CN110128526B

CN110128526B - Long-acting exenatide derivative and salt thereof, and preparation method and application thereof

Info

Publication number: CN110128526B
Application number: CN201910465730.1A
Authority: CN
Inventors: 谷海涛; 赵呈青; 王蔡典; 姜建军
Original assignee: Hangzhou Sinopep Aosainuo Pharmaceutical Technology Development Co ltd; SINOPEP JIANGSU Inc
Current assignee: Hangzhou Sinopep Aosainuo Pharmaceutical Technology Development Co ltd; SINOPEP JIANGSU Inc
Priority date: 2019-05-30
Filing date: 2019-05-30
Publication date: 2021-07-23
Anticipated expiration: 2039-05-30
Also published as: CN110128526A; WO2020237709A1

Abstract

The invention relates to a long-acting exenatide derivative, belonging to the technical field of polypeptide compounds. The exenatide derivative is obtained by optimizing the structure of an exenatide sequence, so that the exenatide derivative has the effects of reducing blood sugar and weight, conjugating twice the amount of exenatide and a single amount of fatty acid chains, and utilizing the fatty acid chains to play a role in combination with serum albumin. The invention also discloses a preparation method of the exenatide derivative, pharmaceutically acceptable exenatide derivative salt thereof, an exenatide derivative medicament, a pharmaceutical composition and application of the exenatide derivative in preparation of medicines for treating and/or preventing diabetes, obesity, hyperlipidemia and non-alcoholic fatty liver. The long-acting exenatide derivative has a weight loss effect on the basis of retaining the activity of reducing blood sugar, the biological half-life period is obviously prolonged compared with that of an exenatide prototype, part of the biological half-life period is more than 36 hours, and the time of reducing blood sugar and weight is greatly prolonged.

Description

Long-acting exenatide derivative and salt thereof, and preparation method and application thereof

Technical Field

The invention relates to the technical field of polypeptide compounds, in particular to an exenatide derivative, a preparation method thereof, a medicament composition and application thereof as a medicament.

Background

The cause of the metabolic syndrome is metabolic abnormality of various substances such as protein, fat, carbohydrate, and the like. Excess nutrition, reduced physical activity, etc. can lead to obesity and obesity related diseases, such as diabetes, etc. In recent years, the incidence of type 2 diabetes and dyslipidemia has been increasing.

Glucagon-like peptide-1 (GLP-1) is a glucose-dependent incretin hormone. It can activate GLP-1 receptor and reduce blood sugar. The most obvious function is to promote the regeneration and repair of beta cells, increase the number of islet beta cells, and avoid the hypoglycemia risk frequently occurring in the diabetes treatment, and the application prospect in the diabetes treatment field is wide. Although the natural GLP-1 has a plurality of advantages in treating diabetes, the natural GLP-1 is easily and rapidly degraded by dipeptidyl peptidase IV (DPP-IV) in vivo, and the half-life period in vivo is only about 3 minutes. Exenatide (Exenatide) extracted from salivary gland of Eremiatis Argi is approved by FDA to market in 2005, and has polypeptide sequence of HGEGTFTSDLSKQMEEEAVRILFIEWLKNGGPSSGAPPPS-NH₂. Exenatide is not a substrate of DPP-4, so that Exenatide is not degraded by DPP-4 existing widely in vivo, and the in vivo half-life of Exenatide is prolonged to about 2.4 hours compared with endogenous GLP-1. However, exenatide is still rapidly filtered and eliminated in the kidney, and the half-life of GLP-1 can be prolonged to a certain extent only by resisting the degradation of DPP-IV enzyme.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a long-acting exenatide derivative, which is subjected to site substitution by glucagon on the basis of exenatide while maintaining the high agonistic activity of the exenatide on a GLP-1 receptor so as to increase the agonistic activity of the exenatide derivative on the glucagon and obtain an exenatide derivative sequence with double-target agonistic activity.

Based on the above purpose, the invention innovatively connects two preferable exenatide derived polypeptide sequences by using lysine and conjugates with fatty acid chains with different lengths. The fatty acid chain can prolong the combination time of the conjugate and serum albumin, and simultaneously, the whole molecular volume is larger than that of the exenatide, so that the rapid filtration of the kidney can be slowed down, the two aspects take effect simultaneously, and the in-vivo action time of the peptide chain is greatly prolonged. Therefore, the double-effect exenatide analogue obviously prolongs the acting time in vivo on the premise of having the activity of reducing blood sugar and weight.

Another object of the present invention is to provide a process for the preparation of exenatide derivatives.

It is still another object of the present invention to provide a pharmaceutically acceptable exenatide derivative salt prepared using the exenatide derivative.

It is still another object of the present invention to provide an exenatide derivative pharmaceutical agent prepared from the exenatide derivative.

It is still another object of the present invention to provide a pharmaceutical composition comprising an exenatide derivative.

Still another object of the present invention is to provide a use of exenatide derivative, a use of exenatide derivative salt, and a use of exenatide derivative medicament.

The object of the present invention is also achieved by the following means. The invention relates to a long-acting exenatide derivative, the amino acid sequence of which is as follows:

His-Xaa1-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Asp-Ser-Arg-Arg-Ala-Gln-Asp-

Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Xaa2-Ser-Pro-Pro-Pro-Ala-Gly-Ser-Ser-Pro-Gly-Gly-Asn-Lys-Leu-Trp-Glu-Ile-Phe-Asp-Gln-Ala-Arg-Arg-Ser-Asp-Met-Gln-Lys-Ser-Leu-Asp-Ser-Thr-Phe-Thr-Gly-Gln-Xaa1-His

wherein:

xaa1 is taken from: aib or Gly

Xaa2 is taken from:

n is a natural number from 5 to 17, preferably 11, 13 or 15.

Preferred long-acting exenatide derivative of the invention may be represented by:

the invention also discloses a pharmaceutically acceptable exenatide derivative salt prepared from the exenatide derivative, wherein the salt is exenatide derivative and hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, sodium hydrogen sulfite, potassium hydrogen sulfite, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.

The invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of at least one exenatide derivative compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier or diluent. Meanwhile, the invention further provides application of the exenatide derivative compound and pharmaceutically acceptable salts thereof, or pharmaceutically acceptable carriers or diluents in preparation of medicines for treating and preventing diabetes.

The invention also discloses an exenatide derivative medicament prepared from the exenatide derivative, and the dosage form of the medicament is selected from tablets, capsules, elixirs, syrup, lozenges, inhalants, sprays, injections, films, patches, powders, granules, blocks, emulsions, suppositories or compound preparations.

The invention also discloses the application of the exenatide derivative, which is characterized in that the application is the application of the exenatide derivative in preparing medicines for treating and/or preventing diabetes, obesity, hyperlipidemia and non-alcoholic fatty liver.

The invention also discloses the application of the exenatide derivative salt, which is characterized in that the application is the application of the exenatide derivative salt in preparing medicines for treating and/or preventing diabetes, obesity, hyperlipidemia and non-alcoholic fatty liver.

The invention also discloses the application of the exenatide derivative medicament, which is characterized in that the application is the application of the exenatide derivative medicament in preparing medicines for treating and/or preventing diabetes, obesity, hyperlipidemia and non-alcoholic fatty liver.

The invention also provides a preparation method and an intermediate of the exenatide derivative polypeptide, the preparation method of the exenatide derivative polypeptide adopts a solid-phase synthesis method to gradually couple each amino acid of the main chain of the hypoglycemic polypeptide, the main chain polypeptide with a protected side chain is obtained by cracking, and lysine connected with a fatty chain reacts with the main chain to obtain the exenatide derivative. The method has simple synthesis steps, high coupling efficiency and easy purification, and is favorable for the industrial production of the polypeptide.

The preferred method for preparing exenatide derivative of the present invention comprises the following steps:

step 1: taking resin, activating, and gradually coupling amino acid to obtain first peptide resin;

step 2: cracking and purifying the first peptide resin to obtain a polypeptide main chain with a protected side chain;

and step 3: reacting lysine connected with a fatty chain with twice amount of main chains, and purifying to obtain the product;

preferably, in the preparation method provided by the invention, the Resin in the step 1 is 2-CTC Resin or Wang Resin.

Preferably, in the preparation method provided by the invention, the cleavage reagent used for cleavage in step 2 is a mixture of TFA and DCM. In some embodiments of the present invention, the present invention provides a method for preparing a peptide, wherein the ratio of the volumes of TFA and DCM in the reagents used for cleavage in step 2 is 0.1: 99.9.

in other embodiments of the present invention, the purification in step 2 and step 3 is performed by chromatography. In some other embodiments of the present invention, the preparation method provided by the present invention, wherein the column used for purification in step 2 and step 3 is a C18 column.

The inventor researches that GLP-1 and glucagon can be obtained after translation shearing of pre-glucagon, and the two have certain sequence homology. Therefore, a part of glucagon sequence is introduced into Exenatide with high agonistic activity to GLP-1, so that a double-effect agonist for simultaneously stimulating GLP-1R and GCGR can be obtained, and a polypeptide compound with good hypoglycemic activity and weight loss effect is obtained.

Compared with the prior art, the invention has the beneficial effects that:

1. the double-receptor excited long-acting exenatide derivative provided by the invention has a weight reduction effect on the basis of retaining the activity of reducing blood sugar, the biological half-life period is obviously prolonged compared with that of an exenatide prototype (-2.4 h), part of the biological half-life period is more than 36 hours, and the time of reducing blood sugar and weight is greatly prolonged.

2. The method adopts the solid-phase synthesis of the exenatide derivative by the orthogonal protection strategy to obtain the crude product of the peptide chain, the purity of the crude product is more than 85 percent, and compared with the conventional synthesis method, the method is greatly improved, and the subsequent purification work is convenient.

3. The method of the invention adopts a solid phase method to synthesize the exenatide derivative with low cost. Because the coupling efficiency is higher, the amino acid required to be protected only needs 2 times excess on average, while the amino acid needs 4 to 5 times excess in the conventional synthetic method, thereby greatly saving the cost.

4. The method for synthesizing the exenatide derivative by adopting the Fmoc/tBu orthogonal protection solid-phase synthesis strategy is easy to realize automation and large-scale production, so that the method is more suitable for industrial production.

5. The exenatide derivative prepared by the solid phase synthesis technology has the advantages of good activity of reducing blood sugar and slowing down weight gain, long drug effect time, high yield, short synthesis period, easy purification of crude products, low production cost and easy industrial automatic production. The prepared exenatide derivative is suitable to be used as an active ingredient of a medicine for treating diabetes and obesity.

Drawings

FIG. 1 shows the results of an intraperitoneal glucose tolerance test of exenatide derivatives SEQ.ID NO. 1-6;

FIG. 2 shows the results of blood glucose stabilization experiments of exenatide derivatives SEQ. ID NO: 1-6.

Detailed Description

The following abbreviations are used throughout the specification:

the present invention is illustrated by the following examples, which are not to be construed as limiting the invention in any way.

Example 1:

synthesis of (2)

1. Synthesis of peptide chains

1.1 swelling of the resin

Weighing 1 g of 2-CTC Resin (the degree of substitution is 0.4 mmol/g), swelling with 10 mL of DCM for 30 min, filtering off the DCM by suction, swelling with 10 mL of NMP for 30 min, and washing with 10 mL of NMP and 10 mL of DCM respectively.

1.2 Synthesis of Fmoc-Ser (tBu) -2-CTC Resin

Fmoc-Ser (tBu) -OH (0.8 mmol) and DIPEA (1.6 mmol) were dissolved in 10 mL of NMP, and the solution was added to the resin obtained in the previous step to react for 2 hours, after which the reaction solution was filtered off, and the resin was washed 3 times with 10 mL each of DCM and NMP.

1.3 removal of Fmoc protecting group

To the washed resin was added a 25% piperidine/NMP (V/V) solution containing 0.1M HOBt to remove Fmoc, and after the reaction was completed, the resin was washed 3 times with 10 mL each of DCM and NMP.

1.4 elongation of peptide chain

Repeating the steps of deprotection and coupling according to the sequence of the exenatide derivative peptide chain, sequentially connecting corresponding amino acids, and sequentially connecting corresponding amino acids until the synthesis of the peptide chain is finished to obtain the peptide resin connected with the exenatide derivative.

1.5 cleavage of Polypeptides on resins

The obtained resin connected with the exenatide derivative peptide chain is put into a reaction bottle, 10 mL of cracking agent (TFA/DCM, 0.1/99.9, V/V) is respectively added, the mixture is firstly shaken for 30 min at 0 ℃, and then the reaction is carried out for 1 h at normal temperature. After the reaction is finished, suction filtration is carried out, and the filtrate is combined and distilled under reduced pressure. Adding the concentrated solution into a large amount of glacial ethyl ether to separate out white flocculent precipitate, and freezing and centrifuging to obtain a polypeptide crude product with a protected side chain. Purifying by adopting preparative liquid chromatography, wherein the chromatographic conditions are as follows: c18 column (320 mm × 28 mm, 5 μm); mobile phase A: 0.1% TFA/water (V/V), mobile phase B: 0.1% TFA/acetonitrile (V/V); gradient of mobile phase: 40-90% of mobile phase B for 20 min; the flow rate was 6 mL/min and the detection wavelength was 214 nm.

Synthesis of (S) -2, 6-diamino-N-dodecylhexanamide

Boc-Lys (Boc) -NH-12-alkane (0.8 mmol) was dissolved in 7 mL of DCM, 1 mL of TFA was slowly added dropwise, reacted for 3 h, concentrated under reduced pressure, and 5mL of 1M aqueous NaOH was added to precipitate a white solid, which was collected by centrifugation to give a white powdery solid.

3. Synthesis of exenatide derivative

Exenatide derivative (0.02 mmol), HBTU (0.02 mmol), HOBt (0.08 mmol) and DIPEA (0.16 mmol) were dissolved in NMP 10 mL, and this solution was added to (S) -2, 6-diamino-N-dodecylhexanamide. The reaction was monitored using HPLC with chromatographic conditions: a C18 column (150 mm × 4.6 mm, 5 μm); mobile phase A: 0.1% TFA/water (V/V), mobile phase B: 0.1% TFA/acetonitrile (V/V); gradient of mobile phase: 35% -85% of mobile phase B for 20 min; the flow rate is 1 mL/min; the column temperature is 40 ℃; the detection wavelength was 214 nm. After the reaction is finished, purifying by adopting a preparative liquid chromatography, wherein the chromatographic conditions are as follows: c18 column (320 mm × 28 mm, 5 μm); mobile phase A: 0.1% TFA/water (V/V), mobile phase B: 0.1% TFA/acetonitrile (V/V); gradient of mobile phase: 40-90% of mobile phase B for 20 min; the flow rate was 6 mL/min and the detection wavelength was 214 nm. The collected solution was lyophilized to give 23.8 mg pure product. The theoretical relative molecular mass is 8710.7. ESI-MS M/z Calcd. [ M +5H ]]⁵⁺1743.1, [M+6H]⁶⁺1452.8; Found [M+5H]⁵⁺1743.5, [M+6H]⁶⁺1453.1。

Example 2:

the synthesis method is the same as example 1, and the collected solution is lyophilized to obtain a pure product 24.9 mg. The theoretical relative molecular mass is 8654.6. ESI-MS M/z Calcd. [ M +5H ]]⁵⁺1731.9, [M+6H]⁶⁺1443.4; Found [M+5H]⁵⁺1732.1, [M+6H]⁶⁺1443.7。

Example 3:

the synthesis method is the same as example 1, and the collected solution is lyophilized to obtain pure product 26.5 mg. The theoretical relative molecular mass is 8738.8. ESI-MS M/z Calcd. [ M +5H ]]⁵⁺1748.8, [M+6H]⁶⁺1457.5; Found [M+5H]⁵⁺1748.9, [M+6H]⁶⁺1458.0。

Example 4:

the synthesis method is the same as example 1, and the collected solution is lyophilized to obtain 22.8 mg of pure product. The theoretical relative molecular mass is 8682.7. ESI-MS M/z Calcd. [ M +5H ]]⁵⁺1737.5, [M+6H]⁶⁺1448.1; Found [M+5H]⁵⁺1737.8, [M+6H]⁶⁺1448.7。

Example 5:

the synthesis method is the same as example 1, and the collected solution is lyophilized to obtain pure product 24.5 mg. The theoretical relative molecular mass is 8766.9. ESI-MS M/z Calcd. [ M +5H ]]⁵⁺1754.4, [M+6H]⁶⁺1462.2; Found [M+5H]⁵⁺1754.9, [M+6H]⁶⁺1462.3。

Example 6:

the synthesis method is the same as example 1, and the collected solution is lyophilized to obtain 23.9 mg of pure product. The theoretical relative molecular mass is 8710.7. ESI-MS M/z Calcd. [ M +5H ]]⁵⁺1743.1, [M+6H]⁶⁺1452.8; Found [M+5H]⁵⁺1743.8, [M+6H]⁶⁺1453.0。

Example 7: the following are the relevant pharmacological experimental methods and results of the exenatide derivative related to the present invention:

1. GLP-1 receptor agonistic activity screening of exenatide derivatives

HEK293 cells were co-transfected with cDNAs encoding GLP-1R or GCGR. In assays to determine compounds, cells were seeded 2 h in 96-well plates, compounds were dissolved in DMSO, diluted to different fold using medium containing 0.1% bovine serum albumin, and added to co-transfected cells. After incubation of the cells for 20 min, fluorescence readings were determined using an ELISA kit from Cisbo and an enzyme reader to establish a standard curveFluorescence readings were converted to corresponding cAMP values and EC of the compounds was calculated using nonlinear regression of Graphpad Prism 5.0 software₅₀Numerical values.

TABLE 1 Exenatide derivatives agonistic Activity on GLP-1R and GCGR

Results are expressed as mean ± SD, **P<0.01 vs Glucagon, ## P<0.01 vs Exenatide.

As shown in Table 1, all compounds still retained a considerably higher degree of agonistic activity towards GLP-1R compared to the Exenatide prototype. Meanwhile, the agonistic activity on GCGR is greatly improved compared with that of an exenatide prototype, and the conjugated fatty acid chain does not have great influence on the agonistic activity.

2. Abdominal glucose tolerance test of exenatide derivative

Normal kunming mice, randomly grouped, 8 mice per group, were housed in standardized animal houses. Fasted for 12 hours prior to the experiment, only drinking water was given. Before administering the exenatide derivative, each group of mice measured an initial blood glucose value, determined to be-30 min, and then injected with 50 nmol/kg of exenatide derivative intraperitoneally. After 30 min, 18 mmol/kg glucose solution was intraperitoneally injected for 0 min, and the control group was injected with the same volume of physiological saline or 50 nmol/kg exenatide. Measuring blood glucose level with a glucometer at 0, 15, 30, 45, 60, 120 min, and detecting the blood glucose reducing activity of exenatide derivative.

As shown in figure 1, the results of blood sugar reduction experiments show that when the administration concentration of the exenatide derivative disclosed by the invention is 50 nmol/kg, the blood sugar reduction effect is equivalent to that of exenatide.

3. Blood sugar stabilization test of exenatide derivative

Blood glucose was measured in STZ-induced diabetic model mice, and mice with values higher than 20 mmol/L were selected for random grouping of six mice per group, with free feeding during the experiment. The positive control group is injected with exenatide or liraglutide in the abdominal cavity, the dosage is 50 nmol/kg, the negative control group is injected with normal saline in the abdominal cavity, and the administration groups are respectively injected with exenatide derivative in the 50 nmol/kg. Compound was administered at 0 h and blood glucose levels were determined using a glucometer at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 60 h, respectively. The evaluation index is the time when the blood sugar value of the mice is lower than 8.35 mmol/L after the compound is injected into the abdominal cavity.

As can be seen from FIG. 2, the blood sugar stabilizing time of exenatide is only 4 h, the blood sugar stabilizing time of liraglutide is 10 h, the blood sugar stabilizing time of the long-acting hypoglycemic polypeptide disclosed by the invention is more than 24 h, and part of the long-acting hypoglycemic polypeptide can exceed 35 h. The blood sugar stabilizing experiment shows that the exenatide derivative has a good long-acting blood sugar reducing effect, can achieve a better long-acting blood sugar reducing effect, and has the potential of being developed into a blood sugar reducing medicament which is administrated once every day.

Sequence listing

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HANGZHOU SINOPEP AOSAINUO PHARMACEUTICAL TECHNOLOGY DEVELOPMENT Co.,Ltd.

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Claims

1. A long-acting exenatide derivative, wherein the exenatide derivative is one of the following compounds:

。

2. a process for producing the exenatide derivative according to claim 1, comprising the steps of:

(1) taking resin, activating, and gradually coupling amino acid to obtain first peptide resin;

(2) cracking and purifying the first peptide resin to obtain a polypeptide main chain with a protected side chain;

(3) reacting lysine connected with fatty chain with twice amount of main chain, and purifying to obtain the final product.

3. A pharmaceutically acceptable exenatide derivative salt as claimed in claim 1, wherein said pharmaceutically acceptable exenatide derivative salt is a salt of an exenatide derivative with an acid, said acid being selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, nicotinic acid, 3-phenylpropionic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectic acid, persulfuric acid, 3-phenylpropionic acid, saprophoric acid, hydracrylic acid, and the like, hydracrylic acid, and the like, Picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.

4. An exenatide derivative pharmaceutical preparation as claimed in claim 1, wherein said pharmaceutical dosage form is selected from the group consisting of tablets, capsules, elixirs, syrups, lozenges, inhalants, sprays, injections, films, patches, powders, granules, blocks, emulsions, suppositories, and combinations thereof.

5. A pharmaceutical composition comprising the exenatide derivative according to claim 1, which comprises a therapeutically effective amount of an exenatide derivative according to claim 1 and a pharmaceutically acceptable carrier or diluent thereof.

6. Use of the exenatide derivative according to claim 1 for the preparation of a medicament for the treatment and/or prevention of diabetes.

7. Use of the pharmaceutically acceptable exenatide derivative salt as claimed in claim 3, for the preparation of a medicament for the treatment and/or prevention of diabetes.

8. Use of the exenatide derivative medicament as claimed in claim 4 for the preparation of a medicament for the treatment and/or prevention of diabetes.