 / 68 D2 -47.82 / M34 No change / D3 -6.85 -18.00 M4 No change No change M5 No change No change M8 No change -2.21 M7 No change No change M38 No change No change M8 No change No change M39 No change -3.3 M9 No change No change M4 0 -1.67 -4.82 M10 No change / M41 -1.66 -5.98 M11 No change / M42 No change -2.93 M13 No change No change M43 No change -1.96 M16 No change / M44 -1.15 -3.76 M19 No change / M45 No change -1.77 M22 No change / M4 6 No change -5.67 M2 4 No change / M47 No change No change Petition 870250089796, dated 02 / 10 / 2025, pp. 71 / 92 64 / 68 change change change M2 7 No change / M4 8 -1 -3.9 M2 9 No change

[0233] Table 7 revealed that there was no significant change in the purity of the calcitonin analogs or derivatives provided in the present application during the accelerated heat stability test under neutral conditions. On Day 7 of the accelerated test, the purity changes of most polypeptide solutions were less than 1%, as determined by reversed-phase chromatography, or even no decrease in purity was observed; and molecules such as M5, M8, M9, and M13 showed a minor change or even almost no perceptible change in purity on Day 26 of the accelerated test, demonstrating great stability in purity. In contrast to an 18% decrease in purity in molecule D3 in the prior art on Day 26 of the accelerated heat test (see Figure 1), the purity of the calcitonin analog M5 of the present application was decreased by only 0.68% at the same time point (see Figure 2).A comparison of the purity changes of the calcitonin derivative M8 provided in this application and D1 (Cagrilintide, Novo Nordisk) in the accelerated heat assay is shown in Table 8, and the reversed-phase chromatography spectra of the M8 molecule before and after the accelerated heat assay are shown in Figure 3.A. Petition 870250089796, dated 02 / 10 / 2025, pp. 72 / 92 The difference between the M8 and D1 structures was clearly demonstrated by the data in Table 8 and Figure 3, with the former showing excellent stability under neutral conditions. Table 8. Comparison of the results of the liquid phase analysis at 26 days of the accelerated heat assay. ID Molecular Reversed-phase Chromatography Change 7d Change 26d D1 -12.73% / M8 No change -0.12%

[0234] As indicated by the data in this application, the calcitonin analogue and derivative molecules provided herein showed significantly greater stability in the accelerated heat assay than those from the prior art. Example 4 Heat-Accelerated Stability Test for Compatibility Testing

[0235] Calcitonin analogue M8 (1 mg / ml), GLP-1 receptor agonist M51 (1 mg / ml), and sodium dihydrogen phosphate (1.42 mg / ml) were mixed and dissolved in ultrapure water, and 5.5 mg / ml of phenol and 14 mg / ml of 1,2-dihydroxypropane were added to the test group with excipients. After the pH was adjusted to approximately 7.4 with hydrochloric acid / sodium hydroxide, stability assays were performed. Petition 870250089796, dated 02 / 10 / 2025, pp. 73 / 92 66 / 68 accelerated tests were performed according to the method of Example 3. The results were shown in Figure 4 (without excipients) and Figure 5 (with excipients), which demonstrated that M8 was well compatible with M51, showing only a small alteration in the reversed-phase chromatography spectra after a one-month accelerated heat assay under the same formulation conditions as M51. Thus, they had the potential to be developed as a co-formulation. As demonstrated in the results of the accelerated heat assays presented herein, the calcitonin analogs or derivatives provided in this document exhibited remarkably good stability, for example, the M8 molecule, which has excellent thermal stability, both as a single drug and when combined with M51 under the same formulation conditions. Example 5: Study of Weight Change and Food Consumption in Animals

[0236] SD (Sprague Dawley) rats weighing 200-250 g were used for this study. The rats were received at least 10 to 14 days before the start of the study so that they could adapt to the experimental environment. Upon arrival, they were exposed to a reverse light / dark cycle (i.e., lights off during the day and on at night) for two weeks and were housed individually during the first week to ensure high data accuracy and test sensitivity. Throughout the acclimation and experiment period, the rats had free access to food and water. 5 to 8 rats Petition 870250089796, dated 02 / 10 / 2025, pp. 74 / 92 67 / 68 rats were assigned to each test group for the derivatives and received the derivatives subcutaneously at a dose of 10 nmol / kg or a vehicle, and the dosing time point was recorded for each group. After dosing, the rats were placed back in cages where they were housed and had access to food and water. Food consumption and weight change of the rats were recorded online or manually every 24 hours.

[0237] The first and second groups of experimental results were shown in Figures 6 and 7 and Figures 8 and 9 respectively, which suggested that the calcitonin analogues and derivatives of the present application produced an appreciable effect in reducing body weight and food intake in rats.

[0238] Figures 6 and 7 further revealed that the calcitonin analogues of the present application had a superior effect to D1 in terms of weight loss and appetite suppression, among which M18, M9 and M13 were particularly effective.

[0239] Figures 8 and 9 further revealed that the calcitonin analogues and derivatives of the present application, such as M8, M19 and M20, had a prominent effect on both reducing body weight and food intake in rats.

[0240] Although the modalities of the present application have been described above, the present application is not limited to the specific modalities described above, which are merely illustrative. Petition 870250089796, dated 02 / 10 / 2025, pp. 75 / 92 68 / 68 and directory, but not restrictive, and to the fields of application. Without departing from the scope of the claims of the present invention, many variants may occur for those of common skill in the art with inspiration from this descriptive report. Petition 870250089796, dated 02 / 10 / 2025, pp. 76 / 92

Claims

1 / 5 CLAIMS 1. A CALCITONIN DERIVATIVE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, characterized by comprising a polypeptide with an amino acid sequence of X0 X1SX3LS TX7VLG RLSX14E LHRLX20 X21X22PRT X26X27GX29X30 S X32NH2, where: X0 is D or E, or is absent; X1 is A, L, V, I, S, E, R or K; X3 is Q, E or D; X7 is A, L, V, I, S, R, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; X29 is S or A; X30 is G or E; and X32 is P or trans-Hyp.

2. DERIVATIVE, according to claim 1, characterized in that a combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE, RD, KE, KD or EE; and a combination of X29-X30 is selected from SE, SG, AG or AE.

3. DERIVATIVE, according to either of the claims 1 or 2, characterized by X3 being Q.

4. DERIVATIVE, according to any one of claims 1 to 3, characterized by X14 being Q, Dou E.

5. DERIVATIVE, according to any one of claims 1 to 4, characterized by X20 being Q.

6. DERIVATIVE, according to any one of claims 1 to 5, characterized by X21 being D.

7. A derivative, according to any one of claims 1 to 6, characterized in that X22 is Y or L.

8. DERIVATIVE, according to any one of claims 1 to 7, characterized in that a combination of X26 and X27 is selected from DV, QS, QV and DS.

9. DERIVATIVE, according to any one of claims 1 to 8, characterized in that the combination of X29-X30 is SG.

10. DERIVATIVE, according to any one of claims 1 to 9, characterized in that X32 is P.

11. DERIVATIVE, according to any one of claims 1 to 4, characterized by comprising a polypeptide with an amino acid sequence of ASQLS TAVLG RLSX14E LHRLX20 DX22PRT DVGX29G SP-NH2, wherein, X14 is Q, D or E; X20 is Q or E, preferably Q; X22 is Y or L; and X29 is S or A.

12. DERIVATIVE, according to claim 11, Petition 870250099872, dated 10 / 31 / 2025, p. 9 / 19 3 / 5 characterized by comprising a polypeptide with an amino acid sequence of ASQLS TAVLG RLSX14E LHRLQ DX22PRT DVGSG SP-NH2, wherein, X14 is Q, D or E, preferably Q or D; and X22 is Y or L.

13. DERIVATIVE, according to claim 1, characterized in that the amino acid sequence is selected from any of the following: SEQ ID NO. 1-SEQ ID NO.

38.

14. DERIVATIVE, according to any one of claims 1 to 8 or 10 to 13, characterized in that the polypeptide sequence is any one of: ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2, ASQLS TAVLG RLSQE LHRLQ DLPRT DVGSG SP-NH2, ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2, ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAG SP-NH2, ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAE SP-NH2, or ASQLS TAVLG RLSQE LHRLE DYPRT DVGSG SP-NH2.

15. DERIVATIVE, according to any one of claims 1 to 14, characterized in that the derivative comprises a fatty acid-containing side chain attached to the N-terminus of the polypeptide.

16. DERIVATIVE, according to claim 15, characterized in that the fatty acid-containing side chain is in the form of Z1+Z2+Z3, where Z1 is a C16-C22 fatty acid diacid; Z2 is selected from any of yGlu, aGlu, pAsp, aAsp, Inp and Trx, or is absent; Petition 870250099872, dated 10 / 31 / 2025, p. 10 / 19 4 / 5 Z3 is n AEEA(s), where n > 0; and Z1, Z2 and Z3 are connected via amide linkages.

17. DERIVATIVE, according to claim 16, characterized in that Z1 is a C20 fatty acid diacid.

18. DERIVATIVE, according to any one of claims 16 or 17, characterized in that Z2 is yGlu.

19. DERIVATIVE, according to any one of claims 16 to 18, characterized in that n is selected from 0, 1, 2, 3, 4, 5 or 6.

20. POLYPEPTIDE, characterized by comprising an amino acid sequence of the derivative, as defined in any one of claims 1 to 14.

21. PHARMACEUTICAL COMPOSITION, characterized by comprising the derivative, as defined in any one of claims 1 to 19, and a pharmaceutically acceptable excipient.

22. PHARMACEUTICAL COMPOSITION, characterized by comprising the polypeptide, as defined in claim 20, and a pharmaceutically acceptable excipient.

23. USE OF CALCITONIN DERIVATIVE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, as defined in any one of claims 1 to 19, characterized by being intended for the manufacture of a medicament to prevent and / or treat overweight and / or obesity and / or type I or type II diabetes and / or osteoporosis and / or neuropathic pain.

24. USE OF CALCITONIN DERIVATIVE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, as defined in any of claims 1 to 19, characterized by being intended for the manufacture of a medicament for reducing food intake. Petition 870250099872, dated 10 / 31 / 2025, page 11 / 19 5 / 5 25. USE OF THE POLYPEPTIDE, as defined in claim 20, characterized by being intended for the manufacture of a medicament to prevent and / or treat overweight and / or obesity and / or type I or type II diabetes and / or osteoporosis and / or neuropathic pain.

26. USE OF THE POLYPEPTIDE, as defined in claim 20, characterized by being intended for the manufacture of a medicine for reducing food intake. Petition 870250099872, dated 10 / 31 / 2025, page 12 / 19

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