CN101400699A - Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions - Google Patents

Abstract

The present invention provides novel human glucagon-like peptide-1 (GLP-1)-receptor modulators that have biological activity similar or superior to native GLP-1 peptide and thus are useful for the treatment or prevention of diseases or disorders associated with GLP activity. Further, the present invention provides novel, chemically modified compounds that not only stimulate insulin secretion in type II diabetics, but also produce other beneficial insulinotropic responses. These synthetic peptide GLP-1 receptor modulators exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration. The compounds of this invention show desirable pharmacokinetic properties and desirable potency in efficacy models of diabetes.

Description

Human glucagon-like-peptide-1 modulators and the purposes in treatment diabetes and associated conditions thereof

The application requires to be filed in the U.S. Patent application 60/758 on January 11st, 2006,165, be filed in the U.S. Patent application 60/758 on January 11st, 2006,164, be filed in the U.S. Patent application 60/758 on January 11st, 2006,096 and the right of priority that is filed in the U.S. Patent application 60/758,107 on January 11st, 2006.At this with every complete being incorporated herein by reference of patent application.

Technical field

The application describes and the theme of requirement provides new human glucagon-like-peptide-1 (GLP-1) peptide receptor modulators, agonist or partial agonist, and it is that GLP-1 demonstrates remarkable (superior) biological property with respect to native peptides.These compounds show the stability of raising to proteolytic cleavage, therefore can be used for treatment of diabetes and improvement.

Background technology

GLP-1 is the important gastrointestinal hormone ` that has regulatory function in glucose metabolism and gastrointestinal secretion and metabolism.People GLP-1 is 30 amino acid peptides that originate from preceding Proglucagon (preproglucagon), its for example in the L-of far-end ileum cell, synthetic in pancreas and in brain.Preceding Proglucagon is processed to generate GLP-1 (7-36) acid amides and GLP-2, and this mainly occurs in L-cell and the brain stem.GLP-1 secretes in response to ingestion of food usually; Carbohydrate and lipid especially stimulate the GLP-1 secretion.GLP-1 has been accredited as the potent and efficient stimulator that glucose dependency Regular Insulin discharges, and it has the risk of reduction for bringing out hypoglycemia.GLP-1 reduces blood plasma hyperglycemic-glycogenolytic factor concentration, and the stomach emptying that slows down stimulates the Regular Insulin biosynthesizing and improves insulin sensitivity (Nauck, Horm.Metab.Res., 29:9 (411-416) 1997).In the experimenter who suffers from glucose tolerance reduction (impaired glucosetolerance), GLP-1 also improves pancreas beta cell impression and in response to the ability (Byrne of glucose, M.M.et al., Eur.J.Clin.Invest., 28 (1): 72-78 (1998)).The pancreotropic hormone effect of GLP-1 in the mankind increased glucose metabolism speed, and part is because the insulin level that improves, and part is (D ' Alessio, Eur.J.Clin.Invest., Vol.15, No.12 2005) because the insulin sensitivity that improves.After treating the type ii diabetes patient, observe the improvement of glucose stable state with GLP-1, the inhibition that hyperglycemic-glycogenolytic factor is discharged is considered to facilitate the other mechanism (Nauck of The above results, M.A.et al., Diabetologia, 36 (8): 741-744 (1993)).The above-mentioned pharmacological properties of GLP-1 makes it become the therapeutical agent of the high expectations of treatment type ii diabetes.

In addition, nearest research has shown that infusion slightly has children outside the state plan the GLP-1 of reason (supraphysiological) amount and significantly improve satiety and reduce ingestion of food (Flint in the normal subjects, A.et al., J.Clin.Invest., 101 (3): 515-520 (1998) and Gutzwiller, J.P.et al., Gut, 44 (1): 81-86 (1999)).Reported that also acting in the obese subjects of ingestion of food and satiety kept (Naslund, E.et al., Int.J.Obes.Relat.Metab.Disord., 23 (3): 304-311 (1999)).

Guess also that in the research of above being quoted GLP-1 has significant effect to stomach emptying.Stomach emptying causes GLPP fluctuation (post-prandial glucose excursion).Shown except that stimulation insulin secretion, the riposte expression of excited transcryption factor pancreas islet-duodenum homology frame-1 (IDX-1) of GLP-1, stimulate B-cell regeneration simultaneously, can be used as the medicine (Stoffers that effectively treats and/or prevents diabetes thus, D.A.et al., Diabetes, 49 (5): 741-748 (2000)).Also shown GLP-1 gastric acid inhibitory secretion (Wettergren, A.etal., Dig.Dis.Sci., 38 (4): 665-673 (1993)), this can provide provide protection with to anti-gastric-ulcer.

Reported also that recently GLP-1 has multiple other pancreas and acts on outward; its for example can cause to heart provide protection, to the provide protection of nerve and to the inducing action of learning and memory (referring to Ahren; B., Horm.Metab.Res., 36 (11-12): 842-845 (2004)).Therefore, also propose GLP-1 and can be used for treatment (Nikolaidis in heart failure, L.A.et al., 955-961 (2004)), ischemia/reperfusion injury (Nikolaidis Circulation, 110 (8):, L.A.et al., Circulation, 962-965 (2004)) and alzheimer's disease (Alzheimer ' sDisease) (Perry, T.et al. 109 (8):, J.Alzheimers Dis., 4 (6): 487-496 (2002)).

GLP-1 is a kind of incretin hormone (for example improving the intestines internal hormone of insulin secretion due to the meals) (Holst, J.J., Curr.Med.Chem., 6 (11): 1005-1017 (1999)).It is the product of the hyperglycemic-glycogenolytic factor gene of coding Proglucagon.Described gene is not only expressed in the A-of pancreas cell, but also expresses in the internal secretion L-of intestinal mucosa cell.Proglucagon is to contain 160 amino acid whose peptides (protein).The further processing of Proglucagon is caused the generation of following material: a) hyperglycemic-glycogenolytic factor, b) the terminal fragment that promptly may non-activity of N-, and c) be commonly referred to the big C-terminal fragment of " main Proglucagon fragment ".The C-terminal fragment is considered to not biologically active.Although this fragment is present in the pancreas and is present in the L-cell of intestines, only in intestines, observe the split product of " main Proglucagon fragment ", described cracking produces two kinds of height homologous compounds that are commonly referred to GLP-1 and GLP-2.These two kinds of compounds have important biological.So, it is identical with the amino acid 78-107 of Proglucagon to be present in the aminoacid sequence of the GLP-1 in the L-cell.

At present, relate to and use the methods of treatment of GLP-1 type molecule great challenge to occur, this is because the serum half-life of this compounds is very short.For example GLP-1 (7-37) has the serum half-life less than five minutes.Therefore, press for GLP-receptor modulators, agonist or the partial agonist of biologically active, it has the pharmacodynamic properties of expansion.The present invention is intended to address that need and other needs.

The invention provides the new compound as GLP-1 receptor modulators, agonist or partial agonist, it is that GLP-1 demonstrates similar or remarkable biological property with respect to native peptides, thereby can be used for the treatment and the improvement of diabetes and associated conditions.

Summary of the invention

The described synthetic isolated compound of the application can be regulated the GLP-1 acceptor as the agonist or the partial agonist of expectation.These synthetic compounds show effect and pharmacokinetic property in the remarkable body with respect to GLP-1, comprise the raising of following of the reduction of postprandial blood sugar and plasma insulin level, therefore make these compounds become ideal treatment material standed for.Described material standed for can come administration by number of ways, comprises subcutaneous preparations, lung preparation, nasal preparation, oral preparation or extended release preparation.

GLP-1 analogue of the present invention can comprise unexistent amino acid in the natural GLP-1 molecule in some positions, and generally includes at least 11 successive amino acid.

The described embodiment of the application is the isolating formula I polypeptide of sequence that comprises:

X _aa1-X _aa2-X _aa3-X _aa4-X _aa5-X _aa6-X _aa7-X _aa8-X _aa9-X _aa10-X _aa11

I

Wherein

X _Aa1The amino acid that exists for the natural or non-natural that comprises imidazolyl, for example Histidine; Wherein said amino acid whose any carbon atom is optional to be replaced by hydrogen or one or more alkyl, and wherein said amino acid whose free amine group is optional to be replaced by following group: hydrogen, alkyl, acyl group, benzoyl, L-lactoyl, alkyl oxy carbonyl, aryloxy carbonyl, arylalkyl oxygen base carbonyl, heterocyclyloxy base carbonyl, heteroarylalkyl oxygen base carbonyl, alkylcarbamoyl group, aromatic yl ammonia methanoyl, arylalkyl carbamyl, heterocyclic radical alkylsulfonyl, alkyl sulphonyl, aryl sulfonyl, aryl alkylsulfonyl, heteroarylalkyl alkylsulfonyl or heteroarylsulfonyl; And X wherein _Aa1Amino optional do not exist, thereby make X _Aa1Be the deaminizating acid of Histidine, wherein any carbon atom is optional to be replaced by hydrogen or one or more alkyl; And X wherein _Aa1Amino optional replaced by hydroxyl;

X _Aa2Be amino acid natural or that non-natural exists, it is selected from L-Ala, alpha-amino group-isopropylformic acid (Aib), N-methyl D-L-Ala, N-ethyl-D-L-Ala, 2-methyl-azetidine-2-carboxylic acid, Alpha-Methyl-(L)-proline(Pro), pipecoline-2-carboxylic acid and isovaline;

X _Aa3Be amino acid natural or that non-natural exists, it comprises the amino acid side chain that contains carboxylic acid, for example aspartic acid or L-glutamic acid; Or X wherein _Aa3Be the amino acid that contains the imidazoles side chain natural or that non-natural exists, for example Histidine, and wherein said amino acid whose any carbon atom is optional to be replaced by one or more alkyl;

X _Aa4Be glycine;

X _Aa5Be amino acid natural or that non-natural exists, it is selected from (L)-Threonine and (L)-norvaline; And wherein said amino acid whose any carbon atom is optional is replaced by one or more alkyl;

X _Aa6Be the amino acid that comprises two replacement α carbon natural or that non-natural exists; One of wherein said amino acid whose side chain contains aromatic ring, for example Alpha-Methyl-phenylalanine, alpha-methyl-2-fluorophenylalanine and alpha-methyl-2,6-two fluorophenylalanine; Wherein said amino acid whose any carbon atom is optional to be replaced by one or more alkyl or one or more halogen;

X _Aa7Be amino acid natural or that non-natural exists, it comprises the amino acid side chain that is replaced by hydroxyl, for example the L-Threonine; Wherein said amino acid whose any carbon atom is optional to be replaced by one or more alkyl;

X _Aa8Be amino acid natural or that non-natural exists, it is selected from L-Serine and L-Histidine; Wherein said amino acid whose one or more carbon atoms are optional to be replaced by one or more alkyl;

X _Aa9Be amino acid natural or that non-natural exists, it comprises the amino acid side chain that contains carboxylic acid, for example L-aspartic acid or L-L-glutamic acid; Wherein said amino acid whose one or more carbon atoms are optional to be replaced by one or more alkyl;

X _Aa10Be formula II amino acid natural or that non-natural exists:

Formula II

R wherein ₁Be selected from hydrogen, alkyl and halogen;

R wherein ₂And R ₃Independently be selected from hydrogen, halogen, methyl, ethyl, alkyl, hydroxyl, methoxyl group and alkoxyl group separately;

Formula II amino acid also can comprise at least one R ₁, R ₂Or R ₃Group, described R ₁, R ₂And R ₃Can be identical or different; And

X _Aa11Can be natural or the formula III amino acid of non-natural existence:

Formula III

The terminal carbonyl carbon of wherein said amino acid whose C-links to each other with nitrogen and forms methane amide (NH ₂);

Wherein encircle A and be selected from aryl and heteroaryl;

R wherein ₄And R ₅Independently be selected from hydrogen, halogen, methyl, ethyl, alkyl, hydroxyl, methoxyl group, alkoxyl group, aryl and heteroaryl separately; And

X wherein ₁And X ₂CH-alkyl, CH respectively do for oneself ₂, NH, S or O.

Formula III amino acid also can comprise at least one R ₄Or R ₅Group is and if exist a plurality of R ₄And R ₅, R so ₄And R ₅Can be identical or different.

X _Aa11Can be natural or the formula IV amino acid of non-natural existence:

Formula IV

The terminal carbonyl carbon of wherein said amino acid whose C-links to each other with nitrogen and forms methane amide (NH ₂);

R wherein ₄Be selected from hydrogen, hydroxyl, methyl, ethyl, alkyl, methoxyl group, alkoxyl group, aryl and heteroaryl;

R wherein ₅Be selected from hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or assorted alkylaryl;

Wherein X is selected from CH ₂, CH ₂CH ₂Or CHCH ₃

Y wherein ₁Be selected from-NH-,-O-and-C=O-;

Wherein if Y ₁Be NH or O, then Y ₂Be selected from-C=O-,-O=C-O-and-SO ₂-;

Wherein if Y ₁Be C=O, then Y ₂Be selected from-NH-,-N-or-O-; And

R wherein ₆Be selected from hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl.

Formula IV amino acid comprises at least one R ₆Group is and if exist a plurality of R ₆, R so ₆Can be identical or different.

X _Aa11Also can be natural or the formula V amino acid of non-natural existence:

Formula V

The terminal carbonyl carbon of wherein said amino acid whose C-links to each other with nitrogen and forms methane amide (NH ₂);

R wherein ₄Be selected from hydrogen, hydroxyl, methyl, ethyl, alkyl, methoxyl group, alkoxyl group, aryl and heteroaryl;

R wherein ₅Be selected from hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or assorted alkylaryl;

X wherein ₁Do not exist or by CH ₂Form;

X wherein ₂Be selected from-CO-, CO-N (-) ₂,-CO-O-,-SO-and-SO ₂-;

R wherein ₆And R ₇Independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl.

Formula V amino acid comprises at least one R ₇Group is and if exist a plurality of R ₇, R so ₇Can be identical or different.

X _Aa11Also can be natural or the formula VI amino acid of non-natural existence:

Formula VI

The terminal carbonyl carbon of wherein said amino acid whose C-links to each other with nitrogen and forms methane amide (NH ₂);

R wherein ₄Be selected from hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or assorted alkylaryl;

R wherein ₅Be selected from hydrogen, hydroxyl, methyl, ethyl, alkyl, methoxyl group and alkoxyl group;

R wherein ₆Be selected from hydrogen, methyl, ethyl, alkyl, cycloalkyl, Heterocyclylalkyl, hydroxyl, methoxyl group and alkoxyl group.

Formula VI molecule also can comprise at least one R ₆Group is and if exist a plurality of R ₆, R so ₆Can be identical or different.

Formula VI molecule also can comprise R ₅And R ₆Group, described R ₅And R ₆Form cycloalkyl, Heterocyclylalkyl, cycloalkyl aryl or cycloalkyl heteroaryl together.

Another embodiment is isolating formula VII polypeptide:

Formula VII

Wherein

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro, 2-methyl-azetidine-2-carboxylic acid, pipecoline-2-carboxylic acid and aminoisobutyric acid (Aib);

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser (L-Serine) and L-His (L-Histidine);

R ₂Be selected from hydrogen, methyl and ethyl;

R ₃Be selected from hydrogen, hydroxyl, methoxyl group and oxyethyl group;

X ₁Be selected from CH ₂And CH ₂CH ₂

R ₇Be selected from hydrogen, methyl, ethyl, alkyl, hydroxyl, methoxyl group, alkoxyl group, aryl, heteroaryl, alkylaryl and miscellaneous alkyl aryl; And

R ₈Be selected from hydrogen, methyl, ethyl, alkyl, hydroxyl, methoxyl group, alkoxyl group, aryl, heteroaryl, alkylaryl and miscellaneous alkyl aryl.

Another embodiment is isolating formula VIII polypeptide:

Formula VIII

Wherein

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro, 2-methyl-azetidine-2-carboxylic acid, pipecoline-2-carboxylic acid and aminoisobutyric acid (Aib);

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be selected from hydrogen, methyl and ethyl;

R ₃Be selected from hydrogen, hydroxyl, methoxyl group and oxyethyl group;

R ₄Be selected from hydrogen and methyl;

X ₂Be selected from-CO-and-SO ₂-; And

R ₇Be selected from alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl.

Formula VIII peptide comprises at least one R ₇Group is and if exist a plurality of R ₇, R so ₇Can be identical or different.

Another embodiment is isolating formula IX polypeptide:

Formula IX

Wherein

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro, 2-methyl-azetidine-2-carboxylic acid, pipecoline-2-carboxylic acid and aminoisobutyric acid (Aib);

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

X ₁Be selected from CH ₂And CH ₂CH ₂

R ₂Be selected from hydrogen, methyl and ethyl;

R ₃Be selected from hydrogen, hydroxyl, methoxyl group and oxyethyl group;

R ₄Be selected from methyl, ethyl, alkyl, aryl, heteroaryl, alkylaryl and miscellaneous alkyl aryl; And

R ₆Be hydrogen.

Another embodiment is isolating formula X polypeptide:

Formula X

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be methyl or ethyl;

R ₃Be selected from hydrogen, methyl, ethyl and methoxyl group;

R ₄Be selected from hydrogen and methyl;

X wherein ₂Be selected from-CO-and-SO ₂-; And

R wherein ₇Be selected from alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl.

Formula X peptide comprises at least one R ₇Group is and if exist a plurality of R ₇, R so ₇Can be identical or different.

Another embodiment is isolating formula I polypeptide, wherein X _Aa1Be the L-Histidine, and wherein terminal amino group is optional is replaced by following group: hydrogen, alkyl, dialkyl group, acyl group, benzoyl, L-lactoyl, alkyl oxy carbonyl, aryloxy carbonyl, arylalkyl oxygen base carbonyl, heterocyclyloxy base carbonyl, heteroarylalkyl oxygen base carbonyl, alkylcarbamoyl group, aromatic yl ammonia methanoyl, arylalkyl carbamyl, heterocyclic radical alkylsulfonyl, alkyl sulphonyl, aryl sulfonyl, aryl alkylsulfonyl, heteroarylalkyl alkylsulfonyl or heteroarylsulfonyl.

Another embodiment is isolating formula I polypeptide, wherein X _Aa1Be selected from L-His, L-N-methyl-His, L-Alpha-Methyl-His, deaminizating-His, 3-(1H-imidazol-4 yl)-2-methylpropionyl and (S)-3-(1H-imidazol-4 yl)-2-hydroxyl propionyl (L-β-imidazole emulsion acyl group).

Another embodiment is isolating formula I polypeptide, wherein X _Aa2Be selected from alpha-amino group-isopropylformic acid (Aib), D-L-Ala, N-methyl D-L-Ala, Alpha-Methyl-(L)-proline(Pro), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid.

Another embodiment is isolating formula I polypeptide, wherein X _Aa3Be selected from L-L-glutamic acid and L-aspartic acid.

Another embodiment is isolating formula I polypeptide, wherein X _Aa4Be Gly (glycine).

Another embodiment is isolating formula I polypeptide, wherein X _Aa5Be selected from L-Thr (L-Threonine) and L-Nva (L-norvaline).

Another embodiment is isolating formula I polypeptide, wherein X _Aa6Be selected from L-α-Me-Phe (L-Alpha-Methyl-phenylalanine), L-α-Me-2-fluoro-Phe and L-α-Me-2,6-two fluoro-Phe.

Another embodiment is isolating formula I polypeptide, wherein X _Aa7Be L-Thr.

Another embodiment is isolating formula I polypeptide, wherein said X _Aa8Be selected from L-Ser and L-His.

Another embodiment is isolating formula I polypeptide, wherein said X _Aa9Be L-Asp (L-aspartic acid).

Another embodiment is isolating formula I polypeptide, and is wherein such suc as formula II, X _Aa10Be selected from 4-phenyl-phenylalanine, 4-[(4 '-methoxyl group-2 '-ethyl) phenyl] phenylalanine, 4-[(4 '-oxyethyl group-2 '-ethyl) phenyl] phenylalanine, 4-[(4 '-methoxyl group-2 '-methyl) phenyl] phenylalanine, 4-[(4 '-oxyethyl group-2 '-methyl) phenyl] phenylalanine, 4-(2 '-ethylphenyl) phenylalanine, 4-(2 '-aminomethyl phenyl) phenylalanine, 4-[(3 ', 5 '-dimethyl) phenyl] phenylalanine and 4-[(3 ', 4 '-dimethoxy) phenyl] phenylalanine.

Another embodiment is isolating formula I polypeptide, wherein X _Aa11For being selected from following amino acid: (S)-2-amino-5-phenyl valeric acid, (S)-2-amino-4-phenoxybutyhc, (S)-2-amino-5-(4-chloro-phenyl-) valeric acid, (S)-2-amino-5-(quinoline-5-yl) valeric acid and (S)-2-amino-4-(2-chlorophenoxy) butyric acid; The terminal carbonyl carbon of wherein said amino acid whose C-links to each other with nitrogen and forms methane amide (NH ₂); And R wherein ₆Be selected from hydrogen and methyl.

Embodiment preferred is isolating formula XI polypeptide:

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, 2-methyl-azetidine-2-carboxylic acid, pipecoline-2-carboxylic acid and α-An Jiyidingsuan (Aib);

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be selected from hydrogen, methyl and ethyl;

R ₃Be selected from hydrogen, hydroxyl, methoxyl group and oxyethyl group;

Z is selected from CH ₂And O;

Wherein encircle A and be selected from aryl and heteroaryl;

R ₄Be selected from hydrogen, fluorine, methyl and ethyl;

R ₅Be selected from hydrogen, methyl and methoxyl group; And

R ₆Be selected from hydrogen and methyl.

Preferred embodiment is isolating formula XII polypeptide, wherein

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro and α-An Jiyidingsuan (Aib);

X is a fluorine;

Y is a hydrogen;

Z is selected from CH ₂And O;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be ethyl;

R ₃Be methoxyl group;

R ₄Be selected from hydrogen, methyl and ethyl;

R ₅Be selected from hydrogen, methyl and ethyl; And

R ₇Be selected from hydrogen.

Another embodiment preferred is isolating formula XII polypeptide:

Formula XII

Wherein

R ₇Be selected from methyl, ethyl,

With

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

Ring A is selected from aryl and heteroaryl;

Z is selected from CH ₂And O;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be methyl or ethyl;

R ₃Be selected from hydrogen, methyl, ethyl and methoxyl group;

R ₄And R ₅Be selected from hydrogen, methyl, ethyl, aryl, halogen or alkoxyl group; And

R ₆Be selected from hydrogen and methyl.

Another embodiment is isolating formula XIII polypeptide:

Formula XIII

Wherein

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro, 2-methyl-azetidine-2-carboxylic acid, pipecoline-2-carboxylic acid and aminoisobutyric acid (Aib);

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be selected from hydrogen, methyl and ethyl;

R ₃Be selected from hydrogen, hydroxyl, methoxyl group and oxyethyl group;

R ₄Be selected from hydrogen or methyl;

R ₅Be selected from hydrogen, halogen, methyl, ethyl, alkyl, hydroxyl, methoxyl group, alkoxyl group, aryl, heteroaryl, alkylaryl and miscellaneous alkyl aryl; And

Described compound can contain at least one R ₅Group is and if exist a plurality of R ₅, R so ₅Can be identical or different.

Another embodiment is isolating formula XIV polypeptide:

Formula XIV

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, 2-methyl-azetidine-2-carboxylic acid, pipecoline-2-carboxylic acid and α-An Jiyidingsuan (Aib);

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be selected from hydrogen, methyl and ethyl;

R ₃Be selected from hydrogen, hydroxyl, methoxyl group and oxyethyl group;

R ₄Be selected from hydrogen and methyl;

R ₅Be selected from alkyl, assorted alkyl, cycloalkyl or Heterocyclylalkyl.

Preferred embodiment is the isolating polypeptide that is selected from formula XIV polypeptide, wherein

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro and α-An Jiyidingsuan (Aib);

X is a fluorine;

Y is a hydrogen;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be ethyl;

R ₃Be methoxyl group;

R ₄Be selected from hydrogen and methyl;

R ₅Be selected from methyl, ethyl, propyl group, butyl, hexyl, cyclohexyl and methylcyclohexyl;

R ₄And R ₅Form circular part (cyclic moiety) together, include, but is not limited to pentamethylene and hexanaphthene.

Another embodiment preferred is isolating formula XV polypeptide:

Formula XV

Wherein

R ₈Be selected from hydrogen, hydroxyl, methyl and alkyl;

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

Z is selected from CH ₂And O;

Ring A is selected from aryl and heteroaryl;

R ₂Be methyl or ethyl;

R ₃Be selected from hydrogen, methyl, methoxyl group and ethyl;

R ₄And R ₅Be selected from hydrogen, methyl, ethyl, aryl, halogen or alkoxyl group; And

R ₆Be selected from hydrogen and methyl.

Another embodiment preferred is isolating formula XV polypeptide, wherein

R ₈Be selected from hydrogen and methyl;

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro and α-An Jiyidingsuan (Aib);

X is a fluorine;

Y is a hydrogen;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be ethyl;

R ₃Be methoxyl group;

R ₄Be selected from methyl and ethyl;

R ₅Be hydrogen; And

R ₆Be selected from hydrogen and methyl.

Another embodiment is isolating formula XVI polypeptide:

Formula XVI

Wherein

R ₉Be selected from methyl, ethyl, With

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be methyl or ethyl;

R ₃Be selected from hydrogen, methyl, ethyl and methoxyl group;

R ₄Be selected from hydrogen, methyl, ethyl, alkyl, aryl or alkoxyl group;

X wherein ₁Be selected from CH ₂, CH ₂CH ₂Or CHCH ₃

Y wherein ₁Be selected from-NH-,-O-and-C=O-;

Wherein if Y ₁Be NH or O, then Y ₂Be selected from-C=O-,-O=C-O-and-SO ₂-;

Wherein if Y ₁Be C=O, then Y ₂Be selected from-NH-,-N-or-O-; And

R wherein ₆Be selected from hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl.

Formula XVI peptide comprises at least one R ₆Group is and if exist a plurality of R ₆, R so ₆Can be identical or different.

Another embodiment is isolating formula XVII polypeptide:

Formula XVII

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be ethyl;

R ₃Be methoxyl group;

R ₄Be selected from hydrogen and methyl;

R ₅Be methyl;

R ₆Be selected from alkyl, assorted alkyl, cycloalkyl and Heterocyclylalkyl.

Another embodiment is isolating formula XVIII polypeptide:

Formula XVIII

Wherein

R ₁₀Be selected from hydrogen, hydroxyl, methyl and alkyl;

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be methyl or ethyl;

R ₃Be selected from hydrogen, methyl, methoxyl group and ethyl;

R ₄Be selected from hydrogen, methyl, ethyl, alkyl, aryl or alkoxyl group;

X wherein ₁Be selected from CH ₂, CH ₂CH ₂Or CHCH ₃

Y wherein ₁Be selected from-NH-,-O-and-C=O-;

Wherein if Y ₁Be NH or O, then Y ₂Be selected from-C=O-,-O=C-O-and-SO ₂-;

Wherein if Y ₁Be C=O, then Y ₂Be selected from-NH-,-N-or-O-; And

R wherein ₆Be selected from hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl.

Formula XVIII peptide also can comprise at least one R ₆Group is and if exist a plurality of R ₆, R so ₆Can be identical or different.

Another embodiment is isolating formula XIX polypeptide:

Formula XIX

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be methyl or ethyl;

R ₃Be selected from hydrogen, methyl, methoxyl group and ethyl;

R ₄Be hydrogen or methyl;

Ring A is selected from cycloalkyl, cycloalkyl aryl, Heterocyclylalkyl or cycloalkyl heteroaryl.

Another embodiment is a formula XX compound:

Formula XX

Wherein

P is hydrogen, fluorenylmethyloxycarbonyl (Fmoc) or tertbutyloxycarbonyl (t-Boc);

Ring A is selected from aryl and heteroaryl;

R is selected from methyl, ethyl, chlorine and fluorine;

R ₆Be selected from hydrogen and methyl;

R ₉Be selected from OH and NH ₂

X is selected from CH ₂, O, NH and S; And

Formula XX peptide also can comprise at least one R group, and if have a plurality of R, R can be identical or different so.

Another embodiment is a formula XXI compound:

Formula XXI

Wherein

P is hydrogen, fluorenylmethyloxycarbonyl (Fmoc) or tertbutyloxycarbonyl (t-Boc);

R is selected from methyl, ethyl, chlorine and fluorine;

R ₆Be selected from hydrogen and methyl;

R ₉Be selected from OH and NH ₂

R ₁₀And R ₁₁Be selected from hydrogen, ethyl or methyl separately;

X is selected from CH ₂, O, NH and S; And

Formula XXI molecule also can comprise at least one R group, and if have a plurality of R, R can be identical or different so.

Embodiment preferred comprises 11 chain links (11-mer) to 15 chain link peptides, and described polypeptide in conjunction with and activate the GLP-1 acceptor.

The application has described the method for the polypeptide of preparation simulation GLP-1 receptor agonist activity.

The described synthetic compound of the application has the ability of simulation GLP-1 peptide biological activity, is preferred for simulating natural GLP-1 activity.These synthetic GLP-1 stand-in demonstrate character in the body of expectation, thereby make it become ideal to be used for treatment material standed for oral or administered parenterally (parenteral administration).

The application has further described isolating formula I polypeptide, and wherein said polypeptide is a pancreas glucagon sample peptide-1-derivative, is preferably glucagon-like peptide-1 derivatives.

The application has further described the isolating peptide that comprises core sequence, and described core sequence is selected from: Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of 2-amino-valeramide; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of 2-amino-butyramide; Thr-His-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of 2-amino-butyramide; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of urea; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaComprise Glu (L-L-glutamic acid); Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of 2-amino-propionic acid; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of 3-amino-succinic diamide; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of 2-amino-propionic acid amide; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of oxopropyl mephenesin Carbamate; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of Isonicotinamide (isonicotinamide); Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of picoline acid amides (methylpicolinamide); Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor further comprising the amino acid of 1-or 2-aminohexanoic acid, carboxylic acid, sad, capric acid, butyric acid, valeric acid and olefin(e) acid (enoicacid); And Thr-Ser-Asp-Bip-X _Aa, X wherein _AaComprise the amino acid that at least one links to each other with benzyl; Wherein said isolating peptide comprises described core sequence, and its combination also activates the GLP-1 acceptor.

The application has further described formula I compound, used the pharmaceutical composition of these compounds and has used these compounds and method for compositions.Especially, the invention provides pharmaceutical composition, its comprise separately or with the formula I compound of the treatment significant quantity of pharmaceutically acceptable carrier combination.

The application further provides treatment or delays the progress of following disease or the method for outbreak: diabetes, especially type ii diabetes comprise diabetic complication, for example retinopathy, neuropathy, ephrosis and the wound healing that delays; And relative disease, for example insulin resistant (glucose stable state impaired (impaired glucose homeostasis)), hyperglycemia, hyperinsulinemia, lipid acid or the raising of glycerine blood levels, obesity, hyperlipidaemia (comprising hypertriglyceridemia), X syndrome, atherosclerosis and hypertension and hdl level improve; In described method, Mammals (for example human) patient of the formula I compound administration of significant quantity in the needs treatment will be treated.

Compound of the present invention can use separately, with other compound coupling of the present invention, or with the described treatment of the application field in one or more other active medicine couplings.

In addition, such as in context definition, the application provides the method for treatment diabetes and relative disease, wherein with the combination medicine-feeding of the treatment significant quantity of formula I compound and at least a other type medicine (for example antidiabetic medicine, blood lipid-lowering medicine or anti-obesity medicine) in the human patients of needs treatment.

Description of drawings

Fig. 1 has shown that subcutaneous injection SEQ ID NO:1 peptide is to the influence of plasma glucose in ob/ob ip in mice GTT model.

Embodiment

Definition

Unless restricted in addition in specific example, the definition that the application provided is applicable to but is not limited to the employed term of this specification sheets in the whole text.

The technician in amino acid and chemistry of peptides field knows that amino acid comprises the compound that following general formula is represented:

L-or S-a-amino acid D-or R-a-amino acid

(if R=H) (if R=H)

Wherein R and R ' describe as the application.Except as otherwise noted, amino and carboxyl that the application uses separately or includes but not limited to as the term " amino acid " that the part of another group is used to link to each other with the same carbon that is called " α " carbon, wherein R and/or R ' can be natural or non-natural side chains, comprise hydrogen.Absolute " S " configuration of " α " carbon is commonly referred to " L " or " natural " configuration.All equal under the situation of hydrogen at R and R ' substituting group, described amino acid is glycine, and is not chirality.

Except as otherwise noted, the application uses separately or includes but not limited to natural or non-natural amino acid as the term " amino-alcohol " that the part of another group is used, wherein carboxyl is replaced (reduction) to be methylol, for example valerian ammonia alcohol (valinol), glycinol (glycinol), Propanolamine (alaninol), the pure and mild heteroaryl Propanolamine of arylprop ammonia.

Except as otherwise noted, the application uses separately or includes but not limited to contain 1 to 40 preferred 1 to 20 carbon of the carbon more preferably straight chain and the branched-chain hydrocarbon of 1 to 8 carbon as the term " alkyl " that the part of another group is used in normal chain, for example methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl and their various branched chain isomers etc.In addition; the defined alkyl of the application can be chosen wantonly on any available carbon atom and be replaced by one or more functional groups that link to each other with described chain usually; to form such as trifluoromethyl; 3-hydroxyl hexyl; 2-carboxyl propyl group; the 2-fluoro ethyl; the carboxyl methyl; such alkyl such as cyano group butyl, described functional group for example is but is not limited to alkyl; aryl; thiazolinyl; alkynyl; hydroxyl; arylalkyl; cycloalkyl; cycloalkylalkyl; alkoxyl group; arylalkyl oxygen base; heteroaryl oxygen base; heteroarylalkyl oxygen base; alkyloyl; halogen; hydroxyl; sulfo-; nitro; cyano group; carboxyl; carbonyl (

), carbamyl, amino, alkylamino, dialkyl amido, amido, alkylamino, aryl amido, heteroaryl amido, azido-, guanidine radicals, amidino groups, phosphono (phosphonic), inferior phosphono (phosphinic), alkylsulfonyl (sulfonic), sulfonamido, halogenated aryl, CF ₃, OCHF ₂, OCF ₃, aryloxy, heteroaryl, cycloalkyl alkoxy alkyl, the assorted alkyl of ring etc.

Except as otherwise noted, the application uses separately or includes but not limited to contain 2 to 40 carbon and one or more pairs of preferred 2 to 20 carbon of key and one to three two key more preferably straight chain and the branched-chain hydrocarbon of 2 to 8 carbon and one or two pair key as the term " thiazolinyl " that the part of another group is used in normal chain, such as above just " alkyl " description, any carbon can be chosen wantonly and be substituted.

Except as otherwise noted, the application uses separately or includes but not limited to contain 2 to 40 carbon and preferred 2 to 20 carbon of one or more three key and one to three three key more preferably straight chain and the straight chain hydrocarbon of 2 to 8 carbon and one or two three key as the term " alkynyl " that the part of another group is used in normal chain, such as above just " alkyl " description, any carbon can be chosen wantonly and be substituted.

Except as otherwise noted, the application uses separately or includes but not limited to contain the saturated of 1 to 3 ring (additional or condense) or part is unsaturated (containing 1 or 2 pair of keys) cyclic hydrocarbon as the term " cycloalkyl " that the part of another group is used, comprise monocycle alkyl, bicyclic alkyl and tricyclic alkyl, contain 3 to 30 one-tenth ring carbon atoms altogether, preferred 4 to 7 carbon form a ring; Described cycloalkyl can with condense with regard to described 1 aromatic ring of aryl, described cycloalkyl comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring decyl, cyclo-dodecyl, cyclohexenyl,

Any described group can be chosen wantonly on any available carbon atom by one or more and be selected from following group and replace: hydrogen, halogen, haloalkyl, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, thiazolinyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, fluorenyl, Heterocyclylalkyl, the Heterocyclylalkyl alkyl, aryl, heteroaryl, arylalkyl, aryloxy, aromatic yloxy yl alkyl, alkoxy aryl, artyl sulfo, the arylazo base, heteroarylalkyl, the heteroaryl thiazolinyl, the heteroaryl heteroaryl, heteroaryl oxygen base, hydroxyl, nitro, oxo, cyano group, carboxyl, carbonyl (

); carbamyl; amino; (wherein said amino comprises 1 or 2 substituting group to the amino that replaces, and described substituting group is an alkyl; aryl or any other aryl compound of in definition, mentioning); amido; azido-; guanidine radicals; amidino groups; phosphono; inferior phosphono; alkylsulfonyl; sulfonamido; sulfydryl; the alkyl sulfenyl; artyl sulfo; the heteroaryl sulfenyl; the artyl sulfo alkyl; the alkoxy aryl sulfenyl; alkyl-carbonyl; aryl carbonyl; alkyl amino-carbonyl; aromatic yl aminocarbonyl; alkoxy carbonyl; aminocarboxyl; the alkyl-carbonyl oxygen base; aryl carbonyl oxygen base; alkyl-carbonyl-amino; aryl-amino-carbonyl; aryl sulfonyl kia; the aryl sulfonyl kia alkyl; arlysulfonylamino or Arenesulfonyl amino carbonyl or any alkyl substituent listed above.

Term " aryl " expression that the application uses separately or uses as the part of another group but be not limited in loop section, contain the monocycle and the bicyclic aromatic group of 6 to 10 carbon (for example phenyl or naphthyl); and can choose wantonly comprise 1 to 3 with other ring of " aryl " condensed (aryl for example; cycloalkyl; heteroaryl or heterocycloalkyl ring); and can choose wantonly on any available carbon atom by one or more and be selected from following group and replace: hydrogen; alkyl; halogen; haloalkyl; alkoxyl group; halogenated alkoxy; thiazolinyl; trifluoromethyl; trifluoromethoxy; alkynyl; cycloalkylalkyl; fluorenyl; Heterocyclylalkyl; the Heterocyclylalkyl alkyl; aryl; heteroaryl; arylalkyl; aryloxy; aromatic yloxy yl alkyl; alkoxy aryl; artyl sulfo; the arylazo base; heteroarylalkyl; the heteroaryl thiazolinyl; heteroaryl oxygen base; heteroarylalkyl oxygen base; heteroarylalkyl oxygen base alkyl; hydroxyl; nitro; oxo; cyano group; amino; (wherein said amino comprises 1 or 2 substituting group to the amino that replaces, and described substituting group is an alkyl; cycloalkyl; Heterocyclylalkyl; heteroaryl or aryl or any other aryl compound of in definition, mentioning); sulfydryl; the alkyl sulfenyl; artyl sulfo; the heteroaryl sulfenyl; the artyl sulfo alkyl; the alkoxy aryl sulfenyl; alkyl-carbonyl; aryl carbonyl; alkyl amino-carbonyl; the cycloalkyl amino carbonyl; aromatic yl aminocarbonyl; the heteroaryl amino carbonyl; the heteroarylalkyl aminocarboxyl; alkoxy carbonyl; aminocarboxyl; the alkyl-carbonyl oxygen base; aryl carbonyl oxygen base; alkyl-carbonyl-amino; aryl-amino-carbonyl; aryl sulfonyl kia; the aryl sulfonyl kia alkyl; arlysulfonylamino or Arenesulfonyl amino carbonyl or any alkyl substituent listed above.

The application uses or includes but not limited to have as the term " arylalkyl " that the part of another group is used the alkyl as defined above of an aryl substituent separately, for example benzyl, styroyl or naphthyl propyl group, wherein said aryl and/or alkyl can be chosen wantonly as above, and definition is substituted.

The alkyl or aryl as defined above that the application uses separately or includes but not limited to as term " alkoxyl group ", " aryloxy ", " heteroaryl oxygen base ", " arylalkyl oxygen base " or " heteroarylalkyl oxygen base " that the part of another group is used to connect by Sauerstoffatom.

The employed term of the application " heterocycle ", " heterocyclic radical " or " heterocyclic " expression but be not limited to the first monocycle ring system of stable 4-, 5-, 6-or 7-that do not replace or replaces, it can be saturated or undersaturated, and is selected from nitrogen, sulphur, oxygen and/or SO or SO by carbon atom and one to four ₂The heteroatoms of group is formed, and wherein nitrogen and sulfur heteroatom can be chosen wantonly oxidizedly, and nitrogen heteroatom can be chosen wantonly by quaternized.Can on any heteroatoms of facilitating rock steady structure to form or carbon atom, connect heterocycle.The example of described heterocyclic group includes but not limited to tetrahydrofuran base, tetrahydro-thienyl, pyrrolidyl, piperidyl, piperazinyl, oxo-pyrrolidine base, oxo piperazinyl, oxo-piperidine Ji He oxadiazole base.Heterocyclic group can be chosen wantonly by one or more functional groups (for example with regard to " alkyl " or " aryl " described functional group) and replace.

The application is separately or term " Heterocyclylalkyl " expression of using as the part of another group but be not limited to have the substituent alkyl as defined above of Heterocyclylalkyl, and is wherein said " heterocycle " and/or alkyl can be chosen wantonly as above, and definition replaces.

The employed term of the application " heteroaryl " is represented but is not limited to contain one or more nitrogen, sulphur, oxygen and/or SO or SO of being selected from ₂Heteroatomic 5-, the 6-of group or 7-unit aromatic heterocycle.Described ring can condense with another aryl rings or heteroaryl ring.And comprise possible N-oxide compound.The example of described heteroaryl includes but not limited to furans, pyrroles, thiophene, pyridine, pyrimidine, pyrazine, pyridazine, isoxazole, oxazole, imidazoles etc.Heteroaryl can be chosen wantonly by one or more functional groups that link to each other with described chain usually (for example with regard to " alkyl " or " aryl " described functional group) and replace.

Term " heteroarylalkyl " expression that the application uses separately or uses as the part of another group but be not limited to have the substituent alkyl as defined above of heteroaryl, wherein said heteroaryl and/or alkyl can be chosen wantonly as above, and definition replaces.

The alkyl as defined above that term " alkoxy carbonyl " expression that the application uses separately or uses as the part of another group but be not limited to links to each other with oxygen on-OC (O)-group, for example CH ₃OC (O)-, CH ₃CH ₂OC (O)-or CH ₂(OH) CH ₂OC (O)-.

The aryl as defined above that term " aryloxy carbonyl " expression that the application uses separately or uses as the part of another group but be not limited to links to each other with oxygen on-OC (O)-group.

The arylalkyl as defined above that term " the arylalkyl oxygen base carbonyl " expression that the application uses separately or uses as the part of another group but be not limited to links to each other with oxygen on-OC (O)-group.

The heterocyclic radical as defined above that term " the heterocyclyloxy base carbonyl " expression that the application uses separately or uses as the part of another group but be not limited to links to each other with oxygen on-OC (O)-group by any carbon atom on the heterocyclic radical.

The heteroarylalkyl as defined above that term " the heteroarylalkyl oxygen base carbonyl " expression that the application uses separately or uses as the part of another group but be not limited to links to each other with oxygen on-OC (O)-group by any carbon atom on the heteroaryl.

The alkyl as defined above that term " alkylcarbamoyl group " expression that the application uses separately or uses as the part of another group but be not limited to links to each other with nitrogen on-NHC (O)-group, for example CH ₃NHC (O)-, CH ₃CH ₂NHC (O)-or (CH ₃) ₂NHC (O)-, and wherein exist 2 alkyl, described alkyl can choose connection wantonly to form 4,5,6 or 7 yuan of rings, for example

Or

The arylalkyl as defined above that term " arylalkyl carbamyl " expression that the application uses separately or uses as the part of another group but be not limited to links to each other with nitrogen on-NHC (O)-group.

The heterocyclic radical as defined above that term " heterocyclic radical carbamyl " expression that the application uses separately or uses as the part of another group but be not limited to links to each other with nitrogen on-NHC (O)-group.

Term " alkyl sulphonyl " expression that the application uses separately or uses as the part of another group but be not limited to and-S (O) ₂The alkyl as defined above that sulphur on the-group links to each other, for example CH ₃S (O) ₂-, CH ₃CH ₂S (O) ₂-or (CH ₃) ₂CHS (O) ₂-.

Term " aryl sulfonyl " expression that the application uses separately or uses as the part of another group but be not limited to and-S (O) ₂The aryl as defined above that sulphur on the-group links to each other.

Term " aryl alkylsulfonyl " expression that the application uses separately or uses as the part of another group but be not limited to and-S (O) ₂The arylalkyl as defined above that sulphur on the-group links to each other.

Term " heteroarylsulfonyl " expression that the application uses separately or uses as the part of another group but be not limited to and-S (O) ₂The heteroaryl as defined above that sulphur on the-group links to each other.

Term " heteroarylalkyl alkylsulfonyl " expression that the application uses separately or uses as the part of another group but be not limited to and-S (O) ₂The heteroarylalkyl as defined above that sulphur on the-group links to each other.

Term " receptor modulators " expression acts on the GLP-1 acceptor and regulates the compound of the ability of downstream signal conduction incident to change the GLP-1 acceptor.The example of receptor modulators comprises standard pharmacology textbook (E.M.Ross and T.P.Kenakin in Goodman andGilman ' s The Pharmacological Basis of Therapeutics for example, 10th Ed., Chapter2, pp.31-43, McGraw Hill, NewYork (2001)) defined agonist, antagonist, partial agonist, inverse agonist, allosteric antagonist and allosteric potentiators in.

Those skilled in the art can easily understand among the present invention and this area in the implication of these terms of being provided.

Term " diabetes and relative disease or associated conditions " is represented but is not limited to type ii diabetes, type i diabetes, glucose tolerance reduction, obesity, hyperglycemia, X syndrome, dysmetabolic syndrome, diabetic complication and hyperinsulinemia.

The employed term of the application " accent fat " or " lipopenicillinase " medicine are represented but the medicine that is not limited to have following mechanism: reduce LDL and/or improve HDL and/or other mechanisms known of triglyceride reducing and/or reducing total cholesterol and/or the disorder of treatment lipid.

The medication of medicine of the present invention includes but not limited to the medicine of the present invention of drug treatment significant quantity.The employed term of the application " treatment significant quantity " expression but be not limited to the amount of medicine, it treats or prevents medicable illness by administration composition of the present invention.Described amount is enough to demonstrate detectable therapeutic action or prophylactic effect or improvement effect.Described effect can comprise such as but not limited to listed treatment of conditions effect of the application or prophylactic effect.The accurate significant quantity that is used for the experimenter depend on the experimenter size and healthy, the sanatory nature and extent of institute, treat doctor's suggestion and the therapy that selection is used for administration or the combination of therapy.Thereby, illustrate that in advance definite significant quantity is otiose.

Described compound of the application and analogue thereof can utilize various solid phase techniques to prepare by chemosynthesis, described solid phase technique is referring to for example G.Barany and R.B.Merrifield, The Peptides:Analysis, Synthesis, Biology, Vol.2, " Special Methods inPeptide Synthesis, Part A ", pp.3-284, E.Gross and J.Meienhofer, eds., Academic Press, New York (1980) and J.M.Stewart and J.D.Young, SolidPhase Peptide Synthesis, 2nd Ed., Pierce Chemical Co., Rockford, IL, (1984).Expectation strategy used in the present invention is used for the alpha-amino temporary protection while tertiary butyl based on Fmoc (9-fluorenylmethyloxycarbonyl) group and is used for the temporary protection of amino acid side chain (referring to for example E.Atherton and R.C.Sheppard; " The FluorenylmethoxycarbonylAmino Protecting Group "; in The Peptides:Analysis; Synthesis; Biology; Vol.9; " Special Methods in Peptide Synthesis; PartC "; pp.1-38, S.Undenfriend and J.Meienhofer, eds.; Academic Press, SanDiego (1987)).

Compound of the present invention can be gone up from the terminal beginning of the C-of compound at insoluble polymer carrier (support) (being also referred to as " resin ") and synthesize in mode progressively.Formation by amido linkage or ester bond is hung (append) on resin with the C-end amino acid of peptide, begins thus to synthesize.This makes the resulting peptide of final release be respectively C-terminal amide or carboxylic acid.

Synthetic employed C-end amino acid and all other amino acid all need to make their alpha-amino group and side chain functionalities (if existence) differentially protected, thereby can optionally remove the alpha-amino group protecting group in building-up process.Amino acid whose coupling is carried out by the following method: activate its carboxyl and make it to become active ester, and make itself and (unblocked) alpha-amino group reaction of separating resistance that is suspended on the-terminal amino acid on the resin.Repeat the amino deprotection and the coupling of said sequence, up to assembling out whole peptide sequence.From the resin release peptide, carry out the deprotection of side chain functionalities simultaneously then, this carries out in the presence of suitable scavenging agent usually, with the restriction side reaction.Resulting peptide comes purifying by reversed-phase HPLC at last.

Needed peptidyl-resin as precursor to final compound synthetic utilize commercially available crosslinked polystyrene polymer resin (Novabiochem, San Diego, CA and AppliedBiosystems, Foster City, CA).For the terminal carboxylic acid amides of C-; preferred solid carrier used in the present invention is 4-(2 '; 4 '-Dimethoxyphenyl-Fmoc-amino methyl)-the phenoxy group ethanoyl-to methyldiphenyl methylamine resin (Rink acid amides mbha resin), 9-Fmoc-amino-xanthene-3-base oxygen base-Merrifield resin (Sieber amide resins) and 4-(9-Fmoc) amino methyl-3,5-dimethoxy phenoxy group) pentanoyl-amino methyl-Merrifield resin (PAL resin).First amino acid and amino acid whose subsequently coupling can utilize HOBT or HOAT active ester to realize, described HOBT or HOAT active ester prepare from DIC/HOBT, HBTU/HOBT, BOP or PyBOP respectively, or prepare from DIC/HOAT or HATU/HOAT.For shielded peptide fragment, preferred solid carrier used in the present invention is 2-chlorine trityl chloride resin and 9-Fmoc-amino-xanthene-3-base oxygen base-Merrifield resin (Sieber amide resins).First amino acid is loaded on the 2-chlorine trityl chloride resin, and this comes to realize best by the following method: make reacted in methylene dichloride and DIEA by the amino acid and the resin of Fmoc protection.If desired, can add a small amount of DMF to promote amino acid whose dissolving.

The synthetic of the described GLP-1 peptide analogs of the application can utilize peptide synthesizer to carry out, and described peptide synthesizer for example is Advanced Chemtech Multiple PeptideSynthesizer (MPS396) or Applied Biosystems Inc. peptide synthesizer (ABI433A).If use MPS396, can be blended into many 96 compounds so simultaneously.If use the ABI433A synthesizer, can synthesize independent compound continuously so.The solid-phase peptide of all utilizing the described Fmoc/ tertiary butyl protection of the application strategy to carry out progressively in both cases is synthetic.

Be in X _Aa11The non-natural non-commercially available amino acid of position is incorporated in the peptide chain with one of two kinds of methods.In first method, utilize synthetic organic chemistry to operate needed alpha-non-natural amino acid directly is structured on the resin.Replacedly, utilize suitable organic synthesis operation to come the alpha-non-natural amino acid that preparation is protected by Boc or Fmoc in solution.Then in peptide progressively synthetic or in the fragment condensation method, use resulting derivative, to assemble final peptide.When at X _Aa6, X _Aa10Or any other X _AaWhen non-natural non-commercially available amino acid need be introduced in the position, the synthetic needed alpha-non-natural amino acid that is subjected to the Fmoc protection in solution.In solid-phase peptide progressively is synthetic, use resulting derivative then.

The present invention expects to use following shown Fmoc amino acid derivative.

(Orthogonally Protected) amino acid that is subjected to orthogonally protect that is used for solid phase synthesis

The shielded amino acid that is used for solid phase synthesis

Fmoc-Aib Fmoc-Gly Fmoc-Nle Fmoc-Phe

-aminoisobutyric acid--nor-leucine-

Fmoc-Pro Fmoc-(S)-a-methyl-Pro Emoc-hhPhe

-Gao hyperphenylalaninemia-Shi II

Peptidyl-the resin precursor of various peptides can utilize any standard operation come cracking or deprotection (referring to for example D.S.King et al.Int.J.Pept.Protein Res., 36 (3): 255-266 (1990)).In the method for expectation, in the presence of water, use TFA and TIS as scavenging agent.Usually, with peptidyl-resin in room temperature at TFA/ water/TIS (94:3:3, v:v:v; 1mL/100mg peptidyl-resin) stirred 2-6 hour in.Filter out the exhausted resin then, and TFA solution is concentrated or drying under reduced pressure.Resulting thick peptide Et ₂O precipitation and washing, or directly be dissolved in again in DMSO or 50% acetic acid aqueous solution, to come purifying by preparation property HPLC.

Can utilize preparation property HPLC (for example on Waters Model 4000 or ShimadzuModel LC-8A liquid chromatography) to carry out the compound that purifying obtains having expectation purity.Crude product in solution is expelled to YMC S5 ODS, and (in 20 * 100mm) posts, and with the MeCN aqueous solution (MeCN and water all cushion with the 0.1%TFA) wash-out of linear gradient, flow velocity is 14-20mL/min, and elutriant absorbs by the UV at 220nm monitors.The structure of the compound of purifying can be analyzed by electron spray(ES) MS and prove conclusively.

Abbreviation

Embodiment and other abbreviation below local use in the application:

Ph=phenyl Bn=benzyl i-Bu=isobutyl-i-Pr=sec.-propyl Me=methyl Et=ethyl Pr=n-propyl Bu=normal-butyl O-Bu tOr trimethyl silicon based TIS of OtBu=tertiary butyl TMS=or TIPS=tri isopropyl silane Et 2O=ether HOAc or AcOH=acetate AcCN or MeCN or CH 3CN=acetonitrile EtOAc=ethyl acetate THF=tetrahydrofuran (THF) TFA=trifluoroacetic acid TFE=α, α, α-trifluoroethanol

DMA=N, N-N,N-DIMETHYLACETAMIDE DMAP=4-(dimethylamino) pyridine DMF=N, dinethylformamide EDAC=3-ethyl-3 '-(dimethylamino) propyl group-carbodiimide hydrochloride (or 1-[(3-(dimethyl) amino) propyl group])-the 3-ethyl-carbodiimide hydrochloride) Fmoc or FMOC=fluorenylmethyloxycarbonyl GTT=glucose tolerance test HATU=O-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-fluorophosphate HBTU=2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-phosphoric acid salt HCTU=2-(6-chloro-1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-hexafluorophosphate HOAT=1-hydroxyl-7-azepine benzotriazole HOBT or HOBTH 2O=1-hydroxy benzotriazole hydrate HPLC=high performance liquid chromatography IP or ip=intraperitoneal LC/MS=high performance liquid chromatography/mass spectrum

Et 2NH=diethylamine NMM=N-methylmorpholine DCM=methylene dichloride n-BuLi=n-Butyl Lithium Pd/C=palladium/carbon PtO 2Min=minute h of=platinum oxide TEA=triethylamine or hr=hour L=rise mL or ml=milliliter μ L=microlitre g=gram mg=milligram mol=mole mmol=mmole meq=milliequivalent rt or RT=room temperature sat or assorted two ring [3.3.1] nonane Boc or the BOC=tertbutyloxycarbonyl DIAD=diisopropyl azo-2-carboxylic acids of the saturated aq.=aqueous solution of sat ' d=mp=fusing point Bip=biphenylalanine Trt=trityl 9-BBN=9-boron

LiBH 4=lithium borohydride MS or Mass Spec=mass spectrum NMP=N-methyl pyrrolidone=1-Methyl-2-Pyrrolidone NMR=nuclear magnetic resonance PyAOP reagent=(7-azepine benzo triazol-1-yl oxygen base) three (pyrrolidinyl) Phosphonium hexafluorophosphate PyBOP reagent=BTA-1-base oxygen base-tripyrrole alkane base Phosphonium hexafluorophosphate Sc or the subcutaneous TLC=thin-layer chromatography of SC=Cbz=benzyl oxygen base carbonyl Cl-HOBt=6-chloro-BTA DIC=N, N '-DIC DIEA=diisopropylethylamine bop reagent=BTA-1-base oxygen base-three (dimethylamino)-Phosphonium hexafluorophosphate (Castro reagent)

Characterize by mass spectrum

Every kind of compound all passes through electrospray ionization mass spectrum (ES-MS) (flow injection pattern or LC/MS pattern) and characterizes.In analyzing, all use the single quadrupole mass spectrometer of Finnigan SSQ7000 (single quadrupole mass spectrometer) (ThermoFinnigan, San Jose, CA) (cation electrodeposition spray pattern and anionic electrodeposition spray pattern).In 300 to 2200amu mass range, obtain complete scan-data, and be 1.0 seconds sweep time.Operate four utmost points with the unit resolution rate.For flow injection analysis, with mass spectrograph and Waters 616 HPLC pumps (Waters Corp., Milford, MA) interface, and be equipped with HTS PAL automatic sampler (CTC Analytics, Zwingen, Switzerland).Sample is expelled to contains 50:50 water: in the moving phase of acetonitrile (containing 0.1% ammonium hydroxide).The flow velocity that is used to analyze is 0.42mL/min, and volume injected is 6 μ l.In all cases, the molecular weight of experiment measuring is all in 0.5 dalton of the list that is calculated-isotopic molecule amount.

Embodiment 1

Utilize Applied Biosystems Model 433A peptide synthesizer to come solid phase synthesis 11 chain link peptide analogs

Below be general description to the described peptide analogs solid phase synthesis of the application, the Applied Biosystems Model 433A peptide synthesizer of described synthetic use upgrading.The synthesizer hardware and software of upgrading can carry out electric conductivity monitoring (conductivitymonitor) to the Fmoc deprotection steps, so that feedback control is carried out in coupling.The synthetic scale that this scheme allowed is 0.05 to 1.0mmol.

Can utilize embodiment 2-5 the operation described to introduce two kinds of non-natural C-end amino acids.It is synthetic that the two peptidyls-resin that protected by Fmoc is used for described ABI.To be added in the container of suitable size on the instrument by the two peptidyls-resin (0.1mmol) of Fmoc protection,, come deprotection by handling twice (being respectively 2 minutes and 8 minutes) then with 22% pyridine/NMP with NMP washing six times.Carry out once again or deprotection steps that secondary is monitored, up to the condition (being last twice difference＜10%) that satisfies the monitoring option based on the deprotection peak of electric conductivity.Total deprotection time is 10-12 minute.Two peptidyls of deprotection-resin is with NMP washing six times, then with next amino acid coupling.

Utilize following method to come coupling Fmoc-Asp (OtBu)-OH: with Fmoc-Asp (OtBu)-OH (1mmol, 10 equivalents) be dissolved among the 2mL NMP, activate by DMF (2.2mL) solution and the 2MDIEA/NMP (1mL) that successively adds 0.45M HBTU/HOBt then.Transferred in the reaction vessel by the amino acid whose solution of Fmoc protection, and carry out coupling, continue 30 to 60 minutes, coupling time depends on the feedback to deprotection steps.Resin washs six times with NMP then, and again it is carried out eight aforesaid deprotection/coupling circulations, so that finish the assembling of expectation sequence.The Fmoc-amino acid that successively uses is Fmoc-Ser (tBu)-OH, Fmoc-Thr (tBu)-OH, Fmoc-Alpha-Methyl-Phe (2-fluorine)-OH or its analogue, Fmoc-Thr (tBu)-OH, Fmoc-Gly-OH, Fmoc-Glu (OtBu)-OH, Fmoc-Aib-OH and Fmoc-His (Trt)-OH.Remove the Fmoc group with the nmp solution of 22% piperidines as mentioned above, peptidyl-resin washs vacuum-drying then six times with NMP and DCM.

Replacedly; use the coupling scheme of changing, activated by DMF (0.52mL) solution and the DIC (40 μ L) that successively adds 0.5M HOAt by the amino acid (0.26mmol) of Fmoc protection, transfer in the reaction vessel; carry out coupling then, continue 14-18 hour.

Cracking/deprotection

By handling with TFA/ water/tri isopropyl silane (96:2:2) solution (3.0mL) to come in two hours the peptide of expectation is carried out cracking/deprotection from various peptidyl-resins.Filter out resin,, then the TFA filtrate that merges is added to 35mL Et with TFA (1.0mL) washing ₂Among the O.Resulting throw out is collected by centrifugal, and is dry then, obtains the thick peptide prod of 100-300mg, is white solid.Product comes purifying by preparation property HPLC.Employed gradient is for to last 40 minutes from 15% to 45% (the 0.1%TFA/ aqueous solution of 0.1%TFA/MeCN).The cut that will contain pure products merges, and freeze-drying then obtains the 10-30mg pure products.

Embodiment 2

Synthesis type II and formula III are represented is in X _Aa10The biphenylalanine analogue of position and be in X _Aa11The high hyperphenylalaninemia analogue of position

In these analogues, be in X _Aa10Position and be in X _Aa11The residue of position represents to be biphenylalanine (biphenylalanine) analogue (Bip analogue) or assorted biphenylalanine (hetero-biphenylalanine) analogue or high hyperphenylalaninemia (homohomophenylalanine) analogue (hhPhe analogue) by the formula II and the formula III amino acid analogue that replace, for the title analogue, utilize one of following method that they are incorporated in the peptide chain.

1. preparation is at X _Aa11The general operation (hydroboration-Su Chuji (Suzuki) coupling) (scheme 1) of amino acid whose Rink acid amides mbha resin shown in the formula III is contained in the position

Scheme 1

A. work as X in the formula III ₁=X ₂General operation during=C

With polystyrene-Rink acid amides mbha resin (the loading level is 640 μ mol/g for 800mg, 512 μ mol) in strainer tube at CH ₂Cl ₂Swelling is ten minutes (8.0mL).Resin is drained, transfer to then in the 20mL scintillation vial.After the transfer, (9.00mL) is added in the resin with the 8:2DMF/ piperidines.With the bottle capping, then content was stirred 90 minutes.Then with resin transfer in strainer tube, drain, use then DMA (3 * 8mL), MeOH (3 * 8mL) and CH ₂Cl ₂(3 * 8mL) washings.Simultaneously (S)-2-(tertbutyloxycarbonyl) penta-obtusilic acid (165mg, 768 μ mol) is added in the new 20mL scintillation vial.Add 1-hydroxyl-7-azepine benzotriazole (1.37mL, the THF solution of 0.6M, 819 μ mol), add 7mL 3:2DMF/CH subsequently ₂Cl ₂Then add 1,3-DIC (0.128mL, 819 μ mol) was reacted five minutes then.The resin of deprotection is added in the reaction soln.With N, N-diisopropylethylamine (0.357mL, 2048 μ mol) is added in the resin slurries then.With the bottle capping, place spend the night on the orbital shaker (140rpm) (18 hours) then.After 18 hours, resin transfer in strainer tube, is drained, use then DMA (3 * 8mL), MeOH (3 * 8mL) and CH ₂Cl ₂(3 * 8mL) washings.

The 20mL scintillation vial of capping is cooled to 0 ℃ in ice bath.9-BBN (the THF solution of 0.5M, 1.60mL, 800 μ mol) is added in the bottle, adds exsiccant Rink-allyl group Gly-Boc resin (125mg, 80 μ mol) subsequently.Make resin 0 ℃ of reaction 5 minutes.Then bottle is removed from ice bath, and stirred two hours.In reaction process, bottle is carried out the several exhaust, to avoid pressure accumulated.

Open scintillation vial, and from bottle sucking-off solution (not removing resin) as much as possible.In the scintillation vial that contains resin, add 1 then, 4-diox (2.0mL).With K ₃PO ₄Solution (0.400mL; The 2M aqueous solution, 800 μ mol) be added in the bottle.Then aromatic bromide (400 μ mol) is added in the bottle, then bottle is placed N ₂In the atmosphere bag glove (glove bag).In bag glove, tetrakis triphenylphosphine palladium (0) catalyzer (9.2mg, 8.0 μ mol) is added in the bottle simultaneously, and seals with the screw-cap that is lined with tetrafluoroethylene (Teflon).Bottle is heated to 80 ℃ to be stirred 18 hours simultaneously.Bottle is cooled to room temperature, then with resin transfer in strainer tube.Resin is drained, use 1:1DMA/H then ₂O (1 * 2mL), DMA (3 * 2mL), THF (1 * 2mL), MeOH (3 * 2mL) and CH ₂Cl ₂(3 * 2mL) washings.Resulting resin is light yellow.In the Boc deprotection, directly use resin (referring to following general operation) then.

B. remove the general operation (scheme 2) of the Boc protecting group of the terminal α-amine of N-

Scheme 2

R ₄And R ₅The side chain that representative is described in formula III

With polystyrene-Rink-amino acid-Boc resin (50mg, 32 μ mol) in plastics tubing at CH ₂Cl ₂Swelling is ten minutes (0.50mL).Resin is drained, add 10%H subsequently ₂SO ₄1,4-diox (0.50mL) solution reacted 30 minutes then, stirred frequently.Resin is drained, uses 1 then, the 4-diox (2 * 0.5mL), 9:1DMF/Et ₃N (2 * 0.5mL), DMF (3 * 0.5mL), MeOH (3 * 0.5mL) and CH ₂Cl ₂(3 * 0.5mL) washings.This operates in and obtains the terminal α-amine of free N-on polystyrene-Rink resin.

C. make 11 the hhphe analogue link coupled general operation (scheme 3) on 10 amino acids and the Rink acid amides mbha resin

Scheme 3

R ₁, R ₂, R ₃, R ₄And R ₅The side chain that representative is described in formula II and formula III

(213mg, 409 μ mol) are added in the 20mL scintillation vial with Fmoc-L-(4 '-methoxyl group-2 '-ethyl) biphenylalanine.In bottle, add I-hydroxybenzotriazole (75mg, 558 μ mol), be dissolved in 2:1DMF/CH then ₂Cl ₂(5.8mL).In bottle, add PyBOP (232mg, 446 μ mol), reacted then five minutes.Add N in reaction soln, N-diisopropylethylamine (0.192mL, 1116 μ mol) adds the hhPhe resin (600mg, 372 μ mol) of α-amine deprotection then.With the bottle capping, stirred then 24 hours.After 24 hours, with resin transfer in strainer tube, and with (3 * 6mL), MeOH (3 * 6mL) and CH ₂Cl ₂(3 * 6mL) washings.

Embodiment 3

Synthesis type II and formula IV are represented is in X _Aa10The biphenylalanine analogue of position and be in X _Aa11The alpha-non-natural amino acid analogue of position

These analogues have the X of being in _Aa10Position and be in X _Aa11Biphenylalanine analogue (Bip analogue) or assorted biphenylalanine analogue that the formula II and the residue the formula IV amino acid analogue as replacement of position promptly is in 10 and aspartic acid or acid amides, ester, sulphonamide or the anti-acid amides (reverse amide) of L-glutamic acid or the ether or the ester analogs of Serine or Threonine that is in 11, for the title analogue, utilize following method that they are incorporated in the peptide chain.

1. preparation is at X _Aa11The general operation (scheme 4) of the Rink acid amides mbha resin of aspartic acid shown in the formula IV or glutamic acid derivatives is contained in the position

Scheme 4

A. load the general operation of mbha resin

Polystyrene-Rink acid amides mbha resin (the loading level is 640 μ mol/g for 400mg, 256 μ mol) is added in the 20mL scintillation vial, adds 8:2DMF/ piperidines (5.00mL) subsequently.With the bottle capping, then content was stirred 45 minutes.Resin transfer in strainer tube, is drained, use then DMF (3 * 5mL), MeOH (3 * 5mL) and CH ₂Cl ₂(3 * 5mL) washings.Boc-L-Glu (OFm)-OH (218mg, 512 μ mol) is added in the new 20mL scintillation vial.Add I-hydroxybenzotriazole (88.2mg, 576 μ mol), add 4mL 1:1 DMF/CH subsequently ₂Cl ₂Add 1,3-DIC (0.090mL, 576 μ mol) was reacted five minutes then.The resin of deprotection is added in the resulting reaction soln.Add N in the resin slurries, N-diisopropylethylamine (0.178mL, 1020 μ mol) with the bottle capping, places spend the night on the orbital shaker (125rpm) (18 hours) then.After 18 hours, resin transfer in strainer tube, is drained, use then DMF (3 * 5mL), MeOH (3 * 5mL) and CH ₂Cl ₂(3 * 5mL) washings.

B. 11 shielded carboxylicesters side chains are carried out the general operation and the acidylate operation (scheme 5) of deprotection

(25mg, 16 μ mol) are added in the strainer tube with PS-Rink-L-Glu (OFm)-Boc resin, and at 0.50mL CH ₂Cl ₂Middle swelling five minutes.Then resin is drained, in resin, add 8:2DMF/ piperidines (0.50mL).Made resin reaction 45 minutes, and stirred frequently.Then resin is drained, and with DMF (3 * 0.5mL), MeOH (3 * 0.5mL) and CH ₂Cl ₂(3 * 0.5mL) washings.I-hydroxybenzotriazole (12.2mg, 80 μ mol) is added in 1 dram (dram) bottle, and is dissolved in 0.6mL 2:1DMF/CH ₂Cl ₂In.With 1,3-DIC (0.013mL, 80 μ mol) is added in the solution, adds the resin of 25mg deprotection subsequently.Add N, N-diisopropylethylamine (0.017mL, 96 μ mol), and make resulting slurry reaction five minutes.In bottle, directly add amine (80 μ mol),, and react 18 hours gentle simultaneously stirrings then with the bottle capping.Then with resin transfer in strainer tube, drain, use then DMF (3 * 0.5mL), MeOH (3 * 0.5mL) and CH ₂Cl ₂(3 * 0.5mL) washings.

Scheme 5

C. 11 shielded amine side chains are carried out the general operation and the acidylate operation of deprotection

Use is similar to the above operation of describing in general operation A, with Boc-3-Fmoc-L-2, (Boc-L-Dap (Fmoc)-OH) is loaded in polystyrene-Rink resin the 3-diaminopropionic acid.(25mg, 16 μ mol) are added in the strainer tube with PS-Rink-L-Dap (Fmoc)-Boc resin, and at 0.50mL CH ₂Cl ₂Middle swelling five minutes.Then resin is drained, and in resin, add 8:2DMF/ piperidines (0.50mL).Made resin reaction 45 minutes, and stirred frequently.Then resin is drained, and with DMF (3 * 0.5mL), MeOH (3 * 0.5mL) and CH ₂Cl ₂(3 * 0.5mL) washings.

Carboxylic acid (80 μ mol) and I-hydroxybenzotriazole (12.2mg, 80 μ mol) are added in the 1 dram bottle, and are dissolved in 0.6mL 2:1 DMF/CH ₂Cl ₂In.In this solution, add 1,3-DIC (0.013mL, 80 μ mol), and reacted ten minutes.The resin of deprotection is added in the resulting coupling solution, adds N subsequently, N-diisopropylethylamine (0.017mL, 96 μ mol).With the bottle capping, react 18 hours gentle simultaneously stirrings then.Then with resin transfer in strainer tube, drain, use then DMF (3 * 0.5mL), MeOH (3 * 0.5mL) and CH ₂Cl ₂(3 * 0.5mL) washings.

Replacedly, use the similar solution of chloro-formic ester (80 μ mol) and pyridine (160 μ mol) to replace carboxylic acid coupling solution, obtain corresponding mephenesin Carbamate.

Replacedly, use the similar solution of isocyanic ester (80 μ mol) to replace carboxylic acid coupling solution, obtain corresponding urea.

D. remove the general operation of the Boc protecting group of the terminal α-amine of N-

With PS-Rink-amino acid-Boc resin (25mg, 16 μ mol) in plastics tubing at CH ₂Cl ₂Swelling is ten minutes (0.50mL).Resin is drained, add 10%H then ₂SO ₄1,4-diox (0.50mL) solution, and reacting 30 minutes stirs frequently.Resin is drained, uses 1 then, the 4-diox (2 * 0.5mL), 9:1DMF/Et ₃N (2 * 0.5mL), DMF (3 * 0.5mL), MeOH (3 * 0.5mL) and CH ₂Cl ₂(3 * 0.5mL) washings.This operates in and obtains the terminal α-amine of free N-on the PS-Rink resin.

2. make 11 the glutamine analogue link coupled general operation (scheme 6) on 10 amino acids and the Rink acid amides mbha resin

Scheme 6

Fmoc-L-Bip (R)-OH (409 μ mol) is added in the 20mL scintillation vial.Add I-hydroxybenzotriazole (75mg, 558 μ mol), and be dissolved in 2:1DMF/CH ₂Cl ₂(5.8mL).Add PyBOP (232mg, 446 μ mol), reacted then five minutes.In reaction soln, add N, N-diisopropylethylamine (0.192mL, 1116 μ mol).11 resins (600mg, 372 μ mol) that in the scintillation vial that contains reaction soln, add α-amine deprotection then.Then with the bottle capping, and stirred 24 hours.After 24 hours, resin transfer in strainer tube, is drained, use then DMF (3 * 6mL), MeOH (3 * 6mL) and CH ₂Cl ₂(3 * 6mL) washings.

Embodiment 4

Synthesis type II and formula V are represented is in X _Aa10The biphenylalanine analogue of position and be in X _Aa11The alpha-non-natural amino acid analogue of position

These analogues have the X of being in _Aa10Position and be in X _Aa11Biphenylalanine analogue (Bip analogue) or the assorted biphenylalanine analogue that the formula II and the residue the formula V amino acid analogue as replacement of position for example is in 10 and the 4-amino methyl phenylalanine (4-amino methyl Phe) or 4-amino-benzene L-Ala (the amino Phe of the 4-) analogue that are in 11, for the title analogue, utilize following method that they are incorporated in the peptide chain.

1. preparation is at X _Aa11The general operation that the Rink acid amides mbha resin of 4-amino methyl Phe shown in formula V and the formula VIII or the amino Phe derivative of 4-is contained in the position (sees also scheme 7 for 4-amino methyl Phe embodiment; The synthetic of the amino Phe analogue of 4-is similar)

Scheme 7

A. load the general operation of mbha resin

Polystyrene-Rink acid amides mbha resin (the loading level is 0.640mmol/g for 1.10g, 0.704mmol) is added in the strainer tube, then at CH ₂Cl ₂Swelling is ten minutes (11.0mL).Resin is drained, in the strainer tube that contains resin, add 8:2DMF/ piperidine solution (11.0mL) then.The Fmoc deprotection reaction was carried out one hour, stir frequently.Pipe is drained, in strainer tube, add new 8:2DMF/ piperidines (11.0mL), and then resin is carried out deprotection, continue 30 minutes.Pipe is drained, then resin with DMF (3 * 15mL), MeOH (3 * 15mL) and CH ₂Cl ₂(3 * 15mL) washings.

(0.546g 1.06mmol) is added in the new 20mL scintillation vial with Boc-L-4-amino methyl Phe (Fmoc)-OH then.(0.189g 1.23mmol), adds 10.0mL 1:1DMF/CH subsequently to add I-hydroxybenzotriazole in bottle ₂Cl ₂Add 1 in containing amino acid whose bottle, (0.193mL 1.23mmol), reacted five minutes the 3-DIC then.The Rink resin of deprotection is added in the resulting reaction soln.Add N in the resin slurries, (0.490mL 2.82mmol), with the bottle capping, places then that (150rpm) spends the night on the orbital shaker (22 hours) to the N-diisopropylethylamine.After 22 hours, resin transfer in strainer tube, is drained, use then DMF (3 * 15mL), MeOH (3 * 15mL) and CH ₂Cl ₂(3 * 15mL) washings.

Scheme 8

B. 11 shielded amine side chains are carried out the general operation and the acidylate operation (scheme 8) of deprotection

(50mg, 32 μ mol) are added in the strainer tube with PS-Rink-L-4-amino methyl Phe (Fmoc)-Boc resin, and at 0.50mL CH ₂Cl ₂Middle swelling five minutes.Then resin is drained, and in resin, add 8:2DMF/ piperidines (0.50mL).Made resin reaction 45 minutes, and stirred frequently.Then resin is drained, and with DMF (3 * 0.5mL), MeOH (3 * 0.5mL) and CH ₂Cl ₂(3 * 0.5mL) washings.In resin, add 1:1DMF/CH ₂Cl ₂Solution (0.5mL) adds N subsequently, N-diisopropylethylamine (0.045mL, 256 μ mol).

(256 μ mol) is added in the 1 dram bottle with selected carboxylic acid.In bottle, add I-hydroxybenzotriazole (39.2mg, 256 μ mol), add 0.5mL 1:1DMF/CH subsequently ₂Cl ₂With 1,3-DIC (0.040mL, 256 μ mol) is added in the resultant solution.The slurries of the resin of the deprotection of above preparation directly are added in the activatory carboxylic acid solution, then with 1 dram bottle capping.Make reaction carry out stirring simultaneously in 22 hours.Then with resin transfer in strainer tube, drain, use then DMF (3 * 0.5mL), MeOH (3 * 0.5mL) and CH ₂Cl ₂(3 * 0.5mL) washings.

Scheme 9

C. remove the general operation (scheme 9) of the Boc protecting group of the terminal α-amine of N-

With PS-Rink-amino acid-Boc resin (50mg, 32 μ mol) in plastics tubing at CH ₂Cl ₂Swelling is ten minutes (0.50mL).Resin is drained, add 10%H then ₂SO ₄1,4-diox (0.50mL) solution, and reacting 30 minutes stirs frequently.Resin is drained, uses 1 then, the 4-diox (2 * 0.5mL), 9:1DMF/Et ₃N (2 * 0.5mL), DMF (3 * 0.5mL), MeOH (3 * 0.5mL) and CH ₂Cl ₂(3 * 0.5mL) washings.This operates in and obtains the terminal α-amine of free N-on the PS-Rink resin.

Scheme 10

2. make 11 the 4-amino methyl Phe analogue link coupled general operations (scheme 10) on 10 amino acids and the Rink acid amides mbha resin

Fmoc-L-Bip (R)-OH (704 μ mol) is added in the 20mL scintillation vial.In bottle, add I-hydroxybenzotriazole (122mg, 800 μ mol), and be dissolved in 2:1DMF/CH ₂Cl ₂(10.0mL).In solution, add PyBOP (416mg, 800 μ mol), reacted then five minutes.In reaction soln, add N, N-diisopropylethylamine (0.334mL, 1920 μ mol).With in resultant solution evenly distribute to the 20 1 dram bottle (about 0.50mL/ bottle), described 1 dram bottle contains 50mg PS-Rink-amino acid/bottle (the loading level is 0.64mmol/g, 32 μ mol/ bottles, 640 μ mol resins altogether).With the bottle capping, react then and stirred simultaneously in 20 hours.Resin transfer in the 1mL strainer tube, is drained, then each Guan Douyong DMF (3 * 0.5mL), MeOH (3 * 0.5mL) and CH ₂Cl ₂(3 * 0.5mL) washings.

Embodiment 5

Synthesis type II and formula VI are represented is in X _Aa10The biphenylalanine analogue of position and be in X _Aa11The alpha-non-natural amino acid analogue of position

These analogues have the X of being in _Aa10Position and be in X _Aa11(for example) L-2-aminocaprylic acid analogue that the formula II that passes through replacement of position and the residue that formula VI amino acid analogue is represented for example are in 10 biphenylalanine analogue (Bip analogue) or assorted biphenylalanine analogue and are in 11, for the title analogue, utilize following method that they are incorporated in the peptide chain.

1. preparation is at X _Aa11The general operation (scheme 11) of the Sieber resin-amino acid dipolymer of amino acid derivative shown in the formula VI is contained in the position

Scheme 11

A. load the general operation of Sieber resin with 11 amino acids

Polystyrene-Sieber amide resins (the loading level is 520 μ mol/g for 48mg, 25 μ mol) is added in the 1 dram bottle.In bottle, add 8:2DMF/ piperidines (0.500mL).Stirred 45 minutes then with the bottle capping, and with content.Resin transfer in strainer tube, is drained, use then DMF (3 * 0.5mL), MeOH (3 * 0.5mL) and CH ₂Cl ₂(3 * 0.5mL) washings.In 1 new dram bottle, add Fmoc-L-2-aminocaprylic acid (38mg, 100 μ mol).Add I-hydroxybenzotriazole (16mg, 100 μ mol) in containing amino acid whose bottle, the content with bottle is dissolved in 0.50mL 2:3DMF/CH then ₂Cl ₂In.In the bottle that contains amino acid solution, add PyBOP (52mg, 100 μ mol), add N subsequently, N-diisopropylethylamine (0.0.087mL, 499 μ mol), and reacted five minutes.The resin of above resulting deprotection is added in this solution,, places then that (125rpm) spends the night on the orbital shaker (18 hours) the bottle capping.After 18 hours, resin transfer in strainer tube, is drained, use then DMF (3 * 0.5mL), MeOH (3 * 0.5mL) and CH ₂Cl ₂(3 * 0.5mL) washings.

B. remove the general operation of the Fmoc protecting group of the terminal α-amine of N-

With PS-Sieber-amino acid-Boc resin (48mg, 25 μ mol) in plastics tubing at CH ₂Cl ₂Swelling is ten minutes (0.50mL).Resin is drained, in resin, add 8:2DMF/ piperidines (0.50mL) then.Make resulting slurry reaction 40 minutes, stir frequently.Resin is drained, use then DMF (3 * 0.5mL), MeOH (3 * 0.5mL) and CH ₂Cl ₂(3 * 0.5mL) washings.This is reflected at and obtains the terminal α-amine of free N-on the PS-Sieber resin.

C. make 11 amino acids link coupled general operations (scheme 12) on 10 amino acids and the Rink acid amides Sieber resin

Scheme 12

With Fmoc-L-Bip (R ₁, R ₂, R ₃)-OH (409 μ mol) is added in the 20mL scintillation vial.Add I-hydroxybenzotriazole (75mg, 558 μ mol), and be dissolved in 2:1DMF/CH ₂Cl ₂(5.8mL).Add PyBOP (232mg, 446 μ mol), reacted then five minutes.In reaction soln, add N, N-diisopropylethylamine (0.192mL, 1116 μ mol).11 the PS-Sieber resins (600mg, 372 μ mol) that in the scintillation vial that contains reaction soln, add α-amine deprotection.With the bottle capping, stirred then 24 hours.After 24 hours, resin transfer in strainer tube, is drained, use then DMF (3 * 6mL), MeOH (3 * 6mL) and CH ₂Cl ₂(3 * 6mL) washings.

Embodiment 6

The general operation for preparing peptide by fragment condensation

Described at embodiment 2, carry out solid phase Su Chuji condensation and standard amino acid coupling operation, with at X _Aa10Position and X _Aa11The position prepares needed formula II and formula III amino acid.Make dipeptides and carrier cracking, and the protecting group that previous (referring to scheme 13) or while (referring to scheme 14) are removed the terminal α-amine of N-.Make dipeptides and side chain be subjected to 9 amino acid whose peptide couplings (vide infra) of protecting fully then.Subsequently side chain is carried out deprotection, carry out purifying then, the 11 chain link peptide prods that obtain expecting.

Solution phase fragment condensation

In this method, carry out solid phase Su Chuji condensation and acidylate (as described in) at embodiment 2, with the dipeptides of preparation with polystyrene-expectation that the Rink amide resins links to each other, the terminal α-amine of its N-is subjected to the Fmoc protection or protected by Boc.At first deprotection cracking then of dipeptides, or directly under acidic conditions with the resin cracking.As shown in scheme 13, the dipeptides that contains the terminal α-amine of N-that is subjected to Fmoc protection at first utilizes the 8:2DMF/ piperidine solution to come deprotection on resin, then under acidic conditions with the resin cracking.As shown in scheme 14, be subjected in acidic cleavage, to carry out the deprotection of α-amine under the situation of Boc protection at the terminal α-amine of N-, usually it is carried out purifying, enter the fragment coupling step afterwards.

1. make the operation of dipeptides and Rink acid amides mbha resin cracked

Scheme 13

R ₁, R ₂, R ₃, R ₄And R ₅The side chain that representative is described in formula II and formula III

A. the dipeptides that is subjected to the Fmoc protection is operated (scheme 13)

To in methylene dichloride (1.5mL), flooded ten minutes by the dipeptides-Rink amide resins (100mg, 64 μ mol) of Fmoc protection.Resin is drained, transfer in the 1 dram bottle, then 8:2DMF/ piperidines (1.5mL) solution is added in the resin.With the bottle capping, stirred then 45-90 minute.Then with resin transfer in strainer tube, drain, use then DMA (3 * 2mL), MeOH (3 * 2mL) and CH ₂Cl ₂(3 * 2mL) washings.Resin transfer in 1 dram vial, is added 5:5:0.25 trifluoroacetic acid/CH then ₂Cl ₂/ tri isopropyl silane solution (1.5mL).With the bottle capping, then resin is carried out cracking, continue two hours.After two hours, solution is filled in the bottle of cleaning, and (1 * 1mL) washing is added to it in cracked solution with MeOH.With new TFA/CH ₂Cl ₂/ TIPS solution is added in the resin, repeats scission reaction then.Merge cracked solution, evaporating solvent then.Resulting product comes purifying by HPLC, and described HPLC uses C-18 post and CH ₃CN/H ₂O/TFA or MeOH/H ₂The O/TFA solvent systems utilizes UV or quality to instruct fraction collection, obtains (behind evaporating solvent) dipeptides, is the trifluoroacetate of α-amine.

Scheme 14

R ₁, R ₂, R ₃, R ₄And R ₅The side chain that representative is described in formula II and formula III

B. the dipeptides that is subjected to the Boc protection is operated (scheme 14)

Be added in the 1 dram vial by the dipeptides-Rink resin (100mg, 64 μ mol) of Boc protection, add 5:5:0.25 trifluoroacetic acid/CH then ₂Cl ₂/ tri isopropyl silane solution (1.5mL).With the bottle capping, then resin is carried out cracking, continue two hours.After two hours, solution is filled in the bottle of cleaning, and (1 * 1mL) washing is added to it in cracked solution with MeOH.With new TFA/CH ₂Cl ₂/ TIPS solution is added in the resin, repeats scission reaction then.Merge cracked solution, evaporating solvent then.Resulting product comes purifying by HPLC, and described HPLC uses C-18 post and CH ₃CN/H ₂O/TFA or MeOH/H ₂The O/TFA solvent systems utilizes UV or quality to instruct fraction collection, obtains (behind evaporating solvent) dipeptides, is the trifluoroacetate of α-amine.

Scheme 15

2. the operation (scheme 15) of the terminal carboxylic acid of the shielded 9 chain link peptide C-of solid phase synthesis side chain

With NMP (5mL) solution of Fmoc-(L)-Ser (tBu)-OH (5 equivalent), 0.5M HOAt/DMF (5 equivalent) and DIC (5 equivalent) with (L)-(3.0g is 2.16mmol) room temperature vortex (vortex) 18 hours for Asp (OtBu)-2-chlorine trityl resin.After NMP washing several times, the Fmoc group is removed by handling twice (5 minutes and 10 minutes) with 1.5M piperidines/DMF.Described coupling and deprotection steps repeat seven times; sequence with the assembling expectation; different is; respectively 1.1 equivalents and 1.5 normal Fmoc-α-Me-Phe (2-R-6-R ")-OH and Boc-(L)-His (Trt)-OH are used for its coupling, and with HATU/HOAt and DIEA (4 equivalent) be used for Fmoc-Thr (tBu)-OH with (S)-coupling of α-Me-Phe (2-R-6-R ")-peptidyl-resin.

After finishing assembling, peptidyl-resin washs with DCM, and shielded then 9 chain link peptide C-terminal carboxylic acids are by (8:1:1 v:v:v) discharges from resin room temperature treatment one hour with DCM/AcOH/TFE.Filter out resin, then filtrate is evaporated to driedly, be dissolved in the AcCN/ water (2:1) again, freeze-drying twice then, obtains 2.777g purity and be 81% product, and it is used for fragment coupling step subsequently under situation about not being further purified.

Scheme 16

R ₁, R ₂, R ₃, R ₄And R ₅The side chain that representative is described in formula II and formula III

3. be used for the operation (scheme 16) of solution phase fragment linked reaction

Be reflected in the 1 dram bottle with the form of simplification compound and in 2ml 96-orifice plate, carry out with the form of compound parallel array.Below describe (scheme 16 is shown) and be used for the situation of simplification compound, but can easily be used for the situation of 96-orifice plate.

The tfa salt (0.01mmol) of dipeptides is dissolved in the 1.5ml vial among the 0.25ml THF (containing 0.2% triethylamine).(the MP-carboxylicesters, 0.03mmol ArgonautTechnologies) is added in the bottle with the macropore carbonate resin.With the bottle capping, stirred two hours in room temperature then.Solution is filtered, and unnecessary solvent is removed in evaporation then.

(HOBt, 0.15ml 9:1 chloroform/N 0.008mmol), dinethylformamide solution are added in the bottle that contains two peptamines will to contain terminal carboxylic acid (0.008mmol) of the shielded 9 chain link peptide C-of side chain and N-hydroxybenzotriazole.(DIC 0.008mmol) is added to 0.05ml 9:1 chloroform/N, in the dinethylformamide solution with DIC.With the bottle capping, then reaction mixture was stirred on orbital shaker 16 hours in room temperature.Evaporate remaining solvent from bottle.

With 0.40ml 95:2.5:2.5 trifluoroacetic acid/water/tri isopropyl silane (TFA/H ₂O/TIS) side chain and the terminal α-amine of N-to 11 chain link peptides carries out deprotection, continues one hour.Evaporate remaining solvent, 11 chain link peptide prods come purifying by HPLC then, and described HPLC uses CH ₃CN/H ₂The O/TFA solvent systems, and trigger effluent liquid by the following method and collect: the quality of expectation product, the [(M+2H of detection expectation product detected ⁺)/2] ⁺Ion or the peak is carried out UV detect.

Embodiment 7

The general operation for preparing peptide by fragment condensation

In this method, carry out solid phase acidylate (as described in Example 3), with at X _Aa10Position and X _Aa11The position prepares needed formula II and formula IV amino acid.Make dipeptides and carrier cracking, and the protecting group that previous (referring to scheme 17) or while (referring to scheme 18) are removed the terminal α-amine of N-.Make dipeptides and side chain be subjected to 9 amino acid whose peptide couplings (scheme 15) of protecting fully then.Subsequently side chain is carried out deprotection, carry out purifying then, the 11 chain link peptide prods that obtain expecting.

1. make the operation of dipeptides and Rink acid amides mbha resin cracked

Scheme 17

A. the dipeptides that is subjected to the Fmoc protection is operated (scheme 17)

Be subjected to Fmoc protection dipeptides-Rink amide resins (100mg, 64 μ mol) in methylene dichloride (1.5mL), flooded ten minutes.Resin is drained, transfer in the 1 dram bottle, then 8:2DMF/ piperidines (1.5mL) solution is added in the resin.With the bottle capping, stirred then 45-90 minute.Then with resin transfer in strainer tube, drain, use then DMA (3 * 2mL), MeOH (3 * 2mL) and CH ₂Cl ₂(3 * 2mL) washings.Resin transfer in 1 dram vial, is added 5:5:0.25 trifluoroacetic acid/CH then ₂Cl ₂/ tri isopropyl silane solution (1.5mL).With the bottle capping, then resin is carried out cracking, continue two hours.After two hours, solution is filled in the bottle of cleaning, and (1 * 1mL) washing is added to it in cracked solution with MeOH.With new TFA/CH ₂Cl ₂/ TIPS solution is added in the resin, repeats scission reaction then.Merge cracked solution, evaporating solvent then.Resulting product comes purifying by HPLC, and described HPLC uses C-18 post and CH ₃CN/H ₂O/TFA or MeOH/H ₂The O/TFA solvent systems utilizes UV or quality to instruct fraction collection, obtains (behind evaporating solvent) dipeptides, is the trifluoroacetate of α-amine.

Scheme 18

B. the dipeptides that is subjected to the Boc protection is operated (scheme 18)

Be added in the 1 dram vial by the dipeptides-Rink resin (100mg, 64 μ mol) of Boc protection, add 5:5:0.25 trifluoroacetic acid/CH then ₂Cl ₂/ tri isopropyl silane solution (1.5mL).With the bottle capping, then resin is carried out cracking, continue two hours.After two hours, solution is filled in the bottle of cleaning, and (1 * 1mL) washing is added to it in cracked solution with MeOH.With new TFA/CH ₂Cl ₂/ TIPS solution is added in the resin, repeats scission reaction then.Merge cracked solution, evaporating solvent then.Resulting product comes purifying by HPLC, and described HPLC uses C-18 post and CH ₃CN/H ₂O/TFA or MeOH/H ₂The O/TFA solvent systems utilizes UV or quality to instruct fraction collection, obtains (behind evaporating solvent) dipeptides, is the trifluoroacetate of α-amine.

Scheme 19

2. be used for the operation (scheme 19) of solution phase fragment linked reaction

Describedly be reflected in the 1 dram bottle with the form of simplification compound and in 2ml 96-orifice plate, carry out with the form of compound parallel array.Below describe (scheme 19 is shown) and be used for the situation of simplification compound, but can easily be used for the situation of 96-orifice plate.

The tfa salt (0.01mmol) of dipeptides is dissolved in the 1.5ml vial among the 0.25ml THF (containing 0.2% triethylamine).(the MP-carboxylicesters, 0.03mmol ArgonautTechnologies) is added in the bottle with the macropore carbonate resin.With the bottle capping, stirred two hours in room temperature then.Solution is filtered, and unnecessary solvent is removed in evaporation then.

(HOBt, 0.15ml 9:1 chloroform/N 0.008mmol), dinethylformamide solution are added in the bottle that contains two peptamines will to contain terminal carboxylic acid (0.008mmol) of the shielded 9 chain link peptide C-of side chain and N-hydroxybenzotriazole.(DIC 0.008mmol) is added to 0.05ml 9:1 chloroform/N, in the dinethylformamide solution with DIC.With the bottle capping, then reaction mixture was stirred on orbital shaker 16 hours in room temperature.Evaporate remaining solvent from bottle.

With 0.40ml 95:2.5:2.5 trifluoroacetic acid/water/tri isopropyl silane (TFA/H ₂O/TIS) side chain and the terminal α-amine of N-to 11 chain link peptides carries out deprotection, continues one hour.Evaporate remaining solvent, 11 chain link peptide prods come purifying by HPLC then, and described HPLC uses CH ₃CN/H ₂The O/TFA solvent systems, and trigger effluent liquid by the following method and collect: the quality of expectation product, the [(M+2H of detection expectation product detected ⁺)/2] ⁺Ion or the peak is carried out UV detect.

Embodiment 8

The general operation for preparing peptide by fragment condensation

In this method, carry out solid phase acidylate (as described in Example 4), with at X _Aa10Position and X _Aa11The position prepares needed formula II and formula V amino acid.Make dipeptides and carrier cracking, and the protecting group that previous (referring to scheme 20) or while (referring to scheme 21) are removed the terminal α-amine of N-.Make dipeptides and side chain be subjected to 9 amino acid whose peptide couplings (scheme 15) of protecting fully then.Subsequently side chain is carried out deprotection, carry out purifying then, the 11 chain link peptide prods that obtain expecting.

1. make the operation of dipeptides and Rink acid amides mbha resin cracked

Scheme 20

A. the dipeptides that is subjected to the Fmoc protection is operated (scheme 20)

Be subjected to Fmoc protection dipeptides-Rink amide resins (100mg, 64 μ mol) in methylene dichloride (1.5mL), flooded ten minutes.Resin is drained, transfer in the 1 dram bottle, then 8:2DMF/ piperidines (1.5mL) solution is added in the resin.With the bottle capping, stirred then 45-90 minute.Then with resin transfer in strainer tube, drain, use then DMA (3 * 2mL), MeOH (3 * 2mL) and CH ₂Cl ₂(3 * 2mL) washings.Resin transfer in 1 dram vial, is added 5:5:0.25 trifluoroacetic acid/CH then ₂Cl ₂/ tri isopropyl silane solution (1.5mL).With the bottle capping, then resin is carried out cracking, continue two hours.After two hours, solution is filled in the bottle of cleaning, and (1 * 1mL) washing is added to it in cracked solution with MeOH.With new TFA/CH ₂Cl ₂/ TIPS solution is added in the resin, repeats scission reaction then.Merge cracked solution, evaporating solvent then.Resulting product comes purifying by HPLC, and described HPLC uses C-18 post and CH ₃CN/H ₂O/TFA or MeOH/H ₂The O/TFA solvent systems utilizes UV or quality to instruct fraction collection, obtains (behind evaporating solvent) dipeptides, is the trifluoroacetate of α-amine.

Scheme 21

B. the dipeptides that is subjected to the Boc protection is operated (scheme 21)

Be added in the 1 dram vial by the dipeptides-Rink resin (100mg, 64 μ mol) of Boc protection, add 5:5:0.25 trifluoroacetic acid/CH then ₂Cl ₂/ tri isopropyl silane solution (1.5mL).With the bottle capping, then resin is carried out cracking, continue two hours.After two hours, solution is filled in the bottle of cleaning, and (1 * 1mL) washing is added to it in cracked solution with MeOH.With new TFA/CH ₂Cl ₂/ TIPS solution is added in the resin, repeats scission reaction then.Merge cracked solution, evaporating solvent then.Resulting product comes purifying by HPLC, and described HPLC uses C-18 post and CH ₃CN/H ₂O/TFA or MeOH/H ₂The O/TFA solvent systems utilizes UV or quality to instruct fraction collection, obtains (behind evaporating solvent) dipeptides, is the trifluoroacetate of α-amine.

Scheme 22

3. be used for the operation (scheme 22) of solution phase fragment linked reaction

Describedly be reflected in the 1 dram bottle with the form of simplification compound and in the 2ml96-orifice plate, carry out with the form of compound parallel array.Below describe (scheme 24 is shown) and be used for the situation of simplification compound, but can easily be used for the situation of 96-orifice plate.

The tfa salt (0.01mmol) of dipeptides is dissolved in the 1.5ml vial among the 0.25ml THF (containing 0.2% triethylamine).(the MP-carboxylicesters, 0.03mmol ArgonautTechnologies) is added in the bottle with the macropore carbonate resin.With the bottle capping, stirred two hours in room temperature then.Solution is filtered, and unnecessary solvent is removed in evaporation then.

(HOBt, 1.22mg, 0.15ml 9:1 chloroform/N 0.008mmol), dinethylformamide solution are added in the bottle that contains two peptamines will to contain terminal carboxylic acid (0.008mmol) of the shielded 9 chain link peptide C-of side chain and N-hydroxybenzotriazole.With 1, (DIC, 1.25 μ L 0.008mmol) are added to 0.05ml 9:1 chloroform/N, in the dinethylformamide solution to the 3-DIC.With the bottle capping, then reaction mixture was stirred on orbital shaker 16 hours in room temperature.Evaporate remaining solvent from bottle then.

With 0.40ml 95:2.5:2.5 trifluoroacetic acid/water/tri isopropyl silane (TFA/H ₂O/TIS) side chain and the terminal α-amine of N-to 11 chain link peptides carries out deprotection, continues one hour.Evaporate remaining solvent, 11 chain link peptide prods come purifying by HPLC then, and described HPLC uses CH ₃CN/H ₂The O/TFA solvent systems, and trigger effluent liquid by the following method and collect: the quality of expectation product, the [(M+2H of detection expectation product detected ⁺)/2] ⁺Ion or the peak is carried out UV detect.

Embodiment 9

The general operation for preparing peptide by fragment condensation

In this method, carry out solid phase acidylate (as described in Example 5), with at X _Aa10Position and X _Aa11The position prepares needed formula II and formula VI amino acid.Make dipeptides and carrier cracking, and the protecting group that previous (referring to scheme 23) or while (referring to scheme 24) are removed the terminal α-amine of N-.Make dipeptides and side chain be subjected to 9 amino acid whose peptide couplings (scheme 15) of protecting fully then.Subsequently side chain is carried out deprotection, carry out purifying then, the 11 chain link peptide prods that obtain expecting.

1. make the operation of dipeptides and Sieber amide resins cracked

Scheme 23

A. the dipeptides that is subjected to the Fmoc protection is operated (scheme 23)

To in methylene dichloride (1.5mL), flooded ten minutes by the dipeptides-Sieber amide resins (100mg, 52 μ mol) of Fmoc protection.Resin is drained, transfer in the 1 dram bottle, then 8:2DMF/ piperidine solution (1.5mL) is added in the resin.With the bottle capping, stirred then 45-90 minute.Then with resin transfer in strainer tube, drain, use then DMA (3 * 2mL), MeOH (3 * 2mL) and CH ₂Cl ₂(3 * 2mL) washings.Resin transfer in 1 dram vial, is added 5:5:0.25 trifluoroacetic acid/CH then ₂Cl ₂/ tri isopropyl silane solution (1.5mL).With the bottle capping, then resin is carried out cracking, continue two hours.After two hours, solution is filled in the bottle of cleaning, and (1 * 1mL) washing is added to it in cracked solution with MeOH.With new TFA/CH ₂Cl ₂/ TIPS solution is added in the resin, repeats scission reaction then.Merge cracked solution, evaporating solvent then.Resulting product comes purifying by HPLC, and described HPLC uses C-18 post and CH ₃CN/H ₂O/TFA or MeOH/H ₂The O/TFA solvent systems utilizes UV or quality to instruct fraction collection, obtains (behind evaporating solvent) dipeptides, is the trifluoroacetate of α-amine.

Scheme 24

B. the dipeptides that is subjected to the Boc protection is operated (scheme 24)

Be added in the 1 dram vial by the dipeptides-Sieber amide resins (100mg, 52 μ mol) of Boc protection, add 5:5:0.25 trifluoroacetic acid/CH then ₂Cl ₂/ tri isopropyl silane solution (1.5mL).With the bottle capping, then resin is carried out cracking, continue two hours.After two hours, solution is filled in the bottle of cleaning, and (1 * 1mL) washing is added to it in cracked solution with MeOH.With new TFA/CH ₂Cl ₂/ TIPS solution is added in the resin, repeats scission reaction then.Merge cracked solution, evaporating solvent then.Resulting product comes purifying by HPLC, and described HPLC uses C-18 post and CH ₃CN/H ₂O/TFA or MeOH/H ₂The O/TFA solvent systems utilizes UV or quality to instruct fraction collection, obtains (behind evaporating solvent) dipeptides, is the trifluoroacetate of α-amine.

Scheme 25

3. be used for the operation (scheme 25) of solution phase fragment linked reaction

Describedly be reflected in the 1 dram bottle with the form of simplification compound and in 2ml 96-orifice plate, carry out with the form of compound parallel array.Below describe (scheme 25 is shown) and be used for the situation of simplification compound, but can easily be used for the situation of 96-orifice plate.

The tfa salt (0.01mmol) of dipeptides is dissolved in the 1.5ml vial among the 0.25ml THF (containing 0.2% triethylamine).(the MP-carboxylicesters, 0.03mmol ArgonautTechnologies) is added in the bottle with the macropore carbonate resin.With the bottle capping, stirred two hours in room temperature then.Solution is filtered, and unnecessary solvent is removed in evaporation then.

(HOBt, 0.15ml 9:1 chloroform/N 0.008mmol), dinethylformamide solution are added in the bottle that contains two peptamines will to contain terminal carboxylic acid (0.008mmol) of the shielded 9 chain link peptide C-of side chain and N-hydroxybenzotriazole.(DIC 0.008mmol) is added to 0.05ml 9:1 chloroform/N, in the dinethylformamide solution with DIC.With the bottle capping, then reaction mixture was stirred on orbital shaker 16 hours in room temperature.Evaporate remaining solvent from bottle.

With 0.40ml 95:2.5:2.5 trifluoroacetic acid/water/tri isopropyl silane (TFA/H ₂O/TIS) side chain and the terminal α-amine of N-to 11 chain link peptides carries out deprotection, continues one hour.Evaporate remaining solvent, 11 chain link peptide prods come purifying by HPLC then, and described HPLC uses CH ₃CN/H ₂The O/TFA solvent systems, and trigger effluent liquid by the following method and collect: the quality of expectation product, the [(M+2H of detection expectation product detected ⁺)/2] ⁺Ion or the peak is carried out UV detect.

Embodiment 10

The synthetic X that is in _Aa10The biphenylalanine analogue of position and formula XI are represented is in X _Aa11The phenoxy group homoserine analogue of position

In these analogues, be in X _Aa10Position and be in X _Aa11The residue of position represents to be biphenylalanine analogue (Bip analogue) or assorted biphenylalanine analogue and phenoxy group homoserine (phenoxy homoSer) analogue by the formula II and the formula XI amino acid analogue that replace, and the title analogue is incorporated in the peptide chain one of by the following method.For example understand the synthetic of SEQ ID NO:64 and 77 peptides.

Embodiment 11

(method A is the synthetic of SEQ ID NO:64 peptide)

Embodiment 11a

The operation of synthetic (S)-2-(t-butoxycarbonyl amino)-4-(2, the 4-dimethyl phenoxy) benzyl butyrate

With DIAD (55 μ l, 0.275mmol) room temperature be added to Boc-Hse-Obzl (77.3mg, 0.25mmol), 2, the 4-xylenol (36.7mg, 0.3mmol) and PPh ₃(72.2mg is 0.275mmol) in the mixture in 1.5mL THF.Solution was stirred four hours under nitrogen.Vacuum-evaporation removes and desolvates.Crude product (S)-2-(t-butoxycarbonyl amino)-4-(2, the 4-dimethyl phenoxy) benzyl butyrate comes purifying by preparation property HPLC-MS, and analyzes by LC-MS.Obtain the product of about 93.44mg expectation, its purity is 95%, and in LC-MS (M+H) ⁺Be (413.15).

Embodiment 11b

The operation of synthetic (S)-1-amino-4-(2, the 4-dimethyl phenoxy)-1-oxo-butanes-2-base ammonia t-butyl formate

(S)-(93mg 0.23mmol) handled 24 hours at 90 ℃ of methanol solutions with the about 7N ammonia of 4mL in sealed tube 2-(t-butoxycarbonyl amino)-4-(2, the 4-dimethyl phenoxy) benzyl butyrate.Make solution be cooled to room temperature, vacuum-evaporation removes and desolvates then.Crude product (S)-1-amino-4-(2, the 4-dimethyl phenoxy)-1-oxo-butanes-2-base ammonia t-butyl formate is prepared into high purity (about 100% yield), and it is directly used in next step.Product is confirmed by analytical LC-MS.

Embodiment 11c

The operation of synthetic (S)-2-amino-4-(2, the 4-dimethyl phenoxy) butyramide

With triethyl silicane (100 μ l, 0.62mmol) and TFA (500 μ l) be added in the 500 μ l DCM solution of thick (S)-1-amino-4-(2, the 4-dimethyl phenoxy)-1-oxo-butanes-2-base ammonia t-butyl formate (about 0.23mmol).Make reaction carry out stirring simultaneously in two hours.Reaction mixture is carried out vacuum-drying.Slightly the tfa salt of (S)-2-amino-4-(2, the 4-dimethyl phenoxy) butyramide is prepared into high purity (about 100% yield), and is directly used in next step.Structure is confirmed by analytical LC-MS.

Embodiment 11d

Synthesize and the operation that separates 1D-1 and 1D-2

With thick amine (R, S)-2-amino-4-(2, the 4-dimethyl phenoxy) butyramide (about 0.22mmol) and Fmoc-L-4 '-methoxyl group-2 '-ethyl biphenyl L-Ala (114.8mg, 0.22mmol), PyAOP (114.5mg, 0.22mmol) and HOBt (33.6mg, 0.22mmol) DMF (about 2mL) solution of mixture is added in the reaction vessel together, add subsequently DIEA (76.5 μ l, 0.44mmol).With reaction mixture vigorous stirring 20 hours.Reaction is monitored by analytical LC-MS.Then 650 μ l piperidines are added in the reaction mixture.Stir after two hours, remove the Fmoc protecting group.Reaction mixture vacuum-evaporation is extremely done.The mixture of crude product 1D-1 and 1D-2 comes purifying and separates by anti-phase preparation HPLC-MS, obtains the tfa salt (47.5mg, flow out fast) of pure 1D-1 and the tfa salt (32.3mg, slowly outflow) of pure 1D-2.Compound is analyzed by LC-MS.The NMR spectral signature of 1D-1 is as follows: ¹H NMR (500MHz, MeOH): δ 0.978 (t, 3H), 2.08 (s, 3H), 2.11 (s, 3H), 2.25 (m, 1H), 2.47 (q, 2H), 3.04 (m, 2H), 3.24 (m, 3H), 3.72 (s, 3H), 3.93 (m, 2H), 4.10 (t, 1H), 4.58 (m, 1H), 6.65 (d, 1H), 6.69 (d, 1H), 6.76 (d, 1H), 6.80 (m, 2H), 6.96 (d, 1H), 7.17 (d, 2H), 7.25 (d, 2H).

Embodiment 11e

The operation for preparing SEQ ID NO:64 peptide by the fragment coupling

The tfa salt (0.015mmol) of dipeptides 1D-1 is dissolved in 0.5ml 9:1 chloroform/N in the 10mL vial, in the dinethylformamide (containing 0.015mmol DIEA).To contain 9 amino acid whose peptides (0.015mmol), N-hydroxybenzotriazole (HOBt that side chain is subjected to appropriate protection then; 0.015mmol) and DIC (DIC; 0.015mmol) 0.5ml 9:1 chloroform/N, dinethylformamide solution is added in the solution of the above-mentioned 1D-1 of containing.With the bottle capping, then with reaction mixture stirring at room 16 hours.Evaporate remaining solvent from bottle.

With 1ml 95:5:5 trifluoroacetic acid/water/tri isopropyl silane (TFA/H ₂O/TIS) side chain and the terminal α-amine of N-to resulting 11 chain link peptides carries out deprotection, continues two hours.Evaporate remaining solvent, 11 chain link peptide prods come purifying by preparation property HPLC-MS then, and described preparation HPLC-MS uses CH ₃CN/H ₂The O/TFA solvent systems, and trigger effluent liquid by the following method and collect: the quality of expectation product, the [(M+2H of detection expectation product detected ⁺)/2] ⁺Ion or the peak is carried out UV detect.Purifying obtains the tfa salt (5.2 μ mol, 35% yield) of SEQ ID NO:64 peptide.LC-MS analyzes and has shown 97% purity and [(M+2H ⁺)/2] ⁺The ionic observed value is 761.93.

Embodiment 12

(method B is the synthetic of SEQ ID NO:77 peptide)

Embodiment 12a

The operation of synthetic (S)-4-bromo-2-(t-butoxycarbonyl amino) methyl-butyrate

(1mL 7.2mmol) is added to (S)-2-amino-4-bromo-butyric acid methyl esters hydrobromate De diox/H with triethylamine ₂In O (10ml) solution.Make reaction flask be cooled to 0 ℃, add once then the tert-Butyl dicarbonate that contracts (di-tert-butyl dicarbonate) (944mg, 4.33mmol).After 30 minutes, remove cooling bath, then with reaction mixture in stirred overnight at room temperature.Reaction mixture is carried out vacuum-evaporation to be concentrated.Resistates H ₂O and EtOAc dilution.Water layer extracts with EtOAc (2 *).The organic layer that merges is used MgSO then with saturated NaCl solution washing ₄Dry.After the filtration, solvent removed in vacuo obtains highly purified thick (S)-4-bromo-2-(t-butoxycarbonyl amino) methyl-butyrate (900mg).This product is directly used in next step reaction.

Embodiment 12b

The operation of synthetic (S)-2-(t-butoxycarbonyl amino)-4-(2, the 3-dimethyl phenoxy) methyl-butyrate

With 2, and the 3-xylenol (48.87mg, 0.375mmol) and K ₂CO ₃(44.4mg is in 1.5mL DMF solution 0.15mmol) (0.6mmol) to be added to (S)-4-bromo-2-(t-butoxycarbonyl amino) methyl-butyrate.Reaction mixture is heated to 75 ℃, and stirred 20 hours.Make solution be cooled to room temperature, then solvent removed in vacuo.Crude product (S)-2-(t-butoxycarbonyl amino)-4-(2, the 3-dimethyl phenoxy) methyl-butyrate comes purifying by preparation property HPLC-MS, and described preparation HPLC-MS uses CH ₃CN/H ₂The O/TFA solvent systems, and detect by the quality to the expectation product and to trigger effluent liquid and collect, the product (45mg) of purifying obtained.

Embodiment 12c

The operation of synthetic (S)-1-amino-4-(2, the 3-dimethyl phenoxy)-1-oxo-butanes-2-base ammonia t-butyl formate

(S)-2-(t-butoxycarbonyl amino)-4-(2, the 3-dimethyl phenoxy) methyl-butyrate (45mg) handled 24 hours with the methanol solutions of the about 7N ammonia of 4mL at 90 ℃ in sealed tube.Make solution be cooled to room temperature, then solvent removed in vacuo.Crude product (S)-1-amino-4-(2, the 3-dimethyl phenoxy)-1-oxo-butanes-2-base ammonia t-butyl formate is prepared into high purity (about 100% yield), and it is directly used in next step then.Product is confirmed by LC-MS.

Embodiment 12d

The operation of synthetic (S)-2-amino-4-(2, the 3-dimethyl phenoxy) butyramide

With triethyl silicane (100 μ l, 0.62mmol) and TFA (500 μ l) be added in the 500 μ l DCM solution of crude product (S)-1-amino-4-(2, the 3-dimethyl phenoxy)-1-oxo-butanes-2-base ammonia t-butyl formate (about 0.135mmol).Make reaction carry out stirring simultaneously in two hours.Reaction mixture is carried out vacuum-drying.The tfa salt of crude product (S)-2-amino-4-(2, the 3-dimethyl phenoxy) butyramide is prepared into high purity (about 100% yield), and it is directly used in next step.Product is confirmed by LC-MS.

Embodiment 12e

Synthesize and the operation that separates 2J-1 and 2J-2

This reaction was carried out with separating to be similar to the described mode of embodiment 11d of resulting diastereomer.The NMR feature of 2J-1 is as follows: ¹H NMR (400MHz, MeOH): δ 1.09 (t, 3H), 2.17 (s, 3H), 2.25 (s, 3H), 2.39 (m, 1H), 2.59 (q, 2H), 3.12 (m, 1H), 3.34 (m, 3H), 3.83 (s, 3H), 4.07 (m, 2H), 4.19 (dd, 1H), 4.58 (dd, 1H), 6.74 (dd, 1H), 6.80 (dd, 1H), 6.87 (d, 1H), 7.00 (t, 1H), 7.07 (d, 1H), 7.28 (d, 2H), 7.35 (d, 2H).

Embodiment 12f

The operation for preparing SEQ ID NO:77 peptide by the fragment coupling

Utilization is similar to the operation (embodiment 11E describes) of preparation SEQ ID NO:64 peptide, uses starting raw material 2J-1 (0.015mmol) to prepare SEQ ID NO:77 peptide.Obtain the tfa salt (5.1 μ mol, 35% yield) of compound 77 by reaction and purifying.LC-MS analyzes and has shown 100% purity and [(M+2H ⁺)/2] ⁺The ionic observed value is 761.94.

Embodiment 13

Synthesizing of SEQ ID NO:145 peptide

Embodiment 13a

The operation of Synthetic 2-(S)-fluorenylmethyloxycarbonyl amino-4-(2-methyl-4-chlorine) phenoxybutyhc

Can begin to prepare title amino acid from (S)-2-(t-butoxycarbonyl amino)-4-((2-methyl-4-chlorine) phenoxy group) methyl-butyrate, described methyl-butyrate can utilize and be similar to embodiment 12a-b the operation described and prepare.After removing methyl ester removal and utilize TFA to remove t-Boc by saponification; can utilize standard operation that resulting amino acid is changed into the derivative that it is subjected to the Fmoc protection, described standard operation is for example for making amino acid and 9-fluorenylmethyloxycarbonyl chlorine (Fmco-Cl) at yellow soda ash (Na ₂CO ₃) react in the solution of the aqueous solution and THF, or with N-(9-fluorenylmethyloxycarbonyl-oxygen base) succinimide (Fmoc-OSu) at sodium bicarbonate (NaHCO ₃) react among the aqueous solution and the THF.

Embodiment 13b

By progressively prolonging the operation of synthesizing SEQ ID NO:145 peptide

A.Fmoc-X _Aa10-X _Aa11Synthesizing of-two peptidyls-Sieber resin

Amount is enough to the amino xanthene of 9-Fmoc--3-base oxygen base-Merrifield resin (the Sieber amide resins of synthetic several 11 amino acid analogues; The loading level is 0.65mmol/g) by coming swelling with DMF washing (1 * 10mL, 20 minutes).Remove the Fmoc group by handle twice (being respectively 5 minutes and 15 minutes) at every turn then with the DMF solution (10mL/g) of 20% piperidines.(7 * 10mL) wash resin with DMF.2-(S)-fluorenylmethyloxycarbonyl amino-4-(2-methyl-4-chlorine) phenoxybutyhc (1.1 equivalent) is dissolved in the DMF solution (1.1 equivalent) of 0.546M HOAt, resulting solution is added in the resin, add DIC (1.1 equivalent) subsequently.Then resin is vibrated or vortex, continue 3.5 days.Utilizing qualitatively ninhydrin reaction to monitor link coupled finishes.Resin is drained, use DMF (4 * 10mL) washings then.

Utilize DIC/HOAt to carry out the manually coupling circulation second time then, it is from following operation: remove the Fmoc group with the DMF solution of 20% piperidines as previously mentioned.With the Fmoc-biphenylalanine (2 '-Et-4 '-OMe)-OH (1.5 equivalent) is dissolved in the DMF solution (1.5 equivalent) of 0.546M HOAt, and resulting solution is added in the resin, uses DMF (1mL) washing subsequently, adds DIC (1.5 equivalent) then.Then resin is vibrated or vortex, continue 16 hours.Utilizing qualitatively ninhydrin reaction to monitor link coupled finishes.Resin is drained, then with DMF washing (4 * 10mL), the two peptidyls-Sieber amide resins that is subjected to the Fmoc protection that obtains expecting.

Be added in the container of suitable size on the instrument by the separatory (0.05mmol) that waits of the two peptidyls-resin of Fmoc protection,, come deprotection by handle twice (being 2 minutes and 8 minutes) at every turn then with 20% piperidines/NMP with NMP washing six times.The deprotection steps of once being monitored again is up to the condition that satisfies the monitoring option.Total deprotection time is 10-12 minute.Two peptidyls of deprotection-resin washs six times with NMP; then with following Fmoc-L-Asp (OtBu)-OH coupling: with Fmoc-L-Asp (OtBu)-OH (1mmol; 20 equivalents) be dissolved among the 2mL NMP, and activate by DMF (2.2mL) solution and the 2M DIEA/NMP (1mL) that adds 0.45M HBTU/HOBt subsequently.

Transferred in the reaction vessel by the amino acid whose solution of Fmoc protection, and carry out coupling, continue 30 to 60 minutes, coupling time depends on the feedback to deprotection steps.Resin washs six times with NMP then, and repeats above-mentioned coupling scheme.Make it accept twice aforesaid deprotection/coupling circulation again, to finish the X of expectation _Aa7-X _Aa11The assembling of sequence.Successively link coupled Fmoc-amino acid is Fmoc-(L)-Ser (tBu)-OH and Fmoc-(L)-Thr (tBu)-OH.

Then following Fmoc-(S)-2-fluoro-α-Me-Phe-OH is carried out coupling: Fmoc-(S)-2-fluoro-α-Me-Phe-OH (3.0 equivalent) is dissolved in the DMF solution (3.0 equivalent) of 0.546M HOAt.Solution is transferred in the reaction vessel, and (2 * 2mL) washed twice add DIC (3.0 equivalent) then to use NMP subsequently.Carry out coupling, continue 16 hours.Resin washs with NMP, removes the Fmoc group then as previously mentioned.

Following Fmoc-(L)-Thr (tBu)-OH is carried out coupling: Fmoc-(L)-Thr (tBu)-OH (10 equivalent) is dissolved in the DMF solution (10 equivalent) of 0.546M HOAt.Solution is transferred in the reaction vessel, and (2 * 2mL) washings add DIC (10 equivalent) to bottle subsequently with NMP then.Carry out linked reaction, continue 16 hours.Resin washs with NMP, and then carries out twice identical coupling circulation, with assembling Fmoc-Gly-OH and Fmoc-Glu (OtBu)-OH.

Then to following Fmoc-[(S)-α-Me-Pro]-OH carries out coupling: with Fmoc-[(S)-α-Me-Pro]-OH (2.0 equivalent) is dissolved in bottle in the DMF solution (2.0 equivalent) of 0.546M HOAt.Solution is transferred in the reaction vessel, and bottle adds DIC (2.0 equivalent) subsequently with NMP (0.12mL) washing then.Carry out linked reaction, continue 16 hours.Resin with NMP (4 * 3mL) and DCM (4 * 5mL) wash.After carrying out the Fmoc deprotection as mentioned above; (8 * 3mL) washings add DIC (5 equivalent) and come Fmoc-(L)-His (Trt)-OH is carried out coupling by add Fmoc-(the L)-solution of His (Trt)-OH (5 equivalent) in the DMF of 0.546M HOAt solution (5 equivalent) in resin resin then subsequently in reaction vessel with DMF.Carry out linked reaction, continue 16 hours.Resin with NMP (4 * 3mL) and DCM (4 * 3mL) wash.As previous coupling just is described, remove the Fmoc group, then with peptidyl-resin transfer in manual reactor.Add DMF (1mL), add solid CH subsequently ₃O-CO-OSu (3 equivalent).Mixture is carried out vortex, continue 16 hours.Resin with NMP (4 * 3mL) and DCM (4 * 3mL) wash, to finish sequence assembling.

The peptide that links to each other with resin by with TFA/ water/TIS (94:3:3) (5mL) handled three hours and with the resin cracking.Resin is filtered, and (2 * 3mL) wash with 90%TFA/ water.The filtrate that is combined is evaporated, and obtains yellow oil, it is ground with ether (10mL), and be cooled to 0 ℃, keeps one hour, obtains solid afterwards.After the drying, thick solid product comes purifying by preparation property HPLC (Phenomenex 100 * 21.2mm post), employed gradient is for to last 20 minutes from 20% to 60% (the 0.1%TFA/ aqueous solution of 0.1%TFA/AcCN), and flow velocity is 14mL/min, carries out effluent liquid at 220nm and detects.Merge the cut that contains pure products, freeze-drying then obtains 13.8mg (32% yield) SEQ ID NO:145, and it has following feature: ES-MS:(M+H) ⁺=1599.8; Analytical HPLC: post is that (4.6 * 50mm), gradient is to last 10min with the flow velocity of the 2.5mL/min A solution from 5% to 80%B to YMC ODS S3, and A is a 0.1%TFA/ water, and B is 0.1%TFA/AcCN; And purity is 95.6%.

Embodiment 14

Synthesizing of SEQ ID NO:324 peptide

Be subjected to the X of Fmoc protection accordingly _Aa1-X _Aa11Peptidyl-resin (0.03mmol) prepares as embodiment 13b is described.Remove Fmoc by DMF (3mL) solution-treated twice (being 5 minutes and 15 minutes) at every turn with 20% piperidines, (8 * 3mL) wash resin with DMF afterwards, then by adding α-(L)-imidazoles (2, the 4-dinitrophenyl)-solution of lactic acid (5 equivalent) in the DMF of 0.546M HOAt solution (5 equivalent) adds DIC (5 equivalent) subsequently and comes α-(L)-imidazoles (2, the 4-dinitrophenyl)-lactic acid is carried out coupling.Carry out linked reaction, continue 16 hours.Resin with NMP (4 * 3mL) and DCM (4 * 3mL) wash.By removing 2 in one hour, the 4-dinitrophenyl with 10% thiophenol/DMF (5mL) process resin.Peptidyl-resin with DMF (4 * 5mL) and DCM (4 * 5mL) wash.

The peptide that links to each other with resin by with TFA/ water/TIS (94:3:3) (5mL) handles the while vortex three hours and with the resin cracking.Resin is filtered, and (2 * 3mL) wash with 90%TFA/ water.The filtrate that is combined is evaporated, and obtains yellow oil.It comes purifying by preparation property HPLC (Phenomenex100 * 21.2mm post), employed gradient is for to last 20 minutes from 25% to 55% (the 0.1%TFA/ aqueous solution of 0.1%TFA/MeCN), flow velocity is 14mL/min, at 220nm effluent liquid is carried out UV and detects.Merge the cut that contains product, freeze-drying then obtains 6.8mg (13% yield) SEQ ID NO:324, and it has following feature: ES-MS:(M+H) ⁺=1542.8; Analytical HPLC: post is YMC ODS S3 (4.6 * 150mm); Gradient is to last 30min with the flow velocity of the 1.0mL/min A solution from 35% to 60%B, and A is a 0.1%TFA/ water, and B is 0.1%TFA/AcCN; And purity is 96.8%.

Embodiment 15

Synthesizing of SEQ ID NO:319 peptide

Be subjected to the X of Fmoc protection accordingly _Aa1-X _Aa11Peptidyl-resin (0.09mmol) prepares as embodiment 13b is described.Remove Fmoc by DMF (3mL) solution-treated twice (being 5 minutes and 15 minutes) at every turn with 20% piperidines, afterwards resin with DMF (4 * 3mL) and DCM (4 * 3mL) wash.Add (1mL) solution of DCM/DMF (4:1) then, add methylsulfonyl chloride (8 equivalent) and diisopropylethylamine (16 equivalent) subsequently.Behind the vortex two hours, resin with DCM/DMF (4:1) (4 * 2mL) and DCM (4 * 2mL) wash.The peptide that links to each other with resin by with TFA/ water/TIS (94:3:3) (3mL) handles the while vortex three hours and with the resin cracking.Resin is filtered, and (2 * 3mL) wash with 90%TFA/ water.The filtrate that is combined is evaporated, and obtains yellow oil, and it is ground with ether (10mL), obtains solid afterwards.After the drying, solid product comes purifying by preparation property HPLC (Phenomenex100 * 21.2mm post), employed gradient is for to last 20 minutes from 20% to 60% (the 0.1%TFA/ aqueous solution of 0.1%TFA/MeCN), and flow velocity is 14mL/min, carries out effluent liquid at 220nm and detects.Merge the cut that contains product, freeze-drying then obtains 6mg (15% yield) SEQ IDNO:319, and it has following feature: ES-MS:(M+H) ⁺=1619.8; Analytical HPLC: post is that (4.6 * 50mm), gradient is to last 10min with the flow velocity of the 2.5mL/min A solution from 20% to 55%B to YMC ODS S3, and A is a 0.1%TFA/ water, and B is 0.1%TFA/AcCN; And purity is 86%.

Embodiment 16

Synthesizing of SEQ ID NO:318 peptide

Be subjected to the X of Fmoc protection _Aa2-X _Aa11Peptidyl-resin (0.035mmol) prepares as embodiment 13b is described, and different is in the case Fmoc-L-His (N-Im-Trt)-OH to be used for the 4th time coupling (X _Aa8).The Fmoc group is removed as described above like that, then by adding CH ₃O-(the L)-solution of His (N-Im-Trt)-OH (5 equivalent) in the DMF of 0.546M HOAt solution (5 equivalent) adds DIC (5 equivalent) subsequently makes CH ₃O-CO-(L)-His (N-Im-Trt)-OH and peptidyl-resin (0.035mmol) coupling.After 16 hours, resin with NMP (4 * 3mL) and DCM (4 * 3mL) wash.The peptide that links to each other with resin utilizes (5mL) vortex next and resin cracking in three hours simultaneously of TFA/ water/TIS (94:3:3).Resin is filtered, and (2 * 3mL) wash with 90%TFA/ water.The filtrate that is combined is evaporated, and obtains yellow oil.It comes purifying by preparation property HPLC (Phenomenex100 * 21.2mm post), employed gradient is for to last 20 minutes from 20% to 60% (the 0.1%TFA/ aqueous solution of 0.1%TFA/MeCN), flow velocity is 14mL/min, at 220nm effluent liquid is carried out UV and detects.Merge the cut that contains product, freeze-drying then obtains 20.2mg (30% yield) SEQ ID NO:318 peptide, and it has following feature: ES-MS:(M+H) ⁺=1651.0; Analytical HPLC: post is that (4.6 * 150mm), gradient is to last 30min with the flow velocity of the 1.0mL/min A solution from 10% to 55%B to YMC ODSS3, and A is a 0.1%TFA/ water, and B is 0.1%TFA/AcCN; And purity is 97%.

Embodiment 17

Synthesizing of SEQ ID NO:320 peptide

This compound comes synthetic as described with regard to SEQ ID NO:319 peptide.Utilize TFA/ water/TIS (94:3:3) to come from the resin release peptide, crude product comes purifying by preparation property HPLC afterwards, employed gradient is for to last 20 minutes from 20% to 60% (the 0.1%TFA/ aqueous solution of 0.1%TFA/MeCN), flow velocity is 14mL/min, at 220nm effluent liquid is carried out UV and detects.Merge the cut that contains product, freeze-drying then obtains 18.1mg (32% yield) SEQ ID NO:320 peptide, and it has following feature: ES-MS:(M+H) ⁺=1671.0; Analytical HPLC: post is that (4.6 * 50mm), gradient is to last 10min with the flow velocity of the 2.5mL/min A solution from 5% to 80%B to YMC ODS S3, and A is a 0.1%TFA/ water, and B is 0.1%TFA/AcCN; And purity is 92%.

Embodiment 18

Synthesizing of SEQ ID NO:321 peptide

Embodiment 18a

The operation of Synthetic 2-(S)-fluorenylmethyloxycarbonyl amino-4-(2-methyl-4-fluorine) phenoxybutyhc

Can utilize and be similar to embodiment 13a the operation described and prepare this amino acid.

Embodiment 18b

The operation of synthesizing SEQ ID NO:321 peptide by fragment condensation

Synthesize by embodiment 6 shown fragment condensations and to be subjected to the peptide (0.033mmol) protected fully.As described in Example 19 prepare shielded N-methoxycarbonyl-X like that _Aa1-X _Aa99 chain links, itself and X _Aa10-X _Aa11-acid amides uses in the fragment condensation step together.The peptide of expectation obtains by the following method: shielded peptide is with TFA/TIS (98:2) (1.0mL) solution-treated 1.5 hours and deprotection.Add Di Iso Propyl Ether (15mL) in this solution, the throw out that forms after a hour is collected by centrifugal.Resulting thick peptide is dissolved in water (4mL) solution of 3% ammonium hydroxide, comes purifying by preparation property HPLC then.Employed gradient is to last 40 minutes from 20% to 60%B A solution.Solvent orange 2 A is the aqueous solution of 0.1%TFA; Solvent B is the acetonitrile solution of 0.1%TFA.Flow velocity is 30mL/min.Post is Phenomenex Luna C18 (2) 5 μ m 250 * 30mm.Merge the cut contain product, freeze-drying then obtains 15.9mg (28% yield), and it has following feature: HPLC: post is that (4.6 * 150mm), gradient is to last 30min with the flow velocity of the 1mL/min A solution from 10% to 70%B to YMC ODS-AS3; ES-MS:(M+H) ⁺=1583.7; And purity is 96%.

Embodiment 19

The operation (scheme 26) of the terminal carboxylic acid of the shielded N-methoxycarbonyl-9 of solid phase synthesis side chain chain link peptide C-

Scheme 26

Utilization is similar to scheme 15 the operation described and prepares 8 chain link peptidyls that side chain N-end is subjected to Fmoc protection-(o-Cl)-trityl resin (3.5mmol).Remove Fmoc, wash with DMF then, peptidyl-resin (3.5mmol) is with N-Alpha-Methyl oxygen base carbonyl-N-im-trityl-L-Histidine (2.4g afterwards, 5.33mmol) at the DMF of 0.546M HOAt (9.8mL, 5.33mmol) solution-treated in the solution, add subsequently DMF (10mL) and DIC (0.633mL, 5.33mmol).Stir after 72 hours; the 9 chain links peptidyl of N derivatize-resin with DMF (4 * 50mL) and DCM (2 * 50mL) wash; then by (8:1:1 v:v:v) came to discharge the terminal carboxylic acid of shielded 9 chain link peptide C-from resin in room temperature treatment in three hours with DCM/AcOH/TFE.Filter out resin, then filtrate is evaporated to driedly, be dissolved in the AcCN/ water (1:1.4) again, freeze-drying twice then, obtains 4.05g purity and be 71% product, and it is used for fragment coupling step subsequently under situation about not being further purified.

Embodiment 20

Synthesizing of SEQ ID NO:322 peptide

With the Sieber amide resins (0.2402g 0.135mmol) is added in (frit-fitted) 8mLSPE tube that scorification is shaped, and utilizes following manual cycle to come deprotection then:

1.DMF wash 1 * 2mL * 5 minute

The DMF solution 1 * 2mL of 2.20% piperidines * 5 minutes

The DMF solution 1 * 2mL of 3.20% piperidines * 15 minutes

4.DMF wash 4 * 2mL * 1 minute

5.NMP wash 4 * 2mL * 1 minute

With 2-(S)-fluorenylmethyloxycarbonyl amino-4-(2-methyl-4-fluorine) phenoxybutyhc (0.083g; 0.185mmol), PyBOP (0.185mmol) and DIEA (0.0704g; 0.545mmol) DMF (1.85mL) solution be added in the resin of deprotection, carry out coupling then, continue 16 hours.Resin is used the DCM solution-treated (1 * 2mLx1 hour) of 10% acetate then with DMF and DCM (4 * 2mL * 1 minute) washing.Resin is with DMF washing (2 * 2mL * 1 minute), and utilizes above-mentioned steps 1 to 5 to remove the Fmoc group.

(0.766g, 1.47mmol) DMF (2.9mL) solution and the pure DMF (5mL) with 0.5M HOAt dissolves Fmoc-2 '-ethyl-4 '-methoxyl group-biphenylalanine.(0.189g, 1.46mmol), it is 10mL that resultant then solution is adjusted to final volume with DMF to add DIC in this solution.This solution of 1.85mL is added in the resin of deprotection, and the mixture vortex is spent the night.Peptide-resin DMF and DCM (4 * 2mL * 1min) washing.The Kaiser ninhydrin reaction is negative.With peptide-resin vacuum-drying three hours, obtain the 0.322g product.

(0.192g 0.075mmol) carries out deprotection to two peptidyls-resin as mentioned above.(0.188g, DMF 0.457mmol) (1mL) and DCM (0.5mL) solution carry out coupling, continue one hour to Fmoc-Asp (OtBu)-OH.In solution, add HCTU (0.186g, 0.451mmol) and DIEA (0.116g, 0.898mmol).With DMF and DCM washing, then spend the night, obtain 0.185g peptidyl-resin as mentioned above by vacuum-drying for resin.(0.140g, 0.23mmol) (0.45mL, 0.23mmol) solution in the solution carries out coupling, continues two hours at the DMF of 0.5M HOAt to Fmoc-His (Trt)-OH.In this solution, add DIC (0.029g, 0.23mmol) and DCM (0.5mL).As mentioned above resin is washed.The Kaiser ninhydrin reaction is negative.

The deprotection circulation is changed as follows:

The DMF solution 1 * 1mL of 1.20% piperidines * 5 minutes

The DMF solution 1 * 1mL of 2.20% piperidines * 15 minutes

3.DMF wash 8 * 1mL * 1 minute

(0.150g, 0.38mmol) (0.75mL, 0.38mmol) solution in the solution carries out coupling, continues 16 hours at the DMF of 0.5M HOAt to Fmoc-Thr (tBu)-OH.(0.047g 0.37mmol), and is adjusted to 2mL with DMF to add DIC.As mentioned above resin is washed.The Kaiser ninhydrin reaction is negative.After removing Fmoc, (0.130g, 0.31mmol) (0.60mL, 0.30mmol) solution in the solution carries out coupling, continues six hours at the DMF of 0.5M HOAt to Fmoc-α-Me-Phe (2-F)-OH.(0.038g 0.31mmol), is adjusted to 2mL with DMF with volume simultaneously to add DIC in this solution.As mentioned above resin is washed and deprotection.(0.300g, 0.75mmol) (1.50mL, 0.75mmol) solution in the solution carries out coupling, continues 72 hours at the DMF of 0.5M HOAt to Fmoc-Thr (tBu)-OH.(0.101g 0.80mmol), is adjusted to 2mL with DMF with volume simultaneously to add DIC in this solution.Resin is washed, and the TFA solution-treated of sample (about 4mg) usefulness 2%TIS is 90 minutes then.HPLC and MS analysis demonstration coupling to institute's releasing product are finished.Come as previous coupling just is described that (0.222g 0.75mmol) carries out coupling, and different is that coupling time is one hour to Fmoc-Gly-OH.As mentioned above peptidyl-resin is washed and deprotection.Come as previous coupling just is described that (0.321g 0.75mmol) carries out coupling, continues 16 hours to Fmoc-Glu (OtBu)-OH.

Wash the deprotection with Fmoc as mentioned above, (0.169g, 0.46mmol) (0.90mL, 0.45mmol) solution in the solution carries out coupling, continues 6.5 hours at the DMF of 0.5M HOAt to Fmoc-α-Me-Pro-OH afterwards.(0.057g 0.45mmol), is adjusted to 2mL with DMF with final volume simultaneously to add DIC.As mentioned above resin is washed, be distributed to then in the hole on the Advanced ChemTech396 Ω synthesizer, with further prolongation.On synthesizer, utilize above step 1 to come peptidyl-resin is carried out deprotection to 3.To CH ₃OCO-His (Trt)-OH (0.0941g, 0.21mmol) solution in 0.5M HOAt/DMF (0.4mL) and DMF (1mL) carries out coupling, continues 12 hours, to wherein adding DIC (0.0261g, 0.21mmol), with DMF final volume is adjusted to 2mL simultaneously.

As mentioned above resin is washed, take out, be added in the 4mL SPE tube, use the TFA solution (0.5mL * 5 * 5min) processing of 2%TIS then from synthesizer.The filtrate that merges was kept one hour in room temperature again.Vacuum is quickened (speed-vac) except that desolvating, and then resistates is ground with di-isopropyl ether (15mL).Collect resulting solid, dry then, obtain the thick peptide of 25.8mg.Thick peptide is dissolved in 1.5% ammonium hydroxide (2mL), simultaneously pH is adjusted to 9.5, come purifying by preparation property HPLC afterwards.Employed gradient is to last 60 minutes from 20% to 50%B A solution.Solvent orange 2 A is the aqueous solution of 0.1%TFA; Solvent B is the acetonitrile solution of 0.1%TFA.Flow velocity is 15mL/min.Post is Phenomenex Luna C18 (2) 5 μ m 250 * 21.2mm.Merge the cut contain product, freeze-drying then, obtaining 7.3mg (24% yield) purity by HPLC is that (HPLC analyzes: post is Phenomenex Luna C18 (2) 5 μ m (4.6 * 150mm) for 99% product; Gradient is to last 25 minutes with the flow velocity of the 1mL/min A solution from 10% to 60%B).ES-MS：(M+H) ⁺＝1634.1。

Embodiment 21

Synthesizing of SEQ ID NO:323 peptide

Be subjected to the X of Fmoc protection _Aa2-X _Aa11-Sieber resin preparing like that and deprotection as described in Example 20.(0.4989g, 0.81mmol) solution in 0.5MHOAt/DMF (0.8mL) and DMF (2mL) carries out coupling, continues 12 hours to Fmoc-His (Trt)-OH.(0.051g 0.40mmol), and is adjusted to 4mL with DMF to add DIC.After the washing, resin is added in the 4mLSPE tube, carries out embodiment 20 described steps 1 then to 3, with deprotection.The alpha-amino group of histidine residues seals (cap) by the following method: (6.8mg, DCM/DMF 0.059mmol) (4:1) be solution reaction two hours (0.5mL), to wherein adding DIEA (21 μ L) to make itself and methylsulfonyl chloride.After washing as mentioned above, coming like that as described in Example 20 carries out cracking/deprotection to peptidyl-resin.Thick peptide is dissolved in 1.5% ammonium hydroxide (2mL), comes purifying by preparation property HPLC afterwards.Employed gradient is to last 60 minutes from 25% to 55%B A solution.Solvent orange 2 A is the aqueous solution of 0.1%TFA; Solvent B is the AcCN solution of 0.1%TFA.Flow velocity is 15mL/min.Post is Phenomenex Luna C18 (2) 5 μ m 250 * 21.2mm.Merge the cut contain product, freeze-drying then, obtaining 11.5mg (24% yield) purity by HPLC is that (analytical HPLC: post is Phenomenex Luna C18 (2) 5 μ m (4.6 * 150mm) for 96% product; Gradient is to last 60 minutes with the flow velocity of the 1mL/min A solution from 15% to 65%B).ES-MS：(M+H) ⁺＝1653.7。

Embodiment 22

X _Aa11The embodiment of side chain

(D-Ser (OBz))-NH2 (S)-1-(2, and 3-diamino (S)-1-(2,3-diamino (S)-1-benzyl-3-(S)-2-amino-3-

-3-oxopropyl)-3--3-oxopropyl) (2,3-diamino-3-(2-o-tolyl second

O-tolyl urea-3-phenylurea oxopropyl) propionic acid amide urea amido)

(S)-and 2-amino-3-(S)-2-amino-4-(S)-2,3-diamino-3-(S)-3-acetylaminohydroxyphenylarsonic acid (S)-3-amino-N1-

(2-phenyl acetyl oxo-4-(amino propionic acid amide (pyridine-2-ylmethyl) of piperidines oxopropyl ammonia first 2-

Amino) propionic acid amide-1-yl) succinamic acid 2-benzyl chloride ester succinic diamide

(S)-3-amino-N1-2-(S)-3-amino-N1-(S)-3-amino-N1-(S)-2,3-diamino-3-(S)-N-(2, the 3-diamino

Methyl-benzyl succinic diamide benzyl succinic diamide isobutyl-succinic diamide oxopropyl ammonia benzyl formate-3-oxopropyl)-2-

Methyl benzamide

Embodiment 23

Other X _Aa11The embodiment of side chain

(S)-2-amino-3-(4-(benzene first (S)-2-amino-3-(4-(phenyl sulphur (S)-2-amino-3-(4-(methyl sulphur

The amido methyl) propionic acid phenyl propionic acid amido methyl phenyl propionic acid amido methyl phenyl)))))

(S)-2-amino-3-(4-((2,3-diformazan (S)-2-amino-3-(4-((2,4 difluorobenzene (S)-2-amino-3-(4-((2, the 4-dimethoxy

Oxygen base benzamido) propionic acid phenyl methyl propionic acid benzamido phenyl methyl propionic acid formamido group phenyl methyl))))))))

(S)-2-amino-3-(4-((2,5-dimethoxy (S)-2-amino-3-(4-((2,6-dichlorophenyl (S)-2-amino-3-(4-((2-chlorobenzene first

The base benzamido) propionic acid phenyl methyl propionic acid amido phenyl methyl propionic acid sulfonamido phenyl methyl))))))))

(S)-2-amino-3-(4-((2-anisole (S)-2-amino-3-(4-((2-methylbenzene first (S)-2-amino-3-(4-((2-aminomethyl phenyl

Formamido group) propionic acid phenyl methyl propionic acid sulfonamido phenyl methyl propionic acid amido phenyl methyl))))))))

(S)-2-amino-3-(4-((3,4-dichloro (S)-2-amino-3-(4-((3,4-dimethoxy (S)-2-amino-3-(4-((benzo [d] [1,3] dioxy

The phenyl sulfonamido) propionic acid phenyl methyl propionic acid heterocyclic pentene-5-formamido group phenyl methyl propionyloxy benzamido phenyl methyl))))))))

(S)-(((3, (((3, (((3, the 5-dimethyl is different for 4-for 5-dimethoxy (S)-2-amino-3-for 4-for 5-dichlorophenyl (S)-2-amino-3-for 4-for 2-amino-3-

Sulfonamido) propionic acid phenyl methyl phenyl) Bing Suan oxazole-4-sulfonamido methyl propionic acid benzamido phenyl methyl)))))))

(S)-2-amino-3-(4-((3-(trifluoromethyl) (S)-2-amino-3-(4-((3-chlorobenzene (S)-2-amino-3-(4-((3-chloro-phenyl-

Benzamido) propionic acid phenyl methyl propionic acid sulfonamido phenyl methyl propionic acid formamido group phenyl methyl))))))))

(S)-2-amino-3-(4-((3-cyano group benzene (S)-2-amino-3-(4-((3-oxyethyl group (S)-2-amino-3-(4-((3-fluorobenzene first

Formamido group) propionic acid phenyl methyl propionic acid amido phenyl methyl propionic acid benzamido phenyl methyl))))))))

(S)-2-amino-3-(4-((3-sec.-propyl (S)-2-amino-3-(4-((3-methoxyl group-4-(S)-2-amino-3-(4-((3-anisole

Benzamido) propionic acid phenyl methyl propionic acid formamido group phenyl methyl propionic acid toluyl amino phenyl methyl))))))))

(S)-2-amino-3-(4-((3-p-methoxy-phenyl (S)-2-amino-3-(4-((3-methylbenzene (S)-2-amino-3-(4-((3-(fluoroform

Sulfonamido) propionic acid phenyl methyl benzamido third acyloxy phenyl methyl propionic acid formamido group phenyl methyl)))))))))

(S)-2-amino-3-(4-((3-phenyl benzene (S)-2-amino-3-(4-(nicotinoyl amino (S)-2-amino-3-(4-((4-butylbenzene

Formamido group) propionic acid phenyl methyl propionic acid formamido group phenyl propionic acid methyl phenyl methyl)))))))

(S)-2-amino-3-(4-((4-chloro-phenyl-(S)-2-amino-3-(4-((4-phenylcyclohexane (S)-2-amino-3-(4-((4-anisole

Sulfonamido) propionic acid phenyl methyl propionic acid formamido group phenyl methyl propionic acid formamido group phenyl methyl))))))))

(S)-2-amino-3-(4-((4-anisole (S)-2-amino-3-(4-((4-methylbenzene (S)-2-amino-3-(4-((4-methyl

Ylsulfonylamino) propionic acid phenyl methyl propionic acid benzamido phenyl methyl propionyloxy sulfonamido phenyl methyl))))))))

(S)-2-amino-3-(4-((4-phenyl benzene (S)-2-amino-3-(4-((4-phenyl benzene (S)-3-(4-(kharophen

Formamido group) phenyl propionic acid methyl phenyl methyl propionyloxy sulfonamido phenyl methyl)))))))-the 2-alanine

(S)-2-amino-3-(4-((4-benzyl (S)-2-amino-3-(4-(hexanaphthene (S)-2-amino-3-(4-((3-methyl

Benzamido) propionic acid phenyl methyl propionic acid butyrylamino phenyl propionic acid formamido group methyl phenyl methyl)))))))

(S)-2-amino-3-(4-(2, and 4-two (S)-2-amino-3-(4-(2,6-dichloro (S)-2-amino-3-(4-(2-chlorobenzene

Methoxybenzoyl amino) propionic acid phenyl propionic acid formamido group phenyl propionic acid phenyl sulfonamido phenyl)))))

(S)-2-amino-3-(4-(2-(S)-2-amino-3-(4-(3, and 4-(S)-2-amino-3-(4-(3, the 4-dimethoxy

Toluyl amino) propionic acid phenyl propionyloxy benzamido phenyl propionic acid dichlorophenyl sulfonamido phenyl)))))

(S)-2-amino-3-(4-(3,5-two (S)-2-amino-3-(4-(3,5-dimethyl (S)-2-amino-3-(4-(3-chlorobenzene

The chloro-phenyl-sulfonamido) propionic acid phenyl propionyloxy sulfonamido phenyl propionic acid isoxazole-4-sulfonamido phenyl)))))

(S)-2-amino-3-(4-(3-(S)-2-amino-3-(4-(S)-2-amino-3-(4-(4-methyl

Toluyl amino) propionic acid phenyl propionic acid phenyl sulfonamido propionic acid (nicotinoyl amino) phenyl phenyl))))

(S)-2-amino-3-(4-(3-phenyl benzene (S)-2-amino-3-(4-(4-biphenyl (S)-2-amino-3-(4-(phenyl sulphur

Formamido group) propionic acid phenyl propionic acid amido phenyl propionyloxy sulfonamido phenyl)))))

(S)-and 2-amino-3-(4-(methyl (S)-2-amino-3-(4-(2,4-two (S)-2-amino-3-(4-(2-chlorobenzene

Sulfonamido) propionic acid phenyl propionic acid formamido group phenyl propionic acid fluorobenzoyl amino phenyl)))))

(S)-2-amino-3-(4-(2-methoxyl group (S)-2-amino-3-(4-(2-methyl (S)-2-amino-3-(4-(3-methoxyl group

Benzamido) propionic acid phenyl propionic acid benzamido phenyl propionic acid phenyl sulfonamido phenyl)))))

(S)-2-amino-3-(4-(3-methoxyl group (S)-2-amino-3-(4-(4-chlorobenzene (S)-2-amino-3-(4-(4-methoxyl group

The phenyl sulfonamido) propionic acid phenyl propionic acid phenyl sulfonamido phenyl propionyloxy sulfonamido phenyl)))))

Embodiment 24

X _Aa11Other embodiment of side chain

1-aminocyclopentanecarboxylic acid (S)-2-aminovaleric acid (R)-2-aminovaleric acid (2S, 3S)-2-amino-3-(S)-2-amino-4-methylpent

Methylvaleric acid-obtusilic acid

(S)-2-amino-3-(R)-2-amino-3-(S)-2-aminohexanoic acid (S)-2-amino-4-(S)-2-amino-4-

Cyclohexylpropionic acid cyclohexylpropionic acid methoxyl group butyric acid cyclohexyl butyric acid

(S)-2-amino-5-(S)-2-aminocaprylic acid (R)-2-aminocaprylic acid (S)-2-amino-3-(S)-2-amino-3-(amino capric acid of 2-(S)-2-

Methylhexanoic acid butoxy propionic acid methoxy ethoxy) propionic acid

Embodiment 25

Other X _Aa11Side chain

(S)-2-amino-4-(S)-2-amino-4-(2, and 3-(S)-2-amino-4-(2,4-(S)-2-amino-4-(2-methyl

The phenoxybutyhc dimethyl phenoxy) butyric acid butyric acid-4-chlorophenoxy butyric acid dimethyl phenoxy))

(S)-and 2-amino-4-(2-methyl-4-(S)-2-amino-4-(2-(S)-2-amino-4-(2,4-(S)-2-amino-4-

Fluorophenoxy) butyric acid (2-fluorophenoxy) butyric acid butyric acid methylphenoxy) butyric acid dichlorophenoxy)

(S)-2-amino-5-(S)-2-amino-5-

Phenylpentanoic acid (2-methyl) phenylpentanoic acid

Embodiment 26

The external test result of selected peptide

To people GLP-1R EC based on cell ₅₀ The description of measuring

With the Chinese hamster ovary celI of stably express people GLP-1 acceptor (HGLP-1R) or mouse GLP-1 acceptor (MGLP-1R) with 2 * 10 ⁴Individual cells/well places aseptic 96-hole white clear bottom Costar plate, and before mensuration incubated overnight.Measuring the same day, extract growth medium out, cell was handled 20 minutes with the compound or the contrast damping fluid of 50 μ l different concns in room temperature afterwards, and described damping fluid is phosphate buffered saline (PBS) (PBS), and it does not contain MgCl ₂And CaCl ₂And contain 0.1mM IBMX and 0.05%BSA.Extract solution then out, and add 50 μ l cell lysis buffer solution immediately, add 70 μ l subsequently and measure damping fluid, it contains ¹²⁵The cAMP tracer agent of I mark, the anti-cAMP antibody of rabbit and covalency are coated with the SPA pearl (Amersham cAMP SPA measures test kit) of anti-rabbit antibody.Incubated at room temperature 12 hours, (Perkin Elmer, Boston counted on MA) at TriLux Microbeta reader afterwards with plate.Utilize the "dead" cAMP of known quantity independently to set up the cAMP typical curve that contains 12 concentration.By in the cAMP typical curve, carrying out interpolation, will change into the cAMP of picomole (pmol) from the cAMP amount of reason cell of living in.Agonist data to compound are carried out normalization method, and mark and draw and become to account for the percentage ratio that responds due to the 10nM GLP-1.

Data and statistical study

The non-linear regression method that is provided by software XL-fit (in build among the TA Activity Base) becomes four parameter logical equatiions (logistic equation) (equation 205) with normalized data fitting, thus to analyzing from the concentration-response data of cAMP functional experiment.Utilize XL-fit, with the EC of compound ₅₀Value defined is for stimulating 50% maximum cAMP synthetic peptide concentration, and described maximum cAMP is synthetic by defining with the positive contrast of 10nM GLP-1 in Chinese hamster ovary celI.

The result of selected compounds is with EC ₅₀The form of value is presented in the table 1.The structure of exemplary compound is provided among the table 2-5.

Table 1

SEQ ID NO：	People GLP-1 cAMP EC 50(nM)
		1	0.013
6	0.009
		7	0.050
22	0.017
		27	0.011
31	0.024
		43	0.033
76	0.013
		80	0.016
83	0.006
		84	0.007
88	0.093
		97	0.037
116	0.017
		126	0.009
134	0.383

SEQ ID NO：	People GLP-1 cAMP EC 50(nM)
		141	0.017
145	0.048
		162	0.006
163	0.043

Table 2

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11
												1	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-phenyl valeramide
2	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(pyridine-2-yl) valeramide
												3	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(pyridin-3-yl) valeramide
4	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(pyrazine-2-yl) valeramide
												5	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(benzo [d] [1,3] dioxole-5-yl) valeramide
6	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3, the 5-3,5-dimethylphenyl) valeramide
												7	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(2-aminomethyl phenyl) valeramide
8	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-aminomethyl phenyl) valeramide
												9	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3-aminomethyl phenyl) valeramide
10	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-p-methoxy-phenyl) valeramide
												11	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(5-picoline-2-yl) valeramide
12	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-propyl group phenyl) valeramide
												13	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(2-ethylphenyl) valeramide
14	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-picoline-2-yl) valeramide
												15	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(2, the 4-3,5-dimethylphenyl) valeramide
16	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3-p-methoxy-phenyl) valeramide
												17	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-phenyl valeramide
18	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-xenyl) valeramide
												19	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3-picoline-2-yl) valeramide
20	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(pyridin-4-yl) valeramide
												21	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(2, the 3-3,5-dimethylphenyl) valeramide
22	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(quinoline-6-yl) valeramide
												23	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(naphthalene-2-yl) valeramide
24	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(6-picoline-2-yl) valeramide
												25	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(2, and 3-dihydrobenzo [b] [1,4] dioxin-6-yl) valeramide
26	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(2,6-lutidine-3-yl) valeramide

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11
												27	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-fluorophenyl) valeramide
28	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3-chloro-phenyl-) valeramide
												29	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-(dimethylamino) phenyl) valeramide
30	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(2-chloro-phenyl-) valeramide
												31	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-(methyl sulphonyl) phenyl) valeramide
32	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(quinoline-5-yl) valeramide
												33	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-(trifluoromethyl) phenyl) valeramide
34	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-fluorophenyl) valeramide
												35	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3-xenyl) valeramide
36	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	4-phenyl butane-1-amine
												37	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(2) valeramide
38	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-isopropyl phenyl) valeramide
												39	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3-xenyl) valeramide
40	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-(dimethylamino) phenyl) valeramide
												41	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3-chloro-phenyl-) valeramide
42	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-fluorophenyl) valeramide
												43	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(2-chloro-phenyl-) valeramide
44	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-(trifluoromethyl) phenyl) valeramide
												45	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-isopropyl phenyl) valeramide
46	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-(methyl sulphonyl) phenyl) valeramide
												47	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(quinoline-5-yl) valeramide
48	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(2) valeramide
												49	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(pyridine-2-yl) valeramide
50	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(pyridin-3-yl) valeramide
												51	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(pyrazine-2-yl) valeramide
52	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(benzo [d] [1,3] dioxole-5-yl) valeramide
												53	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3, the 5-3,5-dimethylphenyl) valeramide
54	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-o-tolyl valeramide
												55	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(6-methoxypyridine-2-yl) valeramide
56	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(2,3-Dihydrobenzofuranes-5-yl) valeramide

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11
												57	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-(4,5-diamino-5-oxo amyl group) Isonicotinamide

Table 3

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11
												58	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(R)-2-amino-4-(2-chlorophenoxy) butyramide
59	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-chlorophenoxy) butyramide
												60	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-chlorophenoxy) butyramide
61	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-phenoxy group butyramide
												62	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-phenoxy group butyramide
63	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2, the 4-dimethyl phenoxy) butyramide
												64	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2, the 4-dimethyl phenoxy) butyramide
65	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methylphenoxy) butyramide
												66	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methylphenoxy) butyramide
67	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-methoxyl group phenoxy group) butyramide
												68	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-methoxyl group phenoxy group) butyramide
69	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-methylphenoxy) butyramide
												70	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-methylphenoxy) butyramide
71	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(5-picoline-2-base oxygen base) butyramide
												72	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(5-picoline-2-base oxygen base) butyramide
73	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-fluorophenoxy) butyramide
												74	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-fluorophenoxy) butyramide
75	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-fluorophenoxy) butyramide
												76	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2,4 dichloro benzene oxygen base) butyramide
77	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2, the 3-dimethyl phenoxy) butyramide
												78	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(3-fluorophenoxy) butyramide
79	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(3-chlorophenoxy) butyramide
												80	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(3-methoxyl group phenoxy group) butyramide
81	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(3-methylphenoxy) butyramide
												82	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(3, the 4-dimethyl phenoxy) butyramide
83	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-phenyl phenoxy group) butyramide

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11
												84	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2,3-dihydro-1H-indenes-5-base oxygen base) butyramide
85	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-chloro-2-methylphenoxy)-N-methylbutyryl amine
												86	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(R)-2-amino-4-(4-(1H-1,2,4-triazol-1-yl-phenoxy group) butyramide
87	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-CN-phenoxy group) butyramide
												88	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-MeO-phenoxy group) butyramide
89	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-phenyl phenoxy group) butyramide
												90	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-CF 3-phenoxy group) butyramide
91	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(3-acetylaminohydroxyphenylarsonic acid phenoxy group) butyramide
												92	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(3-dimethylamino-phenoxy group) butyramide
93	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(3-phenyl phenoxy group) butyramide
												94	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-Cl-2-Me-phenoxy group) butyramide
95	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-phenoxy group-phenoxy group) butyramide
												96	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-CF 3-phenoxy group) butyramide
97	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-sec.-propyl-phenoxy group) butyramide
												98	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(1-naphthyloxy) butyramide
99	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-naphthyloxy) butyramide
												100	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	2-amino-4-(4-(imidazoles-1-yl)-phenoxy group) butyramide
101	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(benzo [d] [1,3] dioxole-5-yl) valeramide
												102	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(3-dimethylamino-phenoxy group) butyramide
103	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	2-amino-4-(quinoline-6-base oxygen base) butyramide
												104	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(3-trifluoromethoxy-phenoxy group) butyramide
105	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	2-amino-4-(4-picoline-2-base oxygen base) butyramide
												106	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	2 (S)-amino-4-(2-(1H-pyrazole-3-yl-phenoxy group) butyramide
107	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	2 (S)-amino-4-(4-(1H-1,2,4-triazol-1-yl-phenoxy group) butyramide

Table 4

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11
												108	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-4-(3,4-diamino-4-oxo butoxy) benzamide
109	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-phenoxy group butyramide
												110	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-fluorophenoxy) butyramide

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11
												111	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-phenyl phenoxy group) butyramide
112	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-4-trifluoromethylphenopendant) butyramide
												113	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methylphenoxy) butyramide
114	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2, the 4-dimethyl phenoxy) butyramide
												115	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(3-kharophen phenoxy group) butyramide
116	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methyl-4-chlorophenoxy) butyramide
												117	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-phenoxy group phenoxy group) butyramide
118	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methoxyl group phenoxy group) butyramide
												119	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-4-trifluoromethylphenopendant) butyramide
120	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2,3-dihydro-1H-indenes-5-base oxygen base) butyramide
												121	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(1-naphthyloxy) butyramide
122	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-naphthyloxy) butyramide
												123	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(benzo [d] [1,3] dioxole-5-base oxygen base) butyramide
124	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(quinoline-6-base oxygen base) butyramide
												125	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-phenyl valeramide
126	Deaminizating His	(S)-a-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3-chloro-phenyl-) valeramide
												127	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(benzo [d] [1,3] dioxole-5-yl) valeramide
128	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3, the 5-3,5-dimethylphenyl) valeramide
												129	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3-p-methoxy-phenyl) valeramide
130	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(naphthalene-2-yl) valeramide
												131	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(6-picoline-2-yl) valeramide
132	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(R)-2-amino-5-(4-chloro-2-aminomethyl phenyl) valeramide
												133	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-chloro-2-methylphenoxy)-N-methylbutyryl amine
134	Deaminizating His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(R)-2-amino-4-(4-chloro-2-methylphenoxy)-N-methylbutyryl amine

Table 5

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11
												135	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-phenyl pentanoyl-NH-Me
136	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-phenoxy group butyramide

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11
												137	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-fluorophenoxy) butyramide
138	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2,4 dichloro benzene oxygen base) butyramide
												139	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-phenyl phenoxy group) butyramide
140	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-4-trifluoromethylphenopendant) butyramide
												141	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methylphenoxy) butyramide
142	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2, the 3-dimethyl phenoxy) butyramide
												143	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(3-kharophen phenoxy group) butyramide
144	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(3-phenyl phenoxy group) butyramide
												145	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methyl-4-chlorophenoxy) butyramide
146	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methyl-4-phenoxy group phenoxy group) butyramide
												147	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methyl-4-methoxyl group phenoxy group) butyramide
148	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methyl-4-4-trifluoromethylphenopendant) butyramide
												149	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2,3-dihydro-1H-indenes-5-base oxygen base) butyramide
150	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(1-naphthyloxy) butyramide
												151	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-naphthyloxy) butyramide
152	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(benzo [d] [1,3] dioxole-5-base oxygen base) butyramide
												153	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(quinolyl-4 oxygen base) butyramide
154	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(quinoline-6-base oxygen base) butyramide
												155	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-phenyl valeramide
156	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(4-chloro-phenyl-) valeramide
												157	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3-chloro-phenyl-) valeramide
158	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(benzo [d] [1,3] dioxole-5-yl) valeramide
												159	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3, the 5-3,5-dimethylphenyl) valeramide
160	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(o-tolyl) valeramide
												161	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(3-p-methoxy-phenyl) valeramide
162	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(naphthalene-2-yl) valeramide
												163	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(6-picoline-2-yl) valeramide
164	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(quinoline-6-yl) valeramide

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11
												165	H 3C-O-CO-His	(S)-α-Me-Pro	E’	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-(2, the 3-3,5-dimethylphenyl) valeramide
166	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	2 (R)-amino-4-(2-Me-4-Cl-phenoxy group) butyramide
												167	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(4-chloro-2-methylphenoxy)-N-methylbutyryl amine
168	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(R)-2-amino-4-(4-chloro-2-methylphenoxy)-N-methylbutyryl amine

The result of selected compounds is with EC ₅₀The form of value is presented in the table 6.The structure of exemplary compound is provided at table 7.

Table 6

SEQ ID NO：	People GLP-1 cAMP EC 50(nM)
		169	0.149
177	0.034
		181	0.092
183	0.079
		185	0.128
191	0.044
		196	0.087
201	0.071
		204	0.040
205	0.033
		206	0.029
207	0.083
		210	0.076
211	0.093
		212	0.020

Table 7

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11-NH 2
												169	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(D-Ser(OBz))-NH 2[i.e. (D-Ser (benzyloxy))-NH 2]
170	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-1-(2,3-diamino-3-oxopropyl)-3-o-tolyl urea
												171	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-1-(2,3-diamino-3-oxopropyl)-3-phenylurea
172	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-1-benzyl-3-(2,3-diamino-3-oxopropyl) urea
												173	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-1-phenyl-3-(2,3-diamino-3-oxopropyl) urea
174	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(2-o-tolyl kharophen) propionic acid amide
												175	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(2-phenyl kharophen) propionic acid amide
176	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-oxo-4-(piperidines-1-yl) butyramide
												177	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2,3-diamino-3-oxopropyl ammonia formic acid 2-benzyl chloride ester
178	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-the amino propionic acid amide of 3-acetylaminohydroxyphenylarsonic acid 2-
												179	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-3-amino-N1-(pyridine-2-ylmethyl) succinic diamide
180	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-3-amino-N1-2-methyl-benzyl succinic diamide

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11-NH 2
												181	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-3-amino-N1-benzyl succinic diamide
182	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-3-amino-N1-isobutyl-succinic diamide
												183	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2,3-diamino-3-oxopropyl ammonia benzyl formate
184	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-N-(2,3-diamino-3-oxopropyl)-2-methyl benzamide
												185	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-N-(2,3-diamino-3-oxopropyl)-3-methyl benzamide
186	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-N-(2,3-diamino-3-oxopropyl)-3-picoline acid amides
												187	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-N-(2,3-diamino-3-oxopropyl)-4-methyl benzamide
188	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-N-(2,3-diamino-3-oxopropyl) benzamide
												189	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-N-(2,3-diamino-3-oxopropyl) Isonicotinamide
190	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (1-(2-amino-ethyl) piperidines)-NH 2
												191	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (1,2,3, the 4-tetrahydroisoquinoline)-NH 2
192	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (2-(2-amino-ethyl) pyridine)-NH 2
												193	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (2-flunamine)-NH 2
194	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (2-methylbenzylamine)-NH 2
												195	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (3-methoxybenzylamine)-NH 2
196	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (3-methoxyl group-N-methylbenzylamine)-NH 2
												197	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu(4-CF 3-benzylamine)-NH 2
198	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (benzylamine)-NH 2
												199	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (dibenzylamine)-NH 2
200	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (isobutylamine)-NH 2
												201	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (isoindoline)-NH 2
202	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (N, N-dimethyl-ethylenediamine)-NH 2
												203	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (n-Butyl Amine 99)-NH 2
204	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (N-ethyl benzyl amine)-NH 2
												205	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (N-methylbenzylamine)-NH 2
206	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu(OBz)-NH 2
												207	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu(OBz)-NH 2
208	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (phenylethylamine)-NH 2
												209	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Glu (piperidines)-NH 2
210	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Ser(Bzl)-NH 2

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11-NH 2
												211	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	Thr(OBz)-NH 2
212	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	L-Asp(OBz)-NH 2

The result of selected compounds is with EC ₅₀The form of value is presented in the table 8.The structure of exemplary compound is provided in the table 9.

Table 8

SEQ ID NO：	People GLP-1 cAMP EC 50(nM)
		224	0.060
227	0.254
		235	0.065
236	0.066
		239	0.043
254	0.385
		255	0.884
267	0.322
		273	0.032
274	0.023
		275	0.029
276	0.084
		287	0.068
288	0.032
		292	0.094

Table 9

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11-NH 2
												213	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(benzene carbon amide ylmethyl) phenyl) propionic acid
214	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(phenyl sulfonamido methyl) phenyl) propionic acid
												215	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(sulfonyloxy methyl amino methyl) phenyl) propionic acid
216	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((2,3-dimethoxy benzamido) methyl) phenyl) propionic acid
												217	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((2,4 difluorobenzene formamido group) methyl) phenyl) propionic acid
218	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((2,4-dimethoxy benzamido) methyl) phenyl) propionic acid
												219	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((2,5-dimethoxy benzamido) methyl) phenyl) propionic acid
220	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((2,6-dichlorophenyl sulfonamido) methyl) phenyl) propionic acid
												221	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((2-chlorobenzoyl amino) methyl) phenyl) propionic acid
222	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((2-methoxybenzoyl amino) methyl) phenyl) propionic acid
												223	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((2-toluyl amino) methyl) phenyl) propionic acid
224	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((2-aminomethyl phenyl sulfonamido) methyl) phenyl) propionic acid
												225	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3,4-dichlorophenyl sulfonamido) methyl) phenyl) propionic acid
226	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3,4-dimethoxy benzamido) methyl) phenyl) propionic acid

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11-NH 2
												227	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((benzo [d] [1,3] dioxole-5-formamido group) methyl) phenyl) propionic acid
228	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3,5-dichlorophenyl sulfonamido) methyl) phenyl) propionic acid
												229	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3,5-dimethoxy benzamido) methyl) phenyl) propionic acid
230	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3,5-dimethyl isoxazole-4-sulfonamido) methyl) phenyl) propionic acid
												231	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-(trifluoromethyl) benzamido) methyl) phenyl) propionic acid
232	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-chlorobenzoyl amino) methyl) phenyl) propionic acid
												233	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-chloro-phenyl-sulfonamido) methyl) phenyl) propionic acid
234	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-cyano group benzamido) methyl) phenyl) propionic acid
												235	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-phenetole formamido group) methyl) phenyl) propionic acid
236	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-fluorobenzoyl amino) methyl) phenyl) propionic acid
												237	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-isopropyl benzene formamido group) methyl) phenyl) propionic acid
238	H	Aib	E	G	T	L-a-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-methoxyl group-4-toluyl amino) methyl) phenyl) propionic acid
												239	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-methoxybenzoyl amino) methyl) phenyl) propionic acid
240	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-anisole ylsulfonylamino) methyl) phenyl) propionic acid
												241	H	Aib	E	G	T	L-α-Me-P he (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-toluyl amino) methyl) phenyl) propionic acid
242	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-(trifluoromethoxy) benzamido) methyl) phenyl) propionic acid
												243	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-phenyl benzamido) methyl) phenyl) propionic acid
244	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(nicotinoyl amino methyl) phenyl) propionic acid
												245	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((4-butylbenzene formamido group) methyl) phenyl) propionic acid
246	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((4-chloro-phenyl-sulfonamido) methyl) phenyl) propionic acid
												247	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((4-phenylcyclohexane formamido group) methyl) phenyl) propionic acid
248	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((4-methoxybenzoyl amino) methyl) phenyl) propionic acid
												249	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((4-aminomethyl phenyl sulfonamido) methyl) phenyl) propionic acid
250	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((4-toluyl amino) methyl) phenyl) propionic acid
												251	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((4-benzyl benzamido) methyl) phenyl) propionic acid
252	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((4-phenyl sulfonamido) methyl) phenyl) propionic acid
												253	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((4-phenyl sulfonamido) methyl) phenyl) propionic acid
254	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-3-(4-(acetylamino methyl) phenyl)-2-alanine

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11-NH 2
												255	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(hexanaphthene formamido group methyl) phenyl) propionic acid
256	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-methylbutyryl amino) methyl) phenyl) propionic acid
												257	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(2,4-dimethoxy benzamido) phenyl) propionic acid
258	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(2,6-dichlorophenyl sulfonamido) phenyl) propionic acid
												259	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(2-chlorobenzoyl amino) phenyl) propionic acid
260	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(2-toluyl amino) phenyl) propionic acid
												261	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(3,4-dichlorophenyl sulfonamido) phenyl) propionic acid
262	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(3,4-dimethoxy benzamido) phenyl) propionic acid
												263	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(3,5-dichlorophenyl sulfonamido) phenyl) propionic acid
264	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(3,5-dimethyl isoxazole-4-sulfonamido) phenyl) propionic acid
												265	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(3-chloro-phenyl-sulfonamido) phenyl) propionic acid
266	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(3-toluyl amino) phenyl) propionic acid
												267	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(nicotinoyl amino) phenyl) propionic acid
268	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(4-aminomethyl phenyl sulfonamido) phenyl) propionic acid
												269	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(3-phenyl benzamido) phenyl) propionic acid
270	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(4-xenyl sulfonamido) phenyl) propionic acid
												271	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(phenyl sulfonamido) phenyl) propionic acid
272	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(sulfonyloxy methyl amino) phenyl) propionic acid
												273	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(2,4 difluorobenzene formamido group) phenyl) propionic acid
274	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(2-chlorobenzoyl amino) phenyl) propionic acid
												275	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(2-methoxybenzoyl amino) phenyl) propionic acid
276	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(2-aminomethyl phenyl sulfonamido) phenyl) propionic acid
												277	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(3-methoxybenzoyl amino) phenyl) propionic acid
278	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(3-anisole ylsulfonylamino) phenyl) propionic acid
												279	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(4-chloro-phenyl-sulfonamido) phenyl) propionic acid
280	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-(4-anisole ylsulfonylamino) phenyl) propionic acid
												281	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((2,3-dimethoxy benzamido) methyl) phenyl) propionic acid
282	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((2,5-dimethoxy benzamido) methyl) phenyl) propionic acid

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11-NH 2
												283	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((benzo [d] [1,3] dioxole-5-formamido group) methyl) phenyl) propionic acid
284	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3,5-dimethoxy benzamido) methyl) phenyl) propionic acid
												285	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-(trifluoromethyl) benzamido) methyl) phenyl) propionic acid
286	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-cyano group benzamido) methyl) phenyl) propionic acid
												287	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-phenetole formamido group) methyl) phenyl) propionic acid
288	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-fluorobenzoyl amino) methyl) phenyl) propionic acid
												289	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-methoxyl group-4-toluyl amino) methyl) phenyl) propionic acid
290	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-toluyl amino) methyl) phenyl) propionic acid
												291	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-(trifluoromethoxy) benzamido) methyl) phenyl) propionic acid
292	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-phenyl benzamido) methyl) phenyl) propionic acid
												293	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((4-butylbenzene formamido group) methyl) phenyl) propionic acid
294	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((4-phenylcyclohexane formamido group) methyl) phenyl) propionic acid
												295	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((4-methoxybenzoyl amino) methyl) phenyl) propionic acid
296	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((4-benzyl benzamido) methyl) phenyl) propionic acid
												297	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-3-(4-(acetylamino methyl) phenyl)-2-alanine
298	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(4-((3-methylbutyryl amino) methyl) phenyl) propionic acid

The result of selected compounds is with EC ₅₀The form of value is presented in the table 10.The structure of exemplary compound is provided in the table 11.

Table 10

SEQ ID NO：	People GLP-1 cAMP EC 50(nM)
		300	0.085
303	0.059
		305	0.061
308	0.023
		310	0.045
311	0.032
		315	0.080
317	0.062

Table 11

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11-NH 2
												299	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-5-methylhexanoic acid
300	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	1-aminocyclopentanecarboxylic acid
												301	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-the 2-aminocaprylic acid

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11-NH 2
												302	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-the amino capric acid of 2-
303	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-aminohexanoic acid
												304	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-methoxyl group butyric acid
305	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-the 2-aminocaprylic acid
												306	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-butoxy propionic acid
307	H	Aib	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(2-methoxy ethoxy) propionic acid
												308	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-butoxy propionic acid
309	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-(2-methoxy ethoxy) propionic acid
												310	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-3-cyclohexylpropionic acid
311	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-cyclohexyl butyric acid
												312	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(R)-2-amino-3-cyclohexylpropionic acid
313	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(2S, 3S)-2-amino-3 methylvaleric acid
												314	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-methylpent-obtusilic acid
315	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-the 2-aminovaleric acid
												316	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(R)-the 2-aminovaleric acid
317	H	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(R)-the 2-aminocaprylic acid

Table 12

SEQ ID NO：	People GLP-1 cAMP EC 50(nM)
		318	0.051
319	0.038
		320	0.073
321	0.035
		322	0.047
323	0.056
		324	0.043

Table 13

SEQ IDNO：	X aa1	X aa2	X aa3	X aa4	X aa5	X aa6	X aa7	X aa8	X aa9	X aa10	X aa11-NH 2
												318	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	H	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methyl-4-chlorophenoxy) butyramide
319	H 3C-SO 2-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methyl-4-chlorophenoxy) butyramide
												320	H 3C-SO 2-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	H	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methyl-4-chlorophenoxy) butyramide
321	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methyl-4-fluorophenoxy) butyramide
												322	H 3C-O-CO-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	H	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methyl-4-fluorophenoxy) butyramide
323	H 3C-SO 2-His	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	H	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methyl-4-fluorophenoxy) butyramide
												324	(L)-β-imidazole emulsion acyl group	(S)-α-Me-Pro	E	G	T	L-α-Me-Phe (2-fluorine)	T	S	D	Bip(2’-Et-4’-OMe)	(S)-2-amino-4-(2-methyl-4-chlorophenoxy) butyramide

Embodiment 27

Research in the body

Compound is dissolved in the suitable carriers (vehicle) with the concentration (nmol/ml) that is equal to dosage (nmol/kg), thereby makes every mouse all can accept the drug solns of giving of equal volume/weight.Based on feed plasma glucose and body weight, male C57BL/6J-ob/ob mouse (10 age in week) is carried out the randomization grouping, every group has six mouse.Behind the overnight fasting, mouse is weighed, place the laboratory then.After in laboratory environment, placing 30 clocks, via end pin mouse is got blood, subcutaneous immediately then (sc) injection carrier or be dissolved in peptide (0.1ml solution/100g body weight) in the carrier at-30min.The time 0 pair of mouse get blood, peritoneal injection 50% glucose (2g/kg) then is with beginning intraperitoneal glucose tolerance test (ipGTT).Behind the injectable dextrose monohydrate, 30,60,120 and 180min mouse is got blood.Blood sample is drawn onto in the EDTA potassium, in research process, places on ice, subsequently at 4 ℃ with the centrifugal 10min of 3000rpm.With 11 times of plasma sample dilutions, be used for carrying out glucose analysis in the Cobas system.(Regular Insulin ELISA measures test kit to another part plasma sample (5 μ l) with 20 μ l diluentses, CrystalChem Inc.) dilution is 5 times, and be stored in-20 ℃, be used for utilizing subsequently the plain ELISA test kit of hypersensitivity mouse islets (Crystal Chem Inc.) to analyze.

In ob/ob mouse (mouse model of insulin resistant) SEQ ID be numbered character that 141,145,167,318,319,320,321,322,323 and 324 compound reduces glucose in the body be summarised in table 14 (below) in.

Embodiment 31

The dog pharmacokinetic study

(n=4 has determined the pharmacokinetic parameter of peptide compounds in the table 14 in 14 ± 1kg) at male beasle dog (beagle dog).Behind the overnight fasting, every animal is all accepted compound (67 μ g/kg) by carry out subcutaneous injection near shoulder blade.Follow cross-over design, every animal is all accepted subcutaneous administration, and the clean-up time in a week is arranged between twice administration.The drug administration carrier that is used for two kinds of route of administration all is 0.2MTris (pH8.0).Serial blood sample is collected in the Eppendorf tube that contains EDTA at following time point: before the administration, behind the intravenous administration 0.083,0.25,0.5,0.75,1,2,4,6,8,24 and 30 hour; Before the administration, behind the subcutaneous administration 0.25,0.5,0.75,1,2,4,6,8,24 and 30 hour.All collect about 0.3mL blood at each time point.Carry out centrifugal at 4 ℃ to blood sample immediately.Resulting blood plasma is freezing with dry ice, and is stored in-20 ℃.Utilize following described LC-MS/MS to measure to determine the drug plasma level.

By LC-MS/MS compound is carried out quantitatively

Plasma sample to the research of ex vivo dog is handled, and to analyze by the following method: the acetonitrile (containing interior mark) with two volumes makes the plasma proteins precipitation.Sample is carried out vortex mixed, centrifugally then remove sedimentary protein.Resulting supernatant liquor is transferred in the 96-orifice plate, injected 10 μ L then and be used for analyzing.Sample is handled with Packard Multiprobe II and Quadra 96 Liquid Handling System.

The HPLC system use two Shimadzu LC10AD pumps (Columbia, MD) and CTC PAL automatic sampler (Leap Technologies, Switzerland).Employed post be YMCHydrosphere C18 (2.0 * 50mm, 3 μ m) (YMC, Inc., Milford, MA).Column temperature remains on 50 ℃, and flow velocity is 0.3mL/ minute.Mobile phase A is made up of the aqueous solution of 10mM ammonium formiate and 0.1% formic acid, and Mobile phase B is made up of the acetonitrile solution of 0.1% formic acid.Initial moving phase consists of 5%B, and keeps one minute at 5%B, so that column equilibration.Last two minutes and make composition become 95%B, and kept again one minute at this.In one minute, make moving phase become starting condition again then.The bulk analysis time is five minutes.Use switching valve.0-1 minute elutriant is gone to waste fluid container.

HPLC and Sciex API 4000 mass spectrographs (Applied Biosystems, Foster City, CA) interface, and the TurboIonspray ionization source is equipped with.The nitrogen that uses ultra-high purity is as spraying and vortex gas.The temperature of vortex gas is set in 300 ℃, and the interface well heater is set in 60 ℃.Data gathering utilizes selected reaction monitoring (SRM).

Disclosed with the claimed compound of the application demonstrates remarkable usefulness (potency) under the situation that contacts (comparableexposure) on an equal basis in the efficacy models (efficacymodel of glucose lowering) (ob/ob mouse model) that glucose reduces; and demonstrate remarkable pharmacokinetic property (measuring by carry out subcutaneous injection in dog), these are presented in the table 14.

Table 14

Peptide SEQ IDNO	Usefulness in the ob/ob mouse: the minimizing percentage ratio of the AUC of plasma glucose behind the subcutaneous injection compound in the ip glucose tolerance test ＊	In dog, contact ＊＊(subcutaneous injection, 67 μ g/kg)
			141	-66％(p<0.001)(10nmol/kg)	517nM*h
145	-43％(p<0.05)(1nmol/kg)	964nM*h
			167	67％(p<0.01)(10nmol/kg)	1030nM*h
318	-62％(p<0.01)(3nmol/kg)	1242nM*h
			319	-38％(p<0.05)(3nmol/kg)	1366nM*h
320	-46％(p<0.05)(1nmol/kg)	815nM*h
			321	-59％(p<0.01)(3nmol/kg)	705nM*h
322	-43％(p<0.01)(1nmol/kg)	601nM*h
			323	-50％(p<0.01)(3nmol/kg)	Not test (N.T.)
324	-43％(p<0.01)(1nmol/kg)	210nM*h

^*The AUC=area under curve.With regard to every animal, use the fasting plasma dextrose equivalent value to calculate the AUC value as baseline.Calculate the percent change of AUC with respect to the AUC of carrier disposal group in the same research.Come by the following method to determine given p value: utilize variance analysis (ANOVA) to come to compare, carry out Fisher cause and effect check (Fisher ' s post-hoc test) subsequently with carrier disposal group. ^*Drug administration carrier is a 0.2M Tris damping fluid (pH8.0).

Purposes and composition

A. purposes

The described theme of the application provides has remarkable character and as the new compound of GLP-1 receptor modulators, these compounds for example have agonist activity for the GLP-1 acceptor.In addition, compare with the GLP-1 native sequences, the described compound of the application shows the stability of raising to proteolytic cleavage.

Therefore, can be with the described compound administration of the application in Mammals, be preferably the mankind, be used for the treatment of various disease conditions and disease, include but not limited to treat or delay the progress or the outbreak of following disease: diabetes (are preferably type ii diabetes, glucose tolerance reduces, insulin resistant and diabetic complication be ephrosis for example, retinopathy, neuropathy and cataract), hyperglycemia, hyperinsulinemia, hypercholesterolemia, free fatty acids or glycerine blood levels improve, hyperlipidaemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis, hypertension, AIDS, enteropathy (necrotic enteritis for example, microvillus inclusion disease or coeliac disease), inflammatory bowel syndrome, the intestinal mucosa atrophy or the damage of phase chemotherapy induced, anorexia nervosa, osteoporosis, dysmetabolic syndrome and inflammatory bowel (for example Crohn's disease (Crohn ' s disease) and ulcerative colitis).The described compound of the application also can be used for improving the blood levels of high-density lipoprotein (HDL) (HDL).

In addition, can utilize the described compounds for treating of the application at Johansson J.Clin.Endocrinol.Metab., 82, the illness that is referred to as " X syndrome " or metabolism syndrome, disease and the sufferer that are described in detail among the 727-34 (1997).

B. composition

The application's description comprises pharmaceutical composition with claimed theme, described pharmaceutical composition contain separately or with at least a formula I compound as the treatment significant quantity of activeconstituents of pharmaceutically acceptable carrier or thinner combination.Randomly, the described compound of the application can use separately, with described other compound coupling of the application, or with one or more other medicines (for example antidiabetic medicine) or other pharmaceutically active substances coupling.

The described compound of the application can or be used for the treatment of other appropriate therapeutic drug combination of above-mentioned disease with other GLP-1 receptor modulators (for example agonist or partial agonist are such as peptide agonists), and described other appropriate therapeutic medicine comprises antidiabetic drug, hyperglycemia medicine, blood lipid-lowering medicine/fat-reducing medicament, anti-obesity medicine (comprising appetite-inhibiting agent/conditioning agent) and antihypertensive drug.In addition, the described compound of the application can with one or more following medicine couplings: aphoria medicine, the medicine of treatment polycystic ovary syndrome, the medicine of treatment growth disease (growth disorder), the medicine of treatment weak (frailty), the medicine of treatment of arthritis, the medicine of allograft rejection during prevention is transplanted, the medicine of treatment autoimmune disorder, anti-AIDS medicine, osteosporosis resistant medicament, the medicine of treatment immunomodulatory disease, anticoagulation medicine, the medicine of treatment cardiovascular disorder, antibacterials, antipsychotics, the medicine of treatment chronic inflammatory bowel disease or syndromic medicine and/or treatment anorexia nervosa.

Comprise biguanides (for example N1,N1-Dimethylbiguanide or phenformin) with the example of the suitable antidiabetic medicine of the described compound coupling of the application, glucosidase inhibitor (for example acarbose or miglitol (miglitol)), insulin type (comprising Drugs Promoting Insulin Secretion or insulin sensitizer), meglitinides (for example repaglinide (repaglinide)), sulfourea (glimepiride (glimepiride) for example, Glyburide, gliclazide, P-607 and Glipizide), biguanides/Glyburide (for example makes up

), thiazolidinediones (for example troglitazone (troglitazone), rosiglitazone (rosiglitazone) and pioglitazone (pioglitazone)), PPAR-alfa agonists, PPAR-gamma agonist, PPAR-α/γ dual agonists, glycogen phosphorylase inhibitors, fatty acid binding protein (aP2) inhibitor, DPP-IV inhibitor and SGLT2 inhibitor.

Other suitable thiazolidinediones comprises that Mitsubishi ' s MCC-555 (is disclosed in United States Patent (USP) 5,594,016), Glaxo-Wellcome ' s GL-262570, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer), Netoglitazone (isaglitazone) (MIT/J﹠amp; J), JTT-501 (JPNT/P﹠amp; U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN) or YM-440 (Yamanouchi).

Suitable PPAR-α/γ dual agonists comprises Mo Geta azoles (muraglitazar) (Bristol-MyersSquibb), AR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck) and in following document disclosed material: Murakami et al, " ANovel Insulin Sensitizer Acts As a Coligandfor PeroxisomeProliferation-Activated Receptor Alpha (PPAR alpha) and PPAR gamma.Effecton PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of ZuckerFatty Rats ", Diabetes 47, the U.S. Patent application 09/644 that 1841-1847 (1998) and on September 18th, 2000 submit to, 598, at this its disclosed content is incorporated herein by reference, use wherein listed dosage, the application preferably uses preferred compound wherein.

Suitable aP2 inhibitor comprises disclosed material in following document: the U.S. Patent application 09/519,079 that the U.S. Patent application 09/391,053 that on September 7th, 1999 submitted to and on March 6th, 2000 submit to, use wherein listed dosage.

Can comprise at WO99/38501 with the suitable DPP4 inhibitor of the described compound coupling of the application, WO99/46272, WO99/67279 (PROBIODRUG), disclosed material among WO99/67278 (PROBIODRUG) and the WO99/61431 (PROBIODRUG), Hughes et al, Biochemistry, 38 (36), 11597-11603,1999 disclosed NVP-DPP728A (1-[[[2-[(5-cyanopyridine-2-yl) amino] ethyl] amino] ethanoyl]-2-cyano group-(S)-tetramethyleneimine) (Novartis), LAF237, saxagliptin, MK0431, Yamada et al, Bioorg.﹠amp; The disclosed TSL-225 of Med.Chem.Lett.8 (1998) 1537-1540 (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), Ashworth et al, Bioorg.﹠amp; Med.Chem.Lett., Vol.6, No.22, pp1163-1166and 2745-2748 (1996) disclosed 2-cyano group pyrrolidide class and 4-cyano group pyrrolidide class are used dosage listed in the above document.

Suitable meglitinides comprises that nateglinide (nateglinide) (Novartis) or KAD1229 (PF/Kissei).

Can comprise that GLP-1 (1-36) acid amides, GLP-1 (7-36) acid amides, GLP-1 (7-37) (are disclosed in the United States Patent (USP) 5 that licenses to Habener with other suitable glucagon-like-peptide-1 (GLP-1) examples for compounds of the described GLP-1 receptor modulators of the application (for example agonist or partial agonist) coupling, 614,492) and C2993 (Amylin), LY-315902 (Lilly) and NN2211 (Novo Nordisk).

Comprise one or more MTP inhibitor, HMG CoA reductase inhibitor, inhibitor for squalene synthetic enzyme, toluylic acid (fibric acid) derivative, ACAT inhibitor, lipoxidase (lipoxygenase) inhibitor, cholesterol absorption inhibitor, ileum Na with the example of the suitable blood lipid-lowering medicine/fat-reducing medicament of the described compound coupling of the application ⁺Adjustment on/bile acide cotransporter inhibitor, the ldl receptor activity, bile acid chelating agent, cholesteryl ester transfer protein (for example CP-529414 (Pfizer)) and/or nicotinic acid and derivative thereof.

Spendable as mentioned above MTP inhibitor comprises disclosed material in following document: United States Patent (USP) 5,595,872, United States Patent (USP) 5,739,135, United States Patent (USP) 5,712,279, United States Patent (USP) 5,760, and 246, United States Patent (USP) 5,827,875, United States Patent (USP) 5,885,983 and United States Patent (USP) 5,962,440, at this it all is incorporated herein by reference.

Can be included in United States Patent (USP) 3 with the HMG CoA reductase inhibitor of one or more formulas I compound coupling, 983, disclosed mevastatin and related compound in 140, at United States Patent (USP) 4,231, disclosed lovastatin (Mevacor (mevinolin)) and related compound in 938, at United States Patent (USP) 4,346, disclosed Pravastatin and related compound and at United States Patent (USP) 4,448 in 227,784 and 4, disclosed Simvastatin and related compound in 450,171.Spendable other HMG CoA reductase inhibitor of the application includes but not limited at United States Patent (USP) 5,354, disclosed fluvastatin in 772, at United States Patent (USP) 5,006,530 and 5,177, disclosed Cerivastatin (cerivastatin) in 080, at United States Patent (USP) 4,681,893,5,273,995,5,385,929 and 5,686, disclosed atorvastatin in 104, at United States Patent (USP) 5,011, disclosed Zarator (atavastatin) in 930 (Buddhist nun of Nissan/Sankyo cut down him spit of fland (nisvastatin) (NK-104)), at United States Patent (USP) 5,260, disclosed Wei Shatating (visastatin) in 440 (Shionogi-Astra/Zeneca (ZD-4522)) and at United States Patent (USP) 5,753, disclosed relevant statin compound in 675, at United States Patent (USP) 4,613, the pyrazole analogs of disclosed mevalonolactone derivative in 610, the indenes analogue of disclosed mevalonolactone derivative in PCT application WO 86/03488, at United States Patent (USP) 4,647, disclosed 6-[2-in 576 (pyrroles of replacement-1-yl)-alkyl) pyran-2-one and derivative thereof, the SC-45355 of Searle (glutaric acid derivatives that 3-replaces) ethyl dichloroacetate, the imidazoles analogue of disclosed mevalonolactone in PCT application WO 86/07054, in French Patent 2,596, disclosed 3-carboxyl-2-hydroxyl-propane-phosphonate derivative in 393, in european patent application 0221025 disclosed 2, the 3-disubstituted pyrroles, furans and thiophene derivant, at United States Patent (USP) 4,686, the naphthyl analogue of disclosed mevalonolactone in 237, at United States Patent (USP) 4,499, disclosed octahydro naphthalene in 289, the keto analog of disclosed Mevacor (lovastatin) and in european patent application 0142146A2 at United States Patent (USP) 5,506,219 and 5, disclosed quinoline and pyridine derivate in 691,322.

The blood lipid-lowering medicine of expectation is Pravastatin, lovastatin, Simvastatin, atorvastatin, fluvastatin, Cerivastatin, Zarator and ZD-4522.

In addition, the phosphinic acid compounds (for example disclosed material in GB 2205837) of inhibition HMG CoA reductase enzyme is suitable for the described compound coupling with the application.

The inhibitor for squalene synthetic enzyme that is suitable for using in this application includes but not limited at United States Patent (USP) 5,712, disclosed α-phosphono-sulphonate in 396; Biller et al; J.Med.Chem., 1988, Vol.31; No.10; the disclosed material of pp 1869-1871 (comprising isoprenoid (phosphino--methyl) phosphonic acid ester) and other known inhibitor for squalene synthetic enzyme (for example at United States Patent (USP) 4,871,721 and 4; 924; 024 and Biller, S.A., Neuenschwander; K.; Ponpipom, M.M., and Poulter; C.D.; Current Pharmaceutical Design, 2, disclosed material among the 1-40 (1996)).

In addition, other inhibitor for squalene synthetic enzyme that is suitable for using in this application comprises P.Ortz deMontellano et al, J.Med.Chem., 1977,20, the disclosed terpene pyrophosphate of 243-249, Corey and Volante, J.A m.Chem.Soc., 1976,98, the disclosed farnesyl bisphosphate of 1291-1293 analogue A and preceding squalene pyrophosphate (PSQ-PP) analogue, McClard, R.W.et al, J.A.C.S., 1987,109,5544 phosphino-phosphoric acid ester and the Capson that reported, T.L., PhDdissertation, June, 1987, Dept.Med.Chem.U of Utah, Abstract, Table ofContents, pp 16,17,40-43,48-51, the cyclopropanes that Summary reported.

Can comprise with the phenylacetic acid derivatives of one or more formulas I compound coupling: fenofibrate, gemfibrozil, clofibrate, bezafibrate, Win-35833, S-8527 etc., at United States Patent (USP) 3, disclosed probucol and related compound in 674,836 (being preferably probucol and gemfibrozil), bile acid chelating agent (for example Colestyramine, colestipol and DEAE-dextrane gel (

,

)) and protect fat appropriate (Rhone-Poulenc), Eisai E-5050 (ethanolamine derivant that N-replaces), imanixil (HOE-402), tetrahydrochysene presses down fat element (tetrahydrolipstatin) (THL), istigmastanylphos-phorylcholine (SPC, Roche), amino cyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivatives), AC-233 (Sumitomo), Sandoz58-035, American Cyanamid CL-277,082 and CL-283,546 (dibasic urea derivativess), nicotinic acid, acipimox, Acifran, Xin Meisu, para-aminosalicylic acid, acetylsalicylic acid, at United States Patent (USP) 4,759, disclosed poly-(diallyl methylamine) derivative in 923, at United States Patent (USP) 4, poly-(chlorination diallyl dimethylammonium) and ionene class and other known serum cholesterol-lowering agents thing of disclosed quaternary amine in 027,009.

Can comprise disclosed material or TS-962 (Taisho Pharmaceutical Co.Ltd): Drugs of the Future 24 in following document with the ACAT inhibitor of one or more formulas I compound coupling, 9-15 (1999), (Avasimibe (avasimibe)); " The ACAT inhibitor; Cl-1011 is effectivein the prevention and regres sion of aortic fatty streak area in hamsters ", Nicolosiet al, Atherosclerosis (Shannon, Irel). (1998), 137 (1), 77-85; " Thepharmacological profile of FCE 27677:a novel ACAT inhibitor with potenthypolipidemic activity mediated by selective suppression of the hepatic secretionof A poB 100-containinglipoprotein ", Ghiselli, Giancarlo, Cardiovasc.DrugRev. (1998), 16 (1), 16-30; " RP 73163:a bioavailablealkylsulfinyl-diphenylimidazole ACAT inhibitor ", Smith, C., et al, Bioorg.Med.Chem.Lett. (1996), 6 (1), 47-50; " ACAT inhibitors:physiologic mechanisms forhypolipidemic and anti-atherosclerotic activities in experimental animals ", Krause et al, Editor (s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation:Mediators Pathways (1995), 173-98, Publisher:CRC, Boca Raton, Fla.; " ACAT inhibitors:potential anti-atherosclerotic agents ", Sliskovic et al, Curr.Med.Chem. (1994), 1 (3), 204-25; " Inhibitors of acyl-CoA:cholesterolO-acyl transferase (ACAT) as hypocholesterolemic agents.6.The firstwater-soluble ACAT inhibitor with lipid-regulating activity.Inhibitors ofacyl-CoA:cholesterol acyltransferase (ACAT) .7.Development of a series ofsubstituted N-phenyl-N '-[(1-phenylcyclopentyl) methyl] ureas with enhancedhypocholesterolemic activity ", Stout et al, Chemtracts:Org.Chem. (1995), 8 (6), 359-62.

Blood lipid-lowering medicine is adjusted for example MD-700 (TaishoPharmaceutical Co.Ltd) and LY295427 (Eli Lilly) on can the LD2 receptor active.

Comprise SCH48461 (Schering-Plough) with the example of the suitable cholesterol absorption inhibitor of the described compound coupling of the application and at Atherosclerosis 115,45-63 (1995) and J.Med.Chem.41, disclosed material in 973 (1998).

Suitable ileum Na with the described compound coupling of the application ⁺The example of/bile acide cotransporter inhibitor is included in Drugs ofthe Future, and 24, disclosed compound among the 425-430 (1999).

Can comprise 15-lipoxidase (15-LO) inhibitor with the lipoxygenase inhibitor of one or more formulas I compound coupling, disclosed benzimidizole derivatives in WO 97/12615 for example, disclosed 15-LO inhibitor in WO97/12613, disclosed isothiazole ketone and Sendobry et al in WO 96/38144, " Attenuation of diet-induced atherosclerosis in rabbits with ahighly selective 15-lipoxygenase inhibitor lacking significant antioxidantproperties ", Brit.J.Pharmacology (1997) 120,1199-1206 and Cornicelli et al, " 15-Lipoxygenase and its Inhibition:A Novel Therapeutic Target for VascularDisease ", Current Pharmaceutical Design, 1999,5, the disclosed 15-LO inhibitor of 11-20.

Comprise Beta-3 adrenergic blocker, calcium channel blocker (L-type and T-type with the example of the suitable antihypertensive drug of the described compound coupling of the application; Diltiazem for example

Verapamil, nifedipine, amlodipine and mybefradil), diuretic(s) (chlorothiazide for example, hydrochlorothiazide, flumethiazide, Hydroflumethiazide, Hydrex, methyl chlorothiazide, trichlormethiazide, polythiazide, benzthiazide, Ethacrynic Acid Tienilic Acid (ethacrynic acid tricrynafen), chlorthalidone, Furosemide, musolimine, bumetanide, triamtrenene, guanamprazine and spironolactone), renin inhibitor, ACE inhibitor (captopril for example, zofenopril, fosinopril, enalapril, ceranopril, Yipingshu (cilazopril), delapril, pentopril, quinapril, Ramipril and lisinopril), AT-1 receptor antagonist (losartan for example, irbesartan and valsartan), ET receptor antagonist (sitaxentan (sitaxsentan) for example, atrasentan (atrsentan) and at United States Patent (USP) 5,612,359 and 6, disclosed compound in 043,265), dual ET/AII antagonist (for example disclosed compound in WO 00/01389), neutral endopeptidase (NEP) inhibitor, vasopeptidase (vasopepsidase) inhibitor (dual NEP-ACE inhibitor) (for example omapatrilat and gemopatrilat) and nitric acid lipid.

Comprise the npy receptor antagonist with the example of the suitable anti-obesity medicine of the described compound coupling of the application, NPY-Y2 or NPY-Y4 receptor stimulant, oxyntomodulin (Oxyntomodulin), the MCH antagonist, the GHSR antagonist, the CRH antagonist, plain energy agonist on β-3 kidney, lipase (lipase) inhibitor, serotonin (and Dopamine HCL) reuptake inhibitor (reuptake inhibitor), thryoid receptor β medicine (thyroid receptor beta drug), CB-1 antagonist and/or apocleisis medicine (anorecticagent).

Can choose wantonly and plainly on β-3 kidney with the described compound coupling of the application can agonist comprise AJ9677 (Takeda/Dainippon), L750355 (Merck) or CP331648 (Pfizer) or at United States Patent (USP) 5,541,204,5,770,615,5,491,134,5,776, disclosed other known beta-3 agonist in 983 and 5,488,064, be preferably AJ9677, L750,355 and CP331648.

The example that can choose wantonly with the lipase inhibitor of the described compound coupling of the application comprises orlistat (orlistat) or ATL-962 (Alizyme), is preferably orlistat.

Serotonin (and Dopamine HCL) reuptake inhibitor that can choose wantonly with the coupling of formula I compound can be sibutramine (sibutramine), topiramate (topiramate) (Johnson ﹠amp; Johnson) or ciliary body neurotrophic factor (axokine) (Regeneron), be preferably sibutramine and topiramate.

Can choose the part that comprises thryoid receptor with the example of the thryoid receptor beta compounds of the described compound coupling of the application wantonly, for example disclosed compound in WO97/21993 (U.Cal SF), WO99/00353 (KaroBio) and WO 00/039077 (KaroBio) is preferably the compound that KaroBio applies for.

The example that can choose wantonly with the CB-1 antagonist of the described compound coupling of the application comprises CB-1 antagonist and Rimonabant (rimonabant) (SR141716A).

The example of NPY-Y2 and NPY-Y4 receptor stimulant comprises PYY (3-36) and pancreatic polypeptide (PP) respectively.

The apocleisis medicine that can choose wantonly with the described compound coupling of the application comprises Dextroamphetamine (dexamphetamine), phentermine (phentermine), Phenylpropanolamine (phenylpropanolamine) or Mazindol (mazindol), is preferably Dextroamphetamine.

The example of suitable antipsychotics comprise leoponex, haloperidol, olanzapine (

),

And Aripiprazole

At this above-mentioned patent and patent application are incorporated herein by reference.

More than other medicine, when with the described compound coupling of the application, can be for example with the amount that in Physician ' s Desk Reference, illustrates, with the amount in above-mentioned patent, listed or with those of ordinary skills the amount determined in addition use.

Dosage and preparation

Suitable formula I peptide can come to patient's administration with treatment diabetes and other relative disease with the form of pharmaceutical preparation by the form of independent compound and/or with available support blended form.The technician in treating diabetes field can easily determine to use (comprising the mankind) to the Mammals of this treatment of needs the dosage and the route of administration of described compound.Route of administration can include but not limited to oral administration, mouthful interior (intraoral) administration, rectal administration, percutaneous dosing, contain administration in clothes (buccal) administration, intranasal administration, pulmonary administration, subcutaneous administration, intramuscular administration, intradermal administration, sublingual administration, colonic administration, eye drops, intravenous administration or the intestines.According to route of administration based on acceptable pharmacy practice (Fingl etal., in " The Pharmacological Basis of Therapeutics ", Ch.1, p.1,1975; " Remington ' s Pharmaceutical Sciences ", 18th ed., Mack Publishing Co, Easton, PA, 1990) prepare compound.

The described pharmaceutically useful peptide combinations of the application can come administration by multiple formulation, for example tablet, capsule (tablet and capsule comprise extended release preparation or time release formulation separately), pill, powder agent, granule, elixir, in-situ gel (in situ gel), microspheres agent, crystalline composites (crystallinecomplexe), liposome, microemulsion, tincture, suspensoid, syrup, sprays and emulsion.The described composition of the application also can be by oral form, intravenously (injecting or infusion) form, intraperitoneal form, subcutaneous form, come administration through skin form or intramuscular form, and form of ownership all uses the known formulation of pharmaceutical field those of ordinary skill.Composition can be individually dosed, but usually with the pharmaceutical carrier administration, and described pharmaceutical carrier is put into practice according to selected route of administration and standard pharmaceutical and selected.

The dosage regimen of the described composition of the application changes with known factor certainly, for example pharmacodynamic profile and the mode of administration and the approach of concrete medicine; Experimenter's species, age, sex, health, medical condition and body weight; The nature and extent of symptom; The kind of current treatment; The frequency of treatment; Route of administration, patients " renal function and liver function; And the effect of expectation.Doctor or animal doctor can determine required effective amount of drug and prescription, with the process of prevention, antagonism or prevention morbid state.

By general guide, activeconstituents when being used for adaptation every day oral dosage scope be about 0.001 to 1000mg/kg body weight, be preferably about 0.01 to 100mg/kg body weight/day, most preferably be about 0.6 to 20mg/kg/ day.For intravenous administration, in the constant rate of speed infusion process, the every day dosage of activeconstituents when being used for adaptation is 0.001ng to 100.0ng/ minute/kg body weight.Described constant intravenous infusion can preferably come administration with the speed of 0.01ng to 50ng/ minute/kg body weight, most preferably comes administration with the speed of 0.01ng to 10.0mg/ minute/kg body weight.The described composition of the application can come administration by single daily dose, maybe can come administration total every day of dosage by the broken dose of every day secondary, three times or four times.The described composition of the application also can come administration by depot formulations (depotformulation), and described depot formulations allows medicine to continue to discharge as expectation in the day/week/period moon.

The described composition of the application can use that carrier comes administration in the suitable nose by form in the nose by the part, or comes administration by using through the skin approach through the skin skin patch.When carrying out administration with the form of transdermal delivery system, medicine gives that yes in whole dosage regimen successive, rather than be interrupted.

Composition is usually to come administration with suitable drug thinner, vehicle or carrier (being referred to as pharmaceutical carrier in this application) blended form, described pharmaceutical carrier is selected suitably in view of the form of medication of expectation, and conform to the conventional pharmaceutical practice, form of medication has oral tablet, capsule, elixir, sprays (containing or do not contain propellent) and syrup.

For example, carry out oral administration for form with tablet or capsule, active medicine component can make up with oral nontoxicity pharmaceutical acceptable inert carriers, and described oral nontoxicity pharmaceutical acceptable inert carriers is such as but not limited to lactose, starch, sucrose, glucose, methylcellulose gum, Magnesium Stearate, Lin Suanergai, calcium sulfate, N.F,USP MANNITOL and sorbyl alcohol; For carrying out oral administration with liquid form, the oral pharmaceutical component can make up with any oral nontoxicity pharmaceutical acceptable inert carriers, and described oral nontoxicity pharmaceutical acceptable inert carriers is such as but not limited to ethanol, G ﹠ W.In addition, when expecting or needing, also suitable binder, lubricant, disintegrating agent and tinting material can be incorporated in the mixture.Suitable binder includes but not limited to starch, gel, natural carbohydrate (such as but not limited to glucose or beta lactose), corn sweetener, natural gum class and synthetical glue class (for example gum arabic, tragcanth or sodium alginate), carboxymethyl cellulose, polyoxyethylene glycol and wax class.The lubricant that uses in these formulations comprises sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate and sodium-chlor.Disintegrating agent includes but not limited to starch, methylcellulose gum, agar, wilkinite and xanthan gum (xanthan gum).

The described composition of the application also can come administration by the form of mixed micelle drug delivery system or liposome administration system, and described drug delivery system for example is small unilamellar vesicle, big unilamellar liposome and multilamellar liposome.Liposome can prepare from multiple phosphatide (for example cholesterol, stearylamide or phosphoric acid Yelkin TTS).Can add penetration enhancer, to improve drug absorption.

Because known prodrug can improve the character (being solubleness, bioavailability, manufacturing etc.) of the multiple expectation of medicine, so the described compound of the application can come administration by the form of prodrug.Thereby the described theme of the application is intended to contain the prodrug of the application's claimed compounds, the method for these prodrugs of administration and the composition that contains these prodrugs.

The described composition of the application also can combine with the soluble polymer as target medicine carrier.Described polymkeric substance can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyl-MAAm-phenol, poly-hydroxyethyl l-asparagine phenol or the polyoxyethylene-polylysine that is replaced by palmitoyl.In addition; the described composition of the application can make up with a class Biodegradable polymeric; be used to realize that controlled delivery of pharmaceutical agents discharges, described Biodegradable polymeric for example be poly(lactic acid), polyglycolic acid, poly(lactic acid) and polyglycolic acid multipolymer, poly epsilon caprolactone lactone, polyhydroxybutyrate, poe (polyorthoester), polyacetal, gather the crosslinked or amphipathic nature block polymer of dihydropyrane, paracyanogen base acylate (polycyanoacylate) and hydrogel.

The formulation (pharmaceutical composition) that is suitable for administration can contain has an appointment 0.01 milligram to about 500 milligrams of activeconstituents/dose units.In these pharmaceutical compositions, by the gross weight of composition, activeconstituents exists with the amount of about 0.5-95% weight usually.

The gelatine capsule agent can contain activeconstituents and powder carrier (for example lactose, starch, derivatived cellulose, Magnesium Stearate and stearic acid).Similarly thinner can be used for preparing compressed tablets.Tablet and capsule all can manufacture the product that continues release, so that the medicine that continues release to be provided in a few hours.Compressed tablets can be sweet tablet or film dressing, to cover any bad taste and to protect tablet to avoid being subjected to air to influence, maybe can be the enteric coating dressing, with optionally disintegration in gi tract.

The liquid preparation of oral administration can contain tinting material and seasonings, to improve patient's acceptability.

The suitable carrier that water, suitable oil, salt solution, dextrose (glucose) aqueous solution and associated sugars solution and glycol (for example propylene glycol or polyoxyethylene glycol) normally are used for parenteral solution agent (parenteral solution).The solution that is used for administered parenterally preferably contains water-soluble salt, suitable stabilizers and the buffer substance (if desired) of activeconstituents.Antioxidant (for example list is used or sodium bisulfite, S-WAT or the xitix of coupling) is a suitable stabilizers.Also use Citric Acid and salt thereof and EDTA sodium.In addition, the parenteral solution agent can contain sanitas (for example benzalkonium chloride, methyl p-hydroxybenzoate or propylparaben and butylene-chlorohydrin).

Suitable pharmaceutical carrier is referring to Remington: " The Science and Practice of Pharmacy ", Nineteenth Edition, Mack Publishing Company, 1995 is the canonical reference book of this area.

Below for example understand the representational pharmaceutical dosage form that is used for the described compound of administration the application:

Capsule

Can prepare a variety of units capsule by two-part hard gelatin capsule with 100 milligrams of Powdered activeconstituentss, 150 milligrams of lactose, 50 milligrams of Mierocrystalline celluloses and 6 milligrams of Magnesium Stearate filling standards.

Gelseal

Can prepare the mixture of activeconstituents in digestible oil (for example soybean oil, Oleum Gossypii semen or sweet oil), by volumetric pump (positive displacement pump) it is expelled in the gelatin then, contains the soft gelatin capsule of 100 milligrams of activeconstituentss with formation.Can wash and drying capsule.

Tablet

Tablet can prepare by routine operation, thereby makes dose unit for example contain 100 milligrams of activeconstituentss, 0.2 milligram of silica colloidal, 5 milligrams of Magnesium Stearates, 275 milligrams of Microcrystalline Celluloses, 11 milligrams of starch and 98.8 milligrams of lactose.Can use suitable dressing, to improve palatability or delayed absorption.

Injection

The injection of the described peptide combinations of the application may need or not need to use vehicle (for example vehicle that management unit ratified).These vehicle include but not limited to solvent and cosolvent, solubilizing agent, emulsifying agent or thickening material, sequestrant, antioxidant and reductive agent, antimicrobial preservative, buffer reagent and pH regulator agent, weighting agent, protective material and tension regulator and special additive.Injection must be aseptic and pyrogen-free, and must be not contain particulate matter with regard to the solution form.

The parenteral composition (parenteral composition) that is suitable for drug administration by injection can prepare by the following method: for example pharmaceutically acceptable buffered soln of 1.5 weight % activeconstituentss is stirred, and described pharmaceutically acceptable buffered soln can contain or not contain cosolvent or other vehicle.Available sodium-chlor oozes solution etc., then sterilization.

Suspensoid

Can prepare the aqueous suspension that is used for oral administration and/or administered parenterally, thereby make for example every 5mL contain the activeconstituents of 100mg fine dispersion, 20mg Xylo-Mucine, 5mg Sodium Benzoate, 1.0g Sorbitol Solution USP (U.S.P.) and 0.025mL Vanillin or other agreeable to the taste seasonings.

The Biodegradable microparticle agent

The parenteral composition that is suitable for the lasting release of drug administration by injection can for example prepare by the following method: suitable biodegradable polymer is dissolved in the solvent, in polymers soln, add activeconstituents to be introduced, and remove from matrix and to desolvate, form polymeric matrix thus, and activeconstituents spreads all in matrix.

Can under instruction of the present invention, carry out multiple change and variation to the application's description and claimed theme.Therefore it should be understood that within the scope of the appended claims, except that the specifically described content of the application, also can implement described other theme of claims.

The described theme of claims should not be confined in the scope of above-mentioned specific embodiments, and these specific embodiments are intended to the single embodiment as claimed theme.And the content described shown except that the application, those skilled in the art also can understand method and the composition that is equal on the function by foregoing description and accompanying drawing.These are changed within the scope of the appended claims.At this with complete being incorporated herein by reference of whole documents that the application quoted.

Claims (62)

1. isolated polypeptide, described polypeptide comprises formula I sequence:

X _aa1-X _aa2-X _aa3-X _aa4-X _aa5-X _aa6-X _aa7-X _aa8-X _aa9-X _aa10-X _aa11

I

Wherein

X _Aa1The amino acid that exists for the natural or non-natural that comprises imidazolyl, for example Histidine; Wherein said amino acid whose any carbon atom is optional to be replaced by hydrogen or one or more alkyl, and wherein said amino acid whose free amine group is optional to be replaced by following group: hydrogen, alkyl, acyl group, benzoyl, L-lactoyl, alkyl oxy carbonyl, aryloxy carbonyl, arylalkyl oxygen base carbonyl, heterocyclyloxy base carbonyl, heteroarylalkyl oxygen base carbonyl, alkylcarbamoyl group, aromatic yl ammonia methanoyl, arylalkyl carbamyl, heterocyclic radical alkylsulfonyl, alkyl sulphonyl, aryl sulfonyl, aryl alkylsulfonyl, heteroarylalkyl alkylsulfonyl or heteroarylsulfonyl; And X wherein _Aa1Amino optional do not exist, thereby make X _Aa1Be the deaminizating acid of Histidine, wherein any carbon atom is optional to be replaced by hydrogen or one or more alkyl;

X _Aa2Be amino acid natural or that non-natural exists, it is selected from D-L-Ala, alpha-amino group-isopropylformic acid (Aib), N-methyl D-L-Ala, N-ethyl-D-L-Ala, 2-methyl-azetidine-2-carboxylic acid, Alpha-Methyl-(L)-proline(Pro), pipecoline-2-carboxylic acid and isovaline;

X _Aa3Be amino acid natural or that non-natural exists, it comprises the amino acid side chain that contains carboxylic acid, for example aspartic acid or L-glutamic acid; Or X wherein _Aa3Be the amino acid that the natural or non-natural that contains the imidazoles side chain exists, for example Histidine, and wherein said amino acid whose any carbon atom is optional to be replaced by one or more alkyl;

X _Aa4Be glycine;

X _Aa5Be amino acid natural or that non-natural exists, it is selected from (L)-Threonine and (L)-norvaline; And wherein said amino acid whose any carbon atom is optional is replaced by one or more alkyl;

X _Aa6Be amino acid natural or that non-natural exists, described amino acid comprises dibasic α carbon; One of wherein said amino acid whose side chain contains aromatic ring, for example Alpha-Methyl-phenylalanine, alpha-methyl-2-fluorophenylalanine and alpha-methyl-2,6-two fluorophenylalanine; Wherein said amino acid whose any carbon atom is optional to be replaced by one or more alkyl or one or more halogen;

X _Aa7Be amino acid natural or that non-natural exists, it comprises the amino acid side chain that is replaced by hydroxyl, for example the L-Threonine; Wherein said amino acid whose any carbon atom is optional to be replaced by one or more alkyl;

X _Aa8Be amino acid natural or that non-natural exists, it is selected from L-Serine and L-Histidine; Wherein said amino acid whose one or more carbon atoms are optional to be replaced by one or more alkyl;

X _Aa9Be amino acid natural or that non-natural exists, it comprises the amino acid side chain that contains carboxylic acid, for example L-aspartic acid or L-L-glutamic acid; Wherein said amino acid whose one or more carbon atoms are optional to be replaced by one or more alkyl;

X _Aa10Be amino acid natural or that non-natural exists, described amino acid has formula II:

Formula II

Wherein

R ₁Be selected from hydrogen, alkyl and halogen; And

R ₂And R ₃Independently be selected from hydrogen, halogen, methyl, ethyl, alkyl, hydroxyl, methoxyl group and alkoxyl group separately;

X _Aa11Be amino acid natural or that non-natural exists, described amino acid has any among formula III, IV, V or the VI, wherein

Formula III is:

Formula III

The terminal carbonyl carbon of wherein said amino acid whose C-links to each other with nitrogen and forms methane amide (NH ₂);

Wherein encircle A and be selected from aryl and heteroaryl;

R wherein ₄And R ₅Independently be selected from hydrogen, halogen, methyl, ethyl, alkyl, hydroxyl, methoxyl group, alkoxyl group, aryl and heteroaryl separately; And

X wherein ₁And X ₂CH-alkyl, CH respectively do for oneself ₂, NH, S or O; And

Formula III also can comprise at least one R ₄Or R ₅Group is and if exist a plurality of R ₄And R ₅, R so ₄And R ₅Can be identical or different;

Formula IV is:

Formula IV

The terminal carbonyl carbon of wherein said amino acid whose C-links to each other with nitrogen and forms methane amide (NH ₂);

R wherein ₄Be selected from hydrogen, hydroxyl, methyl, ethyl, alkyl, methoxyl group, alkoxyl group, aryl and heteroaryl;

R wherein ₅Be selected from hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or assorted alkylaryl;

Wherein X is selected from CH ₂, CH ₂CH ₂Or CHCH ₃

Y wherein ₁Be selected from-NH-,-O-and-C=O-;

Wherein if Y ₁Be NH or O, then Y ₂Be selected from-C=O-,-O=C-O-and-SO ₂-;

Wherein if Y ₁Be C=O, then Y ₂Be selected from-NH-,-N-or-O-; And

R wherein ₆Be selected from hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl; And

Formula IV also comprises at least one R ₆Group is and if exist a plurality of R ₆, R so ₆Can be identical or different;

Formula V is:

Formula V

The terminal carbonyl carbon of wherein said amino acid whose C-links to each other with nitrogen and forms methane amide (NH ₂);

R wherein ₄Be selected from hydrogen, hydroxyl, methyl, ethyl, alkyl, methoxyl group, alkoxyl group, aryl and heteroaryl;

R wherein ₅Be selected from hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or assorted alkylaryl;

X wherein ₁Do not exist or by CH ₂Form;

X wherein ₂Be selected from-CO-, CO-N (-) ₂,-CO-O-,-SO-and-SO ₂-;

R wherein ₆And R ₇Independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl; And

Formula V comprises at least one R ₇Group is and if exist a plurality of R ₇, R so ₇Can be identical or different;

Formula VI is:

Formula VI

The terminal carbonyl carbon of wherein said amino acid whose C-links to each other with nitrogen and forms methane amide (NH ₂);

R wherein ₄Be selected from hydrogen, methyl, ethyl, alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or assorted alkylaryl;

R wherein ₅Be selected from hydrogen, hydroxyl, methyl, ethyl, alkyl, methoxyl group and alkoxyl group;

R wherein ₆Be selected from hydrogen, methyl, ethyl, alkyl, cycloalkyl, Heterocyclylalkyl, hydroxyl, methoxyl group and alkoxyl group;

Formula VI also can comprise at least one R ₆Group is and if exist a plurality of R ₆, R so ₆Can be identical or different, and formula VI also can comprise R ₅And R ₆Group, described R ₅And R ₆Form cycloalkyl, Heterocyclylalkyl, cycloalkyl aryl or cycloalkyl heteroaryl together.

2. the isolated polypeptide of claim 1, wherein said X _Aa1Be the L-Histidine, and wherein terminal amino group is optional is replaced by following group: hydrogen, alkyl, dialkyl group, acyl group, benzoyl, L-lactoyl, alkyl oxy carbonyl, aryloxy carbonyl, arylalkyl oxygen base carbonyl, heterocyclyloxy base carbonyl, heteroarylalkyl oxygen base carbonyl, alkylcarbamoyl group, aromatic yl ammonia methanoyl, arylalkyl carbamyl, heterocyclic radical alkylsulfonyl, alkyl sulphonyl, aryl sulfonyl, aryl alkylsulfonyl, heteroarylalkyl alkylsulfonyl or heteroarylsulfonyl.

3. the isolated polypeptide of claim 1, wherein said X _Aa1Be selected from L-His, L-N-methyl-His, L-Alpha-Methyl-His, deaminizating-His, 3-(1H-imidazol-4 yl)-2-methylpropionyl and (S)-3-(1H-imidazol-4 yl)-2-hydroxyl propionyl (L-β-imidazole emulsion acyl group).

4. the isolated polypeptide of claim 1, wherein said X _Aa2Be selected from alpha-amino group-isopropylformic acid (Aib), D-L-Ala, N-methyl D-L-Ala, Alpha-Methyl-(L)-proline(Pro), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid.

5. the isolated polypeptide of claim 1, wherein said X _Aa3Be selected from L-L-glutamic acid and L-aspartic acid.

6. the isolated polypeptide of claim 1, wherein said X _Aa4Be Gly.

7. the isolated polypeptide of claim 1, wherein said X _Aa5Be selected from L-Thr and L-Nva.

8. the isolated polypeptide of claim 1, wherein said X _Aa6Be selected from L-α-Me-Phe, L-α-Me-2-fluoro-Phe and L-α-Me-2,6-two fluoro-Phe.

9. the isolated polypeptide of claim 1, wherein said X _Aa7Be L-Thr.

10. the isolated polypeptide of claim 1, wherein said X _Aa8Be selected from L-Ser and L-His.

11. the isolated polypeptide of claim 1, wherein said X _Aa9Be L-Asp.

12. the isolated polypeptide of claim 1, the X of wherein said formula II _Aa10Be selected from 4-phenyl-phenylalanine, 4-[(4 '-methoxyl group-2 '-ethyl) phenyl] phenylalanine, 4-[(4 '-oxyethyl group-2 '-ethyl) phenyl] phenylalanine, 4-[(4 '-methoxyl group-2 '-methyl) phenyl] phenylalanine, 4-[(4 '-oxyethyl group-2 '-methyl) phenyl] phenylalanine, 4-(2 '-ethylphenyl) phenylalanine, 4-(2 '-aminomethyl phenyl) phenylalanine, 4-[(3 ', 5 '-dimethyl) phenyl] phenylalanine and 4-[(3 ', 4 '-dimethoxy) phenyl] phenylalanine.

13. the isolated polypeptide of claim 1, wherein said X _Aa11Be formula III amino acid, and be selected from (S)-2-amino-5-phenyl valeric acid, (S)-2-amino-4-phenoxybutyhc, (S)-2-amino-5-(4-chloro-phenyl-) valeric acid, (S)-2-amino-5-(quinoline-5-yl) valeric acid, (S)-2-amino-4-(2-chlorophenoxy) butyric acid, (S)-2-amino-4-(2-methylphenoxy) butyric acid and (S)-2-amino-4-(2-methyl-4-chlorophenoxy) butyric acid, the terminal carbonyl carbon of the wherein said amino acid whose C-formation methane amide (NH2) that links to each other with nitrogen.

14. the isolated polypeptide of claim 1, wherein said X _Aa11Be formula IV amino acid, and be selected from L-Asp (OBz)-OH, L-Glu (OBz)-OH, L-Ser (OBz)-OH, D-Ser (OBz)-OH, L-Thr (OBz)-OH, (S)-2-amino-5-(benzyl (methyl) amino)-5-oxopentanoic acid, (S)-3-((2-benzyl chloride base oxygen base) carbonyl)-2-alanine, (S)-2-amino-5-benzyl (ethyl) amino-5-oxopentanoic acid, (S)-5-((3-methoxy-benzyl) (methyl) amino)-2-amino-5-oxopentanoic acid, (S)-2-amino-4-(benzylamino)-4-ketobutyric acid, (S)-2-amino-3-(3-toluyl amino) propionic acid, (S)-2-amino-3-(2-toluyl amino) propionic acid, (S)-2-amino-5-(isoindoline-2-yl)-5-oxopentanoic acid, (S)-2-amino-3-(benzyl oxygen base carbonyl) propionic acid, (S)-5-(2-methyl-benzyl amino)-2-amino-5-oxopentanoic acid, (S)-5-(2-luorobenzyl amino)-2-amino-5-oxopentanoic acid, (S)-2-amino-4-oxo-4-(piperidines-1-yl) butyric acid, (S)-5-(4-(trifluoromethyl) benzylamino)-2-amino-5-oxopentanoic acid, (S)-2-amino-5-(dibenzyl amino)-5-oxopentanoic acid, (S)-2-amino-3-(3-phenyl urea groups) propionic acid, (S)-2-amino-3-(3-benzyl urea groups) propionic acid, (S)-2-amino-3-(3-o-tolyl urea groups) propionic acid, (S)-2-amino-3-(2-o-tolyl kharophen) propionic acid, (S)-2-amino-5-(benzylamino)-5-oxopentanoic acid, (S)-5-(3-methoxy-benzyl amino)-2-amino-5-oxopentanoic acid, (S)-2-amino-3-(3-picoline amido) propionic acid, (S)-2-amino-3-(different nicotinoyl amino) propionic acid, (S)-2-amino-3-(2-phenyl kharophen) propionic acid, (S)-and 2-amino-5-(3,4-dihydro-isoquinoline-2 (1H)-yl)-5-oxopentanoic acid, (S)-2-amino-5-(butyl amino)-5-oxopentanoic acid, (S)-2-amino-3-benzamido propionic acid, (S)-2-amino-5-oxo-5-(piperidines-1-yl) valeric acid, (S)-2-amino-5-(isobutylamino)-5-oxopentanoic acid, (S)-2-amino-4-oxo-4-(pyridine-2-ylmethyl amino) butyric acid, (S)-4-(2-methyl-benzyl amino)-2-amino-4-ketobutyric acid, (S)-2-amino-4-(isobutylamino)-4-ketobutyric acid, (S)-2-amino-3-(4-toluyl amino) propionic acid, (S)-2-amino-5-oxo-5-(2-(piperidines-1-yl) ethylamino) valeric acid, (S)-2-amino-5-oxo-5-(2-(pyridine-2-yl) ethylamino) valeric acid, (S)-2-amino-5-(2-(dimethylamino) ethylamino)-5-oxopentanoic acid, (S)-2-amino-5-oxo-5-(styroyl amino) valeric acid and (S)-3-acetylaminohydroxyphenylarsonic acid 2-alanine; The terminal carbonyl carbon of wherein said amino acid whose C-links to each other with nitrogen and forms methane amide (NH ₂); And R wherein ₆Be selected from hydrogen and methyl.

15. the isolated polypeptide of claim 1, wherein said X _Aa11For being selected from following formula V amino acid: (S)-2-amino-3-(4-(benzene carbon amide ylmethyl) phenyl) propionic acid, (S)-2-amino-3-(4-(phenyl sulfonamido methyl) phenyl) propionic acid, (S)-2-amino-3-(4-(sulfonyloxy methyl amino methyl) phenyl) propionic acid, (S)-(4-((2 for 2-amino-3-, 3-dimethoxy benzamido) propionic acid phenyl methyl)), (S)-(4-((2 for 2-amino-3-, 4-difluoro benzamido) propionic acid phenyl methyl)), (S)-(4-((2 for 2-amino-3-, 4-dimethoxy benzamido) propionic acid phenyl methyl)), (S)-(4-((2 for 2-amino-3-, 5-dimethoxy benzamido) propionic acid phenyl methyl)), (S)-(4-((2 for 2-amino-3-, 6-dichlorophenyl sulfonamido) propionic acid phenyl methyl)), (S)-2-amino-3-(4-((2-chlorobenzoyl amino) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((2-methoxybenzoyl amino) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((2-toluyl amino) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((2-aminomethyl phenyl sulfonamido) methyl) phenyl) propionic acid, (S)-(4-((3 for 2-amino-3-, 4-dichlorophenyl sulfonamido) propionic acid phenyl methyl)), (S)-(4-((3 for 2-amino-3-, 4-dimethoxy benzamido) propionic acid phenyl methyl)), (S)-2-amino-3-(4-((benzo [d] [1,3] propionic acid phenyl methyl dioxole-5-formamido group))), (S)-(4-((3 for 2-amino-3-, 5-dichlorophenyl sulfonamido) propionic acid phenyl methyl)), (S)-(4-((3 for 2-amino-3-, 5-dimethoxy benzamido) propionic acid phenyl methyl)), (S)-(4-((3 for 2-amino-3-, 5-dimethyl isoxazole-4-sulfonamido) propionic acid phenyl methyl)), (S)-2-amino-3-(4-((3-(trifluoromethyl) benzamido) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((3-chlorobenzoyl amino) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((3-chloro-phenyl-sulfonamido) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((3-cyano group benzamido) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((3-phenetole formamido group) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((3-fluorobenzoyl amino) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((3-isopropyl benzene formamido group) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((3-methoxyl group-4-toluyl amino) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((3-methoxybenzoyl amino) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((3-anisole ylsulfonylamino) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((3-toluyl amino) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((3-(trifluoromethoxy) benzamido) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((3-phenyl benzamido) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-(nicotinoyl amino methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((4-butylbenzene formamido group) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((4-chloro-phenyl-sulfonamido) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((4-phenylcyclohexane formamido group) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((4-methoxybenzoyl amino) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((4-aminomethyl phenyl sulfonamido) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((4-toluyl amino) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((4-benzyl benzamido) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((4-phenyl sulfonamido) methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((4-phenyl sulfonamido) methyl) phenyl) propionic acid, (S)-3-(4-(acetylamino methyl) phenyl)-2-alanine, (S)-2-amino-3-(4-(hexanaphthene formamido group methyl) phenyl) propionic acid, (S)-2-amino-3-(4-((3-methylbutyryl amino) methyl) phenyl) propionic acid, (S)-(4-(2 for 2-amino-3-, 4-dimethoxy benzamido) propionic acid phenyl), (S)-(4-(2 for 2-amino-3-, 6-dichlorophenyl sulfonamido) propionic acid phenyl), (S)-2-amino-3-(4-(2-chlorobenzoyl amino) phenyl) propionic acid, (S)-2-amino-3-(4-(2-toluyl amino) phenyl) propionic acid, (S)-(4-(3 for 2-amino-3-, 4-dichlorophenyl sulfonamido) propionic acid phenyl), (S)-(4-(3 for 2-amino-3-, 4-dimethoxy benzamido) propionic acid phenyl), (S)-(4-(3 for 2-amino-3-, 5-dichlorophenyl sulfonamido) propionic acid phenyl), (S)-(4-(3 for 2-amino-3-, 5-dimethyl isoxazole-4-sulfonamido) propionic acid phenyl), (S)-2-amino-3-(4-(3-chloro-phenyl-sulfonamido) phenyl) propionic acid, (S)-2-amino-3-(4-(3-toluyl amino) phenyl) propionic acid, (S)-2-amino-3-(4-(nicotinoyl amino) phenyl) propionic acid, (S)-2-amino-3-(4-(4-aminomethyl phenyl sulfonamido) phenyl) propionic acid, (S)-2-amino-3-(4-(3-phenyl benzamido) phenyl) propionic acid, (S)-2-amino-3-(4-(4-xenyl sulfonamido) phenyl) propionic acid, (S)-2-amino-3-(4-(phenyl sulfonamido) phenyl) propionic acid, (S)-2-amino-3-(4-(sulfonyloxy methyl amino) phenyl) propionic acid, (S)-2-amino-3-(4-(2,4 difluorobenzene formamido group) phenyl) propionic acid, (S)-2-amino-3-(4-(2-chlorobenzoyl amino) phenyl) propionic acid, (S)-2-amino-3-(4-(2-methoxybenzoyl amino) phenyl) propionic acid, (S)-2-amino-3-(4-(2-aminomethyl phenyl sulfonamido) phenyl) propionic acid, (S)-2-amino-3-(4-(3-methoxybenzoyl amino) phenyl) propionic acid, (S)-2-amino-3-(4-(3-anisole ylsulfonylamino) phenyl) propionic acid, (S)-2-amino-3-(4-(4-chloro-phenyl-sulfonamido) phenyl) propionic acid and (S)-2-amino-3-(4-(4-anisole ylsulfonylamino) phenyl) propionic acid; The terminal carbonyl carbon of wherein said amino acid whose C-links to each other with nitrogen and forms methane amide (NH ₂); And R wherein ₆Be selected from hydrogen and methyl.

16. the isolated polypeptide of claim 1, wherein said X _Aa11For being selected from following formula VI amino acid: (2S, 3S)-2-amino-3 methylvaleric acid, (R)-2-amino-3-cyclohexylpropionic acid, (R)-the 2-aminocaprylic acid, (R)-the 2-aminovaleric acid, (S)-2-amino-3-(2-methoxy ethoxy) propionic acid, (S)-2-amino-3-butoxy propionic acid, (S)-2-amino-3-cyclohexylpropionic acid, (S)-2-amino-4-cyclohexyl butyric acid, (S)-2-amino-4-methoxyl group butyric acid, (S)-2-amino-4-methylpent-obtusilic acid, (S)-2-amino-5-methylhexanoic acid, (S)-the amino capric acid of 2-, (S)-2-aminohexanoic acid, (S)-the 2-aminocaprylic acid, (S)-2-aminovaleric acid and 1-aminocyclopentanecarboxylic acid; The terminal carbonyl carbon of wherein said amino acid whose C-links to each other with nitrogen and forms methane amide (NH ₂); And R wherein ₅Be selected from hydrogen and methyl.

17. the isolated polypeptide of claim 1, described polypeptide has following structure:

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, 2-methyl-azetidine-2-carboxylic acid, pipecoline-2-carboxylic acid and α-An Jiyidingsuan (Aib);

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be selected from hydrogen, methyl and ethyl;

R ₃Be selected from hydrogen, hydroxyl, methoxyl group and oxyethyl group;

Z is selected from CH ₂And O;

Ring A is selected from aryl and heteroaryl;

R ₄Be selected from hydrogen, fluorine, methyl and ethyl;

R ₅Be selected from hydrogen, methyl and methoxyl group;

R ₆Be selected from hydrogen and methyl; And

R ₇Be selected from hydrogen and methyl.

18. the isolated polypeptide of claim 14, wherein

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro and α-An Jiyidingsuan (Aib); Wherein

X is a fluorine;

Y is a hydrogen;

Z is selected from CH ₂And O;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be ethyl;

R ₃Be methoxyl group;

R ₄Be selected from hydrogen, methyl and ethyl;

R ₅Be selected from hydrogen, methyl and ethyl; And

R ₇Be hydrogen.

19. isolated polypeptide, described polypeptide has following structure:

R wherein ₇Be selected from methyl, ethyl,

With

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

Ring A is selected from aryl and heteroaryl;

Z is selected from CH ₂And O;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be methyl or ethyl;

R ₃Be selected from hydrogen, methyl, ethyl and methoxyl group;

R ₄And R ₅Be selected from hydrogen, methyl, ethyl, aryl, halogen or alkoxyl group; And

R ₆Be selected from hydrogen and methyl.

20. the isolated polypeptide of claim 16, wherein R ₇Be selected from methyl and

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro and aminoisobutyric acid (Aib);

X is a fluorine;

Y is a hydrogen;

Z is selected from CH ₂And O;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be ethyl;

R ₃Be methoxyl group;

R ₄Be selected from methyl and ethyl;

R ₅Be selected from halogen and hydrogen; And

R ₆Be selected from hydrogen and methyl.

21. the isolated polypeptide of claim 1, described polypeptide has following structure:

R wherein ₈Be selected from hydrogen, methyl and alkyl;

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

Z is selected from CH ₂And O;

Ring A is selected from aryl and heteroaryl;

R ₂Be selected from methyl and ethyl;

R ₃Be selected from hydrogen, methyl, methoxyl group and ethyl;

R ₄And R ₅Be selected from hydrogen, methyl, ethyl, aryl, halogen or alkoxyl group; And

R ₆Be selected from hydrogen and methyl.

22. the isolated polypeptide of claim 21, wherein R ₈Be selected from hydrogen and methyl;

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro and α-An Jiyidingsuan (Aib);

X is a fluorine;

Y is a hydrogen;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be ethyl;

R ₃Be methoxyl group;

R ₄Be selected from methyl and ethyl;

R ₅Be selected from halogen and hydrogen; And

R ₆Be selected from hydrogen and methyl.

23. the isolated polypeptide of claim 1, described polypeptide has following structure:

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, 2-methyl-azetidine-2-carboxylic acid, pipecoline-2-carboxylic acid and α-An Jiyidingsuan (Aib);

Independently be selected from hydrogen and fluorine separately with Y;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be selected from hydrogen, methyl and ethyl;

R ₃Be selected from hydrogen, hydroxyl, methoxyl group and oxyethyl group;

R ₄And R ₅Be selected from hydrogen, alkyl, alkylaryl, miscellaneous alkyl aryl separately, or R ₄And R ₅Be selected from cycloalkyl, cycloalkyl aryl and cycloalkyl heteroaryl together; And

R ₆Be selected from hydrogen and methyl.

24. the isolated polypeptide of claim 23, wherein

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro and α-An Jiyidingsuan (Aib);

X is a fluorine;

Y is a hydrogen;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be ethyl;

R ₃Be methoxyl group;

R ₄Be selected from methyl, ethyl, alkylaryl and miscellaneous alkyl aryl;

R ₅Be selected from hydrogen, methyl, ethyl, alkylaryl and miscellaneous alkyl aryl; R ₄And R ₅Form circular part together; And

R ₆Be hydrogen.

25. the isolated polypeptide of claim 1, described polypeptide has following structure:

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

X ₁Be selected from CH ₂And CH ₂CH ₂

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be methyl or ethyl;

R ₃Be selected from hydrogen, methyl, ethyl and methoxyl group;

R ₄Be selected from hydrogen, methyl, ethyl, alkyl, hydroxyl, methoxyl group, alkoxyl group, aryl, heteroaryl, alkylaryl and miscellaneous alkyl aryl; And

R ₆Be hydrogen.

26. the isolated polypeptide of claim 1, described polypeptide has following structure:

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be methyl or ethyl;

R ₃Be selected from hydrogen, methyl, methoxyl group and ethyl;

R ₄Be hydrogen or methyl;

Described polypeptide also comprises at least one R ₅Group; And

R ₅Be selected from hydrogen, halogen, methyl, ethyl, alkyl, hydroxyl, methoxyl group, alkoxyl group, aryl, heteroaryl, alkylaryl and miscellaneous alkyl aryl.

27. the isolated polypeptide of claim 26, wherein

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro and α-An Jiyidingsuan (Aib);

X is a fluorine;

Y is a hydrogen;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be ethyl;

R ₃Be methoxyl group;

R ₄Be hydrogen or methyl; And

R ₅Be hydrogen.

28. the isolated polypeptide of claim 1, described polypeptide has following structure:

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, 2-methyl-azetidine-2-carboxylic acid, pipecoline-2-carboxylic acid and α-An Jiyidingsuan (Aib);

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be selected from hydrogen, methyl and ethyl;

R ₃Be selected from hydrogen, hydroxyl, methoxyl group and oxyethyl group;

R ₄Be selected from hydrogen and methyl;

X ₂Be selected from-CO-and-SO ₂-;

Described polypeptide comprises at least one R ₇Group; And

R ₇Be selected from alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl.

29. the isolated polypeptide of claim 1, described polypeptide has following structure:

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be methyl or ethyl;

R ₃Be selected from hydrogen, methyl, ethyl and methoxyl group;

R ₄Be selected from hydrogen and methyl;

X wherein ₂Be selected from-CO-and-SO ₂-;

Described polypeptide comprises at least one R ₇Group; And

R wherein ₇Be selected from alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl.

30. the isolated polypeptide of claim 1, described polypeptide has following structure:

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, 2-methyl-azetidine-2-carboxylic acid, pipecoline-2-carboxylic acid and α-An Jiyidingsuan (Aib);

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be selected from hydrogen, methyl and ethyl;

R ₃Be selected from hydrogen, hydroxyl, methoxyl group and oxyethyl group;

R ₄Be selected from hydrogen and methyl; And

R ₅Be selected from alkyl, assorted alkyl, cycloalkyl or Heterocyclylalkyl.

31. the isolated polypeptide of claim 30, wherein

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro and α-An Jiyidingsuan (Aib);

X is a fluorine;

Y is a hydrogen;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be ethyl;

R ₃Be methoxyl group;

R ₄Be selected from hydrogen and methyl; And

R ₅Be selected from methyl, ethyl, propyl group, butyl, hexyl, cyclohexyl and methylcyclohexyl.

32. the isolated polypeptide of claim 1, described polypeptide has following structure:

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be ethyl;

R ₃Be methoxyl group;

R ₄Be selected from hydrogen and methyl;

R ₅Be methyl; And

R ₆Be selected from alkyl, assorted alkyl, cycloalkyl and Heterocyclylalkyl.

33. the isolated polypeptide of claim 1, described polypeptide has following structure:

Wherein

X _Aa2For being selected from following amino acid: D-Ala, N-methyl D-Ala, Alpha-Methyl-L-Pro, α-An Jiyidingsuan (Aib), 2-methyl-azetidine-2-carboxylic acid and pipecoline-2-carboxylic acid;

X and Y independently are selected from hydrogen and fluorine separately;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be methyl or ethyl;

R ₃Be selected from hydrogen, methyl, methoxyl group and ethyl; And

Ring A is selected from cycloalkyl, cycloalkyl aryl, Heterocyclylalkyl or cycloalkyl heteroaryl.

34. the isolated polypeptide of claim 33, wherein

X _Aa2For being selected from following amino acid: N-methyl D-Ala, Alpha-Methyl-L-Pro and α-An Jiyidingsuan (Aib);

X is a fluorine;

Y is a hydrogen;

X _Aa8For being selected from the amino acid of L-Ser and L-His;

R ₂Be ethyl;

R ₃Be methoxyl group; And

Ring A is a cyclopentyl.

35. the isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from:

SEQ ID NO： X _aa1 X _aa2 X _aa3 X _aa4 X _aa5 X _aa6 X _aa7 X _aa8 X _aa9 X _aa10 X _aa11 1 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-phenyl valeramide 2 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(pyridine-2-yl) valeramide 3 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(pyridin-3-yl) valeramide 4 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(pyrazine-2-yl) valeramide 5 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(benzo [d] [1,3] dioxole-5-yl) valeramide 6 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3, the 5-3,5-dimethylphenyl) valeramide 7 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(2-aminomethyl phenyl) valeramide 8 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-aminomethyl phenyl) valeramide 9 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3-aminomethyl phenyl) valeramide 10 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-p-methoxy-phenyl) valeramide 11 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(5-picoline-2-yl) valeramide 12 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-propyl group phenyl) valeramide 13 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(2-ethylphenyl) valeramide 14 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-picoline-2-yl) valeramide 15 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(2, the 4-3,5-dimethylphenyl) valeramide 16 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3-p-methoxy-phenyl) valeramide 17 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-phenyl valeramide 18 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-xenyl) valeramide 19 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3-picoline-2-yl) valeramide 20 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(pyridin-4-yl) valeramide

21 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(2, the 3-3,5-dimethylphenyl) valeramide 22 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(quinoline-6-yl) valeramide 23 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(naphthalene-2-yl) valeramide 24 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(6-picoline-2-yl) valeramide 25 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(2, and 3-dihydrobenzo [b] [1,4] dioxin-6-yl) valeramide 26 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(2,6-lutidine-3-yl) valeramide 27 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-chloro-phenyl-) valeramide 28 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3-chloro-phenyl-) valeramide 29 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-(dimethylamino) phenyl) valeramide 30 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(2-chloro-phenyl-) valeramide 31 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-(methyl sulphonyl) phenyl) valeramide 32 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(quinoline-5-yl) valeramide 33 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-(trifluoromethyl) phenyl) valeramide 34 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-fluorophenyl) valeramide 35 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3-xenyl) valeramide 36 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) 4-phenyl butane-1-amine 37 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(2) valeramide 38 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-isopropyl phenyl) valeramide 39 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3-xenyl) valeramide 40 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-(dimethylamino) phenyl) valeramide 41 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3-chloro-phenyl-) valeramide 42 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-fluorophenyl) valeramide 43 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(2-chloro-phenyl-) valeramide 44 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-(trifluoromethyl) phenyl) valeramide 45 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-isopropyl phenyl) valeramide 46 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-(methyl sulphonyl) phenyl) valeramide 47 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(quinoline-5-yl) valeramide 48 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(2) valeramide

49 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(pyridine-2-yl) valeramide 50 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(pyridin-3-yl) valeramide 51 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(pyrazine-2-yl) valeramide 52 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(benzo [d] [1,3] dioxole-5-yl) valeramide 53 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3, the 5-3,5-dimethylphenyl) valeramide 54 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-o-tolyl valeramide 55 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(6-methoxypyridine-2-yl) valeramide 56 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(2,3-Dihydrobenzofuranes-5-yl) valeramide 57 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-(4,5-diamino-5-oxo amyl group) Isonicotinamide 58 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (R)-2-amino-4-(2-chlorophenoxy) butyramide 59 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-chlorophenoxy) butyramide 60 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-chlorophenoxy) butyramide 61 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-phenoxy group butyramide 62 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-phenoxy group butyramide 63 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2, the 4-dimethyl phenoxy) butyramide 64 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2, the 4-dimethyl phenoxy) butyramide 65 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methylphenoxy) butyramide 66 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methylphenoxy) butyramide 67 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-methoxyl group phenoxy group) butyramide 68 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-methoxyl group phenoxy group) butyramide 69 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-methylphenoxy) butyramide 70 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-methylphenoxy) butyramide 71 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2 amino-4-(5-picoline-2- 72 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(5-picoline-2-base oxygen base) butyramide 73 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-fluorophenoxy) butyramide 74 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S) 2-amino-4-(4-fluorophenoxy) fourth 75 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-fluorophenoxy) butyramide 76 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2,4 dichloro benzene oxygen base) butyramide

77 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2, the 3-dimethyl phenoxy) butyramide 78 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(3-fluorophenoxy) butyramide 79 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(3-chlorophenoxy) butyramide 80 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(3-methoxyl group phenoxy group) butyramide 81 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(3-methylphenoxy) butyramide 82 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(3, the 4-dimethyl phenoxy) butyramide 83 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-phenyl phenoxy group) butyramide 84 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2,3-dihydro-1H-indenes-5-base oxygen base) butyramide 85 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-chloro-2-methylphenoxy)-N-methylbutyryl amine 86 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (R)-2-amino-4-(4-(1H-1,2,4-triazol-1-yl-phenoxy group) butyramide 87 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-CN-phenoxy group) butyramide 88 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-MeO-phenoxy group) butyramide 89 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-phenyl phenoxy group) butyramide 90 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-CF ₃-phenoxy group) butyramide 91 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(3-acetylaminohydroxyphenylarsonic acid phenoxy group) butyramide 92 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(3-dimethylamino-phenoxy group) butyramide 93 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(3-phenyl phenoxy group) butyramide 94 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-Cl-2-Me-phenoxy group) butyramide 95 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-phenoxy group-phenoxy group) butyramide 96 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-CF ₃-phenoxy group) butyramide 97 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-sec.-propyl-phenoxy group) butyramide 98 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(1-naphthyloxy) butyramide 99 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-naphthyloxy) butyramide 100 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) 2-amino-4-(4-(imidazoles-1-yl)-phenoxy group) butyramide 101 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(benzo [d] [1,3] dioxole-5-yl) valeramide 102 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(3-dimethylamino-phenoxy group) butyramide 103 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) 2-amino-4-(quinoline-6-base oxygen base) butyramide 104 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(3-trifluoromethoxy-phenoxy group) butyramide

105 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) 2-amino-4-(4-picoline-2-base oxygen base) butyramide 106 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) 2 (S)-amino-4-(2-(1H-pyrazole-3-yl-phenoxy group) butyramide 107 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) 2 (S)-amino-4-(4-(1H-1,2,4-triazol-1-yl-phenoxy group) butyramide 108 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-4-(3,4-diamino-4-oxo butoxy) benzamide 109 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-phenoxy group butyramide 110 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-fluorophenoxy) butyramide 111 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-phenyl phenoxy group) butyramide 112 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-4-trifluoromethylphenopendant) butyramide 113 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methylphenoxy) butyramide 114 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2, the 4-dimethyl phenoxy) butyramide 115 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(3-kharophen phenoxy group) butyramide 116 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methyl-4-chlorophenoxy) butyramide 117 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-phenoxy group phenoxy group) butyramide 118 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methoxyl group phenoxy group) butyramide 119 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-4-trifluoromethylphenopendant) butyramide 120 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2,3-dihydro-1H-indenes-5-base oxygen base) butyramide 121 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(1-naphthyloxy) butyramide 122 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-naphthyloxy) butyramide 123 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(benzo [d] [1,3] dioxole-5-base oxygen base) butyramide 124 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(quinoline-6-base oxygen base) butyramide 125 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-phenyl valeramide 126 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3-chloro-phenyl-) valeramide 127 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(benzo [d] [1,3] dioxole-5-yl) valeramide 128 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3, the 5-3,5-dimethylphenyl) valeramide 129 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3-p-methoxy-phenyl) valeramide 130 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(naphthalene-2-yl) valeramide 131 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(6-picoline-2-yl) valeramide 132 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (R)-2-amino-5-(4-chloro-2-aminomethyl phenyl) valeramide

133 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-chloro-2-methylphenoxy)-N-methylbutyryl amine 134 Deaminizating His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (R)-2-amino-4-(4-chloro-2-methylphenoxy)-N-methylbutyryl amine SEQ ID NO： X _aa1 X _aa2 X _aa3 X _aa4 X _aa5 X _aa6 X _aa7 X _aa8 X _aa9 X _aa10 X _aa11 135 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-phenyl pentanoyl-NH-Me 136 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-phenoxy group butyramide 137 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-fluorophenoxy) butyramide 138 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2,4 dichloro benzene oxygen base) butyramide 139 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-phenyl phenoxy group) butyramide 140 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-4-trifluoromethylphenopendant) butyramide 141 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methylphenoxy) butyramide 142 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2, the 3-dimethyl phenoxy) butyramide 143 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(3-kharophen phenoxy group) butyramide 144 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(3-phenyl phenoxy group) butyramide 145 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methyl-4-chlorophenoxy) butyramide 146 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methyl-4-phenoxy group phenoxy group) butyramide 147 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methyl-4-methoxyl group phenoxy group) butyramide 148 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methyl-4-4-trifluoromethylphenopendant) butyramide 149 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2,3-dihydro-1H-indenes-5-base oxygen base) butyramide 150 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(1-naphthyloxy) butyramide 151 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-naphthyloxy) butyramide 152 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(benzo [d] [1,3] dioxole-5-base oxygen base) butyramide 153 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(quinolyl-4 oxygen base) butyramide 154 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(quinoline-6-base oxygen base) butyramide 155 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-phenyl valeramide 156 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(4-chloro-phenyl-) valeramide 157 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3-chloro-phenyl-) valeramide 158 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(benzo [d] [1,3] dioxole-5-yl) valeramide 159 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3, the 5-3,5-dimethylphenyl) valeramide 160 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(o-tolyl) valeramide

161 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(3-p-methoxy-phenyl) valeramide 162 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(naphthalene-2-yl) valeramide 163 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(6-picoline-2-yl) valeramide 164 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(quinoline-6-yl) valeramide 165 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-(2, the 3-3,5-dimethylphenyl) valeramide 166 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) 2 (R)-amino-4-(2-Me-4-Cl-phenoxy group) butyramide 167 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(4-chloro-2-methylphenoxy)-N-methylbutyryl amine 168 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (R)-2-amino-4-(4-chloro-2-methylphenoxy)-N-methylbutyryl amine

36. the isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from:

SEQ IDNO： X _aa1 X _aa2 X _aa3 X _aa4 X _aa5 X _aa6 X _aa7 X _aa8 X _aa9 X _aa10 X _aa11-NH ₂ 169 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (D-Ser(OBz))-NH ₂ 170 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-1-(2,3-diamino-3-oxopropyl)-3-o-tolyl urea 171 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-1-(2,3-diamino-3-oxopropyl)-3-phenylurea 172 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-1-benzyl-3-(2,3-diamino-3-oxopropyl) urea 173 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-1-phenyl-3-(2,3-diamino-3-oxopropyl) urea 174 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(2-o-tolyl kharophen) propionic acid amide 175 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(2-phenyl kharophen) propionic acid amide 176 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-oxo-4-(piperidines-1-yl) butyramide 177 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2,3-diamino-3-oxopropyl ammonia formic acid 2-benzyl chloride ester 178 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-the amino propionic acid amide of 3-acetylaminohydroxyphenylarsonic acid 2- 179 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-3-amino-N1-(pyridine-2-ylmethyl) succinic diamide 180 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-3-amino-N1-2-methyl-benzyl succinic diamide 181 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-3-amino-N1-benzyl succinic diamide 182 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-3-amino-N1-isobutyl-succinic diamide 183 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2,3-diamino-3-oxopropyl ammonia benzyl formate 184 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-N-(2,3-diamino-3-oxopropyl)-2-methyl benzamide 185 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-N-(2,3-diamino-3-oxopropyl)-3-methyl benzamide 186 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-N-(2,3-diamino-3-oxopropyl)-3-picoline acid amides 187 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-N-(2,3-diamino-3-oxopropyl)-4-methyl benzamide 188 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-N-(2,3-diamino-3-oxopropyl) benzamide

SEQ IDNO： X _aa1 X _aa2 X _aa3 X _aa4 X _aa5 X _aa6 X _aa7 X _aa8 X _aa9 X _aa10 X _aa11-NH ₂ 189 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-N-(2,3-diamino-3-oxopropyl) Isonicotinamide 190 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (1-(2-amino-ethyl) piperidines)-NH ₂ 191 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (1,2,3, the 4-tetrahydroisoquinoline)-NH ₂ 192 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (2-(2-amino-ethyl) pyridine)-NH ₂ 193 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (2-flunamine)-NH ₂ 194 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (2-methylbenzylamine)-NH ₂ 195 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (3-methoxybenzylamine)-NH ₂ 196 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (3-methoxyl group-N-methylbenzylamine)-NH ₂ 197 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu(4-CF ₃-benzylamine)-NH ₂ 198 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (benzylamine)-NH ₂ 199 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (dibenzylamine)-NH ₂ 200 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (isobutylamine)-NH ₂ 201 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (isoindoline)-NH ₂ 202 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (N, N-dimethyl-ethylenediamine)-NH ₂ 203 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (n-Butyl Amine 99)-NH ₂ 204 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (N-ethyl benzyl amine)-NH ₂ 205 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (N-methylbenzylamine)-NH ₂ 206 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu(OBz)-NH ₂ 207 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu(OBz)-NH ₂ 208 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (phenylethylamine)-NH ₂ 209 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Glu (piperidines)-NH ₂ 210 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Ser(Bzl)-NH ₂ 211 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) Thr(OBz)-NH ₂ 212 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) L-Asp(OBz)-NH ₂

37. the isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from:

SEQ IDNO： X _aa1 X _aa2 X _aa3 X _aa4 X _aa5 X _aa6 X _aa7 X _aa8 X _aa9 X _aa10 X _aa11-NH ₂ 213 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(benzene carbon amide ylmethyl) phenyl) propionic acid 214 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(phenyl sulfonamido methyl) phenyl) propionic acid 215 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(sulfonyloxy methyl amino methyl) phenyl) propionic acid 216 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((2,3-dimethoxy benzamido) methyl) phenyl) propionic acid

SEQ IDNO： X _aa1 X _aa2 X _aa3 X _aa4 X _aa5 X _aa6 X _aa7 X _aa8 X _aa9 X _aa10 X _aa11-NH ₂ 217 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((2,4 difluorobenzene formamido group) methyl) phenyl) propionic acid 218 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((2,4-dimethoxy benzamido) methyl) phenyl) propionic acid 219 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((2,5-dimethoxy benzamido) methyl) phenyl) propionic acid 220 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((2,6-dichlorophenyl sulfonamido) methyl) phenyl) propionic acid 221 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((2-chlorobenzoyl amino) methyl) phenyl) propionic acid 222 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((2-methoxybenzoyl amino) methyl) phenyl) propionic acid 223 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((2-toluyl amino) methyl) phenyl) propionic acid 224 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((2-aminomethyl phenyl sulfonamido) methyl) phenyl) propionic acid 225 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3,4-dichlorophenyl sulfonamido) methyl) phenyl) propionic acid 226 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3,4-dimethoxy benzamido) methyl) phenyl) propionic acid 227 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((benzo [d] [1,3] dioxole-5-formamido group) methyl) phenyl) propionic acid 228 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3,5-dichlorophenyl sulfonamido) methyl) phenyl) propionic acid 229 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3,5-dimethoxy benzamido) methyl) phenyl) propionic acid 230 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3,5-dimethyl isoxazole-4-sulfonamido) methyl) phenyl) propionic acid 231 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-(trifluoromethyl) benzamido) methyl) phenyl) propionic acid 232 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-chlorobenzoyl amino) methyl) phenyl) propionic acid 233 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-chloro-phenyl-sulfonamido) methyl) phenyl) propionic acid 234 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-cyano group benzamido) methyl) phenyl) propionic acid 235 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-phenetole formamido group) methyl) phenyl) propionic acid 236 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-fluorobenzoyl amino) methyl) phenyl) propionic acid 237 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-isopropyl benzene formamido group) methyl) phenyl) propionic acid 238 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-methoxyl group-4-toluyl amino) methyl) phenyl) propionic acid 239 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-methoxybenzoyl amino) methyl) phenyl) propionic acid 240 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-anisole ylsulfonylamino) methyl) phenyl) propionic acid 241 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-toluyl amino) methyl) phenyl) propionic acid 242 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-(trifluoromethoxy) benzamido) methyl) phenyl) propionic acid 243 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-phenyl benzamido) methyl) phenyl) propionic acid 244 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(nicotinoyl amino methyl) phenyl) propionic acid

SEQ IDNO： X _aa1 X _aa2 X _aa3 X _aa4 X _aa5 X _aa6 X _aa7 X _aa8 X _aa9 X _aa10 X _aa11-NH ₂ 245 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((4-butylbenzene formamido group) methyl) phenyl) propionic acid 246 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((4-chloro-phenyl-sulfonamido) methyl) phenyl) propionic acid 247 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((4-phenylcyclohexane formamido group) methyl) phenyl) propionic acid 248 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((4-methoxybenzoyl amino) methyl) phenyl) propionic acid 249 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((4-aminomethyl phenyl sulfonamido) methyl) phenyl) propionic acid 250 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((4-toluyl amino) methyl) phenyl) propionic acid 251 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((4-benzyl benzamido) methyl) phenyl) propionic acid 252 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((4-phenyl sulfonamido) methyl) phenyl) propionic acid 253 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((4-phenyl sulfonamido) methyl) phenyl) propionic acid 254 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-3-(4-(acetylamino methyl) phenyl)-2-alanine 255 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(hexanaphthene formamido group methyl) phenyl) propionic acid 256 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-methylbutyryl amino) methyl) phenyl) propionic acid 257 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(2,4-dimethoxy benzamido) phenyl) propionic acid 258 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(2,6-dichlorophenyl sulfonamido) phenyl) propionic acid 259 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(2-chlorobenzoyl amino) phenyl) propionic acid 260 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(2-toluyl amino) phenyl) propionic acid 261 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(3,4-dichlorophenyl sulfonamido) phenyl) propionic acid 262 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(3,4-dimethoxy benzamido) phenyl) propionic acid 263 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(3,5-dichlorophenyl sulfonamido) phenyl) propionic acid 264 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(3,5-dimethyl isoxazole-4-sulfonamido) phenyl) propionic acid 265 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(3-chloro-phenyl-sulfonamido) phenyl) propionic acid 266 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(3-toluyl amino) phenyl) propionic acid 267 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(nicotinoyl amino) phenyl) propionic acid 268 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(4-aminomethyl phenyl sulfonamido) phenyl) propionic acid 269 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(3-phenyl benzamido) phenyl) propionic acid 270 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(4-xenyl sulfonamido) phenyl) propionic acid 271 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(phenyl sulfonamido) phenyl) propionic acid 272 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(sulfonyloxy methyl amino) phenyl) propionic acid 273 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(2,4 difluorobenzene formamido group) phenyl) propionic acid

SEQ IDNO： X _aa1 X _aa2 X _aa3 X _aa4 X _aa5 X _aa6 X _aa7 X _aa8 X _aa9 X _aa10 X _aa11-NH ₂ 274 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(2-chlorobenzoyl amino) phenyl) propionic acid 275 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(2-methoxybenzoyl amino) phenyl) propionic acid 276 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(2-aminomethyl phenyl sulfonamido) phenyl) propionic acid 277 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(3-methoxybenzoyl amino) phenyl) propionic acid 278 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(3-anisole ylsulfonylamino) phenyl) propionic acid 279 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(4-chloro-phenyl-sulfonamido) phenyl) propionic acid 280 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-(4-anisole ylsulfonylamino) phenyl) propionic acid 281 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((2,3-dimethoxy benzamido) methyl) phenyl) propionic acid 282 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((2,5-dimethoxy benzamido) methyl) phenyl) propionic acid 283 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((benzo [d] [1,3] dioxole-5-formamido group) methyl) phenyl) propionic acid 284 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3,5-dimethoxy benzamido) methyl) phenyl) propionic acid 285 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-(trifluoromethyl) benzamido) methyl) phenyl) propionic acid 286 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-cyano group benzamido) methyl) phenyl) propionic acid 287 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-phenetole formamido group) methyl) phenyl) propionic acid 288 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-fluorobenzoyl amino) methyl) phenyl) propionic acid 289 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-methoxyl group-4-toluyl amino) methyl) phenyl) propionic acid 290 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-toluyl amino) methyl) phenyl) propionic acid 291 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-(trifluoromethoxy) benzamido) methyl) phenyl) propionic acid 292 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-phenyl benzamido) methyl) phenyl) propionic acid 293 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((4-butylbenzene formamido group) methyl) phenyl) propionic acid 294 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((4-phenylcyclohexane formamido group) methyl) phenyl) propionic acid 295 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((4-methoxybenzoyl amino) methyl) phenyl) propionic acid 296 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((4-benzyl benzamido) methyl) phenyl) propionic acid 297 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-3-(4-(acetylamino methyl) phenyl)-2-alanine 298 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(4-((3-methylbutyryl amino) methyl) phenyl) propionic acid

38. the isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from:

SEQ IDNO： X _aa1 X _aa2 X _aa3 X _aa4 X _aa5 X _aa6 X _aa7 X _aa8 X _aa9 X _aa10 X _aa11-NH ₂ 299 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-5-methylhexanoic acid

SEQ IDNO： X _aa1 X _aa2 X _aa3 X _aa4 X _aa5 X _aa6 X _aa7 X _aa8 X _aa9 X _aa10 X _aa11-NH ₂ 300 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) 1-aminocyclopentanecarboxylic acid 301 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-the 2-aminocaprylic acid 302 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-the amino capric acid of 2- 303 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-aminohexanoic acid 304 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-methoxyl group butyric acid 305 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-the 2-aminocaprylic acid 306 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-butoxy propionic acid 307 H Aib E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(2-methoxy ethoxy) propionic acid 308 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-butoxy propionic acid 309 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-(2-methoxy ethoxy) propionic acid 310 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-3-cyclohexylpropionic acid 311 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-cyclohexyl butyric acid 312 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (R)-2-amino-3-cyclohexylpropionic acid 313 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (2S, 3S)-2-amino-3 methylvaleric acid 314 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-methylpent-obtusilic acid 315 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-the 2-aminovaleric acid 316 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (R)-the 2-aminovaleric acid 317 H (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (R)-the 2-aminocaprylic acid

39. the isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from:

40. the isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from:

41. the isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from:

42. the isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from:

43. the isolated polypeptide of claim 1, wherein said isolated polypeptide is

44. formula XX compound:

Formula XX

Wherein

P is hydrogen, fluorenylmethyloxycarbonyl (Fmoc) or tertbutyloxycarbonyl (t-Boc);

Ring A is selected from aryl and heteroaryl;

R is selected from methyl, ethyl, chlorine and fluorine;

R ₆Be selected from hydrogen and methyl;

R ₉Be selected from OH and NH ₂And

X is selected from CH ₂, O, NH and S.

45. formula XXI compound:

Formula XXI

Wherein

P is hydrogen, fluorenylmethyloxycarbonyl (Fmoc) or tertbutyloxycarbonyl (t-Boc);

R is selected from methyl, ethyl, chlorine and fluorine,

R ₆Be selected from hydrogen and methyl;

R ₉Be selected from OH and NH ₂

R ₁₀And R ₁₁Respectively be selected from hydrogen, ethyl or methyl; And

X is selected from CH ₂, O, NH and S.

46. a pharmaceutical composition, it comprises among the claim 1-43,61 and 62 each isolated polypeptide and pharmaceutically acceptable carrier.

47. a pharmaceutical composition, it comprises among the claim 1-43,61 and 62 each isolated polypeptide and is selected from following at least a medicine: antidiabetic medicine, anti-obesity medicine, antihypertensive drug, Antiatherosclerosis medicine and fat-reducing medicament.

48. the pharmaceutical composition of claim 47, wherein said antidiabetic medicine are selected from biguanides, sulfourea, glucosidase inhibitor, PPAR-gamma agonist, PPAR-α/γ dual agonists, aP2 inhibitor, DPP4 inhibitor, insulin sensitizer, glucagon-like-peptide-1 (GLP-1) analogue, Regular Insulin and meglitinides.

49. the pharmaceutical composition of claim 48, wherein said antidiabetic medicine is selected from N1,N1-Dimethylbiguanide, Glyburide, glimepiride, glyclopyramide, Glipizide, P-607, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, the Mo Geta azoles, Regular Insulin, G1-262570, Netoglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297, AC2993, LY315902, NVP-DPP-728A and saxagliptin.

50. the pharmaceutical composition of claim 47, wherein said anti-obesity medicine are selected from 'beta '3 adrenergic agonists, lipase inhibitor, serotonin (and Dopamine HCL) reuptake inhibitor, thryoid receptor beta compounds, CB-1 antagonist and apocleisis medicine.

51. the pharmaceutical composition of claim 50, wherein said anti-obesity medicine are selected from orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, ciliary body neurotrophic factor, Dextroamphetamine, phentermine, Phenylpropanolamine, Rimonabant (SR141716A) and indoles.

52. the pharmaceutical composition of claim 47, wherein said fat-reducing medicament are selected from adjustment on MTP inhibitor, cholestery ester transfer protein inhibitors, HMG CoA reductase inhibitor, inhibitor for squalene synthetic enzyme, phenylacetic acid derivatives, the ldl receptor activity, lipoxygenase inhibitor and ACAT inhibitor.

53. the pharmaceutical composition of claim 52, wherein said fat-reducing medicament are selected from Pravastatin, lovastatin, Simvastatin, atorvastatin, Cerivastatin, fluvastatin, Buddhist nun and cut down his spit of fland, Wei Shatating, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, CP-529414 and LY295427.

54. treatment or delay the progress of following disease or the method for outbreak: diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistant, hyperglycemia, hyperinsulinemia, X syndrome, diabetic complication, free fatty acids or the raising of glycerine blood levels, hyperlipidaemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, described method comprise each isolated polypeptide among the claim 1-43,61 and 62 of treatment significant quantity are delivered medicine to the Mammals that needs are treated.

55. the method for claim 54, it comprises that also described medicine is selected from antidiabetic drug, anti-obesity medicine, antihypertensive drug, Antiatherosclerosis medicine and fat-reducing medicament with one or more medicines while or administrations successively of treatment significant quantity.

56. treatment or delay the progress of following disease or the method for outbreak: diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistant, hyperglycemia, hyperinsulinemia, X syndrome, diabetic complication, free fatty acids or the raising of glycerine blood levels, hyperlipidaemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, described method comprise each pharmaceutical composition among the claim 48-53 of treatment significant quantity are delivered medicine to the Mammals that needs are treated.

57. the method for each peptide among the administration claim 1-43,61 and 62, it uses parenteral or parenteral external preparation.

58. the method for claim 57, wherein said preparation is to discharge immediately or the form of extended release preparation is come administration.

59. the method for each peptide among the administration claim 1-43,61 and 62, it uses parenteral or parenteral external preparation, and wherein said preparation comprises as any described compound of activeconstituents and pharmaceutically acceptable vehicle.

60. the method for each peptide among the administration claim 1-43,61 and 62, it uses parenteral or parenteral external preparation, and wherein said preparation comprises described peptide activeconstituents and capsule drug delivery system.

61. the isolated polypeptide of claim 1, wherein said isolated polypeptide is selected from:

SEQ IDNO： X _aa1 X _aa2 X _aa3 X _aa4 X _aa5 X _aa6 X _aa7 X _aa8 X _aa9 X _aa10 X _aa11-NH ₂ 318 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T H D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methyl-4-chlorophenoxy) butyramide 319 H ₃C-SO ₂-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methyl-4-chlorophenoxy) butyramide 320 H ₃C-SO ₂-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T H D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methyl-4-chlorophenoxy) butyramide 321 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methyl-4-fluorophenoxy) butyramide 322 H ₃C-O-CO-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T H D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methyl-4-fluorophenoxy) butyramide 323 H ₃C-SO ₂-His (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T H D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methyl-4-fluorophenoxy) butyramide 324 (L)-β-imidazole emulsion acyl group (S)-α-Me-Pro E G T L-α-Me-Phe (2-fluorine) T S D Bip(2’-Et-4’-OMe) (S)-2-amino-4-(2-methyl-4-chlorophenoxy) butyramide

62. comprising, isolating peptide, described peptide be selected from following core sequence: Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of 2-amino-valeramide; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of 2-amino-butyramide; Thr-His-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of 2-amino-butyramide; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of urea; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaComprise Glu; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of 2-amino-propionic acid; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of 3-amino-succinic diamide; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of 2-amino-propionic acid amide; Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of oxopropyl mephenesin Carbamate;

Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of Isonicotinamide;

Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor comprising the amino acid of picoline acid amides;

Thr-Ser-Asp-Bip-X _Aa, X wherein _AaFor further comprising the amino acid of 1-or 2-aminohexanoic acid, carboxylic acid, sad, capric acid, butyric acid, valeric acid and olefin(e) acid; And Thr-Ser-Asp-Bip-X _Aa, X wherein _AaComprise the amino acid that at least one links to each other with benzyl;

The wherein said isolating peptide that comprises described core sequence in conjunction with and activate the GLP-1 acceptor.

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