CN1918177A - Novel glp-1 compounds - Google Patents
Novel glp-1 compounds Download PDFInfo
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- CN1918177A CN1918177A CNA2004800417090A CN200480041709A CN1918177A CN 1918177 A CN1918177 A CN 1918177A CN A2004800417090 A CNA2004800417090 A CN A2004800417090A CN 200480041709 A CN200480041709 A CN 200480041709A CN 1918177 A CN1918177 A CN 1918177A
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Abstract
Pegylated GLP-1 compounds and their therapeutic use.
Description
Invention field
The present invention relates to new GLP-1 compound, comprise the pharmaceutical composition of these compounds and the application of described compound in the treatment disease relevant with diabetes.
Background of invention
Diabetes are Metabolic disorders of utilizing ability partially or completely to lose of a kind of glucose.About 5% suffers from diabetes and this disease near the popular ratio among all groups.Owing to introduced Regular Insulin in the twenties in last century, improved treatment of diabetes so carried out effort in a sustained way.
A kind of peptide that expectation becomes very important in the treatment diabetes is glucagon-like-peptide-1 (GLP-1).People GLP-1 derives from this L-cell in far-end ileum, pancreas and brain the peptide of 37 amino-acid residues of Proglucagon before the synthetic.The important gastrointestinal hormone ` of GLP-1 in glucose metabolism and gastrointestinal secretion and metabolism, having regulatory function.GLP-1 stimulates insulin secretion in glucose dependency mode, stimulates the Regular Insulin biosynthesizing, promotes the beta cell recovery, reduces glucagon secretion, stomach emptying and ingestion of food.People GLP-1 is hydrolyzed into GLP-1 (7-37) and GLP-1 (7-36)-acid amides, and they are the insulinoptropic peptides class.The fragment and the analogue that single system are used to describe this peptide.Therefore, [Gly for example
8] GLP-1 (7-37) refers to by replace the 8th GLP-1 (7-37) analogue of going up naturally occurring amino-acid residue (Ala) and deriving from GLP-1 (7-37) in form with Gly.Similarly, (N
ε 34-myristoyl) [Lys
34] GLP-1 (7-37) refers to such GLP-1 (7-37), wherein goes up the Lys residue for the 34th
ε-amino is by myristoylization.Disclosed the stable derivatives of GLP-1 analogue among PCT open source literature WO 98/08871 and the WO99/43706, they have lipophilic substituent.These stable derivativeses of GLP-1 analogue are compared the action characteristic with prolongation with corresponding GLP-1 analogue.
In nearest 10 years, from the venom of Heloderma suspectum Yi (Heloderma suspectum (Heloderma suspectum) and heloderma harridum (Heloderma horridum)), many peptide classes have been separated.Exendin-4 is for separating the peptide from 39 amino-acid residues of Heloderma suspectum venom, and this peptide and GLP-1 (7-37) have 52% homology in the overlap.Exendin-4 is effective GLP-1 receptor stimulant, verified it can stimulate Regular Insulin to discharge and guarantee that when injecting dog glucose level reduces.Exendin-4 (1-39), its some fragment, the group of its analogue and derivative thereof are effective insulinotropic activity agent.The most important thing is exendin-4 (1-39), its pancreotropic hormone fragment, the group of its pancreotropic hormone analogue and pancreotropic hormone derivative thereof.
The something in common of GLP-1 and exendins is to have synthesized a large amount of variants, and particularly at studying plasma half-life.May be because of due to the chemical stability and kidney removing of peptase (mainly being dipeptides acyl aminopeptidase IV) low plasma half-life.Yet the analogue of these insulinoptropic peptides classes and derivative be by the pulmonary route administration, promptly lacking gratifying bioavailability when carrying out the lower respiratory tract administration by bronchiole or alveolar.
Disclosed the modified exendin agonist of having removed with the minimizing kidney among the WO 00/66629 by lysine residue and polyethylene glycol conjugation.
Disclosed the peptide that works as GLP-1 receptor stimulant and glucagon receptor antagonist among the WO 03/40309.Wherein the peptide class of Pi Luing has two kinds of peptides that pass through C-terminal cysteine (cycteine) residue and polyethylene glycol conjugation.
Disclosed the GLOP-1 peptide class of Pegylation among the WO 2004/093823.
Disclosed the pulmonary administration of GLP-1 peptide class among WO 01/51071 and the WO 00/12116.
The insulinoptropic peptides class that derives from GLP-1 and Exendin-4 only stimulates Regular Insulin to discharge when the danger of the high and low blood sugar effects of glucose level reduces.Therefore, described peptide class is particularly useful for suffering from the diabetic subject who no longer OHA (oral glucose elevating agent) is reacted and should give Regular Insulin from the medical science viewpoint of strictness.The patient, the doctor does not wish to begin insulinize usually before imperative to a certain extent, is because of fearing hypoglycemia or fearing due to the injection/needle head according to inferring.Therefore, to fully effectively and can have demand by the insulinoptropic peptides class of pulmonary route administration.
Therefore, the object of the present invention is to provide and have enough lung's bioavailabilities so that as the alternative insulinoptropic peptides class of parenterai administration with the peptide class.Insulinoptropic peptides class with lung's bioavailability is the balance between effect and the bioavailability.Another object of the present invention is to provide and is not easy to accumulative insulinoptropic peptides class, and this gathering is a well-known difficult problem relevant with the glucagon-like peptide class.Being not easy to assemble this feature helps economic preparation method and described compound can be given by medical infusion pump.
Definition
In this manual, following term has described implication:
Term used herein " polypeptide " and peptide " refer to by at least 5 and form the compound that amino acid is formed by what peptide bond was connected.Described composition amino acid can come the group of free genetic code amino acids coding, and they can be for being not natural amino acid and the synthesizing amino acid by the genetic code coding.The natural amino acid of non-genetic code coding has for example oxyproline, Gla, ornithine, phosphoserine, D-L-Ala and D-glutamine.Synthesizing amino acid comprises the amino acid by the chemosynthesis preparation, promptly by the D-isomer of genetic code amino acids coding, such as D-L-Ala and D-leucine, Aib (α-An Jiyidingsuan), Abu (butyrine), Tle (tertiary butyl glycine), Beta-alanine, 3-amino methyl phenylformic acid, anthranilic acid.
This paper relates to the used term of polypeptide " analogue " and refers to modified peptide, wherein one or more amino-acid residues of this peptide replaced by other amino-acid residue and/or wherein one or more amino-acid residues from this peptide the disappearance and/or wherein one or more amino-acid residues from this peptide the disappearance and/or wherein one or more amino-acid residues be added on this peptide.The interpolation of this amino acid residue or disappearance can be carried out on the C-end of the N-of described peptide end and/or described peptide.Usually single system is used to describe analogue; [Arg for example
34] GLP-1 (7-37) Lys refers to such GLP-1 (7-37) analogue, wherein go up naturally occurring Methionin and replaced for the 34th, and wherein Methionin has been added on the terminal amino acid residue, promptly adds Gly to by arginine
37On.Should understand all amino acid of not describing optically active isomer and refer to the L-isomer.
This paper relates to the used term of peptide " derivative " and refers to peptide or its analogue through chemically modified, and wherein at least one substituting group is not present in not modified peptide or its analogue, promptly by on the peptide of covalent modification.Typically be modified to amides, carbohydrate, alkyl, acyl group, ester class etc.The example of GLP-1 (7-37) derivative is N
ε 26-((4S)-4-(hexadecanoyl amino)-butyryl radicals) [Arg
34, Lys
26] GLP-1-(7-37).
Term used herein " insulinotropic activity agent " refers to the compound as people GLP-1 receptor stimulant, i.e. the compound that forms at the suitable culture medium that contains people GLP-1 acceptor (hereinafter having disclosed so a kind of substratum) moderate stimulation cAMP.Calculate EC by as described below according to dose response curve
50Value is determined the effectiveness of insulinotropic activity agent.
Young hamster kidney (BHK) cell (BHK-467-12A) of cloning by expression people GLP-1 acceptor is grown in the DMEM substratum that has added 100IU/mL penicillin, 100 μ g/mL Streptomycin sulphates, 5% foetal calf serum and 0.5mg/mL Geneticin G-418 (Life Technologies).With cell washed twice and use Versene collection in phosphate-buffered saline.By using Ultraturrax in the middle homogenate of damping fluid 1 (pH 7.4 for 20mM HEPES-Na, 10mM EDTA) and by the cell preparation plasma membrane.With 48,000xg was with centrifugal 15 minutes of homogenate under 4 ℃.The precipitation that suspends by homogenate in the damping fluid 2 (pH 7.4 for 20mM HEPES-Na, 0.1mM EDTA), then under 4 ℃ with 48, centrifugal 15 minutes of 000xg.More than repeating the washing operation step once.Be suspended in final precipitation in the damping fluid 2 and be used at once the test or be stored under-80 ℃.
Carry out the functional receptor test by measuring the ring AMP (cAMP) that stimulates in response to the insulinotropic activity agent.Use AlphaScreen
TMCAMP test kit (Perkin Elmer LifeSciences) carries out quantitatively the cAMP that forms.In half 96-hole microtiter plate, amount to 50 μ L damping fluid 3 (50mM Tris-HCI, 5mM HEPES, 10mM MgCl
2, pH 7.4) and added in the volume of following composition and be incubated: with 20 μ g/mL donor bead, 1mM ATP, 1 μ mGTP, 0.5mM 3-isobutyl-1-methylxanthine (IBMX), 0.01%Tween-20,0.1%BSA, 6 μ g membrane products, the 15 μ g/mL acceptor bead of 6nM biotinyl-cAMP pre-incubation.Dissolving is used to test the compound of agonist activity and dilutes with damping fluid 3.For the equal prepared fresh GTP of each experiment.In the dark with flat board insulation 3 hours, use Fusion subsequently when at room temperature and slowly stirring
TMInstrument (Perkin Elmer Life Sciences) counting.Each compound is drawn concentration-response curve and used 4-parameter logarithmic model and Prism v.4.0 (GraphPad, Carlsbad, CA) estimation EC
50Value.
Term used herein " GLP-1 peptide " refers to the derivative of GLP-1 (7-37) (SEQ ID No 1), GLP-1 (7-37) analogue, GLP-1 (7-37) derivative or GLP-1 (7-37) analogue.In one embodiment, described GLP-1 peptide is the insulinotropic activity agent.
Term used herein " exendin-4 peptide " refers to the derivative of exendin-4 (1-39) (SEQ IDNo 2), exendin-4 (1-39) analogue, exendin-4 (1-39) derivative or exendin-4 (1-39) analogue.In one embodiment, described exendin-4 peptide is the insulinotropic activity agent.
The term " the DPP-IV protection " that this paper relates to polypeptide refers to the polypeptide that is made described compound tolerance blood plasma peptase-dipeptides acyl aminopeptidase-4 (DPP-IV) by chemically modified.DPP-IV enzyme in the known blood plasma relates to the degraded of several peptide hormones, for example GLP-1, GLP-2, Exendin-4 etc.Therefore, carry out analogue and derivative that the polypeptide of the hydrolysis sensitivity that DPP-IV is mediated is researched and developed in sizable effort, so that reduce the degradation rate that DPP-IV causes.In one embodiment, the peptide of DPP-IV protection tolerates DPP-IV more than GLP-1 (7-37) or Exendin-4 (1-39).
The tolerance of the degraded that dipeptides acyl aminopeptidase IV is caused by following degraded test determination peptide:
Under 37 ℃ the aliquot (5nmol) of described peptide is being incubated 10-180 minute with the 1 μ L purifying dipeptides acyl aminopeptidase IV that is equivalent to the 5mU enzymatic activity in 0.1M triethylamine-HCl damping fluid of 100 μ L pH 7.4.Stop enzymatic reaction by adding 5 μ L, 10% trifluoroacetic acid, and the isolated peptides degraded product, use HPLC to analyze and carry out quantitatively.A kind of method of carrying out this analysis is: with the wide hole of Vydac C18 on this mixture (30nm hole, 5 μ m particles) 250 * 4.6mm post, and according to Siegel etc., Regul.Pept.1999; Eur.J.Biochem.1993 such as 79:93-102 and Mentlein; The described flow velocity with 1ml/ minute of 214:829-35 is with the linear stepwise gradient wash-out (0% acetonitrile 3 minutes, 0-24% acetonitrile 17 minutes, 24-48% acetonitrile 1 minute) of the acetonitrile in 0.1% trifluoroacetic acid.The optical density monitoring that can locate at 220nm (peptide bond) or 280nm (aromatic amino acid) by peptide class and degraded product thereof they, and undertaken quantitatively by the integration of its peak area is compared with standard substance.When causing the soaking time that is hydrolyzed less than 10% peptide, estimate the hydrolysis rate of dipeptides acyl aminopeptidase IV to peptide.
Term " mPEG yl " refers to the polymolecularity or the monodispersity group of following structure:
Wherein m is the integer greater than 1.Therefore, m is that 90 mPEG base has about 3991Da, i.e. the molecular weight of about 4kDa.Equally, the mean value with m in the mPEG base of 20kDa molecular-weight average is 454.These molecules have molecular weight distribution usually because of the process that it produces the mPEG base.This distribution is described by heterogeneity index.
Term used herein " heterogeneity index " refers to the ratio of weight-average molecular weight and number-average molecular weight, as known in the polymer chemistry field (for example, referring to " PolymerSynthesis and Characterization ", J.a:Nairn, Uiversity of Utah, 2003).Heterogeneity index is the number more than or equal to 1, and can according to the gel permeation chromatography data estimation it.When heterogeneity index was 1, this product was a monodispersity, therefore was made of unimodal molecular weight.When heterogeneity index greater than 1 the time, it is the tolerance of the polymolecularity of this polymkeric substance, promptly have different molecular weight polymkeric substance be distributed with how wide.
Term " C used herein
1-6-alkyl " refer to saturated, the side chain, straight chain or the cyclic hydrocarbon group that contain 1-6 carbon atom.Representational example includes, but are not limited to methyl, ethyl, n-propyl, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, n-hexyl, isohexyl, hexanaphthene etc.
Term used herein " pharmaceutically acceptable " refers to and is suitable for normal medicinal application, promptly can not produce untoward reaction etc. in the patient.
Term used herein " heavy atom " refers to the atom with the molal weight that is equal to or greater than carbon, for example C, N, O and S.
Term used herein " vehicle " refers to the chemical compound that joins usually in the pharmaceutical composition, for example buffer reagent, tonicity agent (tonicity agent), sanitas etc.
Term used herein " significant quantity " refers to treatment not and compares the dosage that is enough to effectively treat the patient.
Term used herein " pharmaceutical composition " refers to and comprises active compound or its salt and drug excipient such as buffer reagent, sanitas and the product of tension regulator and/or stablizer alternatively.Therefore, pharmaceutical composition is also referred to as pharmaceutical preparation in the art.
Term used herein " treatment disease " refers to control and nurses the patient with disease, illness or illness of having taken place.Therapeutic purpose are to resist described disease, illness or illness.Treatment comprises and gives active compound so that eliminate or control described disease, illness or illness, and alleviation symptom or the complication relevant with described disease, illness or illness.
Description of the invention
Relate to compound among the present invention in one aspect with general formula (I) structure:
Insulinotropic activity agent (Y-C
*)
f-Q (I)
Wherein
The insulinotropic activity agent be derive from the group of the insulinoptropic peptides of people GLP-1 receptors bind or derive from 22 positions in preceding 30 positions and those corresponding positions in GLP-1 on the group of the identical peptide of the residue found on the corresponding position that find or in Exendin-4, and
Y is for making C
*The divalence that is connected with the insulinotropic activity agent connects chemical group, and
C
*Separate chemical group for divalence polarity, wherein the heavy atom of 50-20% is O or N, and
F is 0 or 1, and
Q is selected from
-W-A，-X-B-W-A，
Wherein
A is the polarity chemical group of single molecular size (monodispersity) or several molecule size (polymolecularity), wherein
The heavy atom of 50-20% is oxygen or nitrogen independently, and
W is the divalence chemical group of connection A, and
X connects chemical group for the divalence that connects B, and
B is for connecting or the branching chemical group.
The present invention relates to the compound with general formula (I) structure in one aspect of the method:
Insulinotropic activity agent (Y-C
*)
f-Q (I)
Wherein
The insulinotropic activity agent be derive from the group of the insulinoptropic peptides of people GLP-1 receptors bind or derive from 22 positions in preceding 30 positions and those corresponding positions in GLP-1 on the group of the identical peptide of the residue found on the corresponding position that find or in Exendin-4
Condition is that the C-terminal amino acid residue of described insulinotropic activity agent is not halfcystine, and
Y is for making C
*The divalence that is connected with the insulinotropic activity agent connects chemical group, and
C
*Separate chemical group for divalence polarity, wherein the heavy atom of 50-20% is O or N, and
F is 0 or 1, and
Q is selected from
-W-A，-X-B-W-A
Wherein
A is the polarity chemical group of single molecular size (monodispersity) or several molecule size (polymolecularity), wherein
The heavy atom of 50-20% is oxygen or nitrogen independently, and
W is the divalence chemical group of connection A, and
X connects chemical group for the divalence that connects B, and
B is for connecting or the branching chemical group.
The peptide group of answering the general general formula of following understanding (I) and being contained.
General formula (I) comprises following compounds:
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa
The insulinotropic activity agent is the group that comprises peptide, and the lysine residue place of described peptide on 37 comprises 4 methylene radical.Group A is mPEG base-CH
2CH
2-, wherein the mPEG base has the molecular weight of about 2kDa.With mPEG base-CH
2CH
2-divalence chemical group the W that is connected with the group that derives from insulinoptropic peptides is acid amides-C (O)-NH-.
In one embodiment of the invention, A is for having structure-(CH
2)
1O[(CH
2)
nO]
m(CH
2)
pThe chemical group monodispersity of-H or polymolecularity, wherein l, n and p are the integer of 1-10 independently, m is the integer of 1-5000, and wherein m multiply by n+1 less than 10000.
In another embodiment of the invention, A is for having structure-(CH
2)
1C (=O) O[(CH
2)
nO]
m(CH
2)
pThe chemical group monodispersity of-H or polymolecularity, wherein l, n and p are the integer of 1-10 independently, m is the integer of 1-5000, and wherein m multiply by n+1 less than 10000.
In another embodiment of the invention, n is 2 or 3.In another embodiment of the invention, m is 10-1000 or 20-250.
In another embodiment of the invention, A is for having structure-(Z
1(CH
2)
1O[(CH
2)
2O]
m(CH
2)
p-NR
1)
q-Z
2Chemical group monodispersity or polymolecularity, Z wherein
1For-CO-or-CO-(CH
2)
n-CO-NH-, and Z
2For-R
1,-CO-(CH
2)
n-R
1,-(CH
2)
1O[(CH
2)
2O]
m(CH
2)
p-R
1, wherein l and n and p are the integer of 1-10 independently, and R
1For-OH ,-NH
2,-NH-R
2,-NH (R
2)-R
2,-COOH, C
1-6-alkyl or-NH-CH (R
2)-COOH, and wherein m and q are the integer of 1-20 independently, and wherein l, n and p are the integer of 1-6 independently, and R
2Be hydrogen or C
1-6-alkyl.
In another embodiment of the invention, A is the mPEG base.
In another embodiment of the invention, A be mPEG base-C (=O)-(CH
2)
r-, wherein r is the integer of 1-10.
In another embodiment of the invention, A is a monodispersity, and promptly it only is made of a kind of composition.
In another embodiment of the invention, A has the heterogeneity index of 1.00-1.10.
In another embodiment of the invention, A is a polymolecularity, and preferably has less than 1.2, less than 1.1, less than 1.05, less than 1.03, less than 1.02, less than 1.010, less than 1.008, less than 1.005 or less than 1.0025 heterogeneity index.
In another embodiment of the invention, described branching chemical group B is selected from:
Wherein a, b, c, d, e, f, g, h, i are independently selected from the integer of 0-24.In another embodiment of the invention, described branching group B is:
Wherein a, b, c are independently selected from the integer of 0-24.
In another embodiment of the invention, described branching chemical group B is selected from:
Wherein a, b, c, d, e, f, g, h, i are independently selected from the integer of 0-24.
In another embodiment of the invention, described insulinotropic activity agent is connected with B by the left hand of B is terminal.
In another embodiment of the invention, a+b less than 6 or a+b+c less than 14 or a+b+c+d+e+f+g+h+i less than 16.
In another embodiment of the invention, a be 0 or 1 and b, c, d, e, f, h and i be 0-5.
In another embodiment of the invention, a, c, d, e, g and i be 0 and b, f and h be 1-4.
In another embodiment of the invention, a, c, d, e, g and i be 0 and b, f and h be 1-4.
In another embodiment of the invention, W is independently selected from divalence with X and is connected chemical group, and these groups comprise:
Amides :-C (O)-NR-, wherein R is hydrogen or C
1-6-alkyl;
Amine :-NR-, wherein R is hydrogen or C
1-6-alkyl;
Thioether class :-S-,-S-(CH
2)
2-SO
2-or
Ethers :-O-;
Urethanes :-N (R
1)-CO-N (R
2)-, be R wherein
1And R
2Be hydrogen or C independently
1-6-alkyl; Amino formate :-O-CO-N (R)-, wherein R is hydrogen or C
1-6-alkyl;
The hydrazine class:
Wherein R is hydrogen or C
1-6-alkyl;
Oximes :-O-N=C (R)-, wherein R is hydrogen or C
1-6-alkyl; azoles alkanes or thiazolidines:
Can by make aldehyde derivatives (CO-H) or ketone derivatives (CO-R) with following composition reaction formation general formula
Hydrazine derivative, wherein R is hydrogen or C
1-6-alkyl:
Hydrazine derivative (NH-NH
2) or
Hydrazinecarboxylate derivative (O-C (O)-NH-NH
2) or
Semicarbazide derivative (NH-C (O)-NH-NH
2) or
Sulfo-amino urea derivatives (NH-C (S)-NH-NH
2) or
Carbonic acid two hydrazide derivatives (NHC (O)-NH-NH-C (O)-NH-NH
2) or
Carbohydrazide derivative (NH-NH-C (O)-NH-NH
2) or
Thiocarbohydrazide derivative (NH-NH-C (S)-NH-NH
2) or
Aryl hydrazide derivative (NH-C (O)-C
6H
4-NH-NH
2) or
Hydrazide derivatives (C (O)-NH-NH
2).
Can by make aldehyde (CO-H) or ketone ((R)-oximes, wherein R is hydrogen or C CO-R) to form general formula-O-N=C with the reaction of following composition
1-6-alkyl:
Oxygen base amine (O-NH
2) or
-C (O)-O-NH
2Or
-NH-C (O)-O-NH
2Or
-NH-C(S)-O-NH
2。
In another embodiment of the invention, W is-C (O)-NR-that wherein R is hydrogen or C
1-6-alkyl.
In another embodiment of the invention, described insulinotropic activity agent is connected with W by the left hand end (carbon) of W.
In another embodiment of the invention, described insulinotropic activity agent is connected with W by the right hand extreme (nitrogen) of W.
In another embodiment of the invention, f is 0.
In another embodiment of the invention, C
*For-(CH
2)
N1O[(CH
2)
N2O]
N3(CH
2)
N4-, wherein n1, n2 and n4 are the integer of 1-10 independently, n3 is the integer of 1-5000, and wherein n 3 multiply by n2+1 less than 10000.
In another embodiment of the invention, n2 is 2 or 3.
In another embodiment of the invention, n3 is the integer of 1-20.
In another embodiment of the invention, C
*For-(CH
2)
N5-, wherein n5 is the integer of 1-10.
In another embodiment of the invention, Y is selected from divalence and connects chemical group, and these groups comprise:
Amides :-C (O)-NR-, wherein R is hydrogen or C
1-6-alkyl;
Amine :-NR-, wherein R is hydrogen or C
1-6-alkyl;
Thioether class :-S-,-S-(CH
2)
2-SO
2-or
Ethers :-O-;
Urethanes :-N (R
1)-CO-N (R
2)-, be R wherein
1And R
2Be hydrogen or C independently
1-6-alkyl;
Amino formate :-O-CO-N (R)-, wherein R is hydrogen or C
1-6-alkyl;
The hydrazine class:
Wherein R is hydrogen or C
1-6-alkyl;
Oximes :-O-N=C (R)-, wherein R is hydrogen or C
1-6-alkyl; azoles alkanes or thiazolidines:
R=H or CH
3, X=S or O and
In another embodiment of the invention, described insulinotropic activity agent is the peptide of DPPIV protection.
In another embodiment of the invention, described insulinotropic activity agent has the functional receptor test determination that discloses by this paper and is the EC less than 1nM
50
In another embodiment of the invention, described insulinotropic activity agent has the functional receptor test determination that discloses by this paper for less than 300pM, less than 200pM or less than the EC of 100pM
50
In another embodiment of the invention, described insulinotropic activity agent derives from the peptide with 27-45 amino-acid residue length, in wherein preceding 28 amino-acid residues 22 with corresponding position in GLP-1 (7-37) (SEQ ID No.1) on find or corresponding position in Exendin-4 (1-39) (SEQ ID No.2) on those residues of finding identical.
In another embodiment of the invention, described insulinotropic activity agent derives from the peptide with 28-45 amino-acid residue length, in wherein preceding 28 amino-acid residues 22 with corresponding position in GLP-1 (7-37) on find or corresponding position in Exendin-4 (1-39) on those residues of finding identical.
In another embodiment of the invention, described insulinotropic activity agent is selected from the peptide that comprises aminoacid sequence shown in the general formula (II):
Xaa
7-Xaa
8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa
16-Ser-Xaa
18-Xaa
19-Xaa
20-Glu-Xaa
22-Xaa
23-Ala-Xaa
25-Xaa
26-Xaa
27-Phe-Ile-Xaa
30-Trp-Leu-Xaa
33-Xaa
34-Xaa
35-Xaa
36-Xaa
37-Xaa
38-Xaa
39-Xaa
40-Xaa
41-Xaa
42-Xaa
43-Xaa
44-Xaa
45-Xaa
46
General formula (II) (SEQ ID No:3)
Wherein
Xaa
7Be L-Histidine, D-Histidine, deaminizating-Histidine, 2-amino-Histidine, beta-hydroxy-Histidine, high Histidine, N
α-ethanoyl-Histidine, α-methyl fluoride-Histidine, Alpha-Methyl-Histidine, 3-pyridyl L-Ala, 2-pyridyl L-Ala or 4-pyridyl L-Ala;
Xaa
8Be Ala, D-Ala, Gly, Val, Leu, Ile, Lys, Aib, (the amino cyclopropyl of 1-) carboxylic acid, (the amino cyclobutyl of 1-) carboxylic acid, (1-amino cyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (the amino suberyl of 1-) carboxylic acid or (the amino ring of 1-octyl group) carboxylic acid;
Xaa
16Be Val or Leu;
Xaa
18Be Ser, Lys or Arg;
Xaa
19Be Tyr or Gln;
Xaa
20Be Leu or Met;
Xaa
22Be Gly, Glu or Aib;
Xaa
23Be Gln, Glu, Lys or Arg;
Xaa
25Be Ala or Val;
Xaa
26Be Lys, Glu or Arg;
Xaa
27Be Glu or Leu;
Xaa
30Be Ala, Glu or Arg;
Xaa
33Be Val or Lys;
Xaa
34Be Lys, Glu, Asn or Arg;
Xaa
35Be Gly or Aib;
Xaa
36Be Arg, Gly or Lys;
Xaa
37For Gly, Ala, Glu, Pro, Lys, acid amides or do not exist;
Xaa
38For Lys, Ser, acid amides or do not exist.
Xaa
39For Ser, Lys, acid amides or do not exist;
Xaa
40For Gly, acid amides or do not exist;
Xaa
41For Ala, acid amides or do not exist;
Xaa
42For Pro, acid amides or do not exist;
Xaa
43For Pro, acid amides or do not exist;
Xaa
44For Pro, acid amides or do not exist;
Xaa
45For Ser, acid amides or do not exist;
Xaa
46For acid amides or do not exist;
Condition is if Xaa
38, Xaa
39, Xaa
40, Xaa
41, Xaa
42, Xaa
43, Xaa
44, Xaa
45Or Xaa
46Do not exist, each amino-acid residue in downstream does not exist yet so.
In another embodiment of the invention, described insulinotropic activity agent is for comprising the peptide of aminoacid sequence shown in the general formula (III):
Xaa
7-Xaa
8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Xaa
18-Tyr-Leu-Glu-Xaa
22-Xaa
23-Ala-Ala-Xaa
26-Glu-Phe-Ile-Xaa
30-Trp-Leu-Val-Xaa
34-Xaa
35-Xaa
36-Xaa
37-Xaa
38
General formula (III) (SEQ ID No:4)
Wherein
Xaa
7Be L-Histidine, D-Histidine, deaminizating-Histidine, 2-amino-Histidine, beta-hydroxy-Histidine, high Histidine, N
α-ethanoyl-Histidine, α-methyl fluoride-Histidine, Alpha-Methyl-Histidine, 3-pyridyl L-Ala, 2-pyridyl L-Ala or 4-pyridyl L-Ala;
Xaa
8Be Ala, D-Ala, Gly, Val, Leu, Ile, Lys, Aib, (the amino cyclopropyl of 1-) carboxylic acid, (the amino cyclobutyl of 1-) carboxylic acid, (1-amino cyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (the amino suberyl of 1-) carboxylic acid or (the amino ring of 1-octyl group) carboxylic acid;
Xaa
18Be Ser, Lys or Arg;
Xaa
22Be Gly, Glu or Aib;
Xaa
23Be Gln, Glu, Lys or Arg;
Xaa
26Be Lys, Glu or Arg;
Xaa
30Be Ala, Glu or Arg;
Xaa
34Be Lys, Glu or Arg;
Xaa
35Be Gly or Aib;
Xaa
36Be Arg or Lys;
Xaa
37Be Gly, Ala, Glu or Lys;
Xaa
38Be Lys, NH
2Or do not exist.
In another embodiment of the invention, described insulinotropic activity agent is selected from GLP-1 (7-35), GLP-1 (7-36), GLP-1 (7-36)-acid amides, GLP-1 (7-37), GLP-1 (7-38), GLP-1 (7-39), GLP-1 (7-40), GLP-1 (7-41) or its analogue.
In another embodiment of the invention, described insulinotropic activity agent is compared with GLP-1 (7-37) (SEQ ID No.1) and is comprised being no more than 15 amino-acid residues that are replaced, add or lack or comparing with GLP-1 (7-37) (SEQ ID No.1) and be no more than 10 amino-acid residues that are replaced, add or lack.
In another embodiment of the invention, described insulinotropic activity agent is compared with GLP-1 (7-37) (SEQ ID No.1) and is comprised and be no more than 6 amino-acid residues that are replaced, add or lack.
In another embodiment of the invention, described insulinotropic activity agent comprises and is no more than 4 not by genetic code amino acids coding residue.
In another embodiment of the invention, described insulinotropic activity agent comprises second amino-acid residue of Aib residue as the N-end.
In another embodiment of the invention, the-terminal amino acid residue of described insulinotropic activity agent (general formula I I and III 7) is selected from D-Histidine, deaminizating-Histidine, 2-amino-Histidine, beta-hydroxy-Histidine, high Histidine, N
αThe group that-ethanoyl-Histidine, α-methyl fluoride-Histidine, Alpha-Methyl-Histidine, 3-pyridyl L-Ala, 2-pyridyl L-Ala and 4-pyridyl L-Ala are formed.In another embodiment of the invention, described insulinotropic activity agent is selected from [Arg
34] GLP-1 (7-37), [Arg
26,34] GLP-1 (7-37) Lys, [Lys
36Arg
26,34] GLP-1 (7-36), [Aib
8,22,35] GLP-1 (7-37), [Aib
8,35] GLP-1 (7-37), [Aib
8,22] GLP-1 (7-37), [Aib
8,22,35Arg
26,34] GLP-1 (7-37) Lys, [Aib
8,35Arg
26,34] GLP-1 (7-37) Lys, [Aib
8,22Arg
26,34] GLP-1 (7-37) Lys, [Aib
8,22,35Arg
26,34] GLP-1 (7-37) Lys, [Aib
8,35Arg
26,34] GLP-1 (7-37) Lys, [Aib
8,22,35Arg
26] GLP-1 (7-37) Lys, [Aib
8,35Arg
26] GLP-1 (7-37) Lys, [Aib
8,22Arg
26] GLP-1 (7-37) Lys, [Aib
8,22,35Arg
34] GLP-1 (7-37) Lys, [Aib
8,35Arg
34] GLP-1 (7-37) Lys, [Aib
8,22Arg
34] GLP-1 (7-37) Lys, [Aib
8,22,35Ala
37] GLP-1 (7-37) Lys, [Aib
8,35Ala
37] GLP-1 (7-37) Lys, [Aib
8,22Ala
37] GLP-1 (7-37) Lys, [Aib
8,22,35Lys
37] GLP-1 (7-37), [Aib
8,35Lys
37] GLP-1 (7-37), [Aib
8,22Lys
37] GLP-1 (7-37) or its at the C-end by amidated derivative.
In another embodiment of the invention, described insulinotropic activity agent comprises at least one Aib residue.
In another embodiment of the invention, described insulinotropic activity agent contains two Aib residues.
In another embodiment of the invention, described insulinotropic activity agent or on the 12nd for Exendin-4 (1-39), comprises serine residue on the 18th for GLP-1 (7-37) (SEQ ID.No.1).
In another embodiment of the invention, described insulinotropic activity agent or on the 13rd for Exendin-4 (1-39), comprises tyrosine residues on the 19th for GLP-1 (7-37) (SEQ ID.No.1).
In another embodiment of the invention, described insulinotropic activity agent or on the 16th for Exendin-4 (1-39), comprises glycine residue on the 22nd for GLP-1 (7-37) (SEQ ID.No.1).
In another embodiment of the invention, described insulinotropic activity agent or on the 17th for Exendin-4 (1-39), comprises glutamine residue on the 23rd for GLP-1 (7-37) (SEQ ID.No.1).
In another embodiment of the invention, described insulinotropic activity agent or on the 20th for Exendin-4 (1-39), comprises lysine residue on the 26th for GLP-1 (7-37) (SEQ ID.No.1).
In another embodiment of the invention, described insulinotropic activity agent or on the 21st for Exendin-4 (1-39), comprises glutaminic acid residue on the 27th for GLP-1 (7-37) (SEQ ID.No.1).
In another embodiment of the invention, described insulinotropic activity agent is exendin-4 (1-39).
In another embodiment of the invention, described insulinotropic activity agent is ZP-10, i.e. [Ser
38Lys
39] Exendin-4 (1-39) LysLysLysLysLys-acid amides (SEQ ID No.5).
In another embodiment of the invention, described insulinotropic activity agent is by amino-acid residue and Y-C on the 25-45 position for aminoacid sequence SEQ ID No:1
*-Q or Q connect.
In another embodiment of the invention, amino-acid residue and the Y-C of described insulinotropic activity agent by being selected from one of 10 C-terminal amino acid residues
*-Q or Q connect.
In another embodiment of the invention, described insulinotropic activity agent is by amino-acid residue and Y-C on the 23rd, 26,34,36 or 38 for aminoacid sequence SEQ ID No:1
*-Q or Q connect.
In another embodiment of the invention, described insulinotropic activity agent is by amino-acid residue and Y-C on the 17th, 20,28,30 or 32 for aminoacid sequence SEQ ID No:2
*-Q or Q connect.
In another embodiment of the invention, described insulinotropic activity agent is by C-terminal amino acid residue and Y-C
*-Q or Q connect.
In another embodiment of the invention, described insulinotropic activity agent is by carboxyl, amino, ketone group, hydroxyl, sulfydryl or hydrazide group and Y-C
*-Q or Q connect.
In another embodiment of the invention, described insulinotropic activity agent is by on the lysine residue
ε-amino and Y-C
*-Q or Q connect.
In another embodiment of the invention, described insulinotropic activity agent only comprises a lysine residue.
In another embodiment of the invention, described insulinotropic activity agent only comprises a lysine residue, and it is the C-terminal amino acid residue of described insulinotropic activity agent.
In another embodiment of the invention, compound of the present invention has the functional receptor test be determined as that discloses by this paper less than 1000pM, less than 500pM, less than 300pM, less than 200pM, less than 100pM, less than 50pM or less than the EC of 10pM
50
In another embodiment of the invention, compound of the present invention is selected from the group that following compounds is formed:
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 26-(3-(mPEG yl) propionyl) [Aib
8, Glu
22,30, Lys
33, Asn
34, Gly
35,36, Pro
37] the basic SerSerGly AlaProProProSer of GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl) lysyl amine), wherein the mPEG base is polymolecularity and molecular weight that have about 750Da;
N
ε-[Aib
8,22,35] GLP-1 (7-37) base (S
ε-(1-mPEG base propyl group-2,5-dioxo-tetramethyleneimine-3-yl) half Guang acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 5000Da;
N
α-(3-(3H-imidazol-4 yl)-propionyl [Aib
22,35, Arg
26,34] GLP-1-(8-37)) base (N
ε-(3-(mPEG yl) propionyl) lysyl amine), wherein the mPEG base is polymolecularity and molecular weight that have about 2000Da;
N
ε 26-(3-(mPEG yl) propionyl) [Arg
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa; With
(S)-N-((S)-5-(N-((S)-5-formamyl-5-(mPEG base propionyl amino) amyl group) formamyl)-5-(mPEG base propionyl amino) amyl group)-5-(N
α 7-(3-(4-imidazolyl) propionyl) [Aib
22,35, Arg
26,34] GLP-1-(8-37) base)-2-(mPEG base propionyl amino) hexanamide, wherein the mPEG base is polymolecularity and molecular weight that have about 750Da.
In another embodiment, compound of the present invention is selected from the group that following compounds is formed:
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 3-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa; With
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1 (7-37) Lys acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 40kDa.
In another embodiment, compound of the present invention is selected from the group that following compounds is formed:
N
ε 37-(3-(mPEG yl) propionyl) [Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε37-(3-(mPEG yl) propionyl) [Aib
8, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 36-(3-(mPEG yl) propionyl) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 36-(3-(mPEG yl) propionyl) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 34-(3-(mPEG yl) propionyl) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 34-(3-(mPEG yl) propionyl) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 36-(3-(mPEG yl) propionyl) [Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 36-(3-(mPEG yl) propionyl) [Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 34-(3-(mPEG yl) propionyl) [Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 34-(3-(mPEG yl) propionyl) [Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Ala
8, Arg
26,34,] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
α-[Ala
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 36-(3-(mPEG yl) propionyl) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 36-(3-(mPEG yl) propionyl) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 34-(3-(mPEG yl) propionyl) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 34-(3-(mPEG yl) propionyl) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 20-(3-(mPEG yl) propionyl) [Lys
20] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 32-(3-(mPEG yl) propionyl) [Lys
32] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da;
N
ε 20-(3-(mPEG yl) propionyl) [Lys
20, Arg
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da; With
N
ε 32-(3-(mPEG yl) propionyl) [Lys
32, Arg
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 750Da.
In another embodiment, compound of the present invention is selected from the group that following compounds is formed:
N
ε 37-(3-(mPEG yl) propionyl) [Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 36-(3-(mPEG yl) propionyl) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 36-(3-(mPEG yl) propionyl) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 34-(3-(mPEG yl) propionyl) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 34-(3-(mPEG yl) propionyl) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 36-(3-(mPEG yl) propionyl) [Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 36-(3-(mPEG yl) propionyl) [Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 34-(3-(mPEG yl) propionyl) [Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 34-(3-(mPEG yl) propionyl) [Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Ala
8, Arg
26,34,] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
α-[Ala
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 36-(3-(mPEG yl) propionyl) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 36-(3-(mPEG yl) propionyl) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 34-(3-(mPEG yl) propionyl) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 34-(3-(mPEG yl) propionyl) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 20-(3-(mPEG yl) propionyl) [Lys
20] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 32-(3-(mPEG yl) propionyl) [Lys
32] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da;
N
ε 20-(3-(mPEG yl) propionyl) [Lys
20, Arg
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da; With
N
ε 32-(3-(mPEG yl) propionyl) [Lys
32, Arg
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 2000Da.
In another embodiment, compound of the present invention is selected from the group that following compounds is formed:
N
ε 37-(3-(mPEG yl) propionyl) [Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-Aib
8,22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 36-(3-(mPEG yl) propionyl) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 36-(3-(mPEG yl) propionyl) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 34-(3-(mPEG yl) propionyl) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 34-(3-(mPEG yl) propionyl) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 36-(3-(mPEG yl) propionyl) [Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 36-(3-(mPEG yl) propionyl) [Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 34-(3-(mPEG yl) propionyl) [Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 34-(3-(mPEG yl) propionyl) [Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Ala
8, Arg
26,34,] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
α-[Ala
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 36-(3-(mPEG yl) propionyl) [Ala
8, Ar
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 36-(3-(mPEG yl) propionyl) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 34-(3-(mPEG yl) propionyl) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 34-(3-(mPEG yl) propionyl) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 20-(3-(mPEG yl) propionyl) [Lys
20] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 32-(3-(mPEG yl) propionyl) [Lys
32] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da;
N
ε 20-(3-(mPEG yl) propionyl) [Lys
20, Arg
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da; With
N
ε 32-(3-(mPEG yl) propionyl) [Lys
32, Arg
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 5000Da.
In another embodiment, compound of the present invention is selected from the group that following compounds is formed:
N
ε 37-(3-(mPEG yl) propionyl) [Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 36-(3-(mPEG yl) propionyl) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 36-(3-(mPEG yl) propionyl) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 34-(3-(mPEG yl) propionyl) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 34-(3-(mPEG yl) propionyl) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 36-(3-(mPEG yl) propionyl) [Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 36-(3-(mPEG yl) propionyl) [Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 34-(3-(mPEG yl) propionyl) [Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 34-(3-(mPEG yl) propionyl) [Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Ala
8, Arg
26,34,] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
α-[Ala
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 36-(3-(mPEG yl) propionyl) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 36-(3-(mPEG yl) propionyl) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 34-(3-(mPEG yl) propionyl) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 34-(3-(mPEG yl) propionyl) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 20-(3-(mPEG yl) propionyl) [Lys
20] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 32-(3-(mPEG yl) propionyl) [Lys
32] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa;
N
ε 20-(3-(mPEG yl) propionyl) [Lys
20, Ar
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa; With
N
ε 32-(3-(mPEG yl) propionyl) [Lys
32, Arg
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 10kDa.
In another embodiment, compound of the present invention is selected from the group that following compounds is formed:
N
ε 37-(3-(mPEG yl) propionyl) [Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-(3-(mPEG yl) propionyl) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-(3-(mPEG yl) propionyl) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-(3-(mPEG yl) propionyl) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-(3-(mPEG yl) propionyl) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-(3-(mPEG yl) propionyl) [Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-(3-(mPEG yl) propionyl) [Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-(3-(mPEG yl) propionyl) [Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-(3-(mPEG yl) propionyl) [Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Ala
8, Arg
26,34,] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Ala
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-(3-(mPEG yl) propionyl) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-(3-(mPEG yl) propionyl) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-(3-(mPEG yl) propionyl) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-(3-(mPEG yl) propionyl) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 20-(3-(mPEG yl) propionyl) [Lys
20] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 32-(3-(mPEG yl) propionyl) [Lys
32] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 20-(3-(mPEG yl) propionyl) [Lys
20, Arg
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa; With
N
ε 32-(3-(mPEG yl) propionyl) [Lys
32, Arg
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa.
In another embodiment, compound of the present invention is selected from the group that following compounds is formed:
N
ε 37-(3-(mPEG yl) butyryl radicals) [Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
8, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
8, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
8,22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
8,22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
8,22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 37-(3-(mPEG yl) butyryl radicals) [Aib
8,22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 36-(3-(mPEG yl) butyryl radicals) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 36-(3-(mPEG yl) butyryl radicals) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 34-(3-(mPEG yl) butyryl radicals) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 34-(3-(mPEG yl) butyryl radicals) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 36-(3-(mPEG yl) butyryl radicals) [Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 36-(3-(mPEG yl) butyryl radicals) [Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 34-(3-(mPEG yl) butyryl radicals) [Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 34-(3-(mPEG yl) butyryl radicals) [Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Ala
8, Arg
26,34,] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
α-[Ala
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 36-(3-(mPEG yl) butyryl radicals) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 36-(3-(mPEG yl) butyryl radicals) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 34-(3-(mPEG yl) butyryl radicals) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 34-(3-(mPEG yl) butyryl radicals) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 20-(3-(mPEG yl) butyryl radicals) [Lys
20] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 32-(3-(mPEG yl) butyryl radicals) [Lys
32] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa;
N
ε 20-(3-(mPEG yl) butyryl radicals) [Lys
20, Arg
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa; With
N
ε 32-(3-(mPEG yl) butyryl radicals) [Lys
32, Arg
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 30kDa.
In another embodiment, compound of the present invention is selected from the group that following compounds is formed:
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
22,35, Lys
37] GLP-1-(7-37) acid amides, wherein mPEG base for polymolecularity and have about 20
The Mw of kDa;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Ala
8, Arg
26,34,] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Ala
8, Arg
26,34] GLP-1-(7-37) base (N
ε-((2S)-2,6-two-(mPEG base carbonylamino) caproyl)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 20-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Lys
20] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 32-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Lys
32] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 20-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Lys
20, Arg
10,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa; With
N
ε 32-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Lys
32, Ar
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa.
In another embodiment, compound of the present invention is selected from the group that following compounds is formed:
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
33] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
35] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
22] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
22,35] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8,5, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,35] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8,22, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8,22, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,22] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8,22,35, Lys
37] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 37-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8,22,35, Lys
37] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Aib
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Aib
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Arg
26,34] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Ala
8, Arg
26,34,] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) Methionin, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
α-[Ala
8, Arg
26,34] GLP-1-(7-37) base (N
ε-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals)) lysyl amine, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 36-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Ala
8, Arg
26,34, Lys
36] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 34-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Ala
8, Lys
26, Lys
34] GLP-1-(7-37) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 20-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Lys
20] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 32-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Lys
32] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 20-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Lys
20, Arg
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa;
N
ε 32-(4-(1,3-two (mPEG base B aminocarbonyl oxygen base) third-2-base oxygen base) butyryl radicals) [Lys
32, Arg
12,27] Exendin-4-(1-39) acid amides, wherein the mPEG base is polymolecularity and Mw that have about 20kDa.
Can be synthetic by traditional peptide, for example use synthetic or other technology fully set up of the solid-phase peptide of t-Boc or Fmoc chemical method to produce compound of the present invention, for example referring to Green and Wuts, " Protecting Groups in Organic Synthesis ", John Wiley﹠amp; Sons, 1999.These methods are to be preferred when comprising the peptide of alpha-non-natural amino acid residue in described insulinotropic activity agent.
When described insulinotropic activity agent when only comprising the polypeptide by genetic code amino acids coding residue, can also produce this polypeptide by a kind of like this method, this method comprises cultivates dna sequence dna that contains coding said polypeptide and the host cell that can express described polypeptide under the condition that allows the described polypeptide of expression in suitable nutritional medium, after this from culture, reclaim the gained peptide, then it is derivatized to the compound of general formula (I).
The substratum that is used to cultivate described cell can be for being suitable for the substratum commonly used arbitrarily of host cell growth, such as the limit that contains suitable fill-in or complex medium.Suitable medium can be available from goods providers or can be according to the formulation of announcing (for example in the catalogue of American type culture collection).Can reclaim the peptide that is produced by described cell from substratum by the routine operation step then, described operation steps comprises by centrifugal or filtration separates host cell from substratum.With regard to extracellular products, by the protein component in the following method separation of supernatant: filter; Column chromatography or precipitation, for example micro-filtration, ultrafiltration, isoelectric precipitation; By various chromatographic run step purifying, for example ion-exchange chromatography, hydrophobic interaction chromatography, gel filtration chromatography, affinity chromatography etc., this depends on the type of described polypeptide.With regard in the born of the same parents or with regard to the periplasmic space product, will separate from the lysis of substratum or change thoroughly and extract to reclaim product polypeptide or its precursor.
The dna sequence dna of coding treatment polypeptide can suitably derive from genome or cDNA, for example by preparation genome or cDNA library and by standard technique, use the synthetic oligonucleotide probe screening by hybridization encode described peptide in whole or in part dna sequence dna and obtain (for example, referring to Sambrook, J, Fritsch, EF and Maniatis, T, Molecular Cloning:ALaboratory Manual, Cold Spring Harbor Laboratory Press, NewYork, 1989).Can also be by the standard method of having set up, for example Beaucage and Caruthers are at Tetrahedron Letters 22 (1981), phosphoramidite method described in the 1859-1869 or Matthes etc. are at EMBO Journal 3 (1984), method described in the 801-805 is through synthesizing the dna sequence dna that mode prepares coding said polypeptide.Can also pass through polymerase chain reaction, use Auele Specific Primer, for example as US 4,683,202 or Saiki etc. at Science 239 (1988), prepare dna sequence dna described in the 487-491.
Dna sequence dna can be inserted any carrier that can carry out the recombinant DNA operation expediently, the host cell that it imported is depended in the selection of this carrier usually.Therefore, described carrier can be the carrier of self-replicating, and promptly as the carrier of the outer entity existence of karyomit(e), it duplicates and does not rely on chromosome duplication, for example plasmid.Perhaps, described carrier can be a kind of carrier that is integrated into the host cell gene group and duplicates with the karyomit(e) that it was integrated into when importing host cell.
Described carrier is preferably expression vector, and wherein the dna sequence dna of coded polypeptide is operationally transcribed required extra fragments with DNA and is connected such as promotor.This promotor can be for showing any DNA sequence of transcriptional activity in the host cell of selecting, it can derive from coding and host cell homology or allogenic proteinic gene.Be used for instructing the example of the suitable promotor that the DNA of code book invention peptide transcribes well-known, for example described in the Sambrook above etc. for those skilled in the art at multiple host cell.
If necessary, the dna sequence dna of coding said polypeptide can also be operationally be connected with suitable terminator, polyadenylation signal, transcriptional enhancer sequence and translational enhancer sequence.Recombinant vectors of the present invention may further include the dna sequence dna that carrier is duplicated in the purpose host cell.
Described carrier can also comprise selective marker, and for example its product can remedy the gene of the defective in the host cell; Or produce to medicine the material of the resistance of Ampicillin Trihydrate, kantlex, tsiklomitsin, paraxin, Xin Meisu, Totomycin or methotrexate for example.With regard to scale operation, described selective marker does not preferably have antibiotics resistance, for example, when carrier is used for scale operation, preferably downcuts the antibiotics resistance gene in the carrier.The method of eliminating antibiotics resistance gene is as known in the art, for example, referring to US 6,358,705, the document is incorporated herein by reference.
In order to instruct parent peptide of the present invention to enter the Secretory Pathway of host cell, can in recombinant vectors, provide secretory signal sequence (being also referred to as leader sequence, preceding former sequence (preprosequence) or presequence (pre sequence)).This secretory signal sequence is connected with the dna sequence dna of encoded peptide with correct frame.Secretory signal sequence is usually located at 5 ' side of the dna sequence dna of encoded peptide.This secretory signal sequence can be the sequence that is connected with peptide usually, or comes the gene of the another kind of secretory protein of own coding.
Be used for connecting respectively coding peptide of the present invention, promotor and alternatively terminator and/or secretory signal sequence dna sequence dna and that their are inserted the operation steps that contains the suitable carrier that duplicates information necessary is well-known (for example for those skilled in the art, referring to Sambrook etc., document is the same).
The host cell that imports dna sequence dna or recombinant vectors can comprise bacterium, yeast, fungi and higher eucaryotic cells for producing the arbitrary cell of peptide of the present invention.Well-known and the example suitable host cell that uses in this area has intestinal bacteria, yeast saccharomyces cerevisiae or Mammals BHK or Chinese hamster ovary celI system, but is not limited thereto.
Can pass through routine techniques, Remington ' s PharmaceuticalSciences for example, 1985 or Remington:The Science and Practice of Pharmacy, 19
ThEdition, described in 1995, preparation contains the pharmaceutical composition of The compounds of this invention.
One object of the present invention is to provide the pharmaceutical preparation that comprises The compounds of this invention, and the concentration that exists of described compound is about the about 25mg/ml of 0.1mg/ml-, and wherein said preparation has the pH of 2.0-10.0.Said preparation can further comprise buffering system, sanitas, isotonic agent, sequestrant, stablizer and tensio-active agent.In one embodiment of the invention, described pharmaceutical preparation is an aqueous compositions, promptly wraps aqueous preparation.This class preparation is generally solution or suspension.In another embodiment of the invention, described pharmaceutical preparation is the aqueous solution.Term " aqueous compositions " is defined as comprises the preparation of 50%w/w water at least.Equally, term " aqueous solution " is defined as the solution that comprises 50%w/w water at least and term " aqueous suspension " is defined as comprises the suspension of 50%w/w water at least.
In another embodiment, described pharmaceutical preparation is a freeze-dried preparation, and wherein clinicist or patient add solvent and/or thinner before use.
In another embodiment, described pharmaceutical preparation is to need not the drying agent (for example lyophilize or spraying drying) that any prior dissolving can be used fully.
The present invention relates to the aqueous solution that comprises The compounds of this invention and the pharmaceutical preparation of buffer reagent in one aspect of the method, and the concentration that exists of wherein said compound is 0.1mg/ml or higher, and wherein said preparation has the pH of about 2.0-10.0.
In another embodiment of the invention, the pH of described preparation is about 7.0-about 9.5.In another embodiment of the invention, the pH of described preparation is about 3.0-about 7.0.In another embodiment of the invention, the pH of described preparation is about 5.0-about 7.5.In another embodiment of the invention, the pH of described preparation is about 7.5-about 9.0.In another embodiment of the invention, the pH of described preparation is about 7.5-about 8.5.In another embodiment of the invention, the pH of described preparation is about 6.0-about 7.5.In another embodiment of the invention, the pH of described preparation is about 6.0-about 7.0.
In another embodiment of the invention, it is about 9.0 that the pH of described preparation is about 3.0-, and described pH is apart from least 2.0 pH units of isoelectric pH of The compounds of this invention.
In another embodiment of the invention, described buffer reagent is selected from sodium acetate, yellow soda ash, Citrate trianion, glycylglycine, Histidine, glycine, Methionin, arginine, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, sodium phosphate and the three (group that hydroxymethyl)-aminomethane, N-two (hydroxyethyl) glycine, N-(methylol) methylglycine, oxysuccinic acid, succinate, toxilic acid, fumaric acid, tartrate, aspartic acid or its mixture are formed.In these concrete buffer reagents each all can constitute alternative embodiment of the present invention.
In another embodiment of the invention, described preparation further comprises pharmaceutically acceptable sanitas.In another embodiment of the invention, described sanitas be selected from phenol, neighbour-cresols ,-group that cresols, p-Cresol, methyl p-hydroxybenzoate, propylparaben, 2-phenoxyethyl alcohol, butyl p-hydroxybenzoate, 2-phenylethyl alcohol, benzylalcohol, butylene-chlorohydrin and Thiomersalate, bronopol, phenylformic acid, miaow urea, chlorhexidine (chlorohexidine), sodium dehydroacetate, parachlorometacresol, ethyl p-hydroxybenzoate, benzethonium chloride, chlorphenesin (3p-chlorophenoxy the third-1,2-glycol) or its mixture are formed.In another embodiment of the invention, the concentration that exists of described sanitas is 0.1mg/ml-20mg/ml.In another embodiment of the invention, the concentration that exists of described sanitas is 0.1mg/ml-5mg/ml.In another embodiment of the invention, the concentration that exists of described sanitas is 5mg/ml-10mg/ml.In another embodiment of the invention, the concentration that exists of described sanitas is 10mg/ml-20mg/ml.In these concrete sanitass each all can constitute alternative embodiment of the present invention.The those skilled in the art that base on practicality of sanitas are well-known in pharmaceutical composition.For simplicity, with reference to Remington:The Science and Practice ofPharmacy, 19
ThEdition, 1995.
In another embodiment of the invention, described preparation further comprises isotonic agent.In another embodiment of the invention, described isotonic agent is selected from salt (for example sodium-chlor), sugar or sugar alcohol, amino acid (for example L-glycine, L-Histidine, arginine, Methionin, Isoleucine, aspartic acid, tryptophane, Threonine), alditol (glycerol (glycerine), 1 for example, 2-propylene glycol (propylene glycol), 1, ammediol, 1,3 butylene glycol), the group formed of polyoxyethylene glycol (for example PEG400) or its mixture.Can use sugar arbitrarily, such as single-, two-or polyose or water-soluble glucan, comprise for example fructose, glucose, seminose, sorbose, wood sugar, maltose, lactose, sucrose, trehalose, dextran, Propiram, dextrin, cyclodextrin, Zulkovsky starch, hydroxyethylamyle and carboxymethyl cellulose-Na.In one embodiment, described sugar additives is a sucrose.With sugar alcohol be defined as contain at least one-the C4-C8 hydrocarbon of OH group, comprise for example mannitol, sorbyl alcohol, inositol, melampyrum (galacititol), galactitol, Xylitol and arabitol.In one embodiment, described sugar alcohol additive is a mannitol.Can be used alone or in combination above-mentioned carbohydrate or glycitols.Usage quantity there is not fixed constraints, as long as described sugar or sugar alcohol dissolve in liquid preparation and can not produce detrimentally affect to the stabilization effect that uses the inventive method to realize.In one embodiment, the concentration of described sugar or sugar alcohol is about the about 150mg/ml of 1mg/ml-.In another embodiment of the invention, the concentration that exists of described isotonic agent is 1mg/ml-50mg/ml.In another embodiment of the invention, the concentration that exists of described isotonic agent is 1mg/ml-7mg/ml.In another embodiment of the invention, the concentration that exists of described isotonic agent is 8mg/ml-24mg/ml.In another embodiment of the invention, the concentration that exists of described isotonic agent is 25mg/ml-50mg/ml.In these concrete isotonic agents each all can constitute alternative embodiment of the present invention.In pharmaceutical composition, use isotonic agent well-known as those skilled in the art.For simplicity, with reference to Reming ton:The Science and Practice ofPharmacy, 19
ThEdition, 1995.
In another embodiment of the invention, further comprise sequestrant in the described preparation.In another embodiment of the invention, described sequestrant is selected from salt of ethylenediamine tetraacetic acid (EDTA) (EDTA), citric acid and aspartic acid and composition thereof.In another embodiment of the invention, the concentration that exists of described sequestrant is 0.1mg/ml-5mg/ml.In another embodiment of the invention, the concentration that exists of described sequestrant is 0.1mg/ml-2mg/ml.In another embodiment of the invention, the concentration that exists of described sequestrant is 2mg/ml-5mg/ml.In these concrete sequestrants each all can constitute alternative embodiment of the present invention.In the pharmaceutical composition sequestrant use to those skilled in the art well-known.For simplicity, with reference to Remington:The Science and Practice of Pharmacy, 19
ThEdition, 1995.
In another embodiment of the invention, further comprise stablizer in the described preparation.In the pharmaceutical composition stablizer use to those skilled in the art well-known.For simplicity, with reference to Remington:The Science and Practice of Pharmacy, 19
ThEdition, 1995.
In particular, composition of the present invention is stable composition of liquid medicine, and its therapeutic activity composition comprises and may show the polypeptide that aggregation forms by lay up period in liquid pharmaceutical formulation.So-called " aggregation formation " refers to and cause between the peptide molecule that the physics that oligomer (can keep solvable) or the big visible aggregation that is precipitated out form interacts from solution.So-called " lay up period " in case refer to and prepare, composition of liquid medicine or preparation be not at once to experimenter's administration.But after preparation, with it with liquid form, freezing state or be dissolved into the dried forms of liquid form subsequently again or be suitable for other form of experimenter's administration is packed and stored.So-called " dried forms " refers to by lyophilize (is freeze-drying; For example, referring to Williams and Polli (1984) J.Pa renteral Sci.Technol.38:48-59), spraying drying is (referring to Masters (1991) at Spray-Drying Handbook (5th ed; Longman Scientific and Technical, Essez, U.K.), described in the pp.491-676; Broadhead etc. (1992) Drug Devel.Ind.Pharm.18:1169-1206; With (1994) Pharm.Res.11:12-20 such as Mumenthaler) or air-dry (Carpenter and Crowe (1988) Cryobiology 25:459-470; And Roser (1991) Biopharm.4:47-53) comes drying liquid pharmaceutical composition or preparation.The composition of liquid medicine lay up period forms aggregation by polypeptide will produce detrimentally affect to the biological activity of this polypeptide, thereby causes the therapeutic efficiency forfeiture of this pharmaceutical composition.In addition, aggregation forms and can produce other problem, such as causing pipeline, film or pump to block when the use infusion system contains the pharmaceutical composition of polypeptide.
Pharmaceutical composition of the present invention can further comprise is enough to reduce the amino soda acid that said composition lay up period polypeptide forms the consumption of aggregation.So-called " amino soda acid " refers to amino acid or amino acid whose combination, and wherein designated amino acid exists with its free alkali or its salt form arbitrarily.If use amino acid whose combination, so all amino acid all can exist all and can exist with its salt form with its free alkali form, or some can exist and other exists with its salt form with its free alkali form.In one embodiment, the amino acid that is used to prepare the present composition carries the amino acid of electrically charged side chain for those, such as arginine, Methionin, aspartic acid and L-glutamic acid.Specific amino acids (glycine for example, methionine(Met), Histidine, imidazoles, arginine, Methionin, Isoleucine, aspartic acid, tryptophane, Threonine and composition thereof) any steric isomer (being L, D or DL isomer) or the combination of these steric isomers may reside in the pharmaceutical composition of the present invention, as long as described specific amino acids exists with its free alkali form or its salt form.In one embodiment, use the L-steric isomer.Can also use these amino acid whose analogues to prepare composition of the present invention.So-called " amino acid analogue " refers to naturally occurring amino acid whose derivative, and they can form the required minimizing effect that produces to the aggregation that composition of liquid medicine lay up period of the present invention causes because of polypeptide.Suitable arginine analog comprises for example aminoguanidine, ornithine and N-one ethyl L-arginine; Suitable methionine(Met) analogue comprises S-ethyl homocysteine and S-butyl homocysteine; Suitable cysteine analogs comprises S-methyl-L halfcystine.As for other amino acid, amino acid analogue can be mixed composition with its free alkali form or its salt form.In another embodiment of the invention, to be enough to prevent or delay the concentration use amino acid or the amino acid analogue of protein aggregation.
In another embodiment of the invention, can add methionine(Met) (or the amino acid of other sulfur-bearing or amino acid analogue), so that be to comprise at least one to be easy to take place suppress when methionine residues is oxidized to the polypeptide of methionine residues of this class oxidation of methionine sulfoxide this class oxidation at the polypeptide that works as therapeutical agent.So-called " inhibition " refers to the minimum that methionine(Met) oxidation kind takes place in time and accumulates.Suppressing the methionine(Met) oxidation makes polypeptide keep to a greater degree with its suitable molecular form.Can use any steric isomer (L, D or DL isomer) or its combination of methionine(Met).The amount that add-on should be the oxidation that is enough to suppress methionine residues, make methionine sulfoxide is for the acceptable amount of administration.In general, this means to contain in the composition and be no more than about 30% methionine sulfoxide of about 10%-.In general, can be by adding methionine(Met), make the ratio of the methionine(Met) that adds and methionine residues about 1: about 1000: 1 of 1-, such as 10: the scope that 1-is about 100: 1 realizes this purpose.
In another embodiment of the invention, described preparation further comprises the stablizer in the group that is selected from high-molecular weight polymer or low-molecular weight compound composition.In another embodiment of the invention, described stablizer is selected from: polyoxyethylene glycol (for example PEG 3350); Polyvinyl alcohol (PVA); Polyvinylpyrrolidone; Carboxyl-/hydroxylated cellulose or derivatives thereof (for example HPC, HPC-SL, HPC-L and HPMC); The material of cyclodextrin, sulfur-bearing is as monothioglycerol, Thiovanic acid and 2-methyl sulfo-ethanol; With different salt (for example sodium-chlor).In these concrete stablizers each all can constitute alternative embodiment of the present invention.
Described pharmaceutical composition can also comprise extra stablizer, and they can further strengthen the stability of therapeutic activity polypeptide wherein.Significant especially for the purpose of the present invention stablizer comprise but the methionine(Met) that is not limited to prevent the oxidation of polypeptide generation methionine(Met) with EDTA and prevent the accumulative nonionic surface active agent that the polypeptide generation is relevant with freeze thawing or mechanical shearing.
In another embodiment of the invention, described preparation further comprises tensio-active agent.In another embodiment of the invention, described tensio-active agent is selected from: stain remover; Ethoxylated castor oil; The glyceride type of polysaccharide glycolysis (polyglycolyzedglycerides); The acetyl monoglyceride class; The sorbitan fatty acid esters class; (poloxamer for example is such as Pluronic for polyoxypropylene-polyoxyethylene blocks polymkeric substance
F68, poloxamer 188 and 407, Triton X-100); The polyoxyethylene sorbitan fatty acid esters class; Polyoxyethylene and polyoxyethylene deriv are such as alkylation and alkoxy derivative (tweens, for example Tween-20, Tween-40, Tween-80 and Brij-35); Direactive glyceride class or its ethoxylated derivative; Diglyceride class or its polyoxyethylene deriv; Alcohols; Glycerine; Yelkin TTS and phospholipid (for example phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositols, diphosphatidylglycerol and sphingophospholipid); Phospholipid derivative (for example two palmityl phosphatidic acids) and lysophospholipid class (palmityl hemolytic phosphatidyl-L-Serine and thanomin for example, choline, the 1-acyl group of Serine or Threonine-sn-glycerol-3-phosphate ester class) and the alkyl of hemolytic phosphatidyl and lyso-phosphatidylcholine, alkoxyl group (alkyl ester), alkoxyl group (alkyl oxide)-derivative, lysophosphatidylcholine for example, the lauroyl of dipalmitoyl phosphatidylcholine and mnyristoyl derivative, and polar head group, i.e. choline, ethanolamines, phosphatidic acid, Serine, Threonine, glycerine, inositol and positively charged DODAC, DOTMA, DCP, BISHOP, the modifier of hemolytic phosphatidylserine and hemolytic phosphatidyl Threonine; With glyceryl phosphatide class (for example kephalin class); Glycerose lipid (for example galactopyranoside); Sphingoglycolipid class (for example ceramide type, gangliosides); The dodecylphosphoric acid choline; The egg lysolecithin; Fusidic acid derivatives-(for example sodium taurodihydrofusidate etc.); Longer chain fatty acid and salt C6-C12 thereof (for example oleic acid and sad); Acylcarnitines and derivative; The N of Methionin, arginine or Histidine
α-acylated derivatives or Methionin or arginic side chain acylated derivatives; The N of dipeptide that comprises the arbitrary combination of Methionin, arginine or Histidine and neutrality or acidic amino acid
α-acylated derivatives; The N that comprises the tripeptides of neutral amino acids and two charged amino acid whose arbitrary combination
α-acylated derivatives; DSS (Docusate Sodium, CAS registration number [577-11-7]); Dioctyl calcium sulfosuccinate, CAS registration number [128-49-4]); Docusate potassium, CAS registration number [7491-09-0]); SDS (sodium lauryl sulphate or Sodium Lauryl Sulphate BP/USP); Sodium octoate; The cholic acid or derivatives thereof; Bile acide and salt thereof and glycine or taurine conjugate; Ursodesoxycholic acid; Glycocholate sodium; Sodium deoxycholate; Taurocholic acid sodium salt; NaGC; N-hexadecyl-N, N-dimethyl-3-ammonium-1-propanesulfonic acid salt; Anionic (alkyl-aryl-sulfonic acid salt) monovalence tensio-active agent; Zwitterionics (N-alkyl-N for example, N-diformazan ammonium-1-propanesulfonic acid salt, 3-courage amido-1-propyl group diformazan ammonium-1-propanesulfonic acid salt, cationic surfactant (quaternary ammonium hydroxide) (for example cetyl trimethylammonium bromide, cetylpyridinium chloride); Nonionic surface active agent (for example dodecyl β-D-glucopyranoside), poloxamines (for example Tetronic ' s), they are to derive from propylene oxide and oxyethane and quadrol four functional blocks multipolymers of addition successively, or described tensio-active agent can be selected from the group of imidazolidine derivatives or its mixture.In these concrete tensio-active agents each all can constitute alternative embodiment of the present invention.
In the pharmaceutical composition tensio-active agent use to those skilled in the art well-known.For simplicity, with reference to Remington:The Science and Practice of Pharmacy, 19
ThEdition, 1995.
It is possible having other component in peptide pharmaceutical preparation of the present invention.The extra component of this class can comprise wetting agent, emulsifying agent, antioxidant, weighting agent, tension regulator, sequestrant, metal ion, oil carrier, protein (for example human serum albumin, gelatin or protein) and zwitter-ion (for example amino acid, such as trimethyl-glycine, taurine, arginine, glycine, Methionin and Histidine).Certainly, the extra component of this class should not produce detrimentally affect to the general stability of pharmaceutical preparation of the present invention.
Can be with the pharmaceutical composition that contains The compounds of this invention to the patient of this class treatment of needs in the administration of several positions, for example at part, such as skin and mucosal sites, at the position of walking around absorption, for example in artery, vein, heart, and relating to the position administration of absorption, and for example on skin, administration in subcutaneous, intramuscular or the abdomen.
Pharmaceutical composition of the present invention can be undertaken by several route of administration the patient's of this class treatment of needs administration, for example tongue; The hypogloeeis; Suck; In the oral cavity; Oral; In stomach and the intestines; Nose; Lung is for example by bronchiole and alveolar or its combination; Epidermis; Corium; Transdermal; Vagina; Rectum; Eye for example passes through conjunctiva; Ureter; With non-enteron aisle.
Relate to the pharmaceutical composition that comprises general formula (I) compound and pharmaceutically acceptable vehicle among the present invention in one aspect.
In one embodiment, described pharmaceutical composition is suitable for pulmonary administration.
The present invention relates to the application of compound in preparation pulmonary drug thing of general formula (I) in one aspect of the method.
Composition of the present invention can be with several formulation administrations, for example as solution; Suspension; Emulsion; Microemulsion; Many emulsions; Foam; Ointment; Paste; Plaster (plaster); Ointment; Tablet; Coating tablet; Irrigation; Capsule, for example hard gelatin capsule and soft gelatin capsule; Suppository; Rectal capsule; Drops; Gel; Sprays; Pulvis; Aerosol; Inhalation; Eye drop; Ophthalmic ointment; The eye irrigation; Vaginal suppository; Pesseulum; Vagina ointment; Injection solution; Converted in-situ solution, for example in-situ gelling, anchored in place, in-situ precipitate, in-situ crystallization, infusion solution and implant.
For example, composition of the present invention can be further by covalency, hydrophobic and electrostatic interaction is compound with pharmaceutical carrier, delivery system and senior delivery system or combine in case further strengthen described compound stability, improve bioavailability, improve solvability, reduce untoward reaction, realize the well-known chronotherapy of those skilled in the art and improve patient's compliance or it makes up arbitrarily.The example of carrier, delivery system and senior delivery system includes, but are not limited to: for example Mierocrystalline cellulose and derivative; Polyose, for example dextran and derivative; Starch and derivative; Poly-(vinyl alcohol); Acrylate and methacrylate polymers; Poly(lactic acid) and polyglycolic acid and segmented copolymer thereof; Polyethylene glycols; Carrier proteins, for example white protein; Gel, for example hot glue coagulates system, for example the well-known segmented copolymer of those skilled in the art system; Micella; Liposome; Microballoon; Nanoparticle; Well-known liquid crystal of phase behaviour field those of ordinary skill and dispersion thereof in fat-water system; Polymer micelle; Many emulsions (multiple emulsion); Self-emulsifying, self-emulsifying microemulsion cyclodextrin and derivative thereof; And dendritic macromole (dendrimers).
Composition of the present invention can be used for formulation example as using solid, semisolid, powder and the solution of band scale dosage aerosols, powder inhaler and atomizer compound as described in the pulmonary administration, and it is well-known that all devices are those skilled in the art.
That composition of the present invention is particularly useful for preparing is controlled, continue, prolong, delay and sustained release drug delivery systems.In particular, composition can be used for preparing well-known non-enteron aisle controlled release of those skilled in the art and slow-released system (two kinds of systems all can make administration number of times reduce manyfold), but is not limited thereto.Even more preferably through the controlled release and the slow-released system of subcutaneous administration.The useful controlled release system and the example of composition are hydrogel, oleogel, liquid crystal, polymer micelle, microballoon, nanoparticle, but they do not limit the scope of the invention.
The method that production can be used for the controlled release system of the present composition includes, but are not limited to crystallization, concentrates, altogether-crystallization, precipitation, co-precipitation, emulsification, dispersion, high-pressure homogenization, encapsulated, spraying drying, micro encapsulation, the solvent evaporation of condensing, be separated, produce microballoon, extruding and supercutical fluid method.Generally with reference to Handbook of Pharmaceutical ControlledRelease (Wise, D.L., ed.Marcel Dekker, New York, 2000) and Drugand the Pharmaceutical Sciences vol.99:Protein Formulation and Delivery (MacNally, E.J., ed.Ma rcel Dekker, New York, 2000).
Can be by using syringe, parenterai administration is carried out in subcutaneous, the intramuscular of a class syringe, intraperitoneal or intravenous injection alternatively.Perhaps, can carry out parenterai administration by infusion pump.Another kind is chosen as the solution or the suspension composite that can give The compounds of this invention with nose or lung's spray form.Select as another kind, the pharmaceutical composition that contains The compounds of this invention can also be suitable for transdermal administration, for example by the needle-less injection or from patch (alternatively the iontophoresis patch) or stride mucous membrane (for example sucking) administration.
Term " stable formulation " refers to the physical stability with increase, chemical stability or the physics of increase and the preparation of chemical stability of increase.
The term of protein formulation used herein " physical stability " refer to because of protein contact thermal and mechanical stress and/or with the interface and the surface of stabilization removal, take place to interact and the protein that takes place forms the tendency of bioinactivation and/or insoluble protein aggregation such as water repellent surface and interface.By under differing temps, making preparation contact machinery/physical stress (for example stirring) different time of being filled in the suitable containers (for example cartridge case or bottle) visual inspection and/or turbidity measurement value physical stability of estimating moisture protein formulation after the time limit.The visual inspection of preparation uses vernier focusing light to carry out in dark background.The turbidity of preparation is by the evaluation of the vision grading system of turbidity, for example the grade of 0-3 (it is 0 that the preparation that does not show turbidity is equivalent to the vision scoring, and it is 3 that the preparation that shows the vision turbidity in daylight is equivalent to the vision scoring).When preparation showed the vision turbidity under sight, said preparation was classified as physical instability with regard to protein aggregation.Perhaps, can estimate the turbidity of preparation by the well-known simple turbidity measurement of those skilled in the art.The physical stability that spectrophotometric reagent that can also be by using the protein conformation state or probe are estimated moisture protein formulation.Described probe is preferably small molecules, and it preferentially combines with proteinic non-natural conformer.An example of the small molecules spectrophotometric probe of protein structure is thioflavin T.Thioflavin T detects the fibriilar fluorescence dye of amyloid for being widely used in.Protofibril is being arranged and may also have in the presence of other protein configuration, thioflavin T produces new maximum excitation and launches at about 482nm place generation enhanced at about 450nm place when combining with fibrillin matter form.The essentially no fluorescence of unconjugated thioflavin T under described wavelength.
Other small molecules can be as protein structure from the natural probe that changes to the non-natural state.The protein hydrophobic zonule (patch) that preferential combination exposes is " hydrophobicity zonule " probe for example.General hydrophobicity zonule is embedded in the proteinic tertiary structure of native state, and exposes when protein begins expansion or sex change.The example of these small molecules spectrophotometric probes is the aromatics hydrophobic dye, such as anthracene (antrhacene), acridine, phenanthroline etc.Other spectrophotometric probe is the metal-aminoacid mixture, such as hydrophobic amino acid, such as the cobalt metal composite of phenylalanine, leucine, Isoleucine, methionine(Met) and Xie Ansuan etc.
The chemical covalency that " chemical stability " of term protein preparation used herein refers in the protein structure changes, and this change causes forming to be compared the biological effect that has with the natural protein structure and may can form by chemical degradation product lower and/or that immunogenicity may increase.Various chemical degradation products, this depends on the environment that the type of natural protein is contacted with character and this protein and decides.The elimination of chemical degradation can't be avoided most probably fully, and just as well known to the skilled person, can observe the chemical degradation product of increasing amount usually in the storage of protein formulation and use.Most of protein is easy to desamidization, and the amide side chain base on promptly a kind of glutamy amido or the asparaginyl group residue is hydrolyzed into free carboxy acid's process.Other degradation pathway comprises formation high molecular converted product, wherein two or more protein molecules are each other by transmidation and/or disulfide linkage interaction covalent attachment, cause forming covalently bound dimer, oligomer and polymer degradation products (Stability ofProtein Pharmaceuticals, Ahern.T.J. ﹠amp; Manning M.C., PlenumPress, New York 1992).As for other version of chemical degradation, that can mention has an oxidation (for example oxidation of methionine residues).Can come the chemical stability (for example, can come the accelerated degradation product to form by improving temperature usually) of assess proteins preparation by the amount of after contact varying environment condition, measuring the chemical degradation product at the different time points place.Usually by using chromatographic technique (for example SEC-HPLC and/or RP-HPLC), determine every kind of degraded product amount separately by separating degraded product according to molecular size and/or electric charge.
Therefore, as mentioned above, " stable formulation " refers to the physical stability with increase, chemical stability or the physics of increase and the preparation of chemical stability of increase.In general, preparation must be in use and storage process stable (use and the storage requirement that meet recommendation), till reaching validity period.
In one embodiment of the invention, the pharmaceutical preparation that comprises The compounds of this invention can stably use for 6 weeks above and store more than 3 years.
In another embodiment of the invention, the pharmaceutical preparation that comprises The compounds of this invention can stably use for 4 weeks above and store more than 3 years.
In another embodiment of the invention, the pharmaceutical preparation that comprises The compounds of this invention can stably use for 4 weeks above and store more than 2 years.
In another embodiment of the invention, the pharmaceutical preparation that comprises The compounds of this invention can stably use for 2 weeks above and store more than 2 years.
The present invention relates to the application of The compounds of this invention in the preparation medicine in one aspect of the method.
In one embodiment, compound of the present invention is used to prepare treatment or prevents the medicine of following disease: hyperglycemia, diabetes B, glucose tolerance reduction, type 1 diabetes, obesity, hypertension, X syndrome, dyslipidemia, cognitive disorder, atherosclerosis, myocardial infarction, coronary heart disease and other cardiovascular disorder, apoplexy, inflammatory bowel syndrome, maldigestion and stomach ulcer.
In another embodiment, compound of the present invention is used for preparing the medicine that delays or prevent the disease progression of diabetes B.
In another embodiment, compound of the present invention is used to prepare the apoptosis that reduces ingestion of food, reduce beta cell, increases beta cell function and beta cell group and/or recovers medicine to the glucose-sensitive of beta cell.
Can also use treatment and second kind or the multiple pharmacological active substance coupling of The compounds of this invention, described second kind or multiple pharmacological active substance for example can be selected from antidiabetic drug, diet pill, appetite stimulator, antihypertensive drug, treat and/or prevent because of diabetes and cause or the promoting agent of associated complication and treating and/or preventing because of obesity causes or the promoting agent of associated complication.The example of these pharmacological active substances is: Regular Insulin; Sulfonylurea; Biguanides; Meglitinides; Glucosidase inhibitor; Glucagon antagonist; DPP-I V (the inhibitor of dipeptides acyl aminopeptidase-IV); Relate to the inhibitor that stimulates gluconeogenesis and/or glycogenolytic liver enzyme; The glucose uptake conditioning agent; Change the compound of lipid metabolism, such as antihyperlipidemic, as HMG CoA inhibitor (statins); Reduce the compound of ingestion of food; Rxr agonist and the promoting agent that acts on the ATP-dependency potassium channel of beta cell; Colestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, Pravastatin, Simvastatin, probucol, dextrothyroxine, netaglinide (neteglinide), repaglinide; Beta-Blocking agent is such as alprenolol, atenolol USP 23, timolol, pindolol, Proprasylyte and metoprolol; ACE (angiotensin converting enzyme) inhibitor is such as benazepril, captopril, enalapril, fosinopril, lisinopril, alatriopril, quinapril and Ramipril; Calcium channel blocker is such as nifedipine, felodipine, nicardipine, Isrodipine, nimodipine, diltiazem and verapamil; And α-Zu Zhiji, such as Doxazosin, urapidil, Prazosin and terazosin; CART (transcript that the Cocaine amphetamine is regulated) agonist; NPY (neuropeptide tyrosine) antagonist, MC4 (melanocortin 4) agonist, the aricine antagonist, TNF (tumour necrosis factor) agonist, CRF (corticotropin releasing factor(CRF)) agonist, CRF BP (corticotropin releasing factor(CRF) is conjugated protein) antagonist, the urocortisol agonist, β 3 agonists, MSH (melanotropin) agonist, MCH (melanophore-concentrated hormone) antagonist, CK (cholecystokinin) agonist, serotonin reuptake inhibitor, serotonin and NRI, blended serotonin and norepinephrine energy compound, 5HT (serotonin) agonist, the bombesin agonist, the galanin antagonist, tethelin, growth hormone releasing compounds, TRH (thyroliberin) agonist, UCP2 or 3 (uncoupling protein 2 or 3) conditioning agent, the Leptin agonist, DA agonist (bromocriptine, doprexin), lipase/amylase inhibitor, RXR (retinoids X acceptor) conditioning agent, the TR beta-agonists; Histamine H 3 antagonists.
Should understand The compounds of this invention and one or more above-claimed cpds and alternatively the combination of any appropriate of one or more other pharmacological active substances all be regarded as belonging to scope of the present invention.
Further explain the present invention by the following example, but, they are not regarded as the scope of the present invention that limits.The feature that discloses in foregoing description and the following example respectively and with its arbitrarily array mode as understanding different forms of information of the present invention.
Embodiment
Used abbreviation;
The r.t retention time
The TFE trifluoroethanol
The DIEA diisopropylethylamine
H
2O water
CH
3The CN acetonitrile
DMF NN dimethyl formamide
HBTU 2-(1H-benzotriazole-l-base-)-1,1,3,3 tetramethyl-urea hexafluorophosphates (tetramethyluronium hexafluorophosphate)
HATU O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate
ImPr 3-(1-imidazol-4 yl)-propionyl
Adoc 1-Buddha's warrior attendant carbalkoxy
Fmoc9 H-fluorenes-9-base methoxycarbonyl
The Boc tertbutyloxycarbonyl
The OtBu tert-butyl ester
The tBu tertiary butyl
The Trt trityl
Pmc 2,2,5,7,8-pentamethyl--chroman-6-alkylsulfonyl
Dde 1-(4,4-dimethyl-2,6-dioxo cyclohexylidene) ethyl
IvDde 1-(4,4-dimethyl-2,6-dioxo cyclohexylidene)-3-methyl butyl
The DCM methylene dichloride
The TIS tri isopropyl silane)
TFA: trifluoroacetic acid
Et
2O: ether
NMP 1-methyl-pyrrolidin-2-one
The Aib α-An Jiyidingsuan
Analyze
HPLC at the enterprising enforcement of Waters 2690Separation Module usefulness method A1, B1 that Waters 996 diode-array detectors have been installed and B6 analyzes.(The SeparationsGroup Hesperia) and at 214nm, 254nm, 280nm and 301nm place detects with UV to use Vydac 218TP544.6mm * 250mm 5 μ m C-18 silica columns.
HPLC at the enterprising enforcement usefulness method 01_B4_2 of Waters 600S system that Waters 996 diode-array detectors have been installed analyzes.Use Symmetry300 C18,5 μ m, 3.9mm * 150mm post (waters) and detect with UV at 214nm and 254nm place.
In method A1, use 0.05M NH
4SO
4PH 3.5 balance columns and be used in 0.05M (NH
4)
2SO
40-60%CH among the pH 3.5
3The gradient elution of CN, the time is 50 minutes, and temperature is 42 ℃, and flow velocity is 0.5ml/ minute.
In method B1, use 0.1%TFA/H
2O balance columns and use 0-60%CH
3CN-0.1%TFA/H
2The gradient elution of O, the time is 50 minutes, and temperature is 42 ℃, and flow velocity is 0.5ml/ minute.
In method B6, use 0.1%TFA/H
2O balance columns and use 0-90%CH
3CN-0.1%TFA/H
2The gradient elution of O, the time is 50 minutes, and temperature is 42 ℃, and flow velocity is 0.5ml/ minute.
In method 01_B4_2, be used in 5% acetonitrile balance columns in the water that contains 0.05%TFA and use 5-65%CH
3CN-0.05%TFA/H
2The gradient elution of O, the time is 15 minutes, and temperature is 42 ℃, and flow velocity is 1ml/ minute.
UV detector response by comparative sample is in from having determined that by amino acid analysis the detector response of the hGH standard substance of content calculates proteinic amount.
Carrying out LC-MS on PE-Sciex API 100 mass spectrographs that two Perkin Elmer Series 200 Micropumps, Perkin ElmerSeries 200 automatic samplers, Applied Biosystems 785A UV detector and Sedex75 light scattering detectors have been installed analyzes.At room temperature with 1.5ml/ minute wash-out Waters Xterra 3.0mm * 50mm5 μ C-18 silica column.It is used 5%CH
3CN/0.1%TFA/H
2The O balance, and use 5%CH
3CN/0.1%TFA/H
2O wash-out 1.0 minutes was used to 90%CH in 7 minutes then
3CN/0.1%TFA/H
2The gradient elution of O.By detecting in the UV at 214nm place detection and evaporat light scattering.The fraction of post elutriant is imported PE-Sciex API 100 mass spectrometric ions injection interfaces.The mass range of per 2 seconds run-down 300-2000amu in operational process.
Carrying out Maldi TOF MS with linear model on Bruker Autoflex instrument analyzes.By the thin layer drying sessile drop method, use alpha-cyano-4-hydroxycinnamic acid to prepare sample as matrix.
Embodiment 1
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] preparation of GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa
1.a synthetic protected peptide-based resin
Prepare Boc-His (Boc)-Aib-Glu (OtBu)-Gly-Thr (tBu)-Phe-Thr (tBu)-Ser (tBu)-Asp (OtBu)-Val-Ser (tBu)-Ser (tBu)-Tyr (tBu)-Leu-Glu (OtBu)-Aib-Gln (Trt)-Ala-Ala-Lys (Boc)-Glu (OtBu)-Phe-Ile-Ala-Trp (Boc)-Leu-Val-Lys (Boc)-Aib-Arg (Pmc)-Lys (Dde)-Rink amide resin in the FastMoc UV scheme that Applied Biosystems 433A peptide synthesizer uses manufacturer to provide with the 0.25mmol scale according to the Fmoc strategy, described scheme is used the coupling among the NMP of HBTU mediation and the deprotection of UV Fmoc protecting group is monitored. In order to improve coupling efficiency, use HATU but not HBTU makes these residue couplings of residue behind Aib residue and the Aib as coupling reagent.Be used for synthetic initial resin (438mg) for having the 4-(2 ' of 0.57mmol/g replacement capacity, 4 '-Dimethoxyphenyl-Fmoc-amino methyl)-and phenoxy resin (Rink amide resins) (Merck Biosciences GmbH, Germany.cat.#:01-12-0013) .Used protected amino acid derivative is (25)-6-[1-(4; 4-dimethyl-2; 6-dioxo-cyclohexylidene)-ethylamino]-2-(9H-fluorenes-9-base methoxycarbonyl amino)-caproic acid (Fmoc-Lys (Dde)-OH), Fmoc-Arg (Pmc)-OH, Fmoc-Aib-OH; Fmoc-Lys (Boc)-OH; Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Trp (Boc)-OH; Fmoc-Ala-OH; Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Glu (OtBu)-OH; Fmoc-Gln (Trt)-OH; Fmoc-Tyr (tBu)-OH, Fmoc-Ser (tBu)-OH, Fmoc-Asp (OtBu)-OH; Fmoc-Thr (tBu)-OH, Fmoc-Gly-OH and Boc-His (Boc)-OH
Output is 1.37g exsiccant peptide-based resin.
1.b the sign of peptide-based resin
This resin is characterised in that by with 14 μ l TIS, 14 μ l H
2The mixture of O and 0.5ml TFA it was handled 2 hours and from this resin of 50mg thick peptide under the cracking.By removing by filter resin, and, use Et by the thick peptide of precipitate and separate
2The O washing.Dry sediment is carried out HPLC and LC-MS analysis.
Analytical results:
| Analytical procedure | The result |
| HPLC A1 | R.t.:37.41 minute |
| LC-MS | R.t.3.48 minute.(M+3H +)/3 quality: 1221.3Da, (calculated value: 1220Da) |
1.c the deprotection of Dde
Protected peptide-based resin (1.35g, the 250 μ mol) washed twice that in NMP: DCM 1: 1 (15ml), will produce by (1.a).2% solution of hydrazine hydrate in NMP (20ml) that adds prepared fresh.With this reaction mixture jolting at room temperature 12 minutes, filter then.The hydrazine treatment step is repeated twice.After this use NMP, DCM and NMP thorough washing resin.
1.d Pegylation
The resin of Dde deprotection is suspended among the NMP (20ml).Add 3-(mPEG yl) propionic acid 2,5-dioxo-tetramethyleneimine-1-base ester (2.0g, 1mmol, 4eq.) and DIEA (344 μ l, 2mmol 8eq.) and with this suspension jolting spend the night.Then by the filtering separation resin, with NMP, DCM, 2-propyl alcohol, methyl alcohol and Et
2The O thorough washing, and dry in a vacuum.
1.e the cracking of product
Will from the resin of 1.d at room temperature with 350 μ l TIS, 350 μ l H
2The mixture of O and 14mlTFA stirred 3 hours together.By filtering the taking-up resin and washing with 3ml TFA.In a vacuum the filtrate of collecting is concentrated into 5ml and passes through to add 40ml Et
2O precipitates crude product, and is centrifugal subsequently.Use 40ml Et
2O is with washing of precipitate twice, and is air-dry then.
Result from the HPLC of dry sediment:
| Analytical procedure | The result |
| HPLC A1 | R.t.:36.15 minute |
| HPLC B6 | R.t.:28.573 minute.Estimate purity: 64% |
1.f the purifying of product
Thick peptide is dissolved in H
2O/AcOH (40: 4) (40ml), by carrying out 2 times half preparation HPLCs and purifying using on the silica-filled 25mm * 250mm post of 7 μ C-18.Under 40 ℃ of temperature, use 40-62%CH
3CN-0.1%TFA/H
2The O gradient with 10ml/ minute with this post wash-out 47 minutes.Collection contains the fraction of peptide, with the H of 3 volumes
2O dilution and freeze-drying.Characterize the end product that obtains by HPLC.
| Analytical procedure | The result |
| HPLC A1 | R.t.:36.15 minute |
Embodiment 2
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa
2.a synthetic protected peptide-based resin
Use the synthetic protected peptide-based resin Boc-His (Boc) of operation steps-Aib-Glu (OtBu)-Gly-Thr (tBu)-Phe-Thr (tBu)-Ser (tBu)-Asp (OtBu)-Val-Ser (tBu)-Ser (tBu)-Tyr (tBu)-Leu-Glu (OtBu)-Aib-Gln (Trt)-Ala-Ala-Lys (Boc)-Glu (OtBu)-Phe-Ile-Ala-Trp (Boc)-Leu-Val-Lys (Boc)-Aib-Arg (Pmc)-Lys (the Dde)-2-chlorine trityl resin among the embodiment 1.a; but initial resin is 337mg's (2S)-6-[1-(4; 4-dimethyl-2,6-dioxo cyclohexylidene) ethylamino]-2-(((9H-fluorenes-9-yl) methoxycarbonyl) amino) caproyl 2-chlorine trityl resin (Fmoc-Lys (Dde)-2-ClTrt resin).(Bachem Switzerland.cat.#:D-1965) prepares this Fmoc-Lys (Dde)-2-ClTrt resin by being suspended in the 1g 2-chlorine trityl chloride resin that has 1.15mmol/g replacement capacity in 10ml DCM and the 100 μ lDMF mixtures.To wherein adding 533mgFmoc-Lys (Dde)-OH (Merck Biosciences, Germany cat.#04-12-1121) and 684 μ l DIEA, and this mixture stirred 2 hours.By this resin of filtering separation, use DCM/MeOH/DIEA 17: 2: 1 washing three times of 10ml then, with 10ml DCM washing three times,,, finally dry in a vacuum with 10ml DCM washed twice with 10ml NMP washed twice.Should syntheticly produce the protected peptide-based resin of about 1.2g (air-dry).
2.b the deprotection of Dde and the cracking of protected peptide
With 25ml hydrazine hydrate of 2% in DMF 1.0g was handled 25 minutes from the protected peptide-based resin of 2.a, and by this resin of filtering separation.This step is repeated twice again, after this use DMF, DCM, 2-propyl alcohol, methyl alcohol, Et
2The O ether is thorough washing successively, and is dry in a vacuum then.
Described in embodiment 1.b, characterize this resin.Analytical results:
| Analytical procedure | The result |
| HPLC A1 | R.t.:41.12 minute |
| HPLC B6 | R.t.:29.89 minute |
| LC-MS | R.t.3.18 minute.(M+3H +)/3 quality: 1166.6Da, (calculated value: 1166.6Da) |
Dried resin was stirred 2 hours with 1: 1: 3 mixture of 25ml acetate/TFE/DCM, filter then, and again with this mixture thorough washing of 25ml.In a vacuum filtrate the concentrating of collecting obtained oily matter, use heptane with this oily matter stripping 5 times to remove residual acetic acid.
2.c Pegylation and final deprotection
Under 45 ℃, 100mg is dissolved in 1ml TFE and adds 8.5 μ l DIEA from the thick protected peptide of 2.b.(Alabama is USA) at 100 μ l H for mPEG-SPA m.w.5.000Lot.PT-09B-12, Shearwater to add 100mg mPEG-5000-SPA
2Solution among O and the 900 μ lNMP, and this mixture stirred under r.t. spend the night.After this add 48mlEt
2O and collecting precipitation are used 50ml Et
2The O washed twice, dry in a vacuum.Then with exsiccant material and 2ml TFA, 50 μ l TIS and 50 μ l H
2The mixture of O stirred 1 hour together, by using 50ml Et
2The crude product of O precipitate and separate Pegylation peptide is used 50mlEt
2O washing three times, dry in a vacuum then.Thick peptide is dissolved in 20ml H
2O and characterize as follows:
| Analytical procedure | The result |
| HPLC A1 | R.t.:41.41 minute |
| HPLC B6 | R.t.:30.06 minute |
2.d purifying
Will be from the thick peptide in solution of 2.c by carrying out 1 time half preparation HPLC and purifying using on the silica-filled 25mm * 250mm post of 7 μ m C-18.Under 40 ℃ of temperature, be used in 0.1%TFA/H
230-65%CH among the O
3The CN gradient with 10ml/ minute with this post wash-out 47 minutes.Collection contains the fraction that is equivalent to main peak of peptide, with the H of about 3 volumes
2O is diluted to 30ml and freeze-drying.The gained end product characterizes as follows:
| Analytical procedure | The result |
| HPLC A1 | R.t.:41.12 minute |
| HPLC B6 | R.t.:29.89 minute, output 47.9mg. |
| LC-MS | The broad peak of locating at 3.45 minutes has the mass spectrum of the mass peak of squillion. |
| Maldi TOF MS | Mass spectrum shows the peak group with 8875Da average quality.This result is consistent with the expected structure of target compound. |
Embodiment 3
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa
The similar operation step is by preparing this compound from the protected peptide crude product of the 100mg of 2.b described in use and embodiment 2.c and the 2.b; but main difference is (the mPEG-SPA m.w.20.000Lot PT-05C-11 with 400mg 100mgmPEG-20000-SPA; Shearwater; Alabama USA) is used for Pegylation.
The gained end product characterizes as follows:
| Analytical procedure | The result |
| HPLC A1 | R.t.:47.62 minute |
| HPLC B6 | R.t.:34.47 minute |
| Maldi TOF MS | Mass spectrum shows the peak group with 25304Da average quality.This result is consistent with the expected structure of target compound. |
Embodiment 4
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa
The similar operation step is by preparing this compound from the protected peptide crude product of the 100mg of 2.b described in use and embodiment 2.c and the 2.b; but main difference is (the mPEG2-NHS ester m.w.40.000 Lot.PT-11C-06 with mPEG2-40000-NHS ester; Shearwater; Alabama USA) is used for Pegylation.
The gained end product characterizes as follows:
| Analytical procedure | The result |
| HPLC B6 | R.t.:30.99 minute.Output 3.07mg.Conjugate. |
| NMR | 1H-NMR demonstrates the Pegylation reagents that has polluted about 7mg hydrolysis in the isolating 3.07mg conjugate. |
Embodiment 5
N
ε 26-(3-(mPEG yl) propionyl) [Aib
8, Glu
22,30, Lys
33, Asn
34, Gly
35,36, Pro
37] GLP-1 (7-37) ylSerSerGly AlaProProProSer acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa
Use and be used for described in the embodiment 1a similarly operating procedure by having 0; 61mmol/g replaces 0 of capacity, and 25mmol Rink amide resin prepares complete protected peptide-based resin Boc-His (Boc)-Aib-Glu (OtBu)-Gly-Thr (tBu)-Phe-Thr (tBu)-Ser (tBu)-Asp (OtBu)-Val-Ser (tBu)-Ser (tBu)-Tyr (tBu)-Leu-Glu (OtBu)-Glu (OtBu)-Gln-Ala-Ala-Lys (Dde)-Glu (OtBu)-Phe-Ile-Glu (OtBu)-Trp (Boc)-Leu-Lys (Boc)-Asn (Trt)-Gly-Gly-Pro-Ser (tBu)-Ser (tBu)-Gly-Ala-Pro-Pro-Pro-Ser (tBu)-Rink amide resin. Output is 1.4g.
The analytical results that characterizes as the described resin of embodiment 1.b is:
| Analytical procedure | The result |
| HPLC A1 | R.t.:34.99 minute |
| LC-MS | R.t.3.29 minute.(M+3H +The quality of)/3: 1432.8 Da, (calculated value: 1433.2Da) |
Use the operation of embodiment 1.c; remove the Dde provide protection from the complete protected peptide-based resin of 350mg, (mPEG yl) propionic acid 2 is used in the operation of Application Example 1.d then; 5-dioxo-tetramethyleneimine-1-base ester (Shear-water catalog number (Cat.No.) 2M4MOD01; mPEG-SPA, Mw2000) (0.5g, 0.25mmol; 4 equivalents) and DIEA (43 μ l; 0.25mmol, 4 equivalents), the gained resin carry out PEGization.
Use then and embodiment 1.e. similar operation step peptide of Pegylation under the cracking from this resin, and use and embodiment 1.f similar operation step purifying.
Output is 0.125mg, and is as follows from the result of HPLC and LC-MS analysis:
| Analytical procedure | The result |
| HPLC B6 | R.t.:37.45 minute.The purity of estimating: 96.5% |
| LC-MS | R.t.3.44 minute.(M+2H +) average quality/2:3074Da |
Embodiment 6
N
α-[Aib
8,22,35] GLP-1-(7-36) base (N
ε-(3-(mPEG yl) propionyl) lysyl amine), wherein the mPEG base is polymolecularity and molecular weight that have about 750Da
Use with the described similar operating procedure of embodiment 1a. by having 0; 38mmol/g replaces 0 of capacity, 25mmol PAL-PEG-PS resin (Applied Biosystem Cat.no.GEN 913398) preparation complete protected peptide-based resin Boc-His (Boc)-Aib-Glu (OtBu)-Gly-Thr (tBu)-Phe-Thr (tBu)-Ser (tBu)-Asp (OtBu)-Val-Ser (tBu)-Ser (tBu)-Tyr (tBu)-Leu-Glu (OtBu)-Aib-Gln (Trt)-Ala-Ala-Lys (Boc)-Glu (OtBu)-Phe-Ile-Ala-Trp (Boc)-Leu-Val-Lys (Boc)-Aib-Arg (Pmc)-Lys (ivDde)-PAL-PEG-PS resin. Output is 1.935g.
The following ivDde that removes from protected peptide-based resin protects.Washing resin in NMP (382mg, 90 μ mol).The solution of 2% hydrazine hydrate in NMP (20ml) that adds prepared fresh, and with this reaction mixture jolting at room temperature 12 minutes, filter then.Hydrazine is handled twice of repetition.After this use this resin of NMP thorough washing, and the operation steps of using embodiment 1.d. makes itself and (N-(2-mPEG base-ethyl)-4-(2,5-dioxo-tetramethyleneimine-1-yl)-4-oxo-butyramide (α-methoxyl group-ω-NHS ester PEG, Rapp Polymere GmbH, T ü bingen, FRG, cat no.12750-35) (0.27g, 0.36mmol, 4eq.) coupling.The described similar operation step of peptide of cracking Pegylation, and use then and embodiment 1.e. characterizes from resin.
The result who analyzes from the HPLC of dry sediment and LC-MS:
| Analytical procedure | The result |
| HPLC A1 | R.t.:37.90 minute |
| LC-MS | R.t.3.46 minute.(M+3H +The average quality of)/3: 1410Da |
Use and the thick peptide of the final purifying of embodiment 1.f. similar operation step.Output is the 26mg product, by HPLC and LC-MS it is characterized.
| Analytical procedure | The result |
| HPLC A1 | R.t.:37.90 minute |
| HPLC B1 | R.t.:39.46 minute.Estimate purity: 98% |
| LC-MS | R.t.3.48 minute.(M+3H +)/3 average quality: 1410Da |
Embodiment 7
N
ε-[Aib
8.22,35] GLP-1 (7-37) base (S
ε-(1-mPEG base propyl group-2,5-dioxo-tetramethyleneimine-3-yl) cysteinyl amine, wherein the mPEG base is polymolecularity and molecular weight that have about 5000Da
Use and embodiment 1a. and 1.e similar operation step, by having 0,61mmol/g replaces 0 of capacity, and 25mmol Rink amide resins prepares thick peptide His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Aib-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Aib-Arg-Gly-Cys (H) acid amides.Output is 121mg.
HPLC and LC-MS analytical results from the dry sediment of thick peptide:
| Analytical procedure | The result |
| HPLC A1 | R.t.:36.15 minute |
| LC-MS | R.t.3.51 minute.(M+3H +)/3 quality: 1177.1.3 Da, (calculated value: 1176Da) |
The fraction (10mg, 3 μ mol) of thick peptide is dissolved in phosphate buffered saline buffer (15ml), and with pH regulator to 6.5, (MW 5 for Shearwater cat.no.2D2M0H01, mPEG-MAL to add mPEG-Mal 5000,000) (28mg, 6 μ mol) stir this mixture 30 minutes.Use separates end product with embodiment 1.f similar operation step from this mixture.
Output is 2.2mg, and the result that HPLC and LC-MS analyze is as follows:
| Analytical procedure | The result |
| HPLC A1 | R.t.:37.41 minute |
| LC-MS | R.t.3.56 minute.(M+6H +)/6 average quality: 1058.1Da |
Embodiment 8
N
α-(3-(3H-imidazol-4 yl)-propionyl [Aib
22,35, Arg
26,34] GLP-1-(8-37)) base (N
ε-(3-(mPEG yl) propionyl) lysyl amine), wherein the mPEG base is polymolecularity and molecular weight that have about 2000Da
Use and the described similar operation step of embodiment 1a; with the complete protected resin ImPr of the macro preparation of 1mmol (Adoc)-Ala-Glu (OtBu)-Gly-Thr (tBu)-Phe-Thr (tBu)-Ser (tBu)-Asp (OtBu)-Val-Ser (tBu)-Ser (tBu)-Tyr (tBu)-Leu-Glu (OtBu)-Aib-Gln-Ala-Ala-Arg (Pmc)-Glu (OtBu)-Phe-Ile-Ala-Trp (Boc)-Leu-Val-Arg (Pmc)-Aib-Arg (Pmc)-Gly-Lys (Boc)-Rink amide resins, but in entire synthesis process, HATU is used as coupling reagent.Used resin is a hydrophilic Rink amide resins (HypoGel 200RAM) (Rapp Polymere cat.#SP200110150 230), and the replacement capacity that this resin has is 0,61mmol/g.As described in embodiment 1e and 1f, carry out cracking and purifying.Output is 210mg, and is as follows from the result of HPLC and LC-MS analysis:
Analytical procedure. result: HPLC A1 r.t.:36.51 minute, LC-MS r.t.3.69 minute.(M+3H
+)/3 quality: 1194.4Da, (calculated value: 1193.4Da) the following Pegylation that carries out.The not protected peptide of 20mg is dissolved in reagent (mPEG yl) propionic acid 2 of 600 μ l water and adding 100mg Pegylation; 5-dioxo-tetramethyleneimine-1-base ester) (MW 2 for Shearwater cat.no.2M4M0D01, mPEG-SPA; 000) with 9 μ lDIEA, stirred 24 hours.Use separates end product with similar operation step described in the embodiment 1.f. from this mixture.Output is the 3.7mg title compound, and the result of HPLC and maldi analysis is:
Analytical procedure. result: HPLC 01_B4_2 r.t.:10.96 minute, MALDI-TOF, (M
+) average quality: 5724Da
Embodiment 9
Preparation N
ε 26-(3-(mPEG yl) propionyl) [Arg
34] GLP-1-(7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa
By the not protected [Arg that expression in yeast is obtained
34] carry out acidylate in the solution of GLP-1-(7-37) and prepare this compound.[Arg34] GLP-1-(7-37) peptide (0.3g, 30% peptide content) is dissolved in contains DIEA (101 μ l, water 20e.q.); and (MW 2 for Shearwater Cat.no.2M4M0D01, mPEG-SPA with mPEG SPA2000; 000) (89mg, 1.5e.q.) acidylate 1 hour at room temperature.Use separates end product with the described similar operation step of embodiment 1.f. from this mixture.The output of title compound is 61mg, and the result that HPLC and Maldi TOF MS analyze is:
| Analytical procedure | The result |
| HPLC 02_B4_2 | R.t.:8.48 minute |
| MALDI-TOF | (M +) average quality: 5587.3Da |
Embodiment 10
(S)-N-((S)-5-(N-((S)-5-formamyl-5-(mPEG base propionyl amino) amyl group) formamyl)-5-(mPEG base propionyl amino) amyl group)-5-(N
α 7-(3-(4-imidazolyl) propionyl) [Aib
22,35, Arg
26,34] GLP-1-(8-37) y1)-2-(mPEG base propionyl amino) hexanoic acid amide, wherein the mPEG base is polymolecularity and molecular weight that have about 750Da
Use the synthetic complete protected peptide-based resin Boc-Lys of operation steps among the embodiment 1.a.; (Boc-Lys; (Boc-Lys; (ImPr; (Adoc)-Ala-Glu; (OtBu)-Gly-Thr; (tBu)-Phe-Thr; (tBu)-Ser; (tBu)-Asp; (OtBu)-Val-Ser; (tBu)-Ser; (tBu)-Tyr; (tBu)-Leu-Glu; (OtBu)-Aib-Gln; (Trt)-Ala-Ala-Arg; (Pmc)-Glu; (OtBu)-Phe-Ile-Ala-Trp; (Boc)-Leu-Val-Arg; (Pmc)-Aib-Arg; (Pmc))))-the Rink amide resins.ImPr (Adoc)-OH is used to introduce terminal 3-(4-imidazolyl) propionyl of N-, Boc-Lys (Fmoc)-OH is used for introducing the Lys residue that three side chains connect on this sequence C-end.
Use and the not protected accordingly peptide H-Lys of the described similar operation step of embodiment 1.e. cracking from resin (H-Lys (H-Lys (ImPr-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Aib-Gln-Ala-Ala-Arg-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Aib-Arg))) acid amides, and use and the described similar operation step of embodiment 1.f. purifying.
The characterization result of this intermediate peptide is:
| Analytical procedure | The result |
| HPLC A1 | R.t.:35.39 minute |
| HPLC B1 | R.t.:36.50 minute |
| LC-MS | R.t.3.85 minute.(M+3H+)/3 average quality: 1279.8 Da, (calculated value: 1279.8Da) |
With 3, the peptide of this purifying of 84mg is dissolved in 0,4ml NMP, and by at room temperature with 8mg (N-(2-mPEG base-ethyl-4-(2,5-dioxo-tetramethyleneimine-1-yl)-4-oxo-butyramide (α-methoxyl group-ω-NHS ester PEG, Rapp Polymere GmbH, T ü bingen, FRG, cat no.12750-35) and 7 μ l DIEA stir together and make its Pegylation.
The final use and the described similar operation step of embodiment 1.f. purifying title compound.The result who characterizes is:
| Analytical procedure | The result |
| HPLC A1 | R.t.:41.62 minute |
| HPLC B1 | R.t.:43.02 minute.Output 6.5mg. |
| LC-MS | The broad peak of locating at 4,24 minutes has the mass spectrum of the mass peak of squillion. |
| Maldi TOF MS | Mass spectrum has shown the peak group with 6000Da average quality.This result is consistent with the expected structure of target compound. |
Embodiment 11
Measure the method for lung's bioavailability
This programme has been described method and the material that is used to research and develop the aerocolloidal anesthetized rat model of pulmonary delivery.(the atomizer conduit of mass median aerodynamic diameter (mean mass aerodynamic diameter, MMAD)) produces aerosol to have droplet/granular size of fully determining by use.The atomizer conduit does not have the multi-cavity catheter of the aerocolloidal extruding of baffling for fine particle is provided.It has imported a plurality of (being generally 4-6) gas-chamber around a fluid chamber.Conduit is extended in each chamber, and this conduit is tapered to the thin (～0.5mm diameter) nozzle that has osculum on distal tip.Gas and tight the contact thin aerosol that produce no baffling of liquid between this point.Just be placed in the main bronchus branch by endotracheal intubation guiding atomizer conduit and with it.Aerosol gives with the pulse of being kept by control unit.
Equipment
The equipment that is used for pulmonary delivery available from Trudell Medical International (London, Ontario, Canada).
The atomizer conduit
The atomizer conduit (Aeroprobe ) of many not isostructures and length is provided by manufacturers.These different designs can adapt to different fluids and flow velocity and the aerosol particle size that can be low to moderate 5 μ mMMAD (mass median aerodynamic diameter) is provided.In this experiment, use the conduit with following size: the exocoel gas flow rate is 1.4L/ minute, and the intracavity liquid rate of flow of fluid is 0.7ml/ minute, and MMAD is about 7-8 μ m (PN 104504-050), and length is 50cm (1).
Control unit
LABNeb conduit Controlling System (CCS).The Aeroprobe conduit is connected with Controlling System according to (2).
The air that will have 100psi pressure is generally 98psi as carrier gas and maximum hydraulic pressure.100 μ l syringes are used as storage.LABNeb CCS uses the burst length of 80msec and the gas of 20msec to postpone.Therefore, in each pulse, send 2.3ml air and 0.93 μ l test soln.
Animal
Be weighed as the Sprague Dawley ♂ rat of 250-350g.Animal is shelved under the normalization condition that can freely get food (Altromine 1324) and drinking-water.On the same day of experiment, use the animal under the as fed.
Anesthesia solution
With sterilized water 1+1 dilution Hypnorm (fentanyl 0.2mg/ml, Fluanxol 10mg/ml).With sterilized water 1+1 dilution Dormicum (midazolam 5mg/ml).Two kinds of solution are mixed according to 1+1.
Administration in operation technique and the tracheae
Hyponorm/Dormicum solution 0.25ml/100g BW by the subcutaneous injection preparation brings out anesthesia.Insert endotracheal tube (PE 240, Becton Dickinson) and guide to the position of about 1/2cm in two main bronchus branches.By plastic material barrier around rat any thermosteresis is minimized.
Before test soln is used lung, it is enclosed in the syringe and conduit system that does not all contain bubble.Before in tracheae, using test soln, it is sprayed into bottle so that test the amount that gives by conduit subsequently.By the endotracheal intubation guide catheter, make catheter tip 1-2mm not have cannula distal end then, this test soln is atomized into the lung of anesthetized rat.
Sequence table
<110>Novo Nordisk A/S
＜120〉novel glp-1-1 compound
<130>6752
<140>6752.204-WO
<141>2004-12-16
<160>5
<170>PatentIn version 3.1
<210>1
<211>31
<212>PRT
＜213〉people (homo sapiens)
<400>1
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly
20 25 30
<210>2
<211>39
<212>PRT
<213>heloderma suspectum
<220>
<221>MOD_RES
<222>(39)..(39)
＜223〉amidation of carboxyl
<400>2
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210>3
<211>40
<212>PRT
＜213〉synthetic construct
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉the 1st Xaa is the L-Histidine; the D-Histidine, deaminizating Histidine, 2-amino-Histidine; the beta-hydroxy Histidine; high Histidine, N-α-ethanoyl Histidine, α-methyl fluoride-Histidine; Alpha-Methyl-Histidine; 3-pyridyl L-Ala, 2-pyridyl L-Ala, or 4-pyridyl L-Ala
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉the 2nd Xaa is Ala, D-Ala, Gly, Val, Leu, Ile, Lys, Aib, (the amino cyclopropyl of 1-) carboxylic acid, (the amino cyclobutyl of 1-) carboxylic acid, (1-amino cyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (the amino suberyl of 1-) carboxylic acid or (the amino ring of 1-octyl group) carboxylic acid.
<220>
<221>MISC_FEATURE
<222>(10)..(10)
＜223〉the 10th Xaa is Val or Leu
<220>
<221>MISC_FEATURE
<222>(12)..(12)
＜223〉the 12nd Xaa is Ser, Lys or Arg.
<220>
<221>MISC_FEATURE
<222>(13)..(13)
＜223〉the 13rd Xaa is Tyr or Gln.
<220>
<221>MISC_FEATURE
<222>(14)..(14)
＜223〉the 14th Xaa is Leu or Met.
<220>
<221>MISC_FEATURE
<222>(16)..(16)
＜223〉the 16th Xaa is Gly, Glu or Aib.
<220>
<221>MISC_FEATURE
<222>(17)..(17)
＜223〉the 17th Xaa is Gln, Glu, Lys or Arg.
<220>
<221>MISC_FEATURE
<222>(19)..(19)
＜223〉the 19th Xaa is Ala or Val.
<220>
<221>MISC_FEATURE
<222>(20)..(20)
＜223〉the 20th Xaa is Lys, Glu or Arg.
<220>
<221>MISC_FEATURE
<222>(21)..(21)
＜223〉the 21st Xaa is Glu or Leu.
<220>
<221>MISC_FEATURE
<222>(24)..(24)
＜223〉the 24th Xaa is Ala, Glu or Arg.
<220>
<221>MISC_FEATURE
<222>(27)..(27)
＜223〉the 27th Xaa is Val or Lys.
<220>
<221>MISC_FEATURE
<222>(28)..(28)
＜223〉the 28th Xaa is Lys, Glu, Asn or Arg.
<220>
<221>MISC_FEATURE
<222>(29)..(29)
＜223〉the 29th Xaa is Gly or Aib.
<220>
<221>MISC_FEATURE
<222>(30)..(30)
＜223〉the 30th Xaa is Arg, Gly or Lys.
<220>
<221>MISC_FEATURE
<222>(31)..(31)
＜223〉the 31st Xaa is Gly, Ala, Glu, Pro, Lys, acid amides or shortage
<220>
<221>MISC_FEATURE
<222>(32)..(32)
＜223〉the 32nd Xaa is Lys, Ser, acid amides or shortage
<220>
<221>MISC_FEATURE
<222>(33)..(33)
＜223〉the 33rd Xaa is Ser, Lys, acid amides or shortage.
<220>
<221>MISC_FEATURE
<222>(34)..(34)
＜223〉the 34th Xaa is Gly, acid amides or shortage.
<220>
<221>MISC_FEATURE
<222>(35)..(35)
＜223〉the 35th Xaa is Ala, acid amides or shortage.
<220>
<221>MISC_FEATURE
<222>(36)..(36)
＜223〉the 36th Xaa is Pro, acid amides or shortage.
<220>
<221>MISC_FEATURE
<222>(37)..(37)
＜223〉the 37th Xaa is Pro, acid amides or shortage.
<220>
<221>MISC_FEATURE
<222>(38)..(38)
＜223〉the 38th Xaa is Pro, acid amides or shortage.
<220>
<221>MISC_FEATURE
<222>(39)..(39)
＜223〉the 39th Xaa is Ser, acid amides or shortage.
<220>
<221>MISC_FEATURE
<222>(40)..(40)
＜223〉the 40th Xaa is acid amides or shortage.
<400>3
Xaa Xaa Glu Gly Thr Phe Thr Ser Asp Xaa Ser Xaa Xaa Xaa Glu Xaa
1 5 10 15
Xaa Ala Xaa Xaa Xaa Phe Ile Xaa Trp Leu Xaa Xaa Xaa Xaa Xaa Xaa
20 25 30
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
35 40
<210>4
<211>32
<212>PRT
＜213〉synthetic construct
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉the 1st Xaa is the L-Histidine; the D-Histidine, deaminizating Histidine, the amino Histidine of 2-; the beta-hydroxy Histidine; high Histidine, N-α-ethanoyl-Histidine, α-methyl fluoride-Histidine; Alpha-Methyl-Histidine; 3-pyridyl L-Ala, 2-pyridyl L-Ala, or 4-pyridyl L-Ala.
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉the 2nd Xaa is Ala, D-Ala, Gly, Val, Leu, Ile, Lys, Aib, (the amino cyclopropyl of 1-) carboxylic acid, (the amino cyclobutyl of 1-) carboxylic acid, (1-amino cyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (the amino suberyl of 1-) carboxylic acid or (the amino ring of 1-octyl group) carboxylic acid.
<220>
<221>MISC_FEATURE
<222>(12)..(12)
＜223〉the 12nd Xaa is Ser, Lys or Arg.
<220>
<221>MISV_FEATURE
<222>(16)..(16)
＜223〉the 16th Xaa is Gly, Glu or Aib.
<220>
<221>MISC_FEATURE
<222>(17)..(17)
＜223〉the 17th Xaa is Gln, Glu, Lys or Arg.
<220>
<221>MISC_FEATURE
<222>(20)..(20)
＜223〉the 20th Xaa is Lys, Glu or Arg.
<220>
<221>MISC_FEATURE
<222>(24)..(24)
＜223〉the 24th Xaa is Ala, Glu or Arg.
<220>
<221>MISC_FEATURE
<222>(28)..(28)
＜223〉the 28th Xaa is Lys, Glu or Arg.
<220>
<221>MISC_FEATURE
<222>(29)..(29)
＜223〉the 29th Xaa is Gly or Aib.
<220>
<221>MISC_FEATURE
<222>(30)..(30)
＜223〉the 30th Xaa is Arg or Lys.
<220>
<221>MISC_FEATURE
<222>(31)..(31)
＜223〉the 31st Xaa is Gly, Ala, Glu or Lys.
<220>
<221>MISC_FEATURE
<222>(32)..(32)
＜223〉the 32nd Xaa is Lys, acid amides or shortage.
<400>4
Xaa Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Xaa Tyr Leu Glu Xaa
1 5 10 15
Xaa Ala Ala Xaa Glu Phe Ile Xaa Trp Leu Val Xaa Xaa Xaa Xaa Xaa
20 25 30
<210>5
<211>44
<212>PRT
＜213〉synthetic construct
<220>
<221>MOD_RES
<222>(44)..(44)
＜223〉amidation of carboxyl
<400>5
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
35 40
Claims (70)
1. the compound that has general formula (I) structure:
Insulinotropic activity agent (Y-C
*)
f-Q (I)
Wherein
The insulinotropic activity agent be derive from the group of the insulinoptropic peptides of people GLP-1 receptors bind or derive from 22 positions in preceding 30 positions and those corresponding positions in GLP-1 on the group of the identical peptide of the residue found on the residue found or the corresponding position in Exendin-4, and
Y is for making C
*The divalence that is connected with the insulinotropic activity agent connects chemical group, and
C
*Separate chemical group for divalence polarity, wherein the heavy atom of 50-20% is O or N, and
F is 0 or 1, and
Q is selected from
-W-A ,-X-B-W-A,
With
Wherein
A is the polarity chemical group of single molecular size (monodispersity) or several molecule size (polymolecularity), wherein
The heavy atom of 50-20% is oxygen or nitrogen independently, and
W is the divalence chemical group of connection A, and
X connects chemical group for the divalence that connects B, and
B is for connecting or the branching chemical group.
2. the compound that has general formula (I) structure:
Insulinotropic activity agent (Y-C
*)
f-Q (I)
Wherein
The insulinotropic activity agent be derive from the group of the insulinoptropic peptides of people GLP-1 receptors bind or derive from 22 positions in preceding 30 positions and those corresponding positions in GLP-1 on the group of the identical peptide of the residue found on the residue found or the corresponding position in Exendin-4
Condition is that the C-terminal amino acid residue of described insulinotropic activity agent is not halfcystine, and
Y is for making C
*The divalence that is connected with the insulinotropic activity agent connects chemical group, and
C
*Separate chemical group for divalence polarity, wherein the heavy atom of 50-20% is O or N, and
F is 0 or 1, and
Q is selected from
-W-A ,-X-B-W-A,
With
Wherein
A is the polarity chemical group of single molecular size (monodispersity) or several molecule size (polymolecularity), wherein
The heavy atom of 50-20% is oxygen or nitrogen independently, and
W is the divalence chemical group of connection A, and
X connects chemical group for the divalence that connects B, and
B is for connecting or the branching chemical group.
3. any described compound among the claim 1-2, wherein A is for having structure-(CH
2)
lO[(CH
2)
nO]
m(CH
2)
pThe monodispersity of-H or polymolecularity chemical group, wherein l, n and p independently are the integer of 1-10, m be the integer of 1-5000 and wherein m multiply by n+1 less than 10000.
4. any described compound among the claim 1-2, wherein A is for having structure-(CH
2)
lC (=O) O[(CH
2)
nO]
m(CH
2)
pThe monodispersity of-H or polymolecularity chemical group, wherein l, n and p are the integer of 1-10 independently, m be the integer of 1-5000 and wherein m multiply by n+1 less than 10000.
5. any described compound among the claim 3-4, wherein n is 2 or 3.
6. any described compound among the claim 3-5, wherein m is 10-1000 or 20-250.
7. the described compound of claim 1, wherein A is for having structure-(Z
1(CH
2)
lO[(CH
2)
2O]
m(CH
2)
p-NR
1)
q-Z
2Monodispersity or polymolecularity chemical group, wherein Z
1For-CO-or-CO-(CH
2)
n-CO-NH-and Z
2For-R
1,-CO-(CH
2)
n-R
1,-(CH
2)
lO[(CH
2)
2O]
m(CH
2)
p-R
1, wherein l and n and p independently are the integer of 1-10, R
1For-OH ,-NH
2,-NH-R
2,-NH (R
2)-R
2,-COOH, C
1-6-alkyl or-NH-CH (R
2)-COOH, and wherein m and q are the integer of 1-20 independently, and wherein l, n and p are integer and the R of 1-6 independently
2Be hydrogen or C
1-6-alkyl.
8. any described compound during aforesaid right requires, wherein A is the mPEG base.
9. any described compound among the claim 1-7, wherein A be mPEG base-C (=O)-(CH
2)
r-, wherein r is the integer of 1-10.
10. any described compound during aforesaid right requires, wherein A is a monodispersity, promptly it only is made of a kind of composition.
Any described compound during 11. aforesaid right requires, wherein A be polymolecularity and preferably have less than 1.2, less than 1.1, less than 1.05, less than 1.03, less than 1.02, less than 1.010, less than 1.008, less than 1.005 or less than 1.0025 heterogeneity index.
Any described compound during 12. aforesaid right requires, wherein said branching chemical group B is selected from
-(CH
2)
c-(CH
2)
b-，
Wherein a, b, c, d, e, f, g, h, i are the integer that is independently selected from 0-24.
13. any described compound among the claim 1-11, wherein said branching group B is:
Wherein a, b, c are the integer that is independently selected from 0-24.
Any described compound during 14. aforesaid right requires, wherein said branching group B is selected from
-(CH
2)
c-(CH
2)
b-，
Wherein a, b, c, d, e, f, g, h, i are the integer that is independently selected from 0-24.
15. any described compound among the claim 12-14, wherein said insulinotropic activity agent is connected with B by the left hand of B is terminal.
16. any described compound among the claim 12-14, wherein a+b less than 6 or a+b+c less than 14 or a+b+c+d+e+f+g+h+i less than 16.
17. any described compound among the claim 12-16, wherein a be 0 or 1 and b, c, d, e, f, h and i all in the scope of 0-5.
18. any described compound among the claim 12-17, wherein a, c, d, e, g and i be 0 and b, f and h all in the scope of 1-4.
A described compound arbitrarily during 19. aforesaid right requires, wherein a, c, d, e, g and I be 0 and b, f and h all in the scope of 1-4.
Any described compound during 20. aforesaid right requires, wherein W is independently selected from divalence with X and is connected chemical group, and these groups comprise:
Amides :-C (O)-NR-, wherein R is hydrogen or C
1-6-alkyl;
Amine :-NR-, wherein R is hydrogen or C
1-6-alkyl;
Thioether class :-S-,-S-(CH
2)
2-SO
2-or
Ethers :-O-;
Urethanes :-N (R
1)-CO-N (R
2)-, be R wherein
1And R
2Independent is hydrogen or C
1-6-alkyl;
Amino formate :-O-CO-N (R)-, wherein R is hydrogen or C
1-6-alkyl;
The hydrazine class:
Wherein R is hydrogen or C
1-6-alkyl;
Oximes :-O-N=C (R)-, wherein R is hydrogen or C
1-6-alkyl;
azoles alkanes or thiazolidines:
With
21. the described compound of claim 20, wherein W is :-C (O)-NR-, wherein R is hydrogen or C
1-6-alkyl.
22. the described compound of claim 21, wherein said insulinotropic activity agent is connected with W by the left hand end (carbon) of W.
23. the described compound of claim 21, wherein said insulinotropic activity agent is connected with W by the right hand extreme (nitrogen) of W.
Any described compound during 24. aforesaid right requires, wherein f is 0.
25. any described compound, wherein a C among the claim 1-23
*For-(CH
2)
N1O[(CH
2)
N2O]
N3(CH
2)
N4-, wherein n1, n2 and n4 independently are the integer of 1-10, n3 is the integer of 1-5000, and wherein n3 multiply by n2+1 less than 10000.
26. the described compound of claim 25, wherein n2 is 2 or 3.
27. any described compound among the claim 25-26, wherein n3 is 1-20.
28. any described compound, wherein a C among the claim 1-20
*For-(CH
2)
N5-, wherein n5 is the integer of 1-10.
29. any described compound among the claim 1-20, wherein Y is selected from divalence connection chemical group, and these groups comprise:
Amides :-C (O)-NR-, wherein R is hydrogen or C
1-6-alkyl;
Amine :-NR-, wherein R is hydrogen or C
1-6-alkyl;
Thioether class :-S-,-S-(CH
2)
2-SO
2-or
Ethers :-O-;
Urethanes :-N (R
1)-CO-N (R
2)-, be R wherein
1And R
2Be hydrogen or C independently
1-6-alkyl;
Amino formate :-O-CO-N (R)-, wherein R is hydrogen or C
1-6-alkyl;
The hydrazine class:
Wherein R is hydrogen or C
1-6-alkyl;
Oximes :-O-N=C (R)-, wherein R is hydrogen or C
1-6-alkyl;
azoles alkanes or thiazolidines:
With
Any described compound during 30. aforesaid right requires, wherein said insulinotropic activity agent is the protected peptide of DPPIV.
Any described compound during 31. aforesaid right requires, wherein as what measured by the functional receptor test of this paper disclosure, described insulinotropic activity agent has the EC less than 1nM
50
32. a described compound arbitrarily during aforesaid right requires wherein as by the functional receptor test that this paper discloses is measured, described insulinotropic activity agent has less than 300pM, less than 200pM or less than the EC of 100pM
50
Any described compound during 33. aforesaid right requires, wherein said insulinotropic activity agent derives from the peptide with 27-45 amino-acid residue length, in wherein preceding 28 amino-acid residues 22 with corresponding position in GLP-1 (7-37) (SEQ ID No.1) on find or corresponding position in Exendin-4 (1-39) (SEQ ID No.2) on those residues of finding identical.
Any described compound during 34. aforesaid right requires, wherein said insulinotropic activity agent derives from the peptide with 28-45 amino-acid residue length, and in wherein preceding 28 amino-acid residues 22 identical with those residues of finding on the corresponding position that find or in Exendin-4 (1-39) on the corresponding position in GLP-1 (7-37).
Any described compound during 35. aforesaid right requires, wherein said insulinotropic activity agent is selected from the peptide of the aminoacid sequence that comprises general formula (II):
Xaa7-Xaa8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa
16-Ser-Xaa
18-Xaa
19-Xaa
20-Glu-Xaa
22-Xaa
23-Ala-Xaa
25-Xaa
26-Xaa
27-Phe-Ile-Xaa
30-Trp-Leu-Xaa
33-Xaa
34-Xaa
35-Xaa
36-Xaa
37-Xaa
38-Xaa
39-Xaa
40-Xaa
41-Xaa
42-Xaa
43-Xaa
44-Xaa
45-Xaa
46
General formula (II) (SEQ ID No:3)
Wherein
Xaa
7Be L-Histidine, D-Histidine, deaminizating-Histidine, 2-amino-Histidine, beta-hydroxy-Histidine, high Histidine, N
α-ethanoyl-Histidine, α-methyl fluoride-Histidine, Alpha-Methyl-Histidine, 3-pyridyl L-Ala, 2-pyridyl L-Ala or 4-pyridyl L-Ala;
Xaa
8Be Ala, D-Ala, Gly, Val, Leu, Ile, Lys, Aib, (the amino cyclopropyl of 1-) carboxylic acid, (the amino cyclobutyl of 1-) carboxylic acid, (1-amino cyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (the amino suberyl of 1-) carboxylic acid or (the amino ring of 1-octyl group) carboxylic acid;
Xaa
16Be Val or Leu;
Xaa
18Be Ser, Lys or Arg;
Xaa
19Be Tyr or Gln;
Xaa
20Be Leu or Met;
Xaa
22Be Gly, Glu or Aib;
Xaa
23Be Gln, Glu, Lys or Arg;
Xaa
25Be Ala or Val;
Xaa
26Be Lys, Glu or Arg;
Xaa
27Be Glu or Leu;
Xaa
30Be Ala, Glu or Arg;
Xaa
33Be Val or Lys;
Xaa
34Be Lys, Glu, Asn or Arg;
Xaa
35Be Gly or Aib;
Xaa
36Be Arg, Gly or Lys;
Xaa
37Be Gly, Ala, Glu, Pro, Lys, acid amides or do not exist;
Xaa
38For Lys, Ser, acid amides or do not exist.
Xaa
39For Ser, Lys, acid amides or do not exist;
Xaa
40For Gly, acid amides or do not exist;
Xaa
41For Ala, acid amides or do not exist;
Xaa
42For Pro, acid amides or do not exist;
Xaa
43For Pro, acid amides or do not exist;
Xaa
44For Pro, acid amides or do not exist;
Xaa
45For Ser, acid amides or do not exist;
Xaa
46For acid amides or do not exist;
Condition is if Xaa
38, Xaa
39, Xaa
40, Xaa
41, Xaa
42, Xaa
43, Xaa
44, Xaa
45Or Xaa
46Do not exist, each amino-acid residue in downstream does not exist yet so.
36. any described compound among the claim 1-34, wherein said insulinotropic activity agent are the peptide that comprises the aminoacid sequence of general formula (III):
Xaa
7-Xaa
8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Xaa
18-Tyr-Leu-Glu-Xaa
22-Xaa
23-Ala-Ala-Xaa
26-Glu-Phe-Ile-Xaa
30-Trp-Leu-Val-Xaa
34-Xaa
35-Xaa
36-Xaa
37-Xaa
38
General formula (III) (SEQ ID No:4)
Wherein
Xaa
7Be L-Histidine, D-Histidine, deaminizating-Histidine, 2-amino-Histidine, beta-hydroxy-Histidine, high Histidine, N α-ethanoyl-Histidine, α-methyl fluoride-Histidine, Alpha-Methyl-Histidine, 3-pyridyl L-Ala, 2-pyridyl L-Ala or 4-pyridyl L-Ala;
Xaa
8Be Ala, D-Ala, Gly, Val, Leu, Ile, Lys, Aib, (the amino cyclopropyl of 1-) carboxylic acid, (the amino cyclobutyl of 1-) carboxylic acid, (1-amino cyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (the amino suberyl of 1-) carboxylic acid or (the amino ring of 1-octyl group) carboxylic acid;
Xaa
18Be Ser, Lys or Arg;
Xaa
22Be Gly, Glu or Aib;
Xaa
23Be Gln, Glu, Lys or Arg;
Xaa
26Be Lys, Glu or Arg;
Xaa
30Be Ala, Glu or Arg;
Xaa
34Be Lys, Glu or Arg;
Xaa
35Be Gly or Aib;
Xaa
36Be Arg or Lys;
Xaa
37Be Gly, Ala, Glu or Lys;
Xaa
38Be Lys, NH
2Or do not exist.
37. any described compound among the claim 1-36, wherein said insulinotropic activity agent is selected from GLP-1 (7-35), GLP-1 (7-36), GLP-1 (7-36)-acid amides, GLP-1 (7-37), GLP-1 (7-38), GLP-1 (7-39), GLP-1 (7-40), GLP-1 (7-41) or its analogue.
Any described compound during 38. aforesaid right requires, wherein said insulinotropic activity agent compared with GLP-1 (7-37) (SEQ ID No.1) be no more than 15 amino-acid residues by exchange, add or disappearance, or compared with GLP-1 (7-37) (SEQ ID No.1) be no more than 10 amino-acid residues by exchange, add or disappearance.
39. having compared with GLP-1 (7-37) (SEQ ID No.1), the described compound of claim 38, wherein said insulinotropic activity agent be no more than 6 amino-acid residues by exchange, interpolation or disappearance.
40. any described compound during aforesaid right requires, wherein said insulinotropic activity agent comprise and are no more than 4 and can't help genetic code amino acids coding residue.
41. any described compound during aforesaid right requires, wherein said insulinotropic activity agent comprise the Aib residue as counting second amino-acid residue from the N-end.
Any described compound during 42. aforesaid right requires, the-terminal amino acid residue of wherein said insulinotropic activity agent (general formula I I and III 7) is selected from D-Histidine, deaminizating-Histidine, 2-amino-Histidine, beta-hydroxy-Histidine, high Histidine, N
αThe group that-ethanoyl-Histidine, α-methyl fluoride-Histidine, Alpha-Methyl-Histidine, 3-pyridyl L-Ala, 2-pyridyl L-Ala and 4-pyridyl L-Ala are formed.
Any described compound during 43. aforesaid right requires, wherein said insulinotropic activity agent is selected from [Arg
34] GLP-1 (7-37), [Arg
26,34] GLP-1 (7-37) Lys, [Lys
36Arg
26,34] GLP-1 (7-36), [Aib
8,22,35] GLP-1 (7-37), [Aib
8,35] GLP-1 (7-37), [Aib
8,22] GLP-1 (7-37), [Aib
8,22,35Arg
26,34] GLP-1 (7-37) Lys, [Aib
8,35Arg
26,34] GLP-1 (7-37) Lys, [Aib
8,22Arg
26,34] GLP-1 (7-37) Lys, [Aib
8,22,35Arg
26,34] GLP-1 (7-37) Lys, [Aib
8,35Arg
26,34] GLP-1 (7-37) Lys, [Aib
8,22,35Arg
26] GLP-1 (7-37) Lys, [Aib
8,35Arg
26] GLP-1 (7-37) Lys, [Aib
8,22Arg
26] GLP-1 (7-37) Lys, [Aib
8,22,35Arg
34] GLP-1 (7-37) Lys, [Aib
8,35Arg
34] GLP-1 (7-37) Lys, [Aib
8,22Arg
34] GLP-1 (7-37) Lys, [Aib
8,22,35Ala
37] GLP-1 (7-37) Lys, [Aib
8,35Ala
37] GLP-1 (7-37) Lys, [Aib
8,22Ala
37] GLP-1 (7-37) Lys, [Aib
8,22,35Lys
37] GLP-1 (7-37), [Aib
8,35Lys
37] GLP-1 (7-37), [Aib
8,22Lys
37] GLP-1 (7-37)
Or its group of on the C-end, having been formed by amidated derivative.
Any described compound during 44. aforesaid right requires, wherein said insulinotropic activity agent comprises at least one Aib residue.
Any described compound during 45. aforesaid right requires, wherein said insulinotropic activity agent contains two Aib residues.
Any described compound during 46. aforesaid right requires, wherein said insulinotropic activity agent and comprises serine residue on for Exendin-4 (1-39) the 12nd on the 18th for GLP-1 (7-37) (SEQ ID.No.1).
Any described compound during 47. aforesaid right requires, wherein said insulinotropic activity agent and comprises tyrosine residues on for Exendin-4 (1-39) the 13rd on the 19th for GLP-1 (7-37) (SEQ ID.No.1).
Any described compound during 48. aforesaid right requires, wherein said insulinotropic activity agent and comprises glycine residue on for Exendin-4 (1-39) the 16th on the 22nd for GLP-1 (7-37) (SEQ ID.No.1).
Any described compound during 49. aforesaid right requires, wherein said insulinotropic activity agent and comprises glutamine residue on for Exendin-4 (1-39) the 17th on the 23rd for GLP-1 (7-37) (SEQ ID.No.1).
Any described compound during 50. aforesaid right requires, wherein said insulinotropic activity agent and comprises lysine residue on for Exendin-4 (1-39) the 20th on the 26th for GLP-1 (7-37) (SEQ ID.No.1).
Any described compound during 51. aforesaid right requires, wherein said insulinotropic activity agent and comprises glutaminic acid residue on for Exendin-4 (1-39) the 21st on the 27th for GLP-1 (7-37) (SEQ ID.No.1).
Any described compound during 52. aforesaid right requires, wherein said insulinotropic activity agent is exendin-4 (1-39).
Any described compound during 53. aforesaid right requires, wherein said insulinotropic activity agent is ZP-10, i.e. [Ser
38Lys
39] Exendin-4 (1-39) LysLysLysLysLys-acid amides (SEQ ID No.5).
Any described compound during 54. aforesaid right requires, wherein said insulinotropic activity agent is by amino-acid residue and Y-C on the 25-45 position for aminoacid sequence SEQ ID No:1
*-Q or Q connect.
Any described compound during 55. aforesaid right requires, amino-acid residue and the Y-C of wherein said insulinotropic activity agent by being selected from one of 10 C-terminal amino acid residues
*-Q or Q connect.
Any described compound during 56. aforesaid right requires, wherein said insulinotropic activity agent is by amino-acid residue and Y-C on the 23rd, 26,34,36 or 38 for aminoacid sequence SEQ ID No:1
*-Q or Q connect.
57. any described compound among the claim 1-53, wherein said insulinotropic activity agent is by amino-acid residue and Y-C on the 17th, 20,28,30 or 32 for aminoacid sequence SEQ ID No:2
*-Q or Q connect.
58. any described compound among the claim 1-55, wherein said insulinotropic activity agent is by C-terminal amino acid residue and Y-C
*-Q or Q connect.
Any described compound during 59. aforesaid right requires, wherein said insulinotropic activity agent is by carboxyl, amino, ketone group, hydroxyl, sulfydryl or hydrazide group and Y-C
*-Q or Q connect.
Any described compound during 60. aforesaid right requires, wherein said insulinotropic activity agent is by on the lysine residue
ε-amino and Y-C
*-Q or Q connect.
61. the described compound of claim 60, wherein said insulinotropic activity agent only comprises a lysine residue.
62. the described compound of claim 61, wherein said lysine residue are the C-terminal amino acid residue of described insulinotropic activity agent.
Any described compound during 63. aforesaid right requires, wherein as what measured by the functional receptor test of this paper disclosure, described compound has less than 1000pM, less than 500pM, less than 300pM, less than 200pM, less than 100pM, less than 50pM or less than the EC of 10pM
50
64. any described compound during aforesaid right requires, wherein said compound are selected from the group that following compounds is formed:
N
ε 37-((2S)-2,6-two-(mPEG base carbonylamino) caproyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 20kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37), wherein the mPEG base is polymolecularity and molecular weight that have about 5kDa;
N
ε 37-(3-(mPEG yl) propionyl) [Aib
8,22,35, Lys
37] GLP-1 (7-37) acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
ε 26-(3-(mPEG yl) propionyl) [Aib
8, Glu
22,30, Lys
33, Asn
34, Gly
35,36, Pro
37] GLP-1 (7-37) ylSerSerGly AlaProProProSer acid amides, wherein the mPEG base is polymolecularity and molecular weight that have about 2kDa;
N
α-[Aib
8,22,35] GLP-1-(7-37) base (N
ε-(3-(mPEG yl) propionyl) lysyl amine), wherein the mPEG base is polymolecularity and molecular weight that have about 750Da;
N
ε-[Aib
8,22,35] GLP-1 (7-37) base (S
ε-(1-mPEG base propyl group-2,5-dioxo-tetramethyleneimine-3-yl) cysteinyl amine, wherein the mPEG base is polymolecularity and molecular weight that have about 5000Da;
N
α-(3-(3H-imidazol-4 yl)-propionyl [Aib
22,35, Arg
26,34] GLP-1-(8-37)) base (N
ε-(3-(mPEG yl) propionyl) lysyl amine), wherein the mPEG base is polymolecularity and molecular weight that have about 2000Da;
N
ε 26-(3-(mPEG yl) propionyl) [Arg
34] GLP-1-(7-37), wherein the mPG base is polymolecularity and molecular weight that have about 2kDa; With
(S)-N-((S)-5-(N-((S)-5-formamyl-5-(mPEG base propionyl amino) amyl group) formamyl)-5-(mPEG base propionyl amino) amyl group)-5-(N
α 7-(3-(4-imidazolyl) propionyl) [Aib
22,35, Arg
26,34] GLP-1-(8-37) base)-2-(mPEG base propionyl amino) hexanoic acid amide, wherein the mPEG base is polymolecularity and molecular weight that have about 750Da.
65. pharmaceutical composition wherein comprises compound any among the claim 1-64 and pharmaceutically acceptable vehicle.
66. the described pharmaceutical composition of claim 65, it is suitable for pulmonary administration.
67. any one compound application in preparation pulmonary drug thing among the claim 1-64.
68. any one compound is used for the treatment of or prevents application in the medicine of following disease in preparation among the claim 1-64: hyperglycemia, diabetes B, glucose tolerance reduction, type 1 diabetes, obesity, hypertension, X syndrome, dyslipidemia, cognitive disorder, atherosclerosis, myocardial infarction, coronary heart disease and other cardiovascular disorder, apoplexy, inflammatory bowel syndrome, maldigestion and stomach ulcer.
69. any one compound is used for delaying or prevents application in the medicine of disease progression of diabetes B in preparation among the claim 1-64.
70. the apoptosis that any one compound is used for reducing ingestion of food, reduce beta cell in preparation among the claim 1-64, increase beta cell function and beta cell group and/or recover application to the medicine of the glucose-sensitive of beta cell.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200301885 | 2003-12-18 | ||
| DKPA200301885 | 2003-12-18 | ||
| DKPA200401090 | 2004-07-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1918177A true CN1918177A (en) | 2007-02-21 |
Family
ID=37738656
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004800417090A Pending CN1918177A (en) | 2003-12-18 | 2004-12-17 | Novel glp-1 compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1918177A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101903400A (en) * | 2007-12-11 | 2010-12-01 | 霍夫曼-拉罗奇有限公司 | Insulinotropic peptide synthesis using solid and solution phase combination techniques |
| CN102414220A (en) * | 2009-05-01 | 2012-04-11 | 霍夫曼-拉罗奇有限公司 | Insulinotropic peptide synthesis using solid and solution phase combination techniques |
| CN101444618B (en) * | 2007-11-26 | 2012-06-13 | 杭州九源基因工程有限公司 | Pharmaceutical preparation containing exenatide |
| CN103709243A (en) * | 2013-09-10 | 2014-04-09 | 深圳翰宇药业股份有限公司 | Lixisenatide preparation method |
| WO2020087305A1 (en) * | 2018-10-30 | 2020-05-07 | 刘建宁 | Glp-1 polypeptide having glp-1 receptor agonist activity and uses thereof |
-
2004
- 2004-12-17 CN CNA2004800417090A patent/CN1918177A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101444618B (en) * | 2007-11-26 | 2012-06-13 | 杭州九源基因工程有限公司 | Pharmaceutical preparation containing exenatide |
| CN101903400A (en) * | 2007-12-11 | 2010-12-01 | 霍夫曼-拉罗奇有限公司 | Insulinotropic peptide synthesis using solid and solution phase combination techniques |
| CN101903400B (en) * | 2007-12-11 | 2013-12-18 | 霍夫曼-拉罗奇有限公司 | Insulinotropic peptide synthesis using solid and solution phase combination techniques |
| CN102414220A (en) * | 2009-05-01 | 2012-04-11 | 霍夫曼-拉罗奇有限公司 | Insulinotropic peptide synthesis using solid and solution phase combination techniques |
| CN103709243A (en) * | 2013-09-10 | 2014-04-09 | 深圳翰宇药业股份有限公司 | Lixisenatide preparation method |
| CN103709243B (en) * | 2013-09-10 | 2018-08-21 | 深圳翰宇药业股份有限公司 | A method of preparing lixisenatide |
| WO2020087305A1 (en) * | 2018-10-30 | 2020-05-07 | 刘建宁 | Glp-1 polypeptide having glp-1 receptor agonist activity and uses thereof |
| US11141464B2 (en) | 2018-10-30 | 2021-10-12 | Liu Jianning | GLP-1 polypeptide having GLP-1 receptor agonist activity and use thereof |
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