CN101824087A - Glucagon-like peptide-2 analog as well as preparation method and application thereof - Google Patents
Glucagon-like peptide-2 analog as well as preparation method and application thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
Abstract
The invention relates to a glucagon-like peptide-2 (GLP-2) analog and the medicinal application thereof, and the invention further relates to a medicament composition containing the GLP-2 analog and pharmaceutically acceptable salt thereof. The GLP-2 analog or the medicament composition containing the GLP-2 analog and the pharmaceutically acceptable salt thereof can be widely applied in preventing or treating gastrointestinal related symptoms related to mucosal lesion and lightening the side effects of a chemotherapy and a radiotherapy for gastrointestinal tracts.
Description
Technical field
The present invention relates to glucagon-like-peptide-2 (Glucagon Like Peptide-2, GLP-2) analogue and be used for preventing and/or treating gastrointestinal mucosa damage associated conditions and alleviate chemotherapy and the purposes of the medicine of radiotherapeutic gastrointestinal side effect in preparation.
Background technology
GLP-2 belongs to Proglucagon derived peptide class (proglucagon-derived peptide, PGDP), be Proglucagon (proglucagon, PG) by prohormone convertase (prohormone convertase, PC) one of Jiang Xie product, the single chain polypeptide of forming by 33 amino-acid residues, molecular weight 3900 dalton, its aminoacid sequence has high conservative [Drucker DJ.Glucagon-like peptide 2.JClin Endocrinol Metab in Mammals, 2001,86:1758-1774].GLP-2 is synthetic and release by enteron aisle L endocrine cell, and ingested, factor such as nerve and internal secretion regulates, with the feed carbohydrate containing and fat food to the most important [the Rocca AS.LaGreca J of the stimulation of the secretory activity of L endocrine cell, Kalitsky J, Brubaker PL.Monounsaturated fatty acid diets improve glycemic tolerance through increased secretion of glucagon-like peptide-1.Endocrinology, 2001,142:1148-55].In the normal adult 15 minutes after the meal and 1 hour latter two period, the concentration of GLP-2 raises the most remarkable in the circulation of blood.The principal mode that GLP-2 exists in intestinal submucosa tissue and blood circulation is complete GLP-2, i.e. GLP-2 (1-33).About 7 minutes of the biological half-life in the human body circulation of blood of GLP-2 (1-33), its metabolism is mainly by two acyl peptide peptases, 4 (the dipeptidyl peptidase-4 on renal excretion and the enteron aisle brush border, DPP-4) preceding two residues of its N-terminal of hydrolysis, the GLP-2 (2-33) of formation non-activity.The rat of the GLP-2 analogue that lacks the DDP-4 action site of feeding, its enteric epithelium growing state is significantly better than the rat of the natural GLP-2 that feeds.The clearance rate of GLP-2 is starkly lower than and does not excise the kidney rat in the rat serum of bilateral kidney excision.Yet, GLP-2 (2-33) is proved to be the competitive antagonist of GLP-2 acceptor (GLP-2R) recently, can suppress GLP-2 (1-33) and nutrition inductive intestinal mucosa growth [Shin ED, Estall JL, Izzo A, Drucker DJ, Brubaker PL.Mucosal adaptation to enteral nutrients is dependent on the physiologic actions of glucagons-like peptide-2in mice.Gastroenterology, 2005,128:1340-53].More than the biologic activity of explanation GLP-2 is subjected to the DDP-4 hydrolysis, and its degraded product antagonism and kidney are removed three's adjusting.
GLP-2 comprises the effect of enteron aisle: stimulate the growth of intestinal mucosa specifically, the regeneration behind the enhancing intestinal mucosal injury; The apoptosis that suppresses intestinal epithelial cell and pit cell; (glucose transporter-2, expression GLUT2) and to the transhipment of glucose promote intestinal digestion and absorptive function to strengthen intestinal epithelial cells base side glucose transporter-2; Suppress digestive tract power and gastric acid secretion; Strengthen the intestinal mucosal barrier function; Increasing enteron aisle blood supplies.GLP-2 is irrelevant with age and sex basically to the effect of intestinal mucosa, and quiet notes, intramuscular injection, subcutaneous injection or abdominal injection all have positive effect [Burrin DG, Petersen Y, Stoll B, et al.Glucagon-like peptide 2:a nutrient-responsive gut growth factor.J Nutr, 2001,131:709-712].
GLP-2 acceptor (GLP-2R) is Type B hyperglycemic-glycogenolytic factor-secretin sample g protein coupled receptor superfamily member, and its expression has the height tissue specificity.Immunohistochemistry and hybridization in situ technique are verified, GLP-2R expresses [Yusta B on subcutaneous myofibroblast on human enteroendocrine cell, mouse enteric nervous unit and rat, mouse, the marmoset monkey, Huang L, Munroe D, et al.Enteroendocrine localization of GLP-2receptor expression in humans and rodents.Gastroenterology, 119:744-55; Bjerknes M, Cheng H.Modulation of specific intestinal epithelial progenitors by enteric neurons.Proc Natl Acad Sci.2001,98:12497-502].Lack the expression of GLP-2R on the intestinal cells, illustrate that GLP-2R promotes that hyperplasia and cytoprotection may be indirect.
GLP-2 is to realize by cyclic monophosphate (cAMP) path of specificity GLP-2R mediation in intracellular signal conduction.The GLP-2 activated adenyl cyclase causes that cAMP increases in the cell, latter's activated protein kinase A (PKA), and PKA may promote the genetic transcription of cAMP response element by Ca2+ in the cell and/or InsP3 path then.GLP-2 can the people's intestinal mucosa epithelial cell Caco-2 cell by phosphorylation type extracellular signal-regulated kinase (MEK) phosphorylation vitro culture in two isomer ERK-1 of mitogen activated protein kinase (MAPK) and Threonine and the tyrosine residues of ERK-2, make its active increasing, thereby significantly promote Caco-2 cell proliferation.This interaction energy is respectively by specific tyrosine protein kinase inhibitor (Genistein), phosphatidyl-inositol 3-kinase (PI3-K) inhibitor (LY294002), mitogen activated protein kinase (MAPK) inhibitor (PD098059) blocking-up.On the other hand, the GLP-2R signal activation can suppress cycloheximide inductive BHK-GLP-2R apoptosis, this and its inhibition halfcystine aspartate specific protease-3 (caspase-3) enzymic activity, and it is relevant to reduce the division of poly ADP ribose polymerase.No matter and whether PKA inhibitor H289 exist, GLP-2 can both reduce the division of the caspase-3 that cycloheximide brings out.After the cycloheximide administration, two kinds of kinase inhibitor is under the condition of phosphatidylinositol-3-kinase (PI3-K) inhibitor LY294002 and mitogen activated protein kinase (MAPK) inhibitor PD98054 existence, GLP-2 also can increase cell survival rate [Yusta B, Estall J, Drucker DJ.Glucagon-like peptide-2 recepter activation engages bad and glycogen synthase kinase-3 in a protei kinase A-dependent manner and prevents apoptosis following inhibition of phosphatidylinositol 3-kinase.J Biol Chem, 2002,277:24896-24906; Walsh NA, Yusta B, DaCambra MP, et al.Glucagon-like peptide-2 recepter activation in the rat intestinal mucosa.Endocrinology, 2003,144:4385-4392], illustrate that the intracellular signal conduction of GLP-2 not exclusively relies on PI3-K and MAPK approach.This shows that the very complicated protein kinase approach that had both comprised that cAMP relied on of signal conduction pathway that GLP-2 enteron aisle mechanism of action is related also comprises tyrosine kinase pathway, PI3-K and MAPK approach.GLP-2 effect cutting handset system is not really illustrated at present as yet fully.
The human trial of GLP-2 intestines provide protection also is in the starting stage at present, is confined to short bowel syndrome patient's therapeutic studies.Whether clear and definite GLP-2 has the trophotrophic sorption, but there is the effect that alleviates damage of intestines, promotes the intestines reparation to be still waiting further clinical trial confirm.Though do not find the undesirable action of GLP-2 in the therapeutic process as yet, but the biological action of considering GLP-2 is to find in the research of animal hyperglycemic-glycogenolytic factor induced tumor, and be studies show that of mouse bare subcutaneous injection hyperglycemic-glycogenolytic factor, GLP-2 significantly promotes the intestinal mucosa growth, so whether GLP-2 can stimulate the still difficult final conclusion of growth of intestinal canal tumour.With regard to the treatment of short bowel syndrome, the validity of GLP-2 needs the large-scale crowd randomized control study to confirm.All need more deep research on the dose,optimum of GLP-2 treatment, route of administration, the course of treatment and application opportunity etc.Believe that the special intestines provide protection of GLP-2 has important clinical application value aspect the diseases such as control malabsorption, inflammatory bowel, the damage of irritability gastrointestinal mucosa.
GLP-2 is to have the form secretion of following 33 amino acid whose peptides: His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-A rg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp.GLP-2 is promptly located cutting by enzyme DPPIV at 2 L-Ala (Ala) of nitrogen end in vivo and forms GLP-2 (3-33) and inactivation.Except that kidney was removed, it was about 7 minutes that this quick enzyme liberating mechanism of GLP-2 (1-33) causes the transformation period of this peptide in the human body circulation of blood.
Drucker etc. are at US5, have described the GLP-2 antagonist in 994,500 and to the influence of gastrointestinal tissue's growth, and it proposes described antagonist is mixed with, and medicine is used for the treatment of hyperplasia or induced development is incomplete.The U.S. 5,994,500 for example replace and lack the structure that changes Mammals GLP-2 by sudden change.
US6,184,208, US5,789,379 and US6,184,201 disclose GLP-2 analogue and medicinal use thereof.Described analogue be entirely by people GLP-2 replacement and or disappearance obtain.
DaCambra etc. (Biochemistry2000,39,8888-8894) GLP-2 active structures determinant has been described.The example of such determinant is Phe6 and Thr5, and described Phe6 and Thr5 it is believed that to GLP-2 receptors bind and activation be vital.
Drucker etc. disclose GLP-2 analogue [Gly2] GLP-2 in WO97/39031.Wherein 2 L-Ala is replaced by glycine, so that described peptide opposing DPPIV cutting.Show that the replacement of L-Ala improves the stability and the usefulness of described peptide.This patent application has described how to use the GLP-2 analogue antagonism enteric epithelium mucosal inflammation disease relevant with damage.These diseases comprise the mucositis and the ischemia injury of extensive SBR, inflammatory bowel, phase chemotherapy induced.
WO02/066511 has described the GLP-2 analogue of transformation period prolongation in the body and the purposes that the medicine of gastrointestinal disorder such as inflammatory bowel is treated in conduct thereof.
WO01/14779 has described h[Gly2] GLP-2 is as the apoptosis that suppresses chemotherapy-induced and promote the purposes of the pretreated medicine of cell survival.
Summary of the invention
The object of the present invention is to provide the GLP-2 analogue of a kind of following general formula (I) representative, and pharmacologically acceptable salt and their derivative, this derivative comprises the derivative of the GLP-2 analogue that is produced through longer chain fatty acid and/or polyoxyethylene glycol and/or the modification of other long-actingization, or the derivative of the pharmacologically acceptable salt of GLP-2 analogue:
R1-Z1-X1-X2-X3-Gly-Ser-Phe-Ser-Asp-Glu-X10-X11-Thr-Ile-Leu-X15-X16-Leu?-Ala-Ala-Arg-Asp-Phe-Ile-X24-X25-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-(Z2)-R2(I)，
Wherein Z1, Z2, R1 or R2 be not for existing, or be natural or alpha-non-natural amino acid, or be by the peptide sequence with 2 to 33 amino acid units natural and/or that alpha-non-natural amino acid is formed, and X1, X2, X3, X10, X11, X15, X16, X24 or X25 are natural or alpha-non-natural amino acid.
Preferably, in the GLP-2 analogue of general formula of the present invention (I) representative, X1 is His or D-His.
Preferably, in the GLP-2 analogue of general formula I representative of the present invention, X2 is D-Ala or Gly.
Preferably, in the GLP-2 analogue of general formula I representative of the present invention, X10 is Nle or Met.
Preferably, in the GLP-2 analogue of general formula I representative of the present invention, X15 is Glu or Asp.
Preferably, in the GLP-2 analogue of general formula I representative of the present invention, X3 is Glu or Asp, and X3 is with α carboxyl or β carboxyl and Gly formation peptide bond.
Particularly, the present invention more preferably has the GLP-2 analogue of following sequence:
D-His-D-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Nle-Asn-Thr-Ile-Leu-Glu-Asn-Leu-A?la-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp。
His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Glu-Asn-Leu-Ala-A?la-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp。
His-Gly-Glu-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Glu-Asn-Leu-Ala-A?la-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp。
D-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala?-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp。
D-His-Gly-Glu-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp。
According to record of the present invention, the invention still further relates to a kind of preparation method of GLP-2 analogue of the present invention, it is characterized in that this GLP-2 analogue adopts solid-state synthesis method preparation and uses the reverse phase liquid chromatography purifying.
The invention further relates to a kind of GLP-2 analogue medicinal composition of the present invention for the treatment of effective dose that comprises, it comprises pharmaceutically acceptable carrier and/or cancer chemotherapy medicine.
The formulation of described composition is preferably injection or sustained release dosage.
The invention still further relates to this pharmaceutical composition and be used for preventing and/or treating the purposes that gastrointestinal mucosa damages the associated conditions medicine in preparation, wherein gastrointestinal mucosa damage associated conditions is selected from digestive tract ulcer, malabsorption syndrome, short bowel syndrome, ileocecal valve syndrome disease, inflammatory bowel, abdomen type sprue diarrhoea, hot belt type sprue diarrhoea, hypogammag lobulinemia type sprue diarrhoea, enteritis, regional enteritis, ulcerative colitis, osteoporosis and/or muscular dystrophy that the gastrointestinal mucosa damage causes, chemotherapy or radiotherapeutic gastrointestinal side effect, preferred diarrhoea, abdominal cramp, vomiting, gastroenteritis due to radiation, transmissible gastroenteritis or infection back gastro-enteritis, the gastrointestinal mucosa damage that toxic agent or chemotherapeutic cause or the illness of DPP-IV (dipeptidyl peptidase-IV) mediation.
The invention further relates to described GLP-2 analogue and be used for preventing and/or treating the purposes that gastrointestinal mucosa damages the associated conditions medicine in preparation, wherein gastrointestinal mucosa damage associated conditions is selected from digestive tract ulcer, malabsorption syndrome, short bowel syndrome, ileocecal valve syndrome, inflammatory bowel, abdomen type sprue diarrhoea, hot belt type sprue diarrhoea, hypogammag lobulinemia type sprue diarrhoea, enteritis, regional enteritis, ulcerative colitis, osteoporosis and/or muscular dystrophy that the gastrointestinal mucosa damage causes, chemotherapy or radiotherapeutic gastrointestinal side effect, preferred diarrhoea, abdominal cramp, vomiting, gastroenteritis due to radiation, transmissible gastroenteritis or infection back gastro-enteritis, perhaps the gastrointestinal mucosa damage that causes of toxic agent or chemotherapeutic or the illness of DPP-IV (dipeptidyl peptidase-IV) mediation.
This shows that what the present invention relates to is a kind of new GLP-2 analogue.Compare with known GLP-2, the amino acid of one or more positions is replaced in the sequence of GLP-2 analogue of the present invention, makes GLP-2 analogue of the present invention have bioactive improvement in the body and or the characteristics of improved chemical stability like this.Particularly, preferably, GLP-2 analogue of the present invention comprises the one or more locational replacement in 1,2,3,10,11,15,16,24 or 25 of the GLP-2 sequence and/or replaces combination.The invention provides chemical stability and or bioactive GLP-2 analogue with improvement.
Therefore, the invention provides GLP-2 analogue or its pharmacologically acceptable salt or their derivative of general formula I representative:
R1-Z1-X1-X2-X3-Gly-Ser-Phe-Ser-Asp-Glu-X10-X11-Thr-Ile-L eu-X15-X16-Leu-Ala-Ala-Arg-Asp-Phe-Ile-X24-X25-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-(Z2)-R2 (general formula I), wherein Z1, Z2, R1 or R2 be not for existing, or be natural or alpha-non-natural amino acid, or be by peptide sequences natural or 3 to 20 amino acid units that alpha-non-natural amino acid is formed, and X1, X2, X3, X10, X11, X15, X16, X24 or X25 are natural or alpha-non-natural amino acid.
GLP-2 analogue of the present invention also has the chemical stability of raising, for example at the stability of acid hydrolysis, oxidation and desamidation.The replacement of X3 position can improve GLP-2 analogue of the present invention to acid-hydrolyzed stability, and the replacement of X10 position can improve the oxidative stability of GLP-2 analogue of the present invention.X11, X16 and or the X24 position in the replacement of one or more positions can improve the stability of GLP-2 analogue of the present invention at desamidation.Therefore, with respect to Gly2-GLP-2, GLP-2 analogue of the present invention can demonstrate at degrading in the acidic solution, at desamidation and/or at the enhancing of the stability of oxidative degradation.The replacement of X15 position can improve the productive rate for preparing GLP-2 analogue of the present invention with chemical synthesis.
The GLP-2 analogue can prolong its transformation period in vivo through longer chain fatty acid and/or polyoxyethylene glycol or the modification of other long-actingization.Polyethyleneglycol modifiedly can cover up the analogue parent effectively, reduce analogue by the knowledge of debating of vivo immuning system and body endoproteinase, thereby reduced the immunogenicity of analogue and by the probability of body endoproteinase hydrolysis, thereby prolonged GLP-2 analogue round-robin time in vivo.
On the other hand, the present invention relates to comprise composition with carrier blended GLP-2 analogue of the present invention or its salt or their derivative.In preferred embodiments, described composition is pharmaceutically acceptable composition, and described carrier is pharmaceutically acceptable or pharmaceutical carrier.GLP-2 peptide analogs of the present invention is the pharmaceutically acceptable acid additive salt of GLP-2 analogue of the present invention.
In another aspect, the present invention relates to the GLP-2 analogue of the present invention or its salt that are used for the treatment of.
In another aspect, the present invention relates to the purposes that GLP-2 analogue or its salt or their derivative are used for preparing the medicine that treats and/or prevents the stomach and intestine associated conditions, such as treatment suffer from that intestinal function is impaired, the newborn infant of the illness of osteoporosis or DPP-IV (dipeptidyl peptidase-IV) mediation.For example, described stomach and intestines associated conditions are selected from digestive tract ulcer, gastritis, malabsorption syndrome, short bowel syndrome, ileocecal valve syndrome, inflammatory bowel, abdomen type sprue diarrhoea, hot belt type sprue diarrhoea, hypogammag lobulinemia type sprue diarrhoea, enteritis, regional enteritis, ulcerative colitis, irritable bowel syndrome, injury of small intestine or short bowel syndrome that diarrhoea is relevant.
Available GLP-2 analogue treatment of the present invention maybe can use the GLP-2 analogue to prevent or other illness for the treatment of comprises gastroenteritis due to radiation, transmissible gastroenteritis or infect back gastro-enteritis and because the injury of small intestine that toxic agent or other chemical diagnosis therapeutical agent cause.This may need with chemotherapy or radiotherapeutic medicine simultaneously or after use the GLP-2 analogue, with reduction chemotherapy or for example diarrhoea, abdominal cramp or vomiting of radiotherapeutic side effect, and reduce the enteric epithelium 26S Proteasome Structure and Function damage that causes by chemotherapy or radiotherapy.
The invention still further relates to a kind of treatment medicine box, it comprises cancer chemotherapy medicine, GLP-2 analogue of the present invention and working instructions.
Particularly, in the treatment medicine box, it comprises the cancer chemotherapy medicine as therapeutical agent, GLP-2 analogue of the present invention and working instructions, and each described medicine or all optional the making up with pharmaceutically acceptable carrier of analogue.Described therapeutical agent can separately be packed with use respectively, or can provide in same composition.
Therefore, the invention still further relates to and comprise and the cancer chemotherapy medicine of pharmaceutically acceptable carrier combination and the pharmaceutical composition of GLP-2 analogue of the present invention.
The patient that gastrointestinal mucosa tumorigenesis risk improves may expect to select compound to reduce the risk of side effect or elimination side effect.For example, selection is used for the treatment of suffers from the colon tumorigenesis, or prevention is when having the patient that colon tumorigenesis risk takes place that colon tumorigenesis medicine takes place, select medicine that selectivity to small intestine is higher than colon than non-selective medicine or the selectivity of colon is higher than the medicine of small intestine may be more suitable.
In other respects, the invention still further relates to the GLP-2 analogue and be used for preparing the purposes that treats and/or prevents underfed medicine.
In another aspect, the present invention relates to by using GLP-2 analogue of the present invention or its salt or the purposes of their derivative in the medicine that is used for the treatment of patient's stomach and intestine associated conditions of treatment significant quantity.
In another aspect, the present invention relates to treat or prevent the method for chemotherapy among this patient who needs or radiotherapy side effect, described method comprises GLP-2 analogue of the present invention or its salt or their derivative that uses with the treatment significant quantity.
In another aspect, the invention provides treatment and or prevention underfed method among this patient who needs is arranged, described method comprises GLP-2 analogue or its salt or their derivative of the present invention's definition of using the treatment significant quantity.
Employing well known to a person skilled in the art that solid phase synthesis technique synthesizes GLP-2 analogue peptide of the present invention; its ultimate principle is: earlier the hydroxyl that will synthesize the hydroxyl end amino acid of peptide chain is linked to each other with the same insoluble macromolecule resin of the structure of covalent linkage (solid phase carrier); then with this be combined in amino acid on the solid phase carrier as amino component through the deaminize protecting group and with excessive activated carboxyl component reaction, spreading peptide chain.Repeat (condensation → wash → go protection → washing → next round condensation) and operate, reach the synthetic peptide chain length of wanting, at last peptide chain cracking from the resin is got off, pass through processing such as purifying, promptly get desired polypeptide.What wherein the intermediate controlled of condensation and protective reaction step was taked is the method that triketohydrindene hydrate detects, and promptly when free amino was arranged on the resin peptide chain, detecting through ninhydrin reagent can be apparent blue, and (ninhydrin reagent is originally as yellow) do not develop the color when having free amine group.Therefore after carrying out condensation reaction and finishing; detect by triketohydrindene hydrate; if displaing yellow (color of ninhydrin reagent itself); illustrating then that the coupling of this step finishes can carry out deprotection operation before the next amino acid whose coupling; if show blue; prove then and go back some free amine group on the peptide chain that needing further to repeat coupling or changing existing condensing agent is yellow until resin peptide through the triketohydrindene hydrate detection.
The detection principle of the agonist activity of the GLP-2 analogue that relates among the present invention is that GLP-2R is and the acceptor of Gs albumen coupling, causes cAMP concentration rising in the cell when acceptor combines meeting with agonist.The luciferase reporter gene plasmid of this experiment cotransfection GLP-2R and cAMP response element regulation and control in the HEK293 cell, when compound and receptors bind and activated receptor, luciferase expression will increase.By knowing the activation situation of compound to GLP-2R to the detection of uciferase activity.
Embodiment
In order to illustrate in greater detail the present invention, provide the following example.But protection scope of the present invention is not to be defined in this, and those skilled in the art can replace relevant amino acid and finish the present invention according to the method for technical scheme provided by the invention in conjunction with prior art, obtain the derivative that general formula I limits out.
The solid phase synthesis of embodiment 1 positive compound Teduglutide
The sequence of positive compound Teduglutide is:
H-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-OH
(1) drying of solid phase synthesis resin and swelling
24 hours Fmoc-Asp of weighing vacuum-drying (OtBu)-Wang resin (0.5mmol/g) 40g (20mmol) places 2L bubbling bottle, adds 400mLDMF swelling resin 30 minutes, takes out DMF solution;
(2) Fmoc-Asp (OtBu)-Wang resin removes the Fmoc protecting group
In the bubbling bottle that Fmoc-Asp (OtBu)-Wang resin is housed, add 200mL 20% piperidines/DMF solution, react extraction after 5 minutes, added 200mL 20% piperidines/DMF solution room temperature reaction again 20 minutes.Reaction finishes back DMF 200mL washing resin four times.
(3) solid phase synthesis of Teduglutide
1. condensation Fmoc-Thr (tBu)-OH
Weighing 50mmol Fmoc-Thr (tBu)-OH adds 125mL 0.4M HOBt/DMF dissolving, adds under the 150mL 0.4M DIC/DCM room temperature stirring reaction again 10 minutes; Above-mentioned solution is joined in the resin, feed N2 reaction 4 hours under the room temperature.Reaction is taken out reaction solution after finishing, and uses DMF successively, IPA and DMF washing resin.
2. the prolongation of peptide chain
According to the order (H-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Le u-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gl n-Thr-Lys-Ile-Thr-Asp-OH) of amino acid among the Teduglutide from carboxyl terminal (C-end) to aminoterminal (N-end); the consumption of amino acid and condensation reagent is with Fmoc-Thr (tBu)-OH is identical; protection amino acid is respectively Fmoc-Thr (tBu)-OH; Fmoc-Ile-OH; Fmoc-Lys (Boc)-OH; Fmoc-Gln (Trt)-OH; Fmoc-Leu-OH; Fmoc-Trp (Boc)-OH; Fmoc-Asn (Trt)-OH; Fmoc-Phe-OH; Fmoc-Asp (OtBu)-OH; Fmoc-Arg (Pbf)-OH; Fmoc-Ala-OH; Fmoc-Glu (OtBu)-OH; Fmoc-Met-OH; Fmoc-Ser (tBu)-OH; Fmoc-Gly-OH and Fmoc-His (Trt)-OH; repeat condensation and deprotection two-step reaction, synthetic His (Trt)-Asp-Asp (OtBu)-Gly-Ser (tBu)-Phe-Ser (tBu)-Asp (OtBu)-Glu (OtBu)-Met-Asn (T rt)-Thr (tBu)-Ile-Leu-Glu (OtBu)-Asn (Trt)-Leu-Ala-Ala-Arg (Pbf)-Asp (OtBu)-Phe-Ile-As n (Trt)-Trp (Boc)-Leu-Ile-Gln (Trt)-Thr (tBu)-Lys (Boc)-Ile-Thr (tBu)-Asp (OtBu)-Wang resin.
3. the aftertreatment of Teduglutide resin peptide
2. resulting resin peptide is used DMF successively, and IPA and DMF washing resin with anhydrous diethyl ether washed twice final vacuum drying, get resin peptide.
(4) preparation of Teduglutide crude product peptide
Get dried resin peptide, add the TFA of freshly prepared 10mL/g resin peptide: dithioglycol (EDT): TIS: water=92.5: 2.5: 2.5: the lysate of 2.5 (volume ratios), reaction is 4 hours under the room temperature.Reaction finishes after-filtration, with TFA washing resin secondary, collects and merging filtrate, and rotary evaporation adds a large amount of ice anhydrous diethyl ethers and separates out Teduglutide to 1/3 of original volume, centrifugal final vacuum dry white crude product.
(5) reversed-phase liquid chromatography of Teduglutide preparation
Get crude product peptide 5g and be dissolved in a certain amount of water, separate with RPLC (RP-HPLC) behind 0.45 μ m membrane filtration, moving phase is A 0.1%TFA/H2O, B 0.1%TFA/ acetonitrile.Wherein, chromatographic column is Denali C-18 post (particle diameter 8.3 μ m, 5 * 30cm), column temperature 45 degree, detection wavelength 220nm, flow velocity 120mL/ minute.Collect the product peak, freeze-drying got Teduglutide finished product 1.0g, purity 98.5%, yield 20.0% after concentrating under reduced pressure was removed most of acetonitrile.
The solid phase synthesis of embodiment 2 compounds 1
The sequence of compound 1 is:
D-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Le u-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gl n-Thr-Lys-Ile-Thr-Asp-OH, promptly in general formula (I), X1 is D-His, and X2 is Gly, and X3 is ASP, X10 is Met, X11 is Asn, and X15 is Asp, and X16 is Asn, X24 is Asn, and X25 is Trp.
The preparation method is with embodiment 1.
The solid phase synthesis of embodiment 3 compounds 2
The sequence of compound 2 is:
D-His-Gly-Glu-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Le u-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gl n-Thr-Lys-Ile-Thr-Asp-OH, promptly in general formula (I), X1 is D-His, and X2 is Gly, and X3 is Glu, X10 is Met, X11 is Asn, and X15 is Asp, and X16 is Asn, X24 is Asn, and X25 is Trp.
The preparation method is with embodiment 1.
The solid phase synthesis of embodiment 4 compounds 3
The sequence of compound 3 is:
H-D-His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Glu-Asn-Leu-Ala-A la-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-A sp-OH, promptly in general formula (I), X1 is D-His, and X2 is Ala, and X3 is Asp, X10 is Met, X11 is Asn, and X15 is Glu, and X16 is Asn, X24 is Asn, and X25 is Trp.
The preparation method is with embodiment 1.
The solid phase synthesis of embodiment 5 compounds 4
The sequence of compound 4 is:
H-D-His-Ala-Glu-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Le μ-Glu-Asn-Leu-Ala-A la-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-A sp-OH, promptly in general formula (I), X1 is D-His, and X2 is Ala, and X3 is Glu, X10 is Met, X11 is Asn, and X15 is Glu, and X16 is Asn, X24 is Asn, and X25 is Trp.
The preparation method is with embodiment 1.
The solid phase synthesis of embodiment 6 compounds 5
The sequence of compound 5 is:
H-D-His-D-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Nle-Asn-Thr-Il e-Leu-Glu-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Il e-Gln-Thr-Lys-Ile-Thr-Asp-OH, promptly in general formula (I), X1 is D-His, and X2 is Ala, and X3 is Asp, X10 is Nle, X11 is Asn, and X15 is Glu, and X16 is Asn, X24 is Asn, and X25 is Trp.
The preparation method is with embodiment 1.
The solid phase synthesis of embodiment 7 compounds 6
The sequence of compound 6 is:
H-D-His-D-Ala-Glu-Gly-Ser-Phe-Ser-Asp-Glu-Nle-Asn-Thr-Il e-Leu-Glu-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Il e-Gln-Thr-Lys-Ile-Thr-Asp-OH, promptly in general formula (I), X1 is D-His, and X2 is D-Ala, and X3 is Glu, X10 is Nle, X11 is Asn, and X15 is Glu, and X16 is Asn, X24 is Asn, and X25 is Trp.
The preparation method is with embodiment 1.
The solid phase synthesis of embodiment 8 compounds 7
The sequence of compound 7 is:
H-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Le μ-Glu-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-OH, promptly in general formula (I), X1 is D-His, and X2 is Gly, and X3 is Asp, X10 is Met, X11 is Asn, and X15 is Glu, and X16 is Asn, X24 is Asn, and X25 is Trp.
The preparation method is with embodiment 1.
The solid phase synthesis of embodiment 9 compounds 8
The sequence of compound 8 is:
His-Gly-Glu-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Le μ-Glu-Asn-Leu-Ala-Ala-Ar g-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-OH, promptly in general formula (I), X1 is His, and X2 is Gly, and X3 is Glu, X10 is Met, X11 is Asn, and X15 is Glu, and X16 is Asn, X24 is Asn, and X25 is Trp.
The preparation method is with embodiment 1.
The solid phase synthesis of embodiment 10 compounds 9
The sequence of compound 9 is:
H-D-His-Gly-Glu-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Glu-Asn-Leu-Ala-A la-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-A sp-OH, promptly in general formula (I), X1 is D-His, and X2 is Gly, and X3 is Glu, X10 is Met, X11 is Asn, and X15 is Glu, and X16 is Asn, X24 is Asn, and X25 is Trp.
The preparation method is with embodiment 1.
The solid phase synthesis of embodiment 11 compounds 10
The sequence of compound 10 is:
H-His-Gly-Asp
*(Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Glu-Asn-Leu-Al a-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Th r-Asp-OH, promptly in general formula (I), X1 is His, and X2 is Gly, and X3 is Asp, X10 is Met, X11 is Asn, and X15 is Glu, and X16 is Asn, X24 is Asn, and X25 is Trp.The Asp of X3 place wherein
*: Fmoc-Asp-OtBu.
The preparation method is with embodiment 1.
The agonist activity of 12 pairs of GLP-2 acceptors of embodiment (GLP-2R) detects
GLP-2R is and the acceptor of Gs albumen coupling, causes cAMP concentration rising in the cell when acceptor combines meeting with agonist.The luciferase reporter gene plasmid of present embodiment cotransfection GLP-2R and cAMP response element regulation and control in the HEK293 cell, when GLP-2 analogue and receptors bind and when activating this receptor, luciferase expression will increase.Can obtain the activation situation of GLP-2 analogue by detection to GLP-2R to uciferase activity.The relevant information of each GLP-2 analogue to be measured is as shown in table 1 below:
Table 1 carries out molecular weight, quality and the final concentration of each GLP-2 analogue of GLP-2R agonist activity detection
The electricity consumption shifting method imports the HEK293 cell with GLP-2R and pCRE-Luc expression plasmid, and the cell after the transfection is gone into 96 orifice plates with the density kind of 40,000/hole/100 μ l, hatches 24 hours at 37oC.Add the GLP-2 analogue of the present invention (each concentration is 3 multiple holes) or the positive control GLP-2 of finite concentration gradient, hatched 5 hours at 37oC.The negative contrast of solvent DMSO.50 μ l substratum are taken out in every hole, add 50 μ l luciferase substrates, vibrate 10 minutes.Take out 80 μ l reaction solutions and join in the 96 white orifice plates, on the Invision microplate reader, detect.The EC50 value of described GLP-2 analogue, 95% fiducial limit and maximum reactivity are as shown in table 2 below.
Each GLP-2 analogue EC50 of table 2,95% fiducial limit and maximum reactivity
| GLP-2 or GLP-2 analogue | ??EC 50(nM) | 95% fiducial limit (nM) | Maximum reactivity (%) |
| GLP-2 (positive control) | ??0.03664 | 0.01667 to 0.08054 | ??100 |
| Compound 10 | ??>100 | ??22.08933 | |
| Compound 4 | ??0.1361 | 0.08114 to 0.2282 | ??99.10504 |
| Compound 5 | ??0.1195 | 0.07614 to 0.1877 | ??106.4152 |
| Compound 8 | ??0.08349 | 0.04536 to 0.1537 | ??86.53016 |
| Compound 2 | ??0.01105 | 0.004686 to 0.02607 | ??121.9285 |
| Compound 3 | ??0.2188 | 0.1075 to 0.4454 | ??114.1183 |
| GLP-2 or GLP-2 analogue | ??EC 50(nM) | 95% fiducial limit (nM) | Maximum reactivity (%) |
| Compound 9 | ??1.374 | 0.6168 to 3.061 | ??117.9512 |
| Compound 7 | ??0.1679 | 0.1034 to 0.2727 | ??103.0608 |
| Compound 6 | ??1.178 | 0.5294 to 2.623 | ??83.24433 |
| ??teduglutide | ??0.04348 | 0.008376 to 0.06585 | ??88.78505 |
| Compound 1 | ??0.03585 | 0.01980 to 0.06492 | ??90.61841 |
Wherein, compound 1,2 has all shown GLP receptor agonist activity preferably.
Sequence table
＜110〉Lianyungang HengBang Pharmaceutical Technology Co., Ltd
＜120〉glucagon-like peptide-2 analog and its production and use
<130>890031CG
<160>26
<170>PatentIn?version?3.3
<210>1
<211>33
<212>PRT
＜213〉artificial sequence
<220>
<221>
<222>
＜223〉GLP-2 analogue positive compound Teduglutide
<400>1
His?Gly?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Asp?Asn
1???????????????5????????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>2
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 1
<400>2
His?Gly?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Asp?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>3
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 2
<400>3
His?Gly?Glu?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Asp?Asn
1?????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>4
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 3
<400>4
His?Ala?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1?????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>5
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 4
<400>5
His?Ala?Glu?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>6
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 5
<220>
＜221〉Ala is D-Ala
<222>(2)..(2)
＜223〉the GLP-2 analog compounds 5
<220>
＜221〉Xaa is Nle
<222>(10)..(10)
＜223〉the GLP-2 analog compounds 5
<400>6
His?Ala?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Xaa?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>7
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 6
<220>
＜221〉Ala is D-Ala
<222>(2)..(2)
＜223〉the GLP-2 analog compounds 6
<220>
＜221〉Xaa is Nle
<222>(10)..(10)
＜223〉the GLP-2 analog compounds 6
<400>7
His?Ala?Glu?Gly?Ser?Phe?Ser?Asp?Glu?Xaa?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>8
<211>33
<212>PRT
＜213〉artificial sequence
<220>
<221>
<222>
＜223〉the GLP-2 analog compounds 7
<400>8
His?Gly?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>9
<211>33
<212>PRT
＜213〉artificial sequence
<220>
<221>
<222>
＜223〉the GLP-2 analog compounds 8
<400>9
His?Gly?Glu?Gly?Ser?Phe?SerAsp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>10
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 9
<400>10
His?Gly?Glu?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>11
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉form peptide bond with the β carboxyl between the two
<222>(3)..(4)
＜223〉the GLP-2 analog compounds 10
<400>11
His?Gly?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>12
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 11
<220>
＜221〉Xaa is Nle
<222>(10)..(10)
＜223〉the GLP-2 analog compounds 11
<400>12
His?Gly?Glu?Gly?Ser?Phe?Ser?Asp?Glu?Xaa?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>13
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 12
<220>
＜221〉Ala is D-Ala
<222>(2)..(2)
＜223〉the GLP-2 analog compounds 12
<220>
＜221〉Xaa is Nle
<222>(10)..(10)
＜223〉the GLP-2 analog compounds 12
<220>
＜221〉Ala is L-3-(2-naphthyl)-Ala
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 12
<400>13
His?Ala?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Xaa?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?GlnAla?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>14
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 13
<220>
＜221〉Ala is D-Ala
<222>(2)..(2)
＜223〉the GLP-2 analog compounds 13
<220>
＜221〉Xaa is Nle
<222>(10)..(10)
＜223〉the GLP-2 analog compounds 13
<220>
＜221〉Ala is L-3-(1-naphthyl)-Ala
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 13
<400>14
His?Ala?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Xaa?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Ala?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>15
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 14
<220>
＜221〉Ala is D-Ala
<222>(2)..(2)
＜223〉the GLP-2 analog compounds 14
<220>
＜221〉Xaa is Nle
<222>(10)..(10)
＜223〉the GLP-2 analog compounds 14
<220>
＜221〉Ala is L-3-(2 '-quinoline base)-Ala
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 14
<400>15
His?Ala?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Xaa?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?GlnAla?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>16
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 15
<220>
＜221〉Ala is D-Ala
<222>(2)..(2)
＜223〉the GLP-2 analog compounds 15
<220>
＜221〉Xaa is Nle
<222>(10)..(10)
＜223〉the GLP-2 analog compounds 15
<220>
＜221〉Ala is L-3-(3 '-quinoline base)-Ala
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 15
<400>16
His?Ala?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Xaa?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Ala?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>17
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 16
<220>
＜221〉Ala is D-Ala
<222>(2)..(2)
＜223〉the GLP-2 analog compounds 16
<220>
＜221〉Xaa is Nle
<222>(10)..(10)
＜223〉the GLP-2 analog compounds 16
<220>
＜221〉Trp is D-Trp
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 16
<400>17
His?Ala?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Xaa?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>18
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉Trp is D-Trp
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 17
<400>18
His?Gly?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>19
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉Ala is L-3-(1-naphthyl)-Ala
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 18
<400>19
His?Gly?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Ala?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>20
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉Ala is L-3-(2-naphthyl)-Ala
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 19
<400>20
His?Gly?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Gln?Ala?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>21
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉Ala is L-3-(1 '-quinoline base)-Ala
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 20
<400>21
His?Gly?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Ala?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>22
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉Ala is L-3-(2 '-quinoline base)-Ala
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 21
<400>22
His?Gly?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Ala?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>23
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉Trp is D-Trp
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 22
<400>23
His?Gly?Glu?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Gln?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>24
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉Ala is L-3-(2-naphthyl)-Ala
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 23
<400>24
His?Gly?Glu?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Ala?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>25
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉Ala is L-3-(3 '-quinoline base)-Ala
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 24
<400>25
His?Gly?Glu?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Ala?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
<210>26
<211>33
<212>PRT
＜213〉artificial sequence
<220>
＜221〉His is D-His
<222>(1)..(1)
＜223〉the GLP-2 analog compounds 25
<220>
＜221〉Ala is D-Ala
<222>(2)..(2)
＜223〉the GLP-2 analog compounds 25
<220>
＜221〉Xaa is Nle
<222>(10)..(10)
＜223〉the GLP-2 analog compounds 25
<220>
＜221〉Ala is L-3-(3 '-pyridyl)-Ala
<222>(25)..(25)
＜223〉the GLP-2 analog compounds 25
<400>26
His?Ala?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Xaa?Asn?Thr?Ile?Leu?Glu?Asn
1????????????????5???????????????????10??????????????????15
Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Ala?Leu?Ile?Gln?Thr?Lys?Ile?Thr
20??????????????????25??????????????????30
Asp
Claims (17)
1. the glucagon-like peptide-2 analog of general formula below a kind (I) representative, and pharmacologically acceptable salt and their derivative, this derivative comprises the derivative of the glucagon-like peptide-2 analog that is produced through longer chain fatty acid and/or polyoxyethylene glycol and/or the modification of other long-actingization, or the derivative of the pharmacologically acceptable salt of glucagon-like peptide-2 analog:
R1-Z1-X1-X2-X3-Gly-Ser-Phe-Ser-Asp-Glu-X10-X11-Thr-Ile-Leu-X15-X16-Leu-Ala-Ala-Arg-Asp-Phe-Ile-X24-X25-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-(Z2)-R2(I)，
Wherein Z1, Z2, R1 or R2 be not for existing, or be natural or alpha-non-natural amino acid, or be by the peptide sequence with 2 to 33 amino acid units natural and/or that alpha-non-natural amino acid is formed, and X1, X2, X3, X10, X11, X15, X16, X24 or X25 are natural or alpha-non-natural amino acid.
2. glucagon-like peptide-2 analog according to claim 1, wherein X1 is His or D-His.
3. glucagon-like peptide-2 analog according to claim 1 and 2, wherein X2 is D-Ala or Gly.
4. glucagon-like peptide-2 analog according to claim 1 and 2, wherein X10 is Nle or Met.
5. glucagon-like peptide-2 analog according to claim 1 and 2, wherein X15 is Glu or Asp.
6. glucagon-like peptide 2 analogue according to claim 1 and 2, wherein X3 is Glu or Asp, and X3 is with α carboxyl or β carboxyl and Gly formation peptide bond.
7. glucagon-like peptide-2 analog according to claim 1, it has following sequence:
D-His-D-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Nle-Asn-Thr-Ile-Leu-Glu-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp。
8. glucagon-like peptide-2 analog according to claim 1, it has following sequence:
His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Glu-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp。
9. glucagon-like peptide-2 analog according to claim 1, it has following sequence:
His-Gly-Glu-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Glu-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp。
10. glucagon-like peptide-2 analog according to claim 1, it has following sequence:
D-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp。
11. glucagon-like peptide-2 analog according to claim 1, it has following sequence:
D-His-Gly-Glu-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp。
12. the preparation method of the described glucagon-like peptide-2 analog of claim 1 is characterized in that this glucagon-like peptide-2 analog adopts the solid-phase synthesis preparation and uses the reverse phase liquid chromatography purifying.
13. a pharmaceutical composition that comprises the described glucagon-like peptide-2 analog of claim 1 for the treatment of effective dose, it comprises pharmaceutically acceptable carrier and/or cancer chemotherapy medicine.
14. pharmaceutical composition according to claim 13, its formulation are injection or sustained release dosage.
15. purposes that is used for preventing and/or treating the medicine of gastrointestinal mucosa damage associated conditions as claim 13 or 14 described pharmaceutical compositions in preparation, wherein gastrointestinal mucosa damage associated conditions is selected from digestive tract ulcer, malabsorption syndrome, short bowel syndrome, ileocecal valve syndrome, inflammatory bowel, abdomen type sprue diarrhoea, hot belt type sprue diarrhoea, hypogammag lobulinemia type sprue diarrhoea, enteritis, regional enteritis, ulcerative colitis, osteoporosis and/or muscular dystrophy that the gastrointestinal mucosa damage causes, chemotherapy or radiotherapeutic gastrointestinal side effect, preferred diarrhoea, abdominal cramp, vomiting, gastroenteritis due to radiation, transmissible gastroenteritis or infection back gastro-enteritis, the gastrointestinal mucosa damage that toxic agent or chemotherapeutic cause, or the illness of dipeptidyl peptidase-IV mediation.
16. a glucagon-like peptide 2 analogue as claimed in claim 1 is used for preventing and/or treating the purposes of gastrointestinal mucosa damage associated conditions medicine in preparation, wherein gastrointestinal mucosa damage associated conditions is selected from digestive tract ulcer, malabsorption syndrome, short bowel syndrome, ileocecal valve syndrome, inflammatory bowel, abdomen type sprue diarrhoea, hot belt type sprue diarrhoea, hypogammag lobulinemia type sprue diarrhoea, enteritis, regional enteritis, ulcerative colitis, osteoporosis and/or muscular dystrophy that the gastrointestinal mucosa damage causes, chemotherapy or radiotherapeutic gastrointestinal side effect, preferred diarrhoea, abdominal cramp, vomiting, gastroenteritis due to radiation, transmissible gastroenteritis or infection back gastro-enteritis, the gastrointestinal mucosa damage that toxic agent or chemotherapeutic cause, or the illness of dipeptidyl peptidase-IV mediation.
17. a treatment medicine box, it comprises cancer chemotherapy medicine, the described glucagon-like peptide-2 analog of claim 1 and working instructions.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910126363A CN101824087A (en) | 2009-03-05 | 2009-03-05 | Glucagon-like peptide-2 analog as well as preparation method and application thereof |
| CN201210425221.4A CN102942626B (en) | 2009-03-05 | 2009-03-05 | Glucagon-like peptide-2 analog and its production and use |
| PCT/CN2010/070850 WO2010099746A1 (en) | 2009-03-05 | 2010-03-03 | Glucagon-like peptide-2 analogues, preparation method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910126363A CN101824087A (en) | 2009-03-05 | 2009-03-05 | Glucagon-like peptide-2 analog as well as preparation method and application thereof |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210425221.4A Division CN102942626B (en) | 2009-03-05 | 2009-03-05 | Glucagon-like peptide-2 analog and its production and use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101824087A true CN101824087A (en) | 2010-09-08 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910126363A Pending CN101824087A (en) | 2009-03-05 | 2009-03-05 | Glucagon-like peptide-2 analog as well as preparation method and application thereof |
| CN201210425221.4A Expired - Fee Related CN102942626B (en) | 2009-03-05 | 2009-03-05 | Glucagon-like peptide-2 analog and its production and use |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201210425221.4A Expired - Fee Related CN102942626B (en) | 2009-03-05 | 2009-03-05 | Glucagon-like peptide-2 analog and its production and use |
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| Country | Link |
|---|---|
| CN (2) | CN101824087A (en) |
| WO (1) | WO2010099746A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212127A (en) * | 2011-05-17 | 2011-10-12 | 成都因尔美科技有限公司 | Glucagon-like peptide-2 poly(ethylene glycol) conjugate, and preparation method and application thereof |
| CN104045707A (en) * | 2013-03-14 | 2014-09-17 | 深圳翰宇药业股份有限公司 | Purification method of teduglutide |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104072605B (en) * | 2013-03-27 | 2017-03-29 | 深圳翰宇药业股份有限公司 | A kind of preparation method for degree Shandong peptide |
| CN104072603B (en) * | 2013-03-27 | 2017-09-05 | 深圳翰宇药业股份有限公司 | It is a kind of to synthesize for the method for degree Shandong peptide |
| US20150158926A1 (en) | 2013-10-21 | 2015-06-11 | Opko Biologics, Ltd. | Long-acting polypeptides and methods of producing and administering same |
| CN108226318A (en) * | 2016-12-21 | 2018-06-29 | 鲁南制药集团股份有限公司 | A kind of analyzing detecting method of N- fluorenylmethyloxycarbonyls-l-Alanine |
| CN115636876A (en) * | 2021-07-20 | 2023-01-24 | 重庆派金生物科技有限公司 | Directional chemical conjugate of glucagon-like peptide-2 mutant and application thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5990077A (en) * | 1995-04-14 | 1999-11-23 | 1149336 Ontario Inc. | Glucagon-like peptide-2 and its therapeutic use |
| WO1997039031A1 (en) * | 1996-04-12 | 1997-10-23 | 1149336 Ontario Inc. | Glucagon-like peptide-2 analogs |
| CA2264243C (en) * | 1996-08-30 | 2004-10-05 | Novo Nordisk A/S | Glp-1 derivatives |
| DE19909101C2 (en) * | 1999-03-02 | 2001-06-28 | Danfoss As | Control unit for a thermostatic valve attachment |
| CN1705681A (en) * | 2002-10-14 | 2005-12-07 | 诺沃挪第克公司 | GLP-2 compounds, formulations, and uses thereof |
| AU2006242998B2 (en) * | 2005-05-04 | 2012-03-22 | Zealand Pharma A/S | Glucagon-like-peptide-2 (GLP-2) analogues |
| BRPI0718566A2 (en) * | 2006-11-08 | 2014-03-11 | Zealand Pharma As | PEPTIDE, ANALOG OF THE SAME, PHARMACEUTICAL COMPOSITION, USES OF A PEPTIDE ANALOG, AND OF A NUCLEIC ACID MOLECULE, OF AN EXPRESSION VECTOR, OR A HOSPITAL CELL, MUSCLES OF THE EXECULAUS CULUS, PRODUCE PEPTIDE-2 TYPE-GLUCAGON ANALOGUE (GLP-2), AND, THERAPEUTIC KIT. |
-
2009
- 2009-03-05 CN CN200910126363A patent/CN101824087A/en active Pending
- 2009-03-05 CN CN201210425221.4A patent/CN102942626B/en not_active Expired - Fee Related
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2010
- 2010-03-03 WO PCT/CN2010/070850 patent/WO2010099746A1/en active Application Filing
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212127A (en) * | 2011-05-17 | 2011-10-12 | 成都因尔美科技有限公司 | Glucagon-like peptide-2 poly(ethylene glycol) conjugate, and preparation method and application thereof |
| CN102212127B (en) * | 2011-05-17 | 2015-02-04 | 上海景泽生物技术有限公司 | Glucagon-like peptide-2 poly(ethylene glycol) conjugate, and preparation method and application thereof |
| CN104045707A (en) * | 2013-03-14 | 2014-09-17 | 深圳翰宇药业股份有限公司 | Purification method of teduglutide |
| CN104045707B (en) * | 2013-03-14 | 2017-02-08 | 深圳翰宇药业股份有限公司 | Purification method of teduglutide |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102942626A (en) | 2013-02-27 |
| WO2010099746A1 (en) | 2010-09-10 |
| CN102942626B (en) | 2015-11-04 |
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