US20100081788A1 - Process for the Preparation of Pramlintide - Google Patents
Process for the Preparation of Pramlintide Download PDFInfo
- Publication number
- US20100081788A1 US20100081788A1 US12/553,567 US55356709A US2010081788A1 US 20100081788 A1 US20100081788 A1 US 20100081788A1 US 55356709 A US55356709 A US 55356709A US 2010081788 A1 US2010081788 A1 US 2010081788A1
- Authority
- US
- United States
- Prior art keywords
- asn
- tbu
- trt
- thr
- pro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/815—Protease inhibitors from leeches, e.g. hirudin, eglin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
Definitions
- the present invention relates to the efficient commercial synthesis for the making of pramilintide, a synthetic analog of human amylin which is a peptide hormone.
- Pramilintide is indicated to treat type 1 and type 2 diabetics who use insulin.
- the process for making pramilintide substantially comprises the syntheses of various fragments of the polypeptide and the coupling of the fragments to produce pramilintide.
- pramlintide is disclosed in U.S. Pat. No. 5,686,411, which is herein incorporated in its entirety by reference.
- Pramlintide is known to be prepared by solid phase synthesis that successively adds the desired amino acid to a growing peptide chain.
- an ⁇ -N-carbamoyl protected amino acid and an amino acid attached to the growing peptide chain on a resin support are reacted at room temperature in an inert solvent in the presence of coupling agents such as dicyclohexylcarbodiimide 1-hydroxybenzotriazole in the presence of a base.
- the ⁇ -N-carbamoyl protecting group is removed from the resultant peptide with a reagent such as trifluoroacetic acid or piperidine, and the coupling reaction repeated with the next desired N-protected amino acid.
- a reagent such as trifluoroacetic acid or piperidine
- Suitable N-protecting groups are known in the art, with t-butyloxycarbonyl herein preferred.
- U.S. Pat. No. 5,424,394 provides a classical stepwise approach for the synthesis of amylin and amylin analogues. Single amino acid residues are covalently coupled to a growing peptide chain which is covalently linked to a solid resin support. The synthetic route is very lengthy and inefficiently since several coupling and deprotected steps have to be repeated.
- the present invention provides a more efficient synthesis of pramlintide and the yield and purity of final product will be improved in view of the prior art.
- the present invention provides for an efficient process for making pramlinitide that is high in yield and scalable for commercial production.
- the process comprises the stepwise synthesis of amino acid segments, and the coupling together of these segments to produce pramlinitide.
- the present invention provides for four novel intermediate amino acid segments for the preparation of pramlintide.
- the four segments are synthesized in solid phase synthesis and the coupling reaction is performed in solution phase.
- the segments are produced by coupling a protected designated amino acid to a growing peptide chain that is covalently linked to an insoluble solid resin support.
- the “protected designated amino acid” refers to single amino acid (having protected sidechains and amino termini) which generally proceed from the carboxy-terminal end to the amino-terminal end to give a peptide of specified sequence.
- a “growing peptide chain” refers to a general cycle of synthesis comprising deprotection of the ⁇ -amino group of the resin-bound amino acid or peptide, followed by reaction (coupling) of the free ⁇ -amino group with some carboxyl-activated form of the next ⁇ -amino protected amino acid to form a peptide linkage and to give a support-bound peptide.
- the Fmoc protecting group was removed by treatment with 20% piperidine in DMF twice for 10 min and 30 min, respectively.
- the second amino acid (Fmoc-Cys (Acm)-OH) was introduced to start the first coupling step.
- the Fmoc protected amino acid was activated in situ using 1:1:2 molar ratio of HBTU (O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate)/HOBt (N-Hydroxybenzotriazole)/DIEA in DMF and subsequently coupled to the growing peptide on resin for 3 h.
- the peptide was cleaved from the peptide on resin (8 g) prepared as described above, using 20% TFE solution in DCM for 2 h.
- the peptide solution was solvent replaced by MeOH and concentrated (30 mL).
- the concentrated residue was cooled and the product was precipitated by adding water (30 mL).
- the precipitated product was separated by filtration and washed with mixed solvent of MeOH/water (10 mL/10 mL) twice to give Boc-Lys(Boc)-Cys(Acm)-Asn(Trt)-Thr(tBu)-Ala-Thr(tBu)-Cys(Acm)-Ala-OH(S1a).
- the second amino acid (Fmoc-His(Trt)-OH) was introduced to start the first coupling step.
- the Fmoc protected amino acid was activated in situ using 1:1:2 molar ratio of HBTU/HOBt/DIEA in DMF and subsequently coupled to the growing peptide on resin for 3 h. Completion of the coupling was indicated by a Kaiser test.
- the Fmoc protecting group on the ⁇ -amine was removed with 20% piperidine in DMF twice for 10 min and 30 min, respectively. These steps were repeated each time with another amino acid according to peptide sequence. All amino acids used were Fmoc-N ⁇ protected.
- Trifunctional amino acids were side chain protected as follows: Asn(Trt)-OH, Arg(Pbf)-OH, Gln(Trt)-OH and Thr(tBu)-OH. Three equivalents of the activated amino acids were employed in the coupling reactions. At the end of the synthesis the growing peptide on resin was washed with DMF, MeOH followed by MTBE, and dried under vacuum to give dry peptide on resin.
- the peptide was cleaved from the peptide on resin (24 g) prepared as described above, using 20% TFE solution in DCM for 2 h.
- the peptide solution was solvent replaced by MeOH and concentrated (50 mL).
- the product was absolutely precipitated by adding cool MeOH (50 mL) to the concentrated residue.
- the product was separated by filtration and washed with cool MeOH (20 mL) twice to give S2 (Fmoc-Thr(tBu)-Gln(Trt)-Arg(Pbf)-Leu-Ala-Asn(Trt)-Phe-Leu-Val-His(Trt)-Ser(tBu)-O H, 12 g).
- the Fmoc protected amino acid was activated in situ using 1:1:2 molar ratio of HBTU/HOBt/DIEA in DMF and subsequently coupled to the growing peptide on resin for 3 h. Completion of the coupling was indicated by a Kaiser test. After washing of the resin, the Fmoc protecting group on the ⁇ -amine was removed with 20% piperidine in DMF twice for 10 min and 30 min, respectively. These steps were repeated each time with another amino acid according to peptide sequence. All amino acids used were Fmoc-N ⁇ protected. Trifunctional amino acids were side chain protected as follows: Ser(tBu)-OH, and Asn(Trt)-OH. Three equivalents of the activated amino acids were employed in the coupling reactions. At the end of the synthesis the growing peptide on resin was washed with DMF, MeOH followed by MTBE, and dried under vacuum to give dry peptide on resin.
- the peptide was cleaved from the growing peptide on resin (10 g) prepared as described above, using 1% TFA solution in DCM for 1.5 h. After neutralizing with Pyridine the peptide solution was concentrated (15 mL). The product was precipitated by adding the concentrated residue into Heptanes (50 mL). The product was separated by filtration and washed with mixed solvent of DCM/Heptanes (1 mL/3 mL) three times to give S3 (Fmoc-Ser(tBu)-Asn(Trt)-Asn(Trt)-Phe-Gly-Pro-Ile-Leu-Pro-Pro-OH, 5.2 g).
- the second amino acid (Fmoc-Asn(Trt)-OH) was introduced to start the first coupling step.
- the Fmoc protected amino acid was activated in situ using 1:1:2 molar ratio of HBTU/HOBt/DIEA in DMF and subsequently coupled to the growing peptide on resin for 3 h. Completion of the coupling was indicated by a Kaiser test.
- the Fmoc protecting group on the ⁇ -amine was removed with 20% piperidine in DMF twice for 10 min and 30 min, respectively. These steps were repeated each time with another amino acid according to peptide sequence. All amino acids used were Fmoc-N ⁇ protected.
- Trifunctional amino acids were side chain protected as follows: Ser(tBu)-OH, Asn(Trt)-OH and Thr(tBu)-OH. Three equivalents of the activated amino acids were employed in the coupling reactions. At the end of the synthesis the growing peptide on resin was washed with DMF, MeOH followed by MTBE, and dried under vacuum to give dry peptide on resin.
- the peptide was cleaved from the peptide on resin (23 g) prepared as described above, using 20% TFE solution in DCM for 2 h.
- the peptide solution was solvent replaced by MeOH and concentrated (60 mL).
- the product was precipitated by adding MeOH (50 mL) to the concentrated residue.
- the product was separated by filtration and washed with MeOH/water (20 mL) twice to give S4 (Fmoc-Thr(tBu)-Asn(Trt)-Val-Gly-Ser(tBu)-Asn(Trt)-Thr(tBu)-OH, 10.6 g)
- the reaction mixture is warmed to 20 to 30° C. and kept for 15 hr. Diethylamine (DEA) (0.42 Kg; 10.0 eq.) is charged while maintaining the temperature at 25° C.
- DEA Diethylamine
- the reaction mixture is stirred at 20 to 30° C. for 2 hr.
- Ethyl acetate (EA) (7.38 Kg) and softened potable water (SPW) (50.0 Kg) are slowly added to the reaction mixture while maintaining the temperature at 35° C. until the cloud point is observed and held at cloud point for 1 hr. The remained SPW is added while maintaining the temperature at 35° C.
- the wet cake is purged by nitrogen for 1 hr and dried at 50° C. for 5 hr to get M2 (Thr(tBu)Asn(Trt)ValGlySer(tBu)Asn(Trt)Thr(tBu) Tyr(tBu)-NH 2 ) (about 0.81 Kg).
- Ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride (0.30 Kg; 3.0 eq) is charged into the resulting mixture while maintaining the temperature at 20 to 30° C. and stirred for 3 hr.
- Ethyl acetate (EA) (5.1 Kg) and SPW (43.6 Kg) are slowly added into the reaction mixture while maintaining the temperature at 35° C. until the cloud point is observed and held at cloud point for 1 hr. The remained SPW is added while maintaining the temperature at 35° C.
- the solid is filtered and washed by MeOH twice. The wet cake is purged with nitrogen for 1 hr and dried at 50° C.
- the wet cake is purged with nitrogen for 1 hr and dried at 50° C. for 5 hr to provide M4 (Ser(tBu)Asn(Trt)Asn(Trt)PheGlyProlleLeuProProThr(tBu)Asn(Trt)ValGlySer(tBu) Asn(Trt)Thr(tBu)Tyr(tBu)-NH 2 ) (about 1.32 Kg).
- M5 (2.16 Kg; 1.0 eq) and dichloromethane (DCM) (28.7 Kg) are charged into a suitable reactor under nitrogen. Then piperidine (0.32 Kg; 10.0 eq) is charged while maintaining the temperature at 20 to 30° C. and stirred for 2 hr. Methyl-t-butyl ether (MTBE) (47.9 Kg) is slowly added while maintaining the temperature at 0 to 10° C. until the cloud point is observed and held at cloud point for 1 hr. The remained MTBE is added while maintaining the temperature at 0 to 10° C.
- MTBE Methyl-t-butyl ether
- the wet cake is purged with nitrogen for 1 hr and dried at 50° C. for 5 hr to provide M6 (Thr(tBu)Gln(Trt)Arg(Pbf)LeuAlaAsn(Trt)Phe LeuValHis(Trt)Ser(tBu)Ser(tBu)Asn(Trt)Asn(Trt)PheGlyProlleLeuProProThr(tBu) Asn(Trt)ValGlySer(tBu)Asn(Trt)Thr(tBu)Tyr(tBu)-NH 2 ) (about 1.87 Kg).
- 1-hydroxy-7-azabenzotriazole (0.14 Kg; 3.0 eq.) are charged into a suitable reactor under nitrogen.
- M7 (2.09 Kg) is charged into reactor I under nitrogen.
- the solid is kept at temperature 0 to 10° C.
- SPW 0.52 Kg
- TEA trifluoroacetic acid
- TIS triisopropylsilane
- the mixed solution in reactor II is cooled to 0 to 10° C. and charged into reactor I at 25° C.
- the reaction mixture is stirred at 20-30° C. for 3 hr.
- the reaction mixture is cooled to 0 to 10° C. and the pre-cooled (0 to 10° C.) methyl-t-butyl ether (MTBE) (61.85 Kg) is slowly charged at 15° C. and stirred for 1 hr.
- the solid product is filtered and washed with methyl-t-butylether (MTBE) twice and tetrahydrofuran (THF) twice.
- the wet cake is purged with nitrogen for 1 hr and dried at 50° C. for 6 hr to provide pramlintide acetate (about 1.21 Kg).
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Diabetes (AREA)
- Gastroenterology & Hepatology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Tropical Medicine & Parasitology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Obesity (AREA)
- Analytical Chemistry (AREA)
- Zoology (AREA)
- Emergency Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/553,567 US20100081788A1 (en) | 2008-09-03 | 2009-09-03 | Process for the Preparation of Pramlintide |
US13/113,354 US20110288235A1 (en) | 2008-09-03 | 2011-05-23 | Process for the Preparation of Pramlintide |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US19092808P | 2008-09-03 | 2008-09-03 | |
US12/553,567 US20100081788A1 (en) | 2008-09-03 | 2009-09-03 | Process for the Preparation of Pramlintide |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/113,354 Continuation-In-Part US20110288235A1 (en) | 2008-09-03 | 2011-05-23 | Process for the Preparation of Pramlintide |
Publications (1)
Publication Number | Publication Date |
---|---|
US20100081788A1 true US20100081788A1 (en) | 2010-04-01 |
Family
ID=41726391
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/553,567 Abandoned US20100081788A1 (en) | 2008-09-03 | 2009-09-03 | Process for the Preparation of Pramlintide |
US12/553,482 Active 2030-01-06 US8252896B2 (en) | 2008-09-03 | 2009-09-03 | Process for making bivalirudin |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/553,482 Active 2030-01-06 US8252896B2 (en) | 2008-09-03 | 2009-09-03 | Process for making bivalirudin |
Country Status (11)
Country | Link |
---|---|
US (2) | US20100081788A1 (he) |
EP (2) | EP2334314A4 (he) |
JP (2) | JP5788321B2 (he) |
KR (2) | KR20110056536A (he) |
CN (2) | CN102164608A (he) |
AR (2) | AR073544A1 (he) |
AU (2) | AU2009288036A1 (he) |
CA (2) | CA2736113A1 (he) |
IL (2) | IL211556A0 (he) |
TW (2) | TW201024316A (he) |
WO (2) | WO2010028131A1 (he) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100249370A1 (en) * | 2007-06-29 | 2010-09-30 | Lonza Ag | Process for the production of pramlintide |
CN102180943A (zh) * | 2010-12-16 | 2011-09-14 | 深圳市健元医药科技有限公司 | 一种辅助降血糖多肽药物的生产工艺 |
CN104861045A (zh) * | 2014-02-20 | 2015-08-26 | 复旦大学 | 环肽化合物gg6f及其制备方法 |
USRE46830E1 (en) | 2004-10-19 | 2018-05-08 | Polypeptide Laboratories Holding (Ppl) Ab | Method for solid phase peptide synthesis |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2916716C (en) * | 2008-12-29 | 2018-06-26 | Lonza Braine Sa | Peptide intermediates used in the production of bivalirudin |
WO2013042129A1 (en) * | 2011-09-23 | 2013-03-28 | Natco Pharma Limited | Improved process for preparation of bivalirudin |
WO2014032257A1 (zh) * | 2012-08-30 | 2014-03-06 | 深圳翰宇药业股份有限公司 | 一种比伐卢定的制备方法 |
US10087221B2 (en) | 2013-03-21 | 2018-10-02 | Sanofi-Aventis Deutschland Gmbh | Synthesis of hydantoin containing peptide products |
CA2907521C (en) | 2013-03-21 | 2021-04-13 | Sanofi-Aventis Deutschland Gmbh | Synthesis of cyclic imide containing peptide products |
ES2939036T3 (es) * | 2019-01-24 | 2023-04-18 | Dsm Ip Assets Bv | Método de precipitación de péptidos |
CN111499719B (zh) * | 2020-03-19 | 2022-04-08 | 杭州固拓生物科技有限公司 | 一种合成普兰林肽的方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5998367A (en) * | 1991-03-08 | 1999-12-07 | Amylin Corporation | Pramlintide pro H-amylin salts and compositions |
Family Cites Families (15)
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US5196404B1 (en) | 1989-08-18 | 1996-09-10 | Biogen Inc | Inhibitors of thrombin |
US5240913A (en) * | 1989-08-18 | 1993-08-31 | Biogen, Inc. | Inhibitors of thrombin |
WO1992015317A1 (en) | 1991-03-08 | 1992-09-17 | Amylin Pharmaceuticals, Inc. | Synthetic preparation of amylin and amylin analogues |
GB9708918D0 (en) | 1997-05-01 | 1997-06-25 | Ppl Therapeutics Scotland Ltd | Methods |
US6821954B2 (en) * | 1997-09-18 | 2004-11-23 | Auckland Uniservices Limited | Compounds and uses thereof in treating bone disorders |
ES2245505T3 (es) * | 1998-03-23 | 2006-01-01 | Trimeris Inc. | Metodos y composiciones para la sintesis de peptidos (t-20). |
CN102225966B (zh) | 2004-10-19 | 2012-12-26 | 隆萨股份公司 | 用于固相肽合成的方法 |
BRPI0518390A2 (pt) * | 2004-10-26 | 2008-11-18 | Lonza Ag | mÉtodo de sÍntese de peptÍdeo, e respectivo peptÍdeo |
MX2008003552A (es) | 2005-09-14 | 2008-11-12 | Novetide Ltd | Proceso para la produccion de bivalirudina. |
US20070213505A1 (en) * | 2006-03-08 | 2007-09-13 | David Epstein | Solution Synthesis of Peptide Cell Growth Stimulators |
CN101033249B (zh) | 2006-03-10 | 2011-05-11 | 周逸明 | 固相多肽合成比筏芦定的制备方法 |
WO2008109079A2 (en) | 2007-03-01 | 2008-09-12 | Novetide, Ltd. | High purity peptides |
US20100249370A1 (en) * | 2007-06-29 | 2010-09-30 | Lonza Ag | Process for the production of pramlintide |
US20090062511A1 (en) | 2007-09-05 | 2009-03-05 | Raghavendracharyulu Venkata Palle | Process for the preparation of bivalirudin and its pharmaceutical compositions |
CA2916716C (en) * | 2008-12-29 | 2018-06-26 | Lonza Braine Sa | Peptide intermediates used in the production of bivalirudin |
-
2009
- 2009-09-03 CN CN2009801378950A patent/CN102164608A/zh active Pending
- 2009-09-03 AU AU2009288036A patent/AU2009288036A1/en not_active Abandoned
- 2009-09-03 AU AU2009288027A patent/AU2009288027B2/en not_active Ceased
- 2009-09-03 JP JP2011526190A patent/JP5788321B2/ja not_active Expired - Fee Related
- 2009-09-03 AR ARP090103394A patent/AR073544A1/es unknown
- 2009-09-03 US US12/553,567 patent/US20100081788A1/en not_active Abandoned
- 2009-09-03 CA CA2736113A patent/CA2736113A1/en not_active Abandoned
- 2009-09-03 CN CN2009801379027A patent/CN102164609A/zh active Pending
- 2009-09-03 US US12/553,482 patent/US8252896B2/en active Active
- 2009-09-03 EP EP09812207A patent/EP2334314A4/en not_active Withdrawn
- 2009-09-03 JP JP2011526194A patent/JP2012502045A/ja active Pending
- 2009-09-03 TW TW098129667A patent/TW201024316A/zh unknown
- 2009-09-03 AR ARP090103393A patent/AR073360A1/es unknown
- 2009-09-03 KR KR1020117007671A patent/KR20110056536A/ko not_active Application Discontinuation
- 2009-09-03 CA CA2736126A patent/CA2736126C/en not_active Expired - Fee Related
- 2009-09-03 TW TW098129702A patent/TWI395752B/zh not_active IP Right Cessation
- 2009-09-03 WO PCT/US2009/055867 patent/WO2010028131A1/en active Application Filing
- 2009-09-03 EP EP09812204.7A patent/EP2349307B1/en not_active Not-in-force
- 2009-09-03 WO PCT/US2009/055853 patent/WO2010028122A1/en active Application Filing
- 2009-09-03 KR KR1020117007669A patent/KR101634830B1/ko active IP Right Grant
-
2011
- 2011-03-03 IL IL211556A patent/IL211556A0/en unknown
- 2011-03-03 IL IL211555A patent/IL211555A/he active IP Right Grant
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5998367A (en) * | 1991-03-08 | 1999-12-07 | Amylin Corporation | Pramlintide pro H-amylin salts and compositions |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE46830E1 (en) | 2004-10-19 | 2018-05-08 | Polypeptide Laboratories Holding (Ppl) Ab | Method for solid phase peptide synthesis |
US20100249370A1 (en) * | 2007-06-29 | 2010-09-30 | Lonza Ag | Process for the production of pramlintide |
CN102180943A (zh) * | 2010-12-16 | 2011-09-14 | 深圳市健元医药科技有限公司 | 一种辅助降血糖多肽药物的生产工艺 |
CN104861045A (zh) * | 2014-02-20 | 2015-08-26 | 复旦大学 | 环肽化合物gg6f及其制备方法 |
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