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US20150087808A1 - Process for the manufacture of cyclic undecapeptides - Google Patents

Process for the manufacture of cyclic undecapeptides Download PDF

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Publication number
US20150087808A1
US20150087808A1 US14/399,261 US201314399261A US2015087808A1 US 20150087808 A1 US20150087808 A1 US 20150087808A1 US 201314399261 A US201314399261 A US 201314399261A US 2015087808 A1 US2015087808 A1 US 2015087808A1
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US
United States
Prior art keywords
cyclosporin
compound
methyl
formula
ethyl
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
Application number
US14/399,261
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English (en)
Inventor
Fabrice Gallou
Bernard RISS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
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Application filed by Novartis AG filed Critical Novartis AG
Priority to US14/399,261 priority Critical patent/US20150087808A1/en
Publication of US20150087808A1 publication Critical patent/US20150087808A1/en
Abandoned legal-status Critical Current

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    • 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
    • C07K1/12—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by hydrolysis, i.e. solvolysis in general
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C07K7/645—Cyclosporins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to novel process(es), novel process step(s) and novel intermediate(s) useful for the opening of Cyclosporin derivatives and subsequently for the preparation of cyclic polypeptides, more specifically, cyclic undecapeptides, such as alisporivir (also known as DEB025, Debio025, or Debio).
  • cyclic undecapeptides such as alisporivir (also known as DEB025, Debio025, or Debio).
  • the present invention relates to processes for the preparation of cyclic polypeptides, such as, for example, cyclic undecapeptides, such as alisporivir.
  • Alisporivir is a cyclophilin (Cyp) inhibitor used for the treatment of hepatitis C virus (HCV) infection or HCV induced disorders as described in WO 2006/038088.
  • Cyp cyclophilin
  • WO2009/042892 describes methods for the use of alisporivir in the treatment of multiple sclerosis
  • WO2009/098577 describes methods for the use of alisporivir in the treatment of muscular dystrophy
  • WO2008/084368 describes methods for the use of alisporivir in the treatment of Ullrich congenital muscular dystrophy.
  • Alisporivir and a synthesis thereof are described in WO 00/01715. Alisporivir has been attributed the CAS Registry Number 254435-95-5.
  • AXX1 MeBmt, Bmt, MeLeu, Desoxy-MeBmt, Methylaminooctanoic acid
  • AXX2 Abu, Ala, Thr, Val, Nva
  • AXX6 MeLeu, Leu
  • AXX10 MeLeu, Leu
  • AXX11 MeVal, Val, D-MeVal
  • Cyclic undecapeptides may be obtained bystrain selection, however obtaining most un-natural derivatives requires a chemical transformation which relies on opening of the cyclic polypeptide, for example, of Formula (Ia) or of Formula (Ib) and subsequent amino acid replacement.
  • cyclic polypeptide for example of Formula (Ia) are opened in a highly selective process and an amino acid residue is removed via the Edman degradation to access the opened cyclic polypeptide as a key intermediate (Wenger, R. M. In Peptides 1996; Ramage, R.; Epton, R., Eds.; The European Peptides Society, 1996; pp. 173; Wenger, R. M. et al. Tetrahedron Letters 2000, 41, 7193.). Numerous scientists and companies have used this reliable and selective strategy wherein pure cyclosporin A and purification by column chromatography have been used to obtain cyclic undecapeptides.
  • purification of products involve several steps of purification by liquid chromatography on silica. Beside the moderate overall obtained yield, the major drawback of this purification scheme is the very high costs for the chromatography steps.
  • Large-scale purification processes of such products derived from cyclosporin A or its structural analogues described in the literature generally involve a chromatographic purification or at least a pre-purification by adsorption chromatography. Such pre-purification may be followed, for instance, by extraction, counterflow extraction, and/or supercritical fluid extraction.
  • dimethoxycarbenium ions (described in Novartis patent application EP 0 908 461 A1 for the methylation of Cephalosporine derivatives), do the same chemistry as oxonium ions (trimethyl or triethyloxonium Meerwein salts) in the opening of the macrocyclic polypeptide.
  • the new conditions can advantageously be prepared in situ, thus avoiding the handling of hazardous and hygroscopic substance, can proceed in a variety of solvents such as for example toluene, xylene, anisole, by-passing the need for using the undesirable chlorinated solvents such as dichloromethane or dichloroethane, and avoid the use of oxonium Meerwein salts originating from the genotoxic epichlorhydrin.
  • Either the dedicated carbenium tetrafluoroborate salt or the in situ generated reactive species made by the reaction of boron trifluoride and an orthoester derivative, preferably trimethyl orthoformate, will result in the desired opened polypeptides such as compound 3 below.
  • opened cyclosporin salts such as hydrochloric acid (HCl), fluoroboric acid (HBF 4 ), or hexafluorophosphoric acid (HPF 6 ), can be formed at several stages.
  • the present invention provides novel crystalline intermediates, such as cylosporine esters, such as acetate, pivaloate, and opened cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G salts such as the HCl salt, the HBF 4 salt, or the HPF 6 salt, and processes to generate them.
  • cylosporine esters such as acetate, pivaloate
  • opened cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G salts such as the HCl salt, the HBF 4 salt, or the HPF 6 salt
  • the method includes the steps of acylation of cyclosporin A, to form acetyl-Cyclosporin A; ring opening of the acetyl-Cyclosporin A; and crystallizing the ring opened acetyl-Cyclosporin A to obtain the compound of formula 3.
  • R is methyl, ethyl, propyl or phenyl and R′ is methyl or ethyl.
  • the method includes the steps of Edman degradation of compound of formula 3; and then crystallizing the compound to obtain the compound of formula 4.
  • the method includes the steps of: acylation of cyclosporin A to form acetyl-Cyclosporin A; ring opening of the acetyl-Cyclosporin A; and crystallizing the ring opened acetyl-Cyclosporin A to obtain the compound of formula 3
  • a compound of formula 3 or a salt thereof is provided
  • R is methyl, ethyl, propyl or phenyl and R′ is methyl or ethyl.
  • a compound of formula 4 or a salt thereof is provided
  • R is methyl, ethyl, propyl or phenyl and R′ is methyl or ethyl.
  • FIG. 1 is a proton NMR spectra for compound 3.
  • FIG. 2 is a proton NMR spectra for compound 4.
  • cyclic undecapeptides such as Alisporivir
  • This general scheme can also be used to make cyclic polypeptides, more specifically, cyclic undecapeptides, derived from cyclosporine A, B, D, or G.
  • alisporivir can be made by converting cyclosporin A (compound (1) wherein R 2 is ethyl) into a compound of formula 4 as shown above by acylation of cyclosporin A, to form acetyl-Cyclosporin A (2); ring opening; crystallization to obtain a compound 3, Edman degradation of compound 3; crystallization to obtain a compound 4 and then cyclizing compound 4 to form alisporivir (as shown below).
  • the invention specially relates to the processes described in each section.
  • the invention likewise relates, independently, to every single step described in a process sequence within the corresponding section. Therefore, each and every single step of any process, consisting of a sequence of steps, described herein is itself a preferred embodiment of the present invention.
  • the invention also relates to those embodiments of the process, according to which a compound obtainable as an intermediate in any step of the process is used as a starting material.
  • the invention also relates to intermediates which have been specifically developed for the preparation of the compounds according to the invention, to their use and to processes for their preparation.
  • Cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G or salts thereof, may be prepared, for example by fermentation.
  • the present invention relates to a method for preparing compound of formula 3, comprising the steps of acylation of cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G to form acetyl-Cyclosporin A, B, D, or G; ring opening; and crystallization.
  • the present invention relates to a method for preparing compound of formula 4 or a salt thereof, comprising Edman degradation, a reaction well known in the art, of a compound of formula 3 and crystallization thereof to obtain compound of formula 4.
  • Another embodiment of the present invention relates to a method for preparing a compound of formula 3 or formula 4 wherein the purity of the Cyclosporin A starting material is >80% by weight.
  • Another embodiment of the present invention relates to a method for preparing a compound of formula 3 or formula 4 wherein the purity of the Cyclosporin A starting material is >85% by weight.
  • Another embodiment of the present invention relates to a method for preparing a compound of formula 3 or formula 4 wherein the purity of the Cyclosporin A starting material is 60 to 80%, weight % assay.
  • R is methyl, ethyl, propyl or phenyl
  • R′ is methyl or ethyl
  • R 2 is methyl, ethyl, or propyl
  • R is methyl, ethyl, propyl or phenyl
  • R′ is methyl or ethyl
  • R 2 is methyl, ethyl, or propyl
  • Acetyl-Cyclosporin A (100 g as is) was reacted with trimethyloxonium tetrafluoroborate (32 g) at 20-25° C. in dichloromethane (180 mL). After 20 h, acetonitrile (200 mL) and water (650 mL) were added to perform the hydrolysis. After 3 h, at 20-25° C., the phases were separated and the reaction mixture was dried by azeotropic distillation with 2-Methyl-Tetrahydrofuran (solvent exchange dichloromethane/2-Methyl-Tetrahydrofuran).
  • the “undecapeptide amino acid” precursor (5 to 13% to the overall end mass) dissolved in dichloromethane and the DCC dissolved into dichloromethane were added continuously in parallel in ca. 10 h to a mixture of Cl-HOBT, and NMM in dichloromethane at 40° C. At the end of the addition, the mixture was stirred for an additional 2 h, filtered to remove the DCU salt and concentrated to give Alisporivir as a crude product.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
US14/399,261 2012-05-09 2013-05-08 Process for the manufacture of cyclic undecapeptides Abandoned US20150087808A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/399,261 US20150087808A1 (en) 2012-05-09 2013-05-08 Process for the manufacture of cyclic undecapeptides

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201261644616P 2012-05-09 2012-05-09
US14/399,261 US20150087808A1 (en) 2012-05-09 2013-05-08 Process for the manufacture of cyclic undecapeptides
PCT/EP2013/059672 WO2013167703A1 (en) 2012-05-09 2013-05-08 Process for the manufacture of cyclic undecapeptides

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/059672 A-371-Of-International WO2013167703A1 (en) 2012-05-09 2013-05-08 Process for the manufacture of cyclic undecapeptides

Related Child Applications (1)

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US15/198,152 Continuation US9840534B2 (en) 2012-05-09 2016-06-30 Process for the manufacture of cyclic undecapeptides

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US15/198,152 Expired - Fee Related US9840534B2 (en) 2012-05-09 2016-06-30 Process for the manufacture of cyclic undecapeptides

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US (2) US20150087808A1 (ja)
EP (1) EP2847211A1 (ja)
JP (3) JP2015517481A (ja)
KR (1) KR20150006435A (ja)
CN (2) CN108715606A (ja)
AR (1) AR090964A1 (ja)
AU (2) AU2013257989A1 (ja)
BR (1) BR112014027648A2 (ja)
CA (1) CA2868940A1 (ja)
CL (1) CL2014003014A1 (ja)
CO (1) CO7141428A2 (ja)
EA (1) EA024903B1 (ja)
EC (1) ECSP14030537A (ja)
HK (1) HK1202555A1 (ja)
IL (1) IL235428A0 (ja)
IN (1) IN2014DN08483A (ja)
MA (1) MA20150231A1 (ja)
MX (1) MX2014013613A (ja)
PE (1) PE20142433A1 (ja)
PH (1) PH12014502499A1 (ja)
SG (1) SG11201406303XA (ja)
TN (1) TN2014000411A1 (ja)
TW (1) TW201350508A (ja)
WO (1) WO2013167703A1 (ja)

Families Citing this family (2)

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CN105693820A (zh) * 2014-11-27 2016-06-22 武汉药明康德新药开发有限公司 一种降解环孢菌素a的方法
EP3623378B1 (en) 2017-05-12 2025-07-02 Chugai Seiyaku Kabushiki Kaisha Method for producing cyclic organic compound

Citations (1)

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Publication number Priority date Publication date Assignee Title
US20140005100A1 (en) * 2010-08-12 2014-01-02 Zhuang Su Novel cyclosporin derivatives for the treatment and prevention of a viral infection

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AT401177B (de) 1993-10-22 1996-07-25 Biochemie Gmbh Verfahren zur herstellung von 7-amino-3-cephem-4-carbonsäure-derivaten
CA2335903C (fr) * 1998-07-01 2009-11-10 Debiopharm S.A. Nouvelle cyclosporine ayant un profil d'activite ameliore
DK1150999T3 (da) * 1999-02-05 2006-10-30 Debiopharm Sa Cyclosporinderivater og fremgangsmåde til fremstilling deraf
CA2444278C (en) * 2001-04-20 2011-11-22 Debiopharm S.A. Modified cyclosporine which can be used as a pro-drug and use thereof
ES2266564T3 (es) * 2001-10-19 2007-03-01 Isotechnika Inc. Sintesis de analogos de cicloporinas.
TW200505946A (en) 2003-04-08 2005-02-16 Hoffmann La Roche Process for preparation of cyclosporin a analog
HRP20110169T1 (hr) * 2004-10-01 2011-04-30 Debiopharm S.A. Upotreba [d-meala]3-[etval]4-ciklosporina za liječenje infekcija hepatitisom c
WO2006063470A1 (en) * 2004-12-17 2006-06-22 Isotechnika Inc. Metabolites of cyclosporin analogs
CA2674296C (en) 2007-01-04 2015-11-24 Debiopharm Sa Non-immunosuppressive cyclosporin for treatment of ullrich congenital muscular dystrophy
CA2700536A1 (en) 2007-09-26 2009-04-02 Oregon Health & Science University Cyclic undecapeptides and derivatives as multiple sclerosis therapies
US7910378B2 (en) * 2007-12-14 2011-03-22 Siemens Healthcare Diagnostics Inc. Methods for detection of hydrophobic drugs
WO2009098533A1 (en) 2008-02-08 2009-08-13 Debiopharm Sa Non -immunosuppressive cyclosporin for the treatment of muscular dystrophy
KR20110093858A (ko) 2008-11-06 2011-08-18 데비오 레쉑쉐 빠르마슈띠끄 에스.아 시클로운데카뎁시펩티드 화합물 및 약제로서 상기 화합물의 용도
CA2748389A1 (en) * 2008-12-31 2010-07-08 Scynexis, Inc. Derivatives of cyclosporin a
AU2010208071C1 (en) * 2009-01-30 2013-06-20 Enanta Pharmaceuticals, Inc. Cyclosporin analogues for preventing or treating hepatitis C infection

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US20140005100A1 (en) * 2010-08-12 2014-01-02 Zhuang Su Novel cyclosporin derivatives for the treatment and prevention of a viral infection

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Publication number Publication date
PE20142433A1 (es) 2015-02-02
KR20150006435A (ko) 2015-01-16
PH12014502499A1 (en) 2014-12-22
IL235428A0 (en) 2014-12-31
AR090964A1 (es) 2014-12-17
EP2847211A1 (en) 2015-03-18
MA20150231A1 (fr) 2015-07-31
EA201492036A1 (ru) 2015-02-27
JP2015517481A (ja) 2015-06-22
CN108715606A (zh) 2018-10-30
CL2014003014A1 (es) 2015-03-06
TW201350508A (zh) 2013-12-16
CA2868940A1 (en) 2013-11-14
AU2016222370A1 (en) 2016-09-15
IN2014DN08483A (ja) 2015-05-08
MX2014013613A (es) 2015-02-12
WO2013167703A9 (en) 2014-11-20
CO7141428A2 (es) 2014-12-12
EA024903B1 (ru) 2016-10-31
JP2020033349A (ja) 2020-03-05
AU2013257989A1 (en) 2014-10-23
US9840534B2 (en) 2017-12-12
HK1202555A1 (en) 2015-10-02
CN104284902A (zh) 2015-01-14
AU2016222370B2 (en) 2017-10-05
ECSP14030537A (es) 2015-09-30
TN2014000411A1 (en) 2015-12-21
WO2013167703A1 (en) 2013-11-14
US20160304554A1 (en) 2016-10-20
BR112014027648A2 (pt) 2017-06-27
SG11201406303XA (en) 2014-11-27
JP2018035154A (ja) 2018-03-08

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