CN102229668A - GLP-1 (glucagon-like peptide-1) derivative and application thereof - Google Patents
GLP-1 (glucagon-like peptide-1) derivative and application thereof Download PDFInfo
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Abstract
The invention relates to a glucagon-like peptide-1 and an application thereof. The structure of a GLP-1 derivative is shown as a formula. The invention also relates to an officinal salt, a solvate, a chelate or a non-covalent compound, a prodrug based on the compound, or a mixture thereof, which are composed of the compound shown by the formula. The compound provided by the invention has stable chemical property and is difficult to be degraded by interior dipeptidyl peptidase IV (DPP-IV). When the compound or a drug, which is prepared by taking the compound as active ingredient, is used for reducing the interior blood sugar concentration, a plasma half-life is very long (more than 30 hours) and a sugar-reducing effect is obvious. In the formula, Aib is methylalanine and X is selected from glycine or glycinamide.
Description
Technical field
The present invention relates to the derivative and the application thereof of a kind of glucagon-like-peptide-1 (GLP-1).
Background technology
Diabetes have become the Non Communicable Diseases (NCD) that is number three after cardiovascular and cerebrovascular diseases and tumour, The World Health Organization's prediction: the year two thousand thirty whole world diabetic subject will wherein be type ii diabetes more than 90% above 3.6 hundred million.Type ii diabetes is meant grow up morbidity or non insulin dependent diabetes, is a kind of common disease, and global sickness rate raises year by year.In existing Remedies for diabetes and the scheme, hypoglycemia is the problem that people worry always.In order to overcome this problem, in recent years, glucagon kind polypeptide-1 (
Glucagon-like peptide-1, being called for short GLP-1) and the correlative study progress is rapidly.GLP-1 is a kind of pancreatotrophin by enteron aisle L emiocytosis, have the release that promotes insulin secretion, glucagon suppression, stimulate B cell propagation, induce B cell regeneration, stop the B cell apoptosis, improve insulin sensitivity and increase the effects such as utilization of glucose, in the generation of type ii diabetes, development, play an important role.The type ii diabetes patient, its " secretin's effect " is impaired, mainly showing as the back GLP-1 concentration rising amplitude of having meal reduces to some extent than the normal people, but it is obviously impaired that it promotes that insulin secretion and hypoglycemic effect there is no, so GLP-1 and analogue thereof can be used as an important target spot of type ii diabetes treatment.GLP-1 is as a kind of intestines source sex hormone, particularly just be released into blood under the stimulation of carbohydrate at nutritive substance, its promoting insulin secretion is the glucose concn dependency, promptly only under the situation that glucose level raises, GLP-1 just brings into play blood sugar reducing function, and in glucose level just often, then can not make its further reduction.This glucose concn dependency hypoglycemic characteristic of GLP-1 is the basis and the guarantee of its clinical application security, may cause patient's severe hypoglycaemia to worry thereby exempted people to existing Remedies for diabetes and scheme, in the treating diabetes field, have broad application prospects.
Yet, GLP-1 is applied to the clinical huge problem that also is faced with, the GLP-1 that human body self produces is very unstable, very easily degraded by intravital DPP IV (DPP-IV), only be 1～2min its plasma half-life, promptly must continue intravenous drip or lasting subcutaneous injection could produce curative effect, this has limited the clinical application of GLP-1 greatly.
Summary of the invention
The purpose of this invention is to provide a kind of glucagon-like peptide-1 derivatives and application thereof.
For achieving the above object, the present invention at first provides the compound shown in a kind of structure I, pharmaceutically useful salt, solvate, inner complex or non-covalent complex that this compound became, based on the prodrug on this compound basis, or any mixture of above-mentioned form.
Structural formula I
Among the structural formula I, Aib is a methylalanine, and X is selected from glycine or G-NH2.
The present invention also provides a kind of pharmaceutical composition, and this pharmaceutical composition comprises the above-claimed cpd and at least a pharmaceutically useful auxiliary material of at least a effective therapeutic dose.
The present invention further provides the application of aforementioned pharmaceutical compositions in pharmacy.
As preferably, the application of described pharmaceutical composition in the medicine of the following at least a disease of preparation treatment, described disease comprise that type ii diabetes, sugar tolerance are impaired, type i diabetes, obesity, hypertension, metabolism syndrome, hyperlipemia, cognitive disorder, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disorder, apoplexy, the inflammatory bowel trace integration is levied and/or maldigestion or stomach ulcer.
As preferably, the application of described pharmaceutical composition in the medicine that preparation treatment type ii diabetes drug efficacy delay and/or prevention type ii diabetes worsen.
As preferably, described pharmaceutical composition reduces food intake in preparation, reduces the β apoptosis, increases the beta Cell of islet function, increases beta cell group and/or recovers glucose to the application in the medicine of the susceptibility of beta cell.
The present invention provides also that described compound is used to prepare that treatment comprises that type ii diabetes, sugar tolerance are impaired, type i diabetes, obesity, hypertension, metabolism syndrome, hyperlipemia, cognitive disorder, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disorder, apoplexy, inflammatory bowel trace integration are levied, the application of the medicine of maldigestion and/or stomach ulcer.
As preferably, described compound is used for preparing the application of the medicine that treatment type ii diabetes drug efficacy delay and/or prevention type ii diabetes worsen.
As preferably, described compound is used for preparing treatment and reduces food intake, reduces the β apoptosis, increases the beta Cell of islet function, increases beta cell group and/or recover the application of glucose to the medicine of the susceptibility of beta cell.
The present invention also further provides treatment target has been used the method for described compound with blood sugar in the control agent.
Involved in the present invention to more contents have a detailed description following, perhaps some also can be known from experience in an embodiment of the present invention.
Unless refer else, be used for representing quantity, the reaction conditions of heterogeneity herein, all can be read as " roughly ", " about " meaning in any case.Accordingly, except that clear and definite refering in particular to arranged, the digital parameters of being quoted in following and claim all was a parameter roughly, under experiment condition separately because the difference of standard error might obtain different digital parameters.
Herein, when the chemical structural formula of a compound with chemical name is disagreed or during doubt, definitely define this compound with chemical structural formula.Compound described herein might contain one or more chiral centres, and/or the structure of two keys and the like, also may there be steric isomer, comprises isomer (such as geometrical isomer), enantiomers or the diastereomer of two keys.Accordingly, any chemical structure in this paper describes scope, no matter be to contain above-mentioned similar structures in a part or whole part structure, the all possible enantiomer and the diastereomer that have all comprised this compound have wherein also comprised any one mixtures of any simple steric isomer (as simple geometrical isomer, simple enantiomer or simple diastereomer) and these isomer.The mixture of these racemization isomer and steric isomer utilizes different isolation technique or chiral molecules synthetic method also can further be split into the enantiomer or the steric isomer of its moiety by those skilled in the art.
Compound in structural formula I has comprised, but is not limited in, the optical isomer of these compounds, raceme and/or other mixture.Under the above-mentioned situation, wherein single enantiomer or diastereomer if any the isomer of optically-active, can obtain with the method for asymmetric synthesis or the method for mesotomy.The available diverse ways of the fractionation of raceme is realized, helps the reagent recrystallization of fractionation as the usefulness of routine, or uses chromatographic process, as using chirality high pressure liquid chromatography (HPLC).In addition, compound in structural formula I has also comprised the cis of the two keys of band and/or trans isomer.In the compound shown in the structural formula I, have tautomer (tautomers), the present invention also comprised all tautomers (tautomeric forms) of these compounds.
Compound described in the invention has comprised, but is not limited in, the compound shown in the structural formula I and they all in that pharmaceutically available is multi-form.The pharmaceutically available of these compounds is multi-form to comprise that various pharmaceutically useful salt, solvate, crystal formation comprise multiple crystal formation and complex compound, inner complex, non-covalent mixture and based on any mixture of the prodrug on the above-mentioned substance basis and above-described these forms.In some enforcement of the present invention, compound described in the invention exists with the form of pharmaceutically useful salt." compound " this term has not only comprised compound itself herein, also comprised pharmaceutically useful salt that it became, solvate, inner complex, non-covalent mixture, based on any mixture of the prodrug on the above-claimed cpd basis and above-described these forms.
As above, prodrug is also contained in the scope of described compound, for example, and the ester of the compound shown in the structural formula I or amide derivatives.Term " prodrug " has comprised the compound that can be converted into compound shown in the structural formula I arbitrarily in human body or in the animal body, is converted into compound shown in the structural formula I as the metabolic processes by prodrug.The example of prodrug includes but not limited to, acetyl derivative, formyl derivative, benzoyl derivative and other like derivatives of difference in functionality group (as alcohol or amino group) on the compound shown in the structural formula I.
Compound chemistry stable in properties shown in the structural formula I provided by the invention, be difficult for being degraded by intravital DPP IV (DPP-IV), reach more than 30 hours its plasma half-life, must continue the defective that intravenous drip or lasting subcutaneous injection could produce curative effect thereby overcome GLP-1.In addition, when the compound shown in the structural formula I provided by the invention or this compound were used to reduce in the body blood sugar concentration as the medicine of effective ingredient preparation, existing very long plasma half-life, (more than 30 hours) had significant hypoglycemic effect again.
Embodiment
The present invention is with including, but are not limited to following examples, and following embodiment only is used for further setting forth the preparation method of compound in structural formula I described in the invention.
Following embodiment only is used to illustrate the specific embodiment of the present invention, enabling those skilled in the art to implement the present invention, but is not used in restriction protection scope of the present invention.In the specific embodiment of the present invention, technique means that is not specifically noted or method etc. are the routine techniques means in present technique field or method etc.
Compound shown in the embodiment 1 preparation structural formula I
I, synthetic intermediate (being called Dimer)
The structure of Dimer is as follows:
Concrete synthetic method is as follows:
1. the preparation of compound 01HCl
Below-10 ℃ the 80ml thionyl chloride is dropped in the 250ml methyl alcohol, in 2 hours, dropwise, stirring at room 1 hour.Add L-L-Ala 40g, stirring is spent the night.Then, temperature rising reflux is 4 hours.After the cooling, decompression removes solvent to constant weight, gets crude product 80g compound 01HCl.
2. the preparation of compound 02
40g compound 01HCl is dissolved in 350mlDMF, adds the 113g cylite, under agitation adds the 150g Anhydrous potassium carbonate, stirs after 2 hours in 50 ℃ of insulation reaction 2 hours.Then, reaction solution is with 1200ml water and 400ml ethyl acetate extraction, and separatory, ester layer are with 150ml 6NHCl extraction, and water is neutralized to pH=8 with sodium bicarbonate, uses ethyl acetate extraction again, dry rear pillar separate 57.6g compound 02.
3. the preparation of compound 03
11.7g tetrahydrochysene lithium aluminium is dispersed in the 200ml ether, 0 ℃ drips 02 diethyl ether solution (57.6g/100ml) down, dropwised in 1 hour.Then in 30 ℃ of insulation reaction 0.5 hour.Then, 0 ℃ drips 18g water down, dropwised in 1 hour.Stirred then 1 hour, and filtered, with ethyl acetate rinse filter cake.After filtrate decompression removes solvent, get 36g compound 03 with the sherwood oil crystallization
4. the preparation of compound 05
Carry out following operation below-65 ℃: the 7.6g oxalyl chloride is dissolved in the 150ml methylene dichloride, and the 50ml dichloromethane solution of 9.6g methyl-sulphoxide is added drop-wise to reaction solution, about 0.5 hour of dropping time, stirs then 0.5 hour; Dripped the 100ml dichloromethane solution of 11g compound 03, stirred 1 hour in 1 hour; Drip the 14g triethylamine, dropwised in 1 hour, stirring reaction is 2 hours then.Rise to room temperature, add 50ml water, separatory is with 50ml dichloromethane extraction water.Organic phase is spent the night with anhydrous magnesium sulfate drying after washing respectively with 100ml saturated sodium bicarbonate and 100ml saturated sodium-chloride.Then, remove solvent to constant weight and get 11.7g compound 04.Compound 04 adds the 150mlTHF dissolving, cools to 0 ℃, adds the THF solution (1mol/l) of 2.5mlTBAF, drips the THF solution (9g/50ml) of TMSCF3 again, stirring reaction 15 minutes.Add 35ml concentrated hydrochloric acid (36%) then, stirring reaction 30 minutes.Add water and ethyl acetate then, be neutralized to pH=8 with sodium bicarbonate after, separatory removes solvent after the drying, silicagel column separate compound 05:9.0g.
5. the preparation of compound 06A
17.6g compound 06A0H
2O (commercially available) is dissolved among the 200mlDMF, adds 24g cylite and 36g sodium bicarbonate then, and stirring is spent the night.Add 1200ml water and 400ml ethyl acetate, the separatory after drying, remove the solvent rear pillar separate compound 06A1.Behind 75ml piperidines and the 350ml ethyl acetate mixing, add compound 06A1, stir down in 25 ℃ of reactions 2 hours, remove the solvent rear pillar separate 10g compound 06A, its synthetic route is as follows:
6. the preparation of compound 07
2g compound 05 is dissolved among the 30mlTHF with 0.2gTBAB, is cooled to 0 ℃, adds sodium hydroxide solution (5g/30ml), adds the 2.5g Tosyl chloride again, stirring reaction 30 minutes.Add water and ethyl acetate then, behind the separatory, remove solvent and get 2.7g compound 06.2.7g refluxing, compound 06,3.3g compound 06A and 20ml acetonitrile spend the night.Steam acetonitrile, the residue Petroleum ether extraction, filtrate concentrate rear pillar separate 1.8g 07
7. the preparation of compound 08
1.8g compound 07 is dissolved in 400ml methyl alcohol, adds 0.3g Pd (OH)
2/ C hydrogenolysis is spent the night.Leach catalyzer, steam methyl alcohol and get 0.9g compound 08.
8.Dimer preparation
0.9g compound 08 and 0.9gFmocCl are dispersed in the 40ml dioxane, stirring is spent the night.Leach the solid of generation, after washing with dioxane and sherwood oil respectively, get product Dimer 0.59g.
1HNMR(DMSO-d
6)δ1.04(d，3H)，1.38(s，9H)，1.50-1.91(m，2H)，2.21-2.30(m，2H)，3.06-3.08(m，1H)，3.30-3.37(m，1H)，4.26-4.38(m，4H)，7.32-7.46(m，4H)，7.72-7.76(m，2H)，7.90(d，2H)，8.04(d，1H).
13C?NMR(DMSO-d
6)δ15.20，20.46，27.16，30.55，46.08，48.88，54.75，55.12，55.90，65.66，78.98，119.54，124.68，124.79，126.50，126.75，127.11，140.21，143.07，143.24，156.02，171.37，174.69.
19FNMR(DMSO-d
6)δ70.023.LC-MS?m/z?551(M+H)
The concrete synthetic route of Dimer is as follows:
II, synthetic main chain
1. swelling (Swelling): substituent constant is that the Rink Amide Resin 0.2mmol of 0.42mmol/g soaked in DCM 20 minutes and abundant mixing, drains then.
2. go protection (Deprotection): above-mentioned resin is added among the 20%PIPE/DMF of 10ml fully mixing and soaked 8-10 minute, carry out protective reaction (general-NH
2On Fmoc remove), drain.Then; detect free amino group with ninhydrin method (KT test): get micro-resin (about 30～50) with kapillary; this resin is washed 3 times with DCM; add each two of three kinds of reagent of A, B and C successively; in 115 ℃ of insulation taking-up observations after 5 minutes down; solution and resin all become bluish voilet, show that protective reaction carries out relatively fully.
3. washing (Washing): replace washing resin 6 times with DCM, DMF, fully mixing is drained.
4. coupling (Coupling): preferred DIC (DIC) method, step is as follows: take by weighing amino acid Fmoc-Arg (Pbf)-OH 0.8mmol (4 times of resin mole number, about 0.52g), activating reagent HOBt (1-hydroxyl-1H-benzotriazole) 0.8mmol (about 0.11g), measure DIC (N, the N-DIC) 0.8mmol (about 125 μ l), dissolve with 5mlDMF, add in the resin and reacted 1.5 hours, detect (KT test) free amino group with ninhydrin method: get micro-resin (about 30～50) with kapillary, this resin is washed 3 times with DCM, add reagent A successively, B and C, put into 115 ℃ of well heaters insulation 5 minutes, the equal yellowing of solution and resin or colourless shows that reaction carried out fully.If resin or solution are light blue, showing also needs to continue coupling, prolongs reaction times to 3 hour detection again.If reaction is not still carried out fully, then use urea reagent method instead, ratio of reagents is Amino acid: HATU: HOAt: DIEA=1: 0.95-0.98: 1: 2, after the normal-temperature reaction 1 hour, detect (KT test) free amino group with ninhydrin method, be reacted to solution and resin ninhydrin method detect equal yellowing or colourless till.
5. end-blocking (Capping): peptide chain is connected to after 20 residues, when KT test is can not be entirely yellow, this moment is the unreacted free amino group sealing of minority, reagent is Acetic Anhydride: DIEA (DIEA is a diisopropyl ethyl amine)=1: 3 (mol ratio), be added to the middle normal-temperature reaction of resin (mol ratio of resin and reagent is 1: 5) 15 minutes, and drained.
6. washing (Wash): replace washing resin 5 times with DCM, DMF, abundant mixing is drained then during washing.
7. repeat synthetic main chain of 2-6 step.
8. to hold the 28th amino acids be our company's autonomous design synthetic compound (being called Dimer) to peptide chain C, protects its amino and carboxyl by Fmoc and OtBu respectively.Coupling process DIC method, take by weighing Dimer (resin mole number 5 times) 1.0mmol (about 0.55g), activating reagent HOBt 1mmol (about 0.14g), measure DIC 1mmol (about 160 μ l), dissolve with 5mlDMF, join in the resin and reacted 3 hours down, Dimer is received on the main chain in normal temperature.
9. peptide chain C holds last amino acid His, selects Boc-His (Trt)-OH for use, and coupling process is with synthesizing DIC (DIC) method shown in the step 4 in the main chain, also available urea reagent method.
III, cracking, purifying
1. cracking: peptide resin is washed, drains.Weigh, the ratio in 1 gram peptide resin 10ml lysate adds lysate (TFA: TA: EDT: H with peptide resin
2O: phenol=82.5: 5: 2.5: 5: 5), shook 3 hours, centrifugal with 500ml ice ether sedimentation, wash 4 times, dry naturally, make the compound crude product shown in the structural formula I.
2. purifying: the crude product of the compound shown in the structural formula I is dissolved in 30% acetonitrile/water, ultrasonic back with 0.45 μ m membrane filtration, then filtrate is carried out purifying with conventional preparative chromatography method, obtain the pure product of the compound shown in the structural formula I, do mass spectrum, the result shows: molecular weight is correct, theoretical value 3379, measured value 3379.1.
In the present embodiment, that does not indicate temperature of reaction all refers to normal temperature.Reagent A, B and C be respectively 80% phenol ethanolic soln, heavily steam pyridine and 5g triketohydrindene hydrate adds the solution of preparing in 100 milliliters of ethanol.
Embodiment 2 carbohydrate tolerance tests
1, test grouping:
90 of ICR (Institute of Cancer Researcch) mouse, complete male, be divided into three batches by body weight, 30 every batch.Be divided into 2 groups by blood sugar behind every batch of mouse overnight fasting: the compound group shown in Vehicle group and the structural formula I (being called for short the compound group).Vehicle organizes an injecting normal saline, and the compound group is to add the compound shown in the structural formula I in the physiological saline.
2, process of the test:
First animal: press blood sugar grouping behind the mouse overnight fasting, Day1 subcutaneous injection administration, compound group dosage is 0.3mg/kg, each organize after the mouse administration that 2h gives the 2g/kg glucose load and behind glucose load 30,60min gets blood, measures blood sugar.Day4 respectively organize give 2g/kg glucose load (administration 72h) once more behind the mouse overnight fasting and behind glucose load 30min get blood, measure blood sugar.
Second batch of animal: press blood sugar grouping behind the mouse overnight fasting, Day1 subcutaneous injection administration, compound group dosage is 0.3mg/kg, Day2 respectively organize give 2g/kg glucose load (administration 25h) behind the mouse fasting 8h and behind glucose load 30min get blood, measure blood sugar.
The 3rd batch of animal: press the blood sugar grouping behind the mouse overnight fasting, Day1 subcutaneous injection administration, compound group dosage is 0.3mg/kg, Day3 respectively organize give 2g/kg glucose load (administration 42h) behind the mouse overnight fasting and behind glucose load 30min get blood, measure blood sugar.
Blood sugar detection adopts the complete integrated system for detecting blood sugar of Luo Kang.
3, test-results:
(1) administration 2h
(2) administration 25h
(3) administration 42h
(4) administration 72h
By above-mentioned experimental data as can be seen: the compound group has significant long-acting hypoglycemic activity, can keep hypoglycemic activity 72h to the administration in the mouse body.
The foregoing description is the specific embodiment for proving absolutely that the present invention enumerates only, and protection scope of the present invention is as the criterion with the content of claims, and is not limited to above-mentioned embodiment.Being equal to of flesh and blood of the present invention that do not break away from that those skilled in the art is done on basis of the present invention, substitute or conversion, also all within protection scope of the present invention.
Claims (10)
1. the compound shown in the structural formula I, and
Structural formula I
Pharmaceutically useful salt, solvate, inner complex or non-covalent complex that this compound became, based on the prodrug on this compound basis, or any mixture of above-mentioned formalization compound,
Among the structural formula I:
Aib is a methylalanine;
X is selected from glycine or G-NH2.
2. a pharmaceutical composition is characterized in that: the described compound of claim 1 and at least a pharmaceutically useful auxiliary material that comprise at least a effective therapeutic dose.
3. the application of the described pharmaceutical composition of claim 2 in pharmacy.
4. application according to claim 3, it is characterized in that: the application of described pharmaceutical composition in the medicine of the following at least a disease of preparation treatment, described disease comprise that type ii diabetes, sugar tolerance are impaired, type i diabetes, obesity, hypertension, metabolism syndrome, hyperlipemia, cognitive disorder, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disorder, apoplexy, the inflammatory bowel trace integration is levied and/or maldigestion or stomach ulcer.
5. application according to claim 3 is characterized in that: the application of described pharmaceutical composition in the medicine of preparation treatment type ii diabetes drug efficacy delay and/or the deterioration of prevention type ii diabetes.
6. application according to claim 3 is characterized in that: described pharmaceutical composition reduces food intake in preparation, reduces the β apoptosis, increases the beta Cell of islet function, increases beta cell group and/or recovers glucose to the application in the medicine of the susceptibility of beta cell.
7. the described compound of claim 1 is used to prepare that treatment comprises that type ii diabetes, sugar tolerance are impaired, type i diabetes, obesity, hypertension, metabolism syndrome, hyperlipemia, cognitive disorder, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disorder, apoplexy, inflammatory bowel trace integration are levied, the application of the medicine of maldigestion and/or stomach ulcer.
8. the described compound of claim 1 is used for preparing the application of the medicine for the treatment of type ii diabetes drug efficacy delay and/or the deterioration of prevention type ii diabetes.
9. the described compound of claim 1 is used for preparing treatment minimizing food intake, minimizing β apoptosis, increases the application to the medicine of the susceptibility of beta cell of beta Cell of islet function, increase beta cell group and/or recovery glucose.
10. treatment target is used the method for the described compound of claim 1 with blood sugar in the control agent.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102363633A (en) * | 2011-11-16 | 2012-02-29 | 天津拓飞生物科技有限公司 | Glucagon like peptide-1 mutant polypeptide and preparation method, medicinal composition and use thereof |
| US9764003B2 (en) | 2012-07-01 | 2017-09-19 | Novo Nordisk A/S | Use of long-acting GLP-1 peptides |
| CN111410687A (en) * | 2020-02-21 | 2020-07-14 | 成都奥达生物科技有限公司 | Long-acting G L P-1 compound |
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| CN1683408A (en) * | 2004-04-14 | 2005-10-19 | 贝达医药开发(上海)有限公司 | Glucagon-like peptide analog, its composition and its using method |
| CN101868476A (en) * | 2007-09-05 | 2010-10-20 | 诺沃-诺迪斯克有限公司 | Glucagon-like peptide-1 derivatives and their pharmaceutical use |
| CN101987868A (en) * | 2009-07-30 | 2011-03-23 | 江苏豪森医药集团有限公司 | Derivative or pharmaceutically acceptable salt of GLP-1 analogue and application of derivative or pharmaceutically-acceptable salt of a GLP-1 analogue |
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| CN1683408A (en) * | 2004-04-14 | 2005-10-19 | 贝达医药开发(上海)有限公司 | Glucagon-like peptide analog, its composition and its using method |
| CN101868476A (en) * | 2007-09-05 | 2010-10-20 | 诺沃-诺迪斯克有限公司 | Glucagon-like peptide-1 derivatives and their pharmaceutical use |
| CN101987868A (en) * | 2009-07-30 | 2011-03-23 | 江苏豪森医药集团有限公司 | Derivative or pharmaceutically acceptable salt of GLP-1 analogue and application of derivative or pharmaceutically-acceptable salt of a GLP-1 analogue |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102363633A (en) * | 2011-11-16 | 2012-02-29 | 天津拓飞生物科技有限公司 | Glucagon like peptide-1 mutant polypeptide and preparation method, medicinal composition and use thereof |
| CN102363633B (en) * | 2011-11-16 | 2013-11-20 | 天津拓飞生物科技有限公司 | Glucagon like peptide-1 mutant polypeptide and preparation method, medicinal composition and use thereof |
| US9764003B2 (en) | 2012-07-01 | 2017-09-19 | Novo Nordisk A/S | Use of long-acting GLP-1 peptides |
| US10335462B2 (en) | 2012-07-01 | 2019-07-02 | Novo Nordisk A/S | Use of long-acting GLP-1 peptides |
| CN111410687A (en) * | 2020-02-21 | 2020-07-14 | 成都奥达生物科技有限公司 | Long-acting G L P-1 compound |
| CN111410687B (en) * | 2020-02-21 | 2023-06-27 | 成都奥达生物科技有限公司 | Long-acting GLP-1 compound |
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