WO2015022575A2 - Procédé de préparation d'un agoniste de gc-c - Google Patents

Procédé de préparation d'un agoniste de gc-c Download PDF

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Publication number
WO2015022575A2
WO2015022575A2 PCT/IB2014/001570 IB2014001570W WO2015022575A2 WO 2015022575 A2 WO2015022575 A2 WO 2015022575A2 IB 2014001570 W IB2014001570 W IB 2014001570W WO 2015022575 A2 WO2015022575 A2 WO 2015022575A2
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WO
WIPO (PCT)
Prior art keywords
cys
formula
resin
linaclotide
trt
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PCT/IB2014/001570
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English (en)
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WO2015022575A3 (fr
Inventor
Agasaladinni NAGANA GOUD
Vadlamani SURESH KUMAR
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Auro Peptides Ltd
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Publication of WO2015022575A2 publication Critical patent/WO2015022575A2/fr
Publication of WO2015022575A3 publication Critical patent/WO2015022575A3/fr

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    • 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
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • 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

Definitions

  • the present invention relates to a process for the preparation of Linaclotide of formula I.
  • Linaclotide is a guanylate cyclase-C (GC-C) agonist.
  • Guanylate cyclase C refers to a transmembrane form of guanylate cyclase that acts as the intestinal receptor for the heat-stable toxin (ST) peptides secreted by enteric bacteria.
  • ST heat-stable toxin
  • Guanylate cyclase C is also the receptor for the naturally occurring peptides guanylin and uroguanylin.
  • Linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. In animal models, Linaclotide has been shown to both accelerate GI transit and reduce intestinal pain.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • Linaclotide-induced reduction in visceral pain in animals is thought to be mediated by increased extracellular cGMP, which was shown to decrease the activity of pain-sensing nerves.
  • Linaclotide is a peptide having 14 amino acids, with the sequence Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr. This molecule is cyclical by forming three disulfide bonds between Cysi and Cys 6 , between Cys 2 and Cysi 0 and between Cys 5 and Cys 13 .
  • Linaclotide is marketed in USA under the trade name LINZESS in the form of capsules having dosage forms 145 meg and 290 meg for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation.
  • Linaclotide for first time disclosed in US 7,304,036 discloses two different methods for the preparation of Linaclotide either by solid phase synthesis or by recombinant DNA technology.
  • Solid-phase synthesis is carried out by sequential addition of amino acids (Boc/Fmoc strategy) using an automated peptide synthesizer such as Cyc(4-CH2Bxl)-OCH2-4-(oxymethyl)-phenylacetamidomethyl resin to yield linear protected Linaclotide, which is deprotected and cleaved from resin using hydrogen fluoride, dimethyl sulfide, anisole and p-thiocresol. Thereafter obtained linear Linaclotide is oxidized, then purified using RP-HPLC and lyophilized to obtain Linaclotide in 10-20% yield.
  • Biopolymers, Issue 96, Volume 1 , Pages 69-80 also discloses synthesis of Linaclotide by solid phase synthesis, following sequential addition of amino acids to the supported resin (Wang or 2-chlorotrityl resin) and thereafter cleaved from resin and de-protection is carried out in two steps.
  • the above processes disclose synthesis of Linaclotide by sequential addition of amino acids to a solid support resin.
  • the disadvantage of this process is that the final compound is obtained with inconsistent yields, because of premature loss of peptide during synthesis.
  • WO 2012/1 18972 discloses a process for the preparation of Linaclotide by coupling the two fragments in solution phase in presence of a coupling agents HBTU, Cl-HOBt, DIPEA, DMF to obtain linear protected Linaclotide, which is deprotected in presence of TFA:EDT:TIS:H 2 0 and oxidation in presence of sodium bicarbonate and glutathione hydrochloride, followed by purification using preparative RP-HPLC and lyophilization.
  • the disadvantage of the above process is that the end product will be contaminated with many impurities which are difficult to remove latter.
  • the present inventors have found a new process of making Linaclotide, which is simple and industrially scalable with consistent yields. Further, the Linaclotide obtained by the process of the present invention results in higher yield and purity.
  • An objective of the present invention is to provide a process for preparing Linaclotide, which is simple, industrially applicable and economically viable.
  • Another objective of the present invention is to provide a process for preparing Linaclotide, which is having high purity.
  • the present invention relates to a process for the preparation of Linaclotide of formula I.
  • FIGURES Figure 1 Synthesis of Linaclotide by coupling two fragments on solid phase peptide synthesis.
  • the present invention relates to a process for the preparation of Linaclotide by coupling of two protected suitable fragments in presence of a coupling agent, cleavage and de- protection of peptide, oxidation and isolation of Linaclotide.
  • Linaclotide The use of two or three suitable fragments to prepare Linaclotide according to the present invention leads to a better quality product, particularly with low level of impurities. Further, such process is easier to use and less time-consuming; furthermore, such process leads to a higher yield of Linaclotide.
  • the yield of the crude Linaclotide (protected) by fragment coupling method was greater than 80% when cleaved it from the insoluble support, whereas in straight-through synthesis there was inconsistency in the yields and loss of peptide due to premature cleavage during straight through synthesis.
  • the Linaclotide prepared using the process of the present invention results in substantially high yield.
  • the present invention relates to the preparation of Linaclotide of high purity.
  • one or more of the different factors relating to the agents and their quantities which are used in carrying out the various steps to prepare Linaclotide; the manner in which the steps are carried out; the methods used; and the various process parameters such as the temperature, pH, concentration, etc. are optimized and controlled in proper manner so as to obtain the desired product in a consistent manner.
  • the present invention relates to a process for the preparation of Linaclotide by coupling of two protected suitable fragments by solid phase synthesis in presence of a coupling agent, cleavage and de-protection of peptide, oxidation and isolation of Linaclotide.
  • the present invention relates to a process for the preparation of Linaclotide by coupling of two protected suitable fragments by solid phase synthesis in the presence of a coupling agent.
  • the coupling agent are selected from the group comprising of HOBt, TBTU, DCC, DIC, HBTU, BOP, PyBOP, PyBrOP, PyClOP, Oxyma Pure, TCTU, EEDQ, COMU, DEPBT and the like, and mixtures thereof.
  • the coupling takes place in one of the solvents selected from the group comprising of DMF, DCM, THF, NMP, DMAC or mixtures thereof.
  • the solid phase synthesis is carried out on an insoluble polymer which is acid sensitive.
  • An acid sensitive resin is selected from a group comprising CTC, Sasrin, Wang Resin, 4-methytrityl chloride, TentaGel S and TentaGel TGA.
  • the linear protected peptide is de- protected with a mixture of reagents selected from the group comprising of TFA, TIS, DTT, EDT, ammonium iodide, 2,2'-(ethylenedioxy)diethane and acetyl cystein, DMS, phenol, cresol and thiocresol.
  • a mixture of reagents selected from the group comprising of TFA, TIS, DTT, EDT, ammonium iodide, 2,2'-(ethylenedioxy)diethane and acetyl cystein, DMS, phenol, cresol and thiocresol.
  • the oxidation step in the process of preparation of Linaclotide comprises the use of an oxidizing agent.
  • the oxidizing agent is selected from a group comprising of hydrogen peroxide, dimethyl sulfoxide (DMSO), glutathione, and the like, and a mixture thereof.
  • the oxidation is carried out in a buffer.
  • the buffer is selected from a group comprising of ammonium acetate, sodium carbonate, ammonium bicarbonate, water, and the like, and a mixture thereof.
  • the oxidation is carried out in a buffer solution at a pH range of about 7 to about 9.
  • the final isolation of Linaclotide is carried out by lyophilization.
  • the lyophilization is earned out in a controlled manner such that the stability of Linaclotide is not affected.
  • purification of Linaclotide is carried out by Reverse Phase HPLC and size exclusion chromatography.
  • purification of Linaclotide is carried out by Reverse Phase HPLC using ammonium acetate and a mixture of solvents comprising TFA, water, acetic acid and acetonitrile.
  • the purity of Linaclotide achieved by the fragment coupling was greater than 97%, preferably 99% (by analytical HPLC and size exclusion chromatography) and it was free from dimer and multimer impurities.
  • the suitable fragments for the preparation of Linaclotide are as follows:
  • a process for the preparation of Linaclotide comprises of the following steps:
  • Another embodiment of the present invention relates to synthesis of fragment of Formula II by sequential addition of amino acids to a solid support.
  • synthesis of fragment of Formula III either by sequential addition of amino acids to a solid support or coupling of two suitable fragments using solid phase synthesis.
  • Yet another embodiment of the present invention relates to the synthesis of fragment of Formula III, by coupling the fragments Formula IV and Formula V using solid phase synthesis.
  • Z represents thiol protecting group
  • X represents carboxyl, phenolic and alcoholic protecting groups
  • Y represents amino protecting group
  • ⁇ represents resin
  • the thiol protecting groups are selected from but not limited to a group comprising Tit, Acm, StBu, Tmob, Tacm, MMT, and the like.
  • the carboxyl, phenolic and alcoholic groups are protected with groups selected from but not limited to a group comprising DMT, MMT, Trt, tert-butyl, t-butoxy carbonyl, and the like.
  • the amino protecting groups are selected from but not limited to a group comprising Fmoc, Boc, Cbz, Bpoc, and the like.
  • CTC Resin 2-ChloroTrityl Resin (150 g) (1.6mmol/g) was transferred to a glass reaction vessel containing a sintered disk.
  • Anhydrous dichloromethane (1 100 ml) was added to the glass vessel and drained after two min.
  • a clear solution of Fmoc-Pro-OH (56 g, 1.2 eqv) dissolved in dry dichloromethane (785 ml) and N,N di-isopropyl ethylamine (1 15 ml) was added.
  • the reaction mixture was stirred mechanically for 3 hrs and the solution was drained out, and the resin was washed with 1% DIPEA in DCM (800 ml).
  • the peptide resin was washed with a mixture of 1 : 1 [10% DIPEA: Methanol; 600 ml]; 1%DIPEA in DCM and with 0.5% DIPEA in MTBE and dried under vacuum.
  • Step (2) Coupling of Fmoc-Asn (Trt) to Pro-CTC-Resin:
  • Fmoc-Pro-Resin from step (1 ) was swelled in dichloromethane (700 ml) for 20 min and dimethylformamide (DMF) (700 ml) for 20 min. 20% piperidine in DMF (750 ml) (5+15 min) was added to the Fmoc-Pro-Resin and the resin was washed with DMF (750 ml), Isopropylalcohol (IPA) (450 ml) and DMF (750 ml). Thereafter resin beads were taken out and checked for Kaiser Test (positive) and chloranil test (positive).
  • DMF dimethylformamide
  • Step (3) Coupling of Fmoc-Cys(Trt)-OH to Asn (Trt)-Pro-Resin.
  • Step (5) Coupling of Fmoc-Tyr(OtBu)-OH to Cys(Trt)-Cys(Trt)-Asn(Trt)-Pro- Resin.
  • Step (6) Coupling of Fmoc-Glu(OtBu)-OH to Tyr(OtBu)-Cys(Trt)-Cys(Trt)- Asn(Trt)-Pro-Resin.
  • Step (7) Coupling of Fmoc-Cys(Trt)-OH to Glu(OtBu)-Tyr(OtBu)-Cys(Trt)- Cys(Trt)-Asn(Trt)-Pro-Resin.
  • Step (8) Coupling of Fmoc-Cys(Trt)-OH to Cys(Trt)-Glu(OtBu)-Tyr(OtBu)- Cys(Trt)-Cys(Trt)-Asn(Trt)-Pro-Resin. 20% piperidine in DMF (750 ml) (5+15 min) was added to Fmoc-Cys(Trt)-Glu(OfBu)- Tyr(OtBu)-Cys (Trt)-Cys(Trt)-Asn(Trt)-Pro-Resin.
  • Step (9) Cleavage of protected peptide from the resin
  • the protected octapeptide (450 g) was cleaved from the solid support by using 0.8% TFA in DCM (4 X 800 ml) and the resulting solution was neutralized by using 10% DIPEA in DCM (4 X 200 ml). The fractions which were found to be UV positive were collected, combined and evaporated.
  • the crude was dissolved in ethyl acetate (2.5 L) and the organic layer was washed with water (500 ml); and 0.1 M NaCl Solution (700 ml). The organic layer was dried over sodiumsulphate, filtered and evaporated to a solid. The solid was treated with MTBE, filtered and dried under vacuum for 16 hrs. Weight: 262 g
  • CTC Resin 2-ChloroTrityl Resin (CTC Resin) (65 g) (1.6mmol/g) was transferred to a glass reaction vessel containing a sintered disk. Anhydrous dichloromethane (400 ml) was added to the glass vessel and drained after two min. A clear solution of Fmoc- Tyr(OtBu)-OH (29 g, 1.1 eqv.) dissolved in dry DCM (300 ml) and N.N di- isopropylethylamine (41 ml) was added. The reaction mixture was stirred mechanically for 3 hrs and the solution was drained out, and the resin was washed with 1 % DIPEA in DCM (400 ml).
  • the peptide resin was washed with a mixture of 1 : 1 [ 10% DIPEA: Methanol; 300 ml], 1% DIPEA in DCM (400 ml), 0.5% DIPEA in MTBE (300 ml) and dried under vacuum.
  • Step (2) Coupling of Fmoc-Cys (Trt) to Tyr (OtBu)-CTC-Resin
  • Fmoc-Tyr(OtBu)-Resin from step (1) was swelled in dichloromethane (250 ml) for 20 min and dimethylformamide (DMF) (250 ml) for 20 min. 20% piperidine in DMF (300 ml) (5+15 min) was added to the Fmoc-Tyr (OtBu)-Resin and the resin was washed with DMF (300 ml), Isopropylalcohol (IP A) (200 ml) and DMF (300 ml). Thereafter resin beads were taken out and checked for Kaiser Test (positive) and chloranil test (positive).
  • Step (3) Coupling of Fmoc-Gly-OH to Cys(Trt)-Tyr-(OtBu)-Resin
  • Step (5) Coupling of Fmoc-Cys(Trt)-OH to Thr(OtBu)-Gly-Cys(Trt)-Tyr(OtBu)- Resin
  • Step (6) Coupling of Fmoc-Ala-OH to Cys-(Trt)-Thr-(OtBu)-Gly-Cys-(Trt)-Tyr- (OtBu)-Resin
  • the experiment conducted for cleavage of Linaclotide (protected) from the peptide resin (190 g) is carried out by using 1% TFA in DCM (4X300 ml) and the resulting solution was neutralized by using 10% DIPEA in DCM (4X100 ml). The fractions which were found to be UV positive were collected, combined and evaporated.
  • the crude was dissolved in ethyl acetate (1.5 L) and the organic layer was washed with water (250 ml); and 0.1 M NaCl Solution (250 ml). The organic layer was dried over sodium sulphate, filtered and evaporated to a solid. The solid was treated with MTBE, filtered and dried under vacuum for 16 hrs.
  • PROCESS FOR PREPARING LINACLOTIDE Linear Linaclotide (10 g) was dissolved in degassed 0.01 M Ammonium bicarbonate (10 L) (pH 8.1 ). After dissolving the compound slowly bubbled the compressed air and added the hydrogen peroxide ( 1 ml). After 18 hrs the completion of the reaction was monitored by reverse phase analytical HPLC. The oxidized product was purified by reverse phase HPLC.
  • the oxidized crude peptide solution obtained from the example 5 was passed through Novasep lab system RP-HPLC system, wavelength 220nm, 1 10 X 700mm column of C I 8 reverse phase column, mobile phase: A : 0.01 M ammonium acetate ; mobile phase B: acetonitrile flow rate: 400 ml / min, peaks of fractions were collected and pooled the fractions having the purity greater than 80%.
  • stage-1 The main pool obtained from the stage-1 were diluted with equal amount of water and passed through Novasep lab system RP-HPLC system, wavelength 220nm, 1 10 X 700mm column of C I 8 reverse phase column, mobile phase: A: 0.1 % TFA in water; mobile phase B: acetonitrile flow rate: 400 ml / min, fractions collected and analyzed by RPHPLC and SEC the fractions having the purity greater than 98% were taken and pooled and taken to the next stage.
  • Stage-3 The main pool obtained from the stage-1 were diluted with equal amount of water and passed through Novasep lab system RP-HPLC system, wavelength 220nm, 1 10 X 700mm column of C I 8 reverse phase column, mobile phase: A: 0.1 % TFA in water; mobile phase B: acetonitrile flow rate: 400 ml / min, fractions collected and analyzed by RPHPLC and SEC the fractions having the purity greater than 98% were taken and pooled and taken to the next
  • the main pool obtained from the stage-2 were diluted with equal amount of water and passed through Novasep lab system RP-HPLC system, wavelength 220nm, 1 10 X 700mm column of C I 8 reverse phase column, mobile phase: A: 0.1% acetic acid in water; mobile phase B: acetonitrile flow rate: 400 ml / min, fractions collected and analyzed by RPHPLC and SEC the fractions having the purity greater than 99% were collected, pooled together, concentrated using rotary evaporation and lyophilized to give pure Linaclotide.

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Abstract

La présente invention concerne un procédé de préparation de Linaclotide par le couplage de deux ou trois fragments appropriés par une synthèse en phase solide.
PCT/IB2014/001570 2013-08-13 2014-08-11 Procédé de préparation d'un agoniste de gc-c WO2015022575A2 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016038497A1 (fr) * 2014-09-08 2016-03-17 Auro Peptides Ltd Procédé de préparation de linaclotide
WO2017134687A1 (fr) * 2016-02-03 2017-08-10 Cipla Limited Procédé de préparation d'agoniste de guanylate cyclase 2c
US20180186838A1 (en) * 2014-12-26 2018-07-05 Bgi Shenzhen CONOTOXIN PEPTIDE k-CPTX-BTL01, PREPARATION METHOD THEREFOR, AND USES THEREOF
US10179802B2 (en) * 2014-12-26 2019-01-15 Bgi Shenzhen Conotoxin peptide κ-CPTX-BTL04, preparation method therefor, and uses thereof
EP3392266A4 (fr) * 2015-12-18 2019-08-14 Hybio Pharmaceutical Co., Ltd Procédé de synthèse de linaclotide
US10556927B2 (en) * 2014-12-26 2020-02-11 Bgi Shenzhen Conotoxin peptide κ-CPTx-btl03, preparation method therefor, and uses thereof
CN111732632A (zh) * 2020-07-16 2020-10-02 台州吉诺生物科技有限公司 一种利那洛肽的合成方法
CN112321681A (zh) * 2020-10-29 2021-02-05 杭州信海医药科技有限公司 一种利那洛肽的制备方法
EP4194464A1 (fr) 2021-12-13 2023-06-14 Chemi SPA Procédé de fabrication pour la production de linaclotide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7304036B2 (en) 2003-01-28 2007-12-04 Microbia, Inc. Methods and compositions for the treatment of gastrointestinal disorders
WO2012118972A2 (fr) 2011-03-01 2012-09-07 Synegy Pharmaceuticals Inc. Procédé de préparation d'agonistes du guanylate cyclase c

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7304036B2 (en) 2003-01-28 2007-12-04 Microbia, Inc. Methods and compositions for the treatment of gastrointestinal disorders
WO2012118972A2 (fr) 2011-03-01 2012-09-07 Synegy Pharmaceuticals Inc. Procédé de préparation d'agonistes du guanylate cyclase c

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BIOPOLYMERS, vol. 1, no. 96, 2011, pages 69 - 80

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016038497A1 (fr) * 2014-09-08 2016-03-17 Auro Peptides Ltd Procédé de préparation de linaclotide
US10501498B2 (en) * 2014-12-26 2019-12-10 Bgi Shenzhen Conotoxin peptide κ-CPTx-BTL01, preparation method therefor, and uses thereof
US20180186838A1 (en) * 2014-12-26 2018-07-05 Bgi Shenzhen CONOTOXIN PEPTIDE k-CPTX-BTL01, PREPARATION METHOD THEREFOR, AND USES THEREOF
US10179802B2 (en) * 2014-12-26 2019-01-15 Bgi Shenzhen Conotoxin peptide κ-CPTX-BTL04, preparation method therefor, and uses thereof
US10556927B2 (en) * 2014-12-26 2020-02-11 Bgi Shenzhen Conotoxin peptide κ-CPTx-btl03, preparation method therefor, and uses thereof
EP3392266A4 (fr) * 2015-12-18 2019-08-14 Hybio Pharmaceutical Co., Ltd Procédé de synthèse de linaclotide
US10442838B2 (en) 2015-12-18 2019-10-15 Hybio Pharmaceutical Co., Ltd. Linaclotide synthesis method
WO2017134687A1 (fr) * 2016-02-03 2017-08-10 Cipla Limited Procédé de préparation d'agoniste de guanylate cyclase 2c
CN111732632A (zh) * 2020-07-16 2020-10-02 台州吉诺生物科技有限公司 一种利那洛肽的合成方法
CN112321681A (zh) * 2020-10-29 2021-02-05 杭州信海医药科技有限公司 一种利那洛肽的制备方法
CN112321681B (zh) * 2020-10-29 2021-12-14 杭州信海医药科技有限公司 一种利那洛肽的制备方法
EP4194464A1 (fr) 2021-12-13 2023-06-14 Chemi SPA Procédé de fabrication pour la production de linaclotide
WO2023110781A1 (fr) 2021-12-13 2023-06-22 Chemi Spa Procédé de fabrication pour produire du linaclotide

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