Calcitonin analogs and their derivatives, and their use

Abstract

Calcitonin analogs and their derivatives or pharmaceutically acceptable salts. Pharmaceutical compositions containing an analog or its derivative or pharmaceutically acceptable salt, and further comprising a pharmaceutically acceptable excipient. Use of analogs or its derivative or pharmaceutically acceptable salts and compositions in the field of disease prevention / treatment.

Description

[Technical Field]

[0001] Technical field This application relates to the technical field of polypeptides, specifically calcitonin analogs and derivatives, and their uses. [Background technology]

[0002] background Amylin is a polypeptide hormone consisting of 37 amino acids, secreted by pancreatic islet β-cells along with insulin, and is deficient in diabetic patients. This substance functions in several different organ systems, primarily through amylin receptors 1-3 (AMYR1-3). Amylin can inhibit glucagon secretion, slow gastric emptying, signal satiety, and suppress appetite. Clinical studies have shown that amylin receptor agonists may be used to treat overweight, obesity, type 1 diabetes, and / or type 2 diabetes. An amylin analog known as pramulintide (trade name Simulin) can lower blood glucose levels and may be used to treat patients with diabetes who are taking insulin. However, pramulintide has a half-life of less than one hour and is administered with meals, so patients need to take this drug several times a day for treatment. Pramulintide is unstable, prone to fibrillation at neutral pH, and precipitates, rendering it ineffective, so it is supplied in an acidic solution.

[0003] Calcitonin is a hormone produced by the thyroid gland that regulates the concentration of calcium and phosphate in the blood. Calcitonin receptors are present in many tissues throughout the body and are involved in regulating bone remodeling. Salmon calcitonin, currently marketed under the name Miacalsic, is useful in treating conditions such as hypercalcemia and osteoporosis. Calcitonin is also unstable at neutral pH and is therefore supplied in acidic solutions. Salmon calcitonin has a half-life of less than 2 hours and needs to be administered to patients at least once a day. Currently marketed calcitonin drugs are salmon calcitonin and elcatonin (calcitonin from eels), but due to their low molecular weight, they require daily administration by injection. Furthermore, their desirable stability is only observed under acidic conditions, and they are unstable under neutral conditions, which poses a significant obstacle to the pharmaceutical use and formulation development of these molecules.

[0004] Because natural amyrin and calcitonin receptor agonists have short half-lives, extending their half-lives is a development goal for such drugs. Furthermore, since amyrin and calcitonin receptor agonists have low stability at neutral pH and a strong tendency to fibrillate, improving their stability at physiological pH is another development goal. [Overview of the project] [Problems that the invention aims to solve]

[0005] Summary of the Invention Therefore, this application relates to modifying an agonist polypeptide for the amyrin receptor in order to obtain an analogue or derivative thereof or a pharmaceutically acceptable salt thereof with improved in vivo efficacy and increased stability. [Means for solving the problem]

[0006] Specifically, this application provides the following technical solutions: X0X1SX3LS TX7VLG RLSX 14 E LHRLX 20 X 21 X22 PRT X 26 X 27 GX 29 X 30 S X 32 [[ID=II]]-NH2 (wherein X0 is D or E, or does not exist, 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, X 14 is Q, D, E, Aib, S or T, X 20 is Q or E, X 21 is D or E, X 22 is Y, L or F, X 26 is D or Q, X 27 is V or S, X 29 is S or A, X 30 is G or E, and X 32 is P or trans-Hyp) A derivative of calcitonin or a pharmaceutically acceptable salt thereof, comprising a polypeptide having the amino acid sequence of relates to.

[0007] In a preferred embodiment, the derivative of calcitonin or a pharmaceutically acceptable salt thereof has the following amino acid sequence: X0X1SX3LS TX7VLG RLSX 14 E LHRLX 20 X 21 X 22 PRT X 26 X 27 GX 29 X 30 S X 32 -NH2 (wherein X0 is D or E, or does not exist, The combination of X1 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. X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, X 21 It is either D or E, X 22 is Y, L, or F, X 26 is either D or Q, X 27 is either V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, and X 32 (This is P or trans-Hyp) Contains polypeptides having

[0008] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0010] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is VV, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0011] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is II, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X21 is D or E, X 22 is Y, L or F, X 26 is D or Q, X 27 is V or S, X 29 -X 30 The combination of is selected from S-G, A-G, A-E or S-E, X 32 is P or trans Hyp.

[0013] In a preferred embodiment, X0 does not exist, the combination of X1 and X7 is A-S, X3 is Q, E or D, X 14 is Q, D, E, Aib, S or T, X 20 is Q or E, X 21 is D or E, X 22 is Y, L or F, X 26 is D or Q, X 27 is V or S, X 29 -X 30 The combination of is selected from S-G, A-G, A-E or S-E, X 32 is P or trans Hyp.

[0014] In a preferred embodiment, X0 does not exist, the combination of X1 and X7 is S-A, X3 is Q, E or D, X 14 is Q, D, E, Aib, S or T, X 20 is Q or E, X 21 is D or E, X 22 is Y, L or F, X 26 is D or Q, X 27 is V or S, X 29 -X 30 The combination of is selected from S-G, A-G, A-E or S-E, X 32 is P or trans Hyp.

[0015] In a preferred embodiment, X0 does not exist, the combination of X1 and X7 is E-R, X3 is Q, E or D, X 14 is Q, D, E, Aib, S or T, X20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0016] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RE, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0021] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, X3 is Q, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0022] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is LL, X3 is Q, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0023] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is VV, X3 is Q, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0024] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is II, X3 is Q, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0025] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SS, X3 is Q, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0026] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AS, X3 is Q, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0027] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SA, X3 is Q, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0028] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is ER, X3 is Q, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0029] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RE, X3 is Q, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0030] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RD, X3 is Q, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0031] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KE, X3 is Q, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0032] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KD, X3 is Q, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0033] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is EE, X3 is Q, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X3 is D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0035] 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, and X3 is E, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0036] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, X3 is Q, E, or D, and X 14 is Q, D, or E, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, or E, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, or E, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, or E, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, or E, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0041] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AS, X3 is Q, E or D, and X 14 is Q, D, or E, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, or E, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, or E, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, or E, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0045] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RD, X3 is Q, E, or D, and X 14 is Q, D, or E, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0046] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KE, X3 is Q, E or D, and X 14 is Q, D, or E, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, or E, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, or E, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X3 is Q, E, or D, X 14 Q is X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0050] 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, and X3 is Q, E, or D, X14 D is X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0051] 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, and X3 is Q, E, or D, X 14 E is X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X3 is Q, E, or D, X 14 Aib and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X32 This 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, and X3 is Q, E, or D, X 14 S is X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0054] 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, and X3 is Q, E, or D, X 14 is T, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0055] 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, and X3 is Q, E, or D, X14 is Q, D, E, Aib, S, or T, X 20 E is X 21 is D or E, and X 22 is Y, L, or F, and X 29 -X 30 The combination 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, and X 14 is Q, D, E, Aib, S, or T, X 20 Q is X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 Q is X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 Q is X 21is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0059] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is II, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 Q is X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 Q is X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 Q is X21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 Q is X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 Q is X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0064] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RE, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S, or T, X 20Q is X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0065] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RD, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 Q is X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 Q is X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X20 Q is X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 Q is X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0069] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 E is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0070] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is LL, X3 is Q, E, or D, and X 14is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 E is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0071] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is VV, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 E is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0072] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is II, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 E is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0073] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SS, X3 is Q, E or D, and X14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 E is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0074] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AS, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 E is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0075] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SA, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 E is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 E is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 E is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 E is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 E is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0080] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KD, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 E is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 E is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 D is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 D is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 D is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0085] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is II, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 D is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 D is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 D is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 D is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 D is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0090] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RE, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 D is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 D is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 D is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 D is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 D is X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0095] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 Y is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0096] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is LL, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 Y is X 26 is D or Q, and X 27 is V or S, X 29 -X30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0097] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is VV, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 Y is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 Y is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 Y is X 26 is D or Q, and X 27 is V or S, X 29-X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 Y is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0101] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SA, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 Y is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0102] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is ER, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 Y is X 26 is D or Q, and X 27 is V or S, X29 -X 30 The combination of is selected from S-G, A-G, A-E or S-E, and X 32 is P or trans Hyp.

[0103] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is R-E, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S or T, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, and X 26 is D or Q, and X 27 is V or S, and X 29 -X 30 The combination of is selected from S-G, A-G, A-E or S-E, and X 32 is P or trans Hyp.

[0104] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is R-D, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S or T, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, and X 26 is D or Q, and X 27 is V or S, and X 29 -X 30 The combination of is selected from S-G, A-G, A-E or S-E, and X 32 is P or trans Hyp.

[0105] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is K-E, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S or T, and X 20 is Q or E, and X 21 is D or E, and X 22 is Y, and X 26 is D or Q, and X 27is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0106] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is KD, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 Y is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 Y is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 L is X 26 is D or Q, and X27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 L is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 L is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0111] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is II, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 L is X 26is D or Q, X 27 is V or S, X 29 -X 30 The combination of is selected from S-G, A-G, A-E or S-E, X 32 is P or trans Hyp.

[0112] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is S-S, X3 is Q, E or D, X 14 is Q, D, E, Aib, S or T, X 20 is Q or E, X 21 is D or E, X 22 is L, X 26 is D or Q, X 27 is V or S, X 29 -X 30 The combination of is selected from S-G, A-G, A-E or S-E, X 32 is P or trans Hyp.

[0113] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is A-S, X3 is Q, E or D, X 14 is Q, D, E, Aib, S or T, X 20 is Q or E, X 21 is D or E, X 22 is L, X 26 is D or Q, X 27 is V or S, X 29 -X 30 The combination of is selected from S-G, A-G, A-E or S-E, X 32 is P or trans Hyp.

[0114] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is S-A, X3 is Q, E or D, X 14 is Q, D, E, Aib, S or T, X 20 is Q or E, X 21 is D or E, X 22 is L, X26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 L is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0116] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RE, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 L is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22L is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 L is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 L is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X22 L is X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0121] 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, and X3 is Q or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0122] 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, and X3 is Q or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 -X 27 The combination is DV, and X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[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, and X3 is Q or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 -X 27 The combination is QS, and X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[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, and X3 is Q or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 -X 27 The combination is QV, and X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0125] 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, and X3 is Q or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 -X 27 The combination is DS, X29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0126] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is AA, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 SG is X 32 This is P or trans-Hyp.

[0127] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is LL, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 SG is X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30SG is X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 SG is X 32 This is P or trans-Hyp.

[0130] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is SS, X3 is Q, E or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 SG is X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 SG is X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 SG is X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 SG is X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 SG is X 32 This is P or trans-Hyp.

[0135] In a preferred embodiment, X0 is absent, the combination of X1 and X7 is RD, X3 is Q, E, or D, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 SG is X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 SG is X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 SG is X 32 This 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, and X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 SG is X 32 This 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, and X3 is Q or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 AG and X 32 This is P or trans-Hyp.

[0140] 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, and X3 is Q or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 is AE, X 32 This 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, and X3 is Q or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 is SE, X 32 This 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, and X3 is Q or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 P 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, and X3 is Q or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is a trans-Hyp.

[0144] In a preferred embodiment, X0 is D, the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE, or EE, and X3 is Q or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0145] In a preferred embodiment, X0 is E, the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, ER, RE, or EE, and X3 is Q or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y, L, or F, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0146] In a preferred embodiment, X0 is either 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, and X3 is Q, E, or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y or L, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0147] In a preferred embodiment, X0 is either 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, and X3 is Q, E, or D, X 14 is Q, D, E, Aib, S, or T, X 20 -X 21 The combination is EE, and X 22 is Y or L, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0148] In a preferred embodiment, X0 is either 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, and X3 is Q, E, or D, X 14 -X 22 The combination is DL, and X 20 is Q or E, and X 21 is D or E, and X26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0149] In a preferred embodiment, X0 is either 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, and X3 is Q, E, or D, X 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y or L, and X 26 -X 27 QS and X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0150] In a preferred embodiment, X0 is either D or E, or absent, and the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, RE, RD, KE, or KD, and X3-X 14 -X 20 EEE and X 21 is D or E, and X 22 is Y or L, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0151] In a preferred embodiment, X0 is either D or E, or is absent, the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, or RE, and X3 is Q, E, or D. 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y or L, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0152] In a preferred embodiment, X0 is either D or E, or is absent, the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, or RE, and X3 is Q, E, or D. 14 is Q, D, E, Aib, S, or T, X 20 -X 21 is EE, and X 22 is Y or L, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0153] In a preferred embodiment, X0 is either D or E, or is absent, the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, or RE, and X3 is Q, E, or D. 14 -X 22 DL is X 20 is Q or E, and X 21 is D or E, and X 26 is D or Q, and X 27 is V or S, X29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0154] In a preferred embodiment, X0 is either D or E, or is absent, the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, or RE, and X3 is Q, E, or D. 14 is Q, D, E, Aib, S, or T, X 20 is Q or E, and X 21 is D or E, and X 22 is Y or L, and X 26- X 27 QS and X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0155] In a preferred embodiment, X0 is either D or E, or absent, and the combination of X1 and X7 is selected from AA, LL, VV, II, SS, AS, SA, or RE, and X3-X 14 -X 20 EEE and X 21 is D or E, and X 22 is Y or L, and X 26 is D or Q, and X 27 is V or S, X 29 -X 30 The combination is selected from SG, AG, AE, or SE, X 32 This is P or trans-Hyp.

[0156] In preferred embodiments, the derivative or a pharmaceutically acceptable salt thereof is ASQLS TAVLG RLSX 14 E LHRLX 20 DX 22 PRT DVGX 29 G SP-NH2 (In the formula, X 14 is Q, D, or E, X 20 is Q or E, preferably Q. X 22 is Y or L, and X 29 (is S or A) It contains a polypeptide having the amino acid sequence.

[0157] In preferred embodiments, the derivative or a pharmaceutically acceptable salt thereof is ASQLS TAVLG RLSX 14 E LHRLQ DX 22 PRT DVGSG SP-NH2 (In the formula, X 14 is Q, D, or E, preferably Q or D, and X 22 (This is either Y or L) It contains a polypeptide having the amino acid sequence.

[0158] In preferred embodiments, a derivative of calcitonin or a pharmaceutically acceptable salt thereof comprises an amino acid sequence selected from any one of SEQ ID NOs: 1 to 38 in Table 2.

[0159] In preferred embodiments, a derivative of calcitonin or a pharmaceutically acceptable salt thereof comprises an amino acid sequence selected from any one of the following: ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 (Sequence ID 7), ASQLS TAVLG RLSQE LHRLQ DLPRT DVGSG SP-NH2 (Sequence ID 17), ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 (Sequence ID 8), ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAG SP-NH2 (Sequence ID 18), ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAE SP-NH2 (Sequence ID 19), or ASQLS TAVLG RLSQE LHRLE DYPRT DVGSG SP-NH2 (Sequence ID 12).

[0160] In preferred embodiments, a derivative of calcitonin or a pharmaceutically acceptable salt thereof includes a side chain for modifying the amino acid, preferably a fatty acid-containing side chain.

[0161] In preferred embodiments, a derivative of calcitonin or a pharmaceutically acceptable salt thereof includes a fatty acid-containing side chain attached to the N-terminus of the amino acid sequence.

[0162] In a preferred embodiment, the fatty acid-containing side chain is in the form of Z1+Z2+Z3, where Z1 is a C16-C22 fatty diacid. Z2 is selected from one of γGlu, αGlu, βAsp, αAsp, Inp, and Trx, or is absent, and Z3 is nAEEA, and n≧0.

[0163] Z1, Z2, and Z3 are linked via amide bonds.

[0164] In a preferred embodiment, n is selected from 0, 1, 2, 3, 4, 5, or 6.

[0165] In a preferred embodiment, n is 6.

[0166] In a preferred embodiment, n is 4.

[0167] In a preferred embodiment, n is 2.

[0168] In a preferred embodiment, n is 0.

[0169] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + γGlu.

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

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

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

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

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

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

[0176] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty acid) + γGlu + 2 AEEA.

[0177] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty acid) + γGlu + 4 AEEA.

[0178] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty acid) + γGlu + 6 AEEA.

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

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

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

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

[0183] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty acid) + Trx + 2 AEEA.

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

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

[0186] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid diacid) + βAsp.

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

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

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

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

[0191] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid) + γGlu + 2 AEEA.

[0192] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid) + γGlu + 4 AEEA.

[0193] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid) + γGlu + 6 AEEA.

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

[0195] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid) + βAsp + 2 AEEA.

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

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

[0198] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty acid) + Trx + 2 AEEA.

[0199] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C22 fatty acid) + γGlu + 2 AEEA.

[0200] In a preferred embodiment, the fatty acid-containing side chain is in the form of (C22 fatty acid) + γGlu + 4 AEEA.

[0201] This application also provides polypeptide analogs, which are polypeptides containing any one of the amino acid sequences of the above derivatives.

[0202] This application also provides pharmaceutical compositions comprising one or more analogs, derivatives, or pharmaceutically acceptable salts thereof described herein. Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients, such as non-toxic fillers, stabilizers, diluents, carriers, solvents, etc.

[0203] This application also provides the use of the above analogues or derivatives or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prevention and / or treatment of overweight, and / or obesity, and / or type 1 or type 2 diabetes, and / or osteoporosis, and / or neuropathic pain.

[0204] This application also provides the use of the above analogues or derivatives or pharmaceutically acceptable salts thereof in the manufacture of, for example, healthcare products, foods or pharmaceuticals for reducing food intake and / or body weight.

[0205] This application 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 a preventive or therapeutically effective amount of an analog, derivative, or pharmaceutically acceptable salt thereof or pharmaceutical composition described herein to the subject.

[0206] This application also provides a method for reducing food intake, comprising administering an effective amount of an analog, derivative thereof, or a pharmaceutically acceptable salt or pharmaceutical composition described herein to the subject.

[0207] Brief explanation of the drawing The drawings are intended to provide a better understanding of this application, rather than to impose an excessive limitation. [Brief explanation of the drawing]

[0208] [Figure 1] This is a reverse-phase chromatography spectral diagram of molecule D3 (Mimylin) on day 26 of a thermally accelerated assay. [Figure 2] This is a reverse-phase chromatography spectral diagram of calcitonin analog M5 on day 26 of a thermally accelerated assay. [Figure 3] This is a spectral diagram of reverse-phase chromatography of molecule M8 alone on day 26 of a thermally accelerated assay under neutral conditions. [Figure 4]This is a spectral diagram of reverse-phase chromatography obtained one month after a thermally accelerated assay of M8 and M51 in neutral buffer without excipients. [Figure 5] This is a spectral diagram of reverse-phase chromatography obtained one month after a thermally accelerated assay of M8 and M51 in a neutral buffer containing excipients. [Figure 6] This is a trend chart showing the effect of the first group of calcitonin analogs or derivatives on the body weight change of rats in an experiment. [Figure 7] This is a trend chart showing the effect of the first group of calcitonin analogs or derivatives on the cumulative food intake of rats in an experiment. [Figure 8] This is a trend chart showing the effect of a second group of calcitonin analogs or derivatives on body weight change in rats in an experiment. [Figure 9] This is a trend chart showing the effect of a second group of calcitonin analogs or derivatives on the cumulative food intake of rats in an experiment. [Modes for carrying out the invention]

[0209] Detailed explanation As used herein, “analog” means a compound formed from a particular polypeptide molecule in which at least one amino acid residue is substituted with another amino acid residue, and / or at least one amino acid residue is deleted, and / or at least one amino acid residue is added to the N-terminus or C-terminus, and / or at least one amino acid residue is inserted between any two amino acids.

[0210] The terms “polypeptide” and “analogous,” and their corresponding forms as used in a composition, have the same meaning and are interchangeable in this application unless otherwise specified in the context. In some cases, the terms “calcitonin” and “calcitonin analog” have the same meaning and are interchangeable, for example, “derivative of calcitonin analog” and “derivative of calcitonin.”

[0211] As used herein, "derivative" refers to a product resulting from the modification of a functional group (e.g., an amino acid residue) of a biomolecule (e.g., a polypeptide or protein) with a specific group or structure (e.g., a specific small molecule structure). Examples of modifications include, but are not limited to, acylation, amidation, esterification, and thioesterification.

[0212] Abbreviation The corresponding names or structures of some of the abbreviations used in the embodiments of this application are as follows:

[0213] [Table 1]

[0214] Exemplary embodiments of this application are described below, but various details of the embodiments in this application are included for the sake of clarity and should be interpreted as illustrative only. Accordingly, it will be understood by those skilled in the art that many variations and modifications can be made to the embodiments described herein without departing from the scope and spirit of this application. For clarity and conciseness, descriptions of well-known functions and structures are also omitted in the following description. [Examples]

[0215] Examples Example 1 Preparation of polypeptide derivatives Polypeptides were synthesized by solid-phase organic synthesis, specifically by solid-phase peptide synthesis (SPPS) using Fmoc-protected amino acids, followed by cleavage, oxidation, and purification to obtain the target product. Taking the compound caglirintide (referred to as "D1") as an example, the synthesis process is as follows.

[0216] 1.1 Solid phase synthesis Using Fmoc-linker MBHA resin S=0.32 mmol / g and employing Fmoc / tBu treatment, amino acids were sequentially condensed from the C-terminus to the N-terminus (right to left) according to the peptide sequence, as shown in Table 1.

[0217] [Table 2]

[0218] The following amino acids were coupled in order: A-01 Fmoc-Pro-OH, A-02 Fmoc-Thr(tBu)-OH, A-03 Fmoc-Asn(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, A-09 Fmoc-Pro-OH, A-10 Fmoc-Pro-OH, A-11 Fmoc-Leu-OH, A-12 Fmoc-Ile-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 Fmoc-Ser(tBu)-OH, A-19 Fmoc-Ser(tBu)-OH, A-20 Fmoc-His(Trt)-OH, A-21 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 Fmoc-Thr(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 and A-39 C20 diacid.

[0219] Finally, polypeptide derivatives were formed on the resin.

[0220] The polypeptide derivatives on the resin were washed, removed, and dried to a certain weight for cutting.

[0221] 1.2 Cutting Formula of the cleavage reagent: The cleavage reagent was TFA:H2O:EDT:TIS = 95:1:2:2, and the amount used was 10 mL ± 2 mL per gram of peptide-on resin. The H2O, TFA, EDT, and TIS components of the required cleavage reagent were added sequentially to the cleavage reaction flask, and the temperature was controlled to 0-10°C. The cleavage reagent was added to the resin under stirring, and after the system temperature stabilized, it was stirred for a further 2.5 hours at a controlled temperature of 25-30°C. The cleavage solution was filtered and precipitated using 5 times the volume of liquid ice diethyl ether. The precipitate was filtered, washed three times with 3 times the volume of liquid ice diethyl ether, and then dried under reduced pressure at room temperature to obtain the crude solid product.

[0222] 1.3 Oxidation The crude product was finely ground and slowly added to purified water while stirring, dropwise adding an aqueous acetonitrile solution. After the crude product was added and completely dissolved, a methanol solution of iodine was added and the mixture was stirred for 30 minutes.

[0223] 1.4 Purification and freeze-drying The oxidizing solution described above was filtered through a 0.45 μm microporous filtration membrane. The crude product was separated and purified at room temperature using a column prepared with a C-18 column packing material having a suitable gradient, and then the target product was recovered, detected, analyzed, and sorted. A purity of 90% or higher was required. The off-specification target product was recovered, separated and purified again with a suitable gradient, and a suitable liquid peak was obtained. The above suitable liquid samples were freeze-dried under reduced pressure to obtain a freeze-dried powder of the purified polypeptide.

[0224] Table 2 shows polypeptides and derivatives prepared using a method similar to that described in Example 1 of this application. D2 represents the sequence of natural salmon calcitonin, D1 and D3 represent the sequences of modified calcitonin in the prior art, and the remainder are calcitonin analogs or derivatives provided in this application, wherein the fatty acid moiety of the polypeptide derivative is located outside the fatty acid-containing side chain for modification of the amino acid sequence and is therefore located at the distal end of the binding of the side chain to the amino acid sequence.

[0225] [Table 3]

[0226] [Table 4]

[0227] [Table 5]

[0228] [Table 6]

[0229] Example 2 Activity test of derivatives in cells The purpose of this assay is to test the activity or potency of calcitonin analogs or derivatives against the human amyrin receptor in vitro using a luciferase assay.

[0230] 2.1 Construction of an amyrin receptor / CRE-luc cell line Using a standard protocol, CHO-K1 / 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 with multiple copies of the cAMP response element (CRE). The cells were cultured in F12 medium containing 200 ug / mL zeosin, 2 ug / mL puromycin, 100 ug / mL hygromycin, and 400 ug / mL G418 to obtain a stably transfected amyrin receptor / CRE-luc cell line.

[0231] 2.2 Amylin Luciferase Assay The lyophilized powder obtained according to the method of Example 1 was dissolved in 20 mM phosphate buffer at pH 7.0 and diluted with growth medium (F12 culture medium containing 10% FBS) to obtain a derivative sample with an initial concentration of 10 nM. This sample was then subjected to 5-fold serial dilution with growth medium to obtain seven samples at concentrations including 10 nM, 2 nM, and 0.4 nM. 50 μL of the tested sample solution at each concentration was added to each well of a white 96-well plate.

[0232] Stable transfected amyrin receptor / CRE-luc CHO cells were resuspended in growth medium at a constant density, and 50 μL of the cell suspension was added to a white 96-well plate containing the test sample solution at a density of approximately 20,000 cells per well. After incubation at 37°C and 5% CO2 for 24 hours, 100 μL of luciferase substrate was added to each well and incubated for 3 minutes. Finally, luminescence was tested using SpectraMax L (Molecular Devices) with SoftMax Pro 7.0.3 GxP software. A standard curve was plotted using fluorescence intensity to calculate EC50. The results are shown in Table 3 below.

[0233] [Table 7]

[0234] The data in the table shows that most of the calcitonin analogs or derivatives provided in this application have strong activity against intracellular amyrin receptors, and that some derivatives have activity values ​​an order of magnitude higher than those of prior art calcitonin analogs or derivatives.

[0235] Example 3: Thermally Accelerated Stability Assay 3.1 Materials and Devices A stability testing chamber (BINDER GmbH), a 0.01 mg reading balance (METTLER TOLEDO), a pH meter (METTLER TOLEDO), a biosafety cabinet (ESCO), a T2G-II small motor-driven capping machine (Changsha zhongya pharmaceutical equipment co. LTD), a high-speed refrigerated centrifuge (Eppendorf), a sterilization 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.

[0236] Reagents and consumables include ultrapure water (18.2 MΩ, automated), 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.), vials, rubber stoppers, disposable syringes, and sterile filters.

[0237] 3.2 Assay Method Lyophilized powder (1 mg / mL) of a calcitonin analog or derivative prepared according to the method of Example 1 was mixed with sodium dihydrogen phosphate (1.42 mg / mL) and dissolved in ultrapure water in the indicated mass-to-volume ratio. After adjusting the pH to approximately 7.4 with hydrochloric acid / sodium hydroxide, the solution was filtered into a sterile vial in a clean bench using a 0.22 μm sterile filter. The vial was then capped and placed in a stability test chamber at 40°C. Detection was performed on day 7 (7d) and day 26 (26d), and changes in the characteristics and properties of the polypeptide were observed and recorded during the assay. The mixture was then centrifuged at 10000 rpm at 4°C for 3 minutes, and the supernatant was transferred to a liquid-phase sample vial. The polypeptide concentration and purity were detected using the following liquid-phase chromatography (where polypeptide concentration = peak area / injection volume / extinction coefficient / 60 × flow rate, polypeptide purity = target peak area / total peak area × 100%).

[0238] The conditions for reversed-phase chromatography were: flow rate: 1.0 ml / min, autosampler temperature: 15°C, column temperature: 25°C, detection wavelengths: 280 nm and 214 nm, mobile phase A: 100% H2O + 0.05% TFA, mobile phase B: 100% ACN. The elution gradient is shown in Table 4.

[0239] [Table 8]

[0240] 3.3 Assay Results The results are shown in Tables 5, 6, and 7. A difference of 5% or more in content compared to the initial value was generally assumed to be a significant change (for example, as defined in the Chinese Pharmacopoeia (2020 edition)). Within a reasonable margin of error, a decrease of less than 1% from the initial value to the detected content is indicated below as "no change".

[0241] [Table 9]

[0242] As shown in Table 5, the calcitonin analogs or derivatives provided in this application showed no significant changes in properties or characteristics in a thermally accelerated stability assay under neutral conditions. On day 7 of the accelerated test, the solution remained clear, indicating little to no characteristic or property changes in the polypeptide. Molecules such as M8, M9, and M13 showed no significant changes in properties or characteristics, and remained in a clear solution even on day 26 of the accelerated test, demonstrating fairly stable properties and characteristics.

[0243] [Table 10]

[0244] Table 6 shows that there was no significant change in the concentration of the calcitonin analogs or derivatives provided in this application during thermally accelerated stability assays under neutral conditions. The concentration change was less than 4% for all on day 7 of the accelerated test, and for some calcitonin analogs or derivatives, it was close to 1% (e.g., M5) or even less than 1% (indicated as "no change," e.g., M8 and M13). M8 and M13 showed high concentration stability, with a concentration change of less than 2% on day 26 of the accelerated test compared to day 0.

[0245] [Table 11]

[0246] Table 7 shows that there was no significant change in the purity of the calcitonin analogs or derivatives provided in this application during the thermally accelerated stability assay under neutral conditions. On day 7 of the accelerated test, the purity change of most polypeptide solutions was less than 1% as determined by reverse-phase chromatography, or no decrease in purity was observed at all. Molecules such as M5, M8, M9, and M13 were further found to have less change in purity or even less significant change on day 26 of the accelerated test, demonstrating high purity stability. In contrast to the 18% purity decrease of molecule D3 in the prior art on day 26 of the thermally accelerated assay (see Figure 1), the purity of the calcitonin analog M5 of this application decreased by only 0.68% at the same point (see Figure 2). A comparison of the purity changes of the calcitonin derivative M8 provided in this application and D1 (caglirintide, Novo Nordisk) in the thermally accelerated assay is shown in Table 8, and the reverse-phase chromatography spectra of molecule M8 before and after the thermally accelerated assay are shown in Figure 3. The differences in the backbones of M8 and D1 are evident from the data in Table 8 and Figure 3, with the former exhibiting superior stability under neutral conditions.

[0247] [Table 12]

[0248] As demonstrated by the data in this application, the calcitonin analogs and derivatives provided herein exhibited significantly higher stability in thermo-enhanced assays compared to those of the prior art.

[0249] Example 4 Thermally accelerated stability assay for suitability testing Calcitonin analog 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. 5.5 mg / ml of phenol and 14 mg / ml of 1,2-dihydroxypropane were further added to the test group containing the excipients. After adjusting the pH to approximately 7.4 with hydrochloric acid / sodium hydroxide, an accelerated stability assay was performed according to the method of Example 3. The results are shown in Figure 4 (without excipients) and Figure 5 (with excipients). M8 was well miscible with M51 and showed only slight changes in the reverse-phase chromatography spectrum after a 1-month thermal accelerated assay under the same formulation conditions as M51. Therefore, they had the potential to be developed as co-formulations. As shown in the results of this thermal accelerated assay, the calcitonin analogs or derivatives provided herein exhibit remarkably good stability, for example, molecule M8, which has excellent thermal stability both as a single drug and in combination with M51 under the same formulation conditions.

[0250] Example 5: Tests on body weight changes and food consumption in animals This study used Sprague Dolly (SD) rats weighing 200–250 g. Rats were received at least 10–14 days prior to the start of the experiment to allow for adaptation to the experimental environment. Upon arrival, rats were exposed to a reverse light-dark cycle (lights off during the day, lights on at night) for two weeks, and individually housed for the first week to improve data accuracy and test sensitivity. Throughout the acclimatization and experimental periods, rats had free access to food and water. Five–eight rats were assigned to each derivative test group, and a dose of 10 nmol / kg of the derivative or vehicle was administered subcutaneously, with the administration time recorded for each group. After administration, rats were returned to cages and provided with access to food and water. Rats' food intake and body weight changes were recorded online or manually every 24 hours.

[0251] The experimental results for Group 1 and Group 2 are shown in Figures 6 and 7, and Figures 8 and 9, respectively. The calcitonin analogs and derivatives of this application were suggested to have a significant effect in reducing rat body weight and food intake.

[0252] Figures 6 and 7 further demonstrate that the calcitonin analogs of this application have superior effects compared to D1 in terms of weight loss and appetite suppression, and that M18, M9, and M13 are particularly effective.

[0253] Figures 8 and 9 further demonstrate that the calcitonin analogs and derivatives of this application, such as M8, M19, and M20, have a significant effect on reducing both body weight and food intake in rats.

[0254] While embodiments of this application have been described above, this application is merely illustrative and indicative, and is not limited to the specific embodiments and fields of application described above. Many variations can be conceived by those skilled in the art without departing from the claims of this application.

Claims

1. X ０ X １ SX ３ LS TX ７ VLG RLSX １４ E LHRLX ２０ X ２１ X ２２ PRT X ２６ X ２７ GX ２９ X ３０ S X ３２ -NH ２ (In the formula, X ０ is either D or E, or does not exist. X １ is A, L, V, I, S, E, R, or K, X ３ is Q, E, or D, X ７ is A, L, V, I, S, R, E, or D, X １４ is Q, D, E, Aib, S, or T, X ２０ is Q or E, X ２１ is either D or E, X ２２ is Y, L, or F, X ２６ is either D or Q, X ２７ is either V or S, X ２９ is either S or A, X ３０ is G or E, and X ３２ (This is P or Trans-Hyp) A derivative of calcitonin or a pharmaceutically acceptable salt thereof, comprising a polypeptide having the amino acid sequence.

2. X １ and X ７ The combinations are selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, E-R, R-E, R-D, K-E, K-D, or E-E, and X ２９ -X ３０ The combination is selected from S-E, S-G, A-G, or A-E, and is the derivative or pharmaceutically acceptable salt thereof according to claim 1.

3. X ３ The derivative or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Q is Q.

4. X １４ The derivative according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is Q, D, or E.

5. X ２０ Q is a derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. X ２１ The derivative according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein D is [the derivative].

7. X ２２ The derivative according to any one of claims 1 to 6, wherein is Y or L, or a pharmaceutically acceptable salt thereof.

8. X ２６ and X ２７ The combination is selected from D-V, Q-S, Q-V and D-S, and is a derivative according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. X ２９ -X ３０ The aforementioned combination is S-G, the derivative according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. X ３２ The derivative according to any one of claims 1 to 9, wherein P is P, or a pharmaceutically acceptable salt thereof.

11. ASQLS TAVLG RLSX １４ E LHRLX ２０ DX ２２ PRT DVGX ２９ G SP-NH ２ (In the formula, X １４ is Q, D, or E, X ２０ is Q or E, preferably Q. X ２２ is Y or L, and X ２９ (is S or A) A derivative according to any one of claims 1 to 4, comprising a polypeptide having the amino acid sequence, or a pharmaceutically acceptable salt thereof.

12. ASQLS TAVLG RLSX １４ E LHRLQ DX ２２ PRT DVGSG SP-NH ２ (In the formula, X １４ is Q, D, or E, preferably Q or D, and X ２２ (This is either Y or L) A derivative according to claim 11 or a pharmaceutically acceptable salt thereof, comprising a polypeptide having the amino acid sequence.

13. The derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the amino acid sequence is selected from any one of SEQ ID NOs: 1 to 38.

14. The sequence of the polypeptide is ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH ２ 、 ASQLS TAVLG RLSQE LHRLQ DLPRT DVGSG SP-NH ２ 、 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH ２ 、 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAG SP-NH ２ 、 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAE SP-NH ２ , or ASQLS TAVLG RLSQE LHRLE DYPRT DVGSG SP-NH ２ A derivative according to any one of claims 1 to 8 or 10 to 13, or a pharmaceutically acceptable salt thereof, which is any one of the above.

15. The derivative is the derivative according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the derivative comprises a fatty acid-containing side chain bonded to the N-terminus of the polypeptide.

16. The fatty acid-containing side chain is in the form of Z1 + Z2 + Z3, where Z1 is a C16-C22 fatty diacid. Z2 is selected from one of γGlu, αGlu, βAsp, αAsp, Inp, and Trx, or is absent. Z3 is nAEEA, n≧0, and The derivative according to claim 15 or a pharmaceutically acceptable salt thereof, wherein Z1, Z2, and Z3 are linked via amide bonds.

17. The derivative according to claim 16 or a pharmaceutically acceptable salt thereof, wherein Z1 is a C20 fatty acid.

18. The derivative or pharmaceutically acceptable salt thereof according to claim 16 or 17, wherein Z2 is γGlu.

19. n is selected from 0, 1, 2, 3, 4, 5, or 6, and is a derivative or pharmaceutically acceptable salt thereof according to any one of claims 16 to 18.

20. A polypeptide comprising the amino acid sequence of a derivative according to any one of claims 1 to 14.

21. A pharmaceutical composition comprising a derivative according to any one of claims 1 to 19 or a polypeptide according to claim 20 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

22. Use of a derivative according to any one of claims 1 to 19 or a polypeptide according to claim 20 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for preventing and / or treating overweight, and / or obesity, and / or type 1 or type 2 diabetes, and / or osteoporosis, and / or neuropathic pain.

23. The use of a derivative according to any one of claims 1 to 19 or a polypeptide according to claim 20 or a pharmaceutically acceptable salt thereof in reducing food intake.

24. 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 a preventive or therapeutically effective amount to a subject of a derivative according to any one of claims 1 to 19, a polypeptide according to claim 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21.

25. A method for reducing food intake, comprising administering an effective amount of a derivative according to any one of claims 1 to 19, a polypeptide according to claim 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, to a subject.

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