DK2655398T3 - Effektive peptidkoblinger og anvendelse heraf i syntesen og isoleringen af et cyclopenta (g)- quinazolintrinatriumsalt - Google Patents

Effektive peptidkoblinger og anvendelse heraf i syntesen og isoleringen af et cyclopenta (g)- quinazolintrinatriumsalt Download PDF

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DK2655398T3
DK2655398T3 DK11850150.1T DK11850150T DK2655398T3 DK 2655398 T3 DK2655398 T3 DK 2655398T3 DK 11850150 T DK11850150 T DK 11850150T DK 2655398 T3 DK2655398 T3 DK 2655398T3
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glu
acid
solution
amino
cyclopenta
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DK11850150.1T
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James Alan Kerschen
Alexander James Bridges
Milind D Choubal
Sean Mark Dalziel
Thomas Elliott Jacks
Andrew S Thompson
James Robert Zeller
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Btg Int Ltd
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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
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/08—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents
    • C07K1/088—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents containing other elements, e.g. B, Si, As
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • C07K5/06095—Arg-amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1896—Compounds having one or more Si-O-acyl linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • 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
    • C07K1/10—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using coupling agents
    • 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
    • C07K1/14—Extraction; Separation; Purification
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    • 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
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/36—Extraction; Separation; Purification by a combination of two or more processes of different types
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Claims (15)

1. Fremgangsmåde til syntesen af et L-Glu-y-D-Glu-dipeptid, hvilken fremgangsmåde omfatter følgende trin: a) aktivering af γ-carboxylsyren fra et Ν-αΟ-dibeskyttet L-Glu-derivat; b) silylering af D-glutaminsyre og c) omsætning af det aktiverede carboxylsyrederivat fremstillet i trin a) med det silylerede produkt fra trin b) for at give en beskyttet L-Glu-y-D-Glu-art.
2. Fremgangsmåde ifølge krav 1, hvor i trin a) aktivering omfatter omdannelse af det N-aO-dibeskyttede L-Glu-derivat til et aktiveret derivat.
3. Fremgangsmåde ifølge krav 2, hvorved det IV-aO-dibeskyttede L-Glu-derivat tilsættes langsomt til en opløsning af et alkylchlorformiat og en tertiær aminbase ved en temperatur på -10 °C til -50 °C.
4. Fremgangsmåde ifølge krav 3, hvor alkylchlorformiat er isobutylchlorformiat.
5. Fremgangsmåde ifølge krav 3 eller 4, hvor den tertiære aminbase er N-methylmorpholin.
6. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 5, hvor det N-aO-dibeskyttede L-Glu-derivat er N-benzyloxycarbonyl-L-glutaminsyre-a-benzylester.
7. Fremgangsmåde ifølge et hvilket som helst af de foregående krav, hvor i trin b) silylering omfatter behandling af D- glutaminsyre med et silylerende middel.
8. Fremgangsmåde ifølge krav 7, hvor det silylerende middel er O, IV-bis-(trimethylsilyl) acetamid (BSA) .
9. Fremgangsmåde ifølge krav 7 eller 8, hvor i trin b) D- glutaminsyre opløses med adskillige ækvivalenter til et silylerende middel og, i trin c), den opløsning tilsættes til en kold opløsning af carboxylsyrederivatet fra trin a) for at danne en silylesterificeret opløsning af en beskyttet L-Glu-y-D-Glu-art.
10. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 9, hvilken fremgangsmåde endvidere omfatter: d) fjernelse af beskyttelsen af en beskyttet L-Glu-y-D-Glu- art.
11. Fremgangsmåde ifølge krav 10, hvor fjernelsen af beskyttelsen omfatter fjernelse af benzyl og/eller benzyloxycarbonylbeskyttelsesgrupper for at fremstille L-Glutamyl-y-D-glutaminsyre.
12. Fremgangsmåde ifølge krav 10 eller 11, hvor fjernelsen af beskyttelsen omfatter hydrogenolyse.
13. Fremgangsmåde ifølge et hvilket som helst af kravene 10-12, hvor, efter fjernelsen af beskyttelsen, produktet behandles med thiosilicagel for at opnå et produkt, der indeholder <10 ppm palladium.
14. Fremgangsmåde ifølge et hvilket som helst af kravene 1-13, hvilken fremgangsmåde endvidere omfatter; silylering af L-Glu-y-D-Glu-dipeptidet for at give en silylbeskyttet L-Glu-γ-D-Glu-art og dernæst kobling af den silylbeskyttede L-Glu-y-D-Glu-art med ( 65)-4 , JV-( (2-(hydroxymethyl)-4-oxo-3,4,7,8-tetrahydro-3i7-cyclopenta [ g] quinazolin-6-yl) -N-(prop-2-ynyl)amino)benzoesyre for at danne (2,R)-((4,5)-carboxy-4- (4,iV-(( (65)-2- (hydroxymethyl) -4-oxo-3,4,7,8-tetrahydro-3i7-cyclopenta [g] quinazolin-6-yl) -N- (prop-2-ynyl)amino)benzamido)butanamid)pentandisyre, eller et farmaceutisk acceptabelt salt eller solvat deraf.
15. Fremgangsmåde ifølge krav 14, hvilken fremgangsmåde endvidere omfatter trinnene med: (i) fremstilling af en opløsning af (2,R)-((4,5)-carboxy-4-(4, N- ( ( (6S) -2- (hydroxymethyl) -4-oxo-3,4,7,8-tetrahydro-3i7-cyclopenta[g]quinazolin-6-yl)-N- (prop-2- ynyl)amino)benzamido)butanamid)pentandisyre i en vandig natriumbase; (ii) tilpasning af pH'et til intervallet 7,5-9,0, hvis det er nødvendigt; (iii) søjlekromatografi; (iv) eventuel opkoncentration af det eluerede produkt fra trin (iii) og (v) frysetørring for at danne trinatriumsaltet af (2,R)-((4,S)-carboxy-4-(4, N- ( ( (65) -2- (hydroxymethyl) -4-oxo-3,4,7,8-tetrahydro-3i7-cyclopenta[g]quinazolin-6-yl)-N- (prop-2- ynyl)amino)benzamid)butanamid)pentandisyre (ONX-0801).
DK11850150.1T 2010-12-22 2011-12-19 Effektive peptidkoblinger og anvendelse heraf i syntesen og isoleringen af et cyclopenta (g)- quinazolintrinatriumsalt DK2655398T3 (da)

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US201061459952P 2010-12-22 2010-12-22
PCT/US2011/065752 WO2012087888A2 (en) 2010-12-22 2011-12-19 Efficient peptide couplings and their use in the synthesis and isolation of a cyclopenta (g) quinazoline trisodium salt

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US (1) US9458188B2 (da)
EP (1) EP2655398B1 (da)
JP (1) JP2014513663A (da)
KR (1) KR20130132481A (da)
CN (1) CN103748106A (da)
AU (1) AU2011349551A1 (da)
BR (1) BR112013015600A2 (da)
CA (1) CA2819510A1 (da)
CO (1) CO6721028A2 (da)
DK (1) DK2655398T3 (da)
EA (1) EA201390635A1 (da)
HU (1) HUE028918T2 (da)
IL (1) IL226452A0 (da)
MX (1) MX2013007006A (da)
SG (1) SG191269A1 (da)
WO (1) WO2012087888A2 (da)
ZA (1) ZA201303821B (da)

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CN104151398A (zh) * 2014-08-06 2014-11-19 四川同晟氨基酸有限公司 一种合成以谷氨酸为首个氨基酸残基二肽的方法
GB201707864D0 (en) * 2017-05-16 2017-06-28 Inst Of Cancer Research: Royal Cancer Hospital Platinum-reistant cancer treatment
CN107236021B (zh) * 2017-06-12 2020-12-01 湖北泓肽生物科技有限公司 一种多肽衍生物的合成方法
CA3078393A1 (en) * 2017-10-03 2019-04-11 Nissan Chemical Corporation Method for producing peptide compound
EP3939959A4 (en) * 2019-03-15 2022-11-23 Nissan Chemical Corporation METHOD OF PREPARING A GLYCOSIDE COMPOUND

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GB8827083D0 (en) * 1988-11-19 1988-12-21 Porton Prod Ltd Trialkylsilyl esters of amino acids & their use in synthesis of peptides
GB9223352D0 (en) * 1992-11-06 1992-12-23 Ici Plc Tricyclic compounds
GB9408936D0 (en) * 1994-05-05 1994-06-22 Cancer Res Inst Anti-cancer compounds
GB0121214D0 (en) * 2001-08-31 2001-10-24 Btg Int Ltd Synthetic method
ATE483722T1 (de) * 2001-08-31 2010-10-15 Btg Int Ltd Antikrebs-cyclopentaag chinazoline-derivate
ES2373644T3 (es) * 2001-08-31 2012-02-07 Btg International Limited Uso de derivados de ciclopenta[g]quinazolina para el tratamiento del c�?ncer.
WO2004087142A1 (en) * 2003-04-04 2004-10-14 Novartis Ag Quinoline-2-one-derivatives for the treatment of airways diseases
US8466111B2 (en) * 2008-03-18 2013-06-18 Btg International Limited Cyclopenta{G}quinazoline derivatives for the treatment of rheumatoid arthritis or acute myeloid leukaemia

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EP2655398B1 (en) 2016-08-24
AU2011349551A1 (en) 2013-06-27
CN103748106A (zh) 2014-04-23
WO2012087888A2 (en) 2012-06-28
US9458188B2 (en) 2016-10-04
IL226452A0 (en) 2013-07-31
KR20130132481A (ko) 2013-12-04
WO2012087888A3 (en) 2014-03-06
MX2013007006A (es) 2013-07-30
EA201390635A1 (ru) 2014-09-30
ZA201303821B (en) 2014-04-30
BR112013015600A2 (pt) 2018-05-22
CO6721028A2 (es) 2013-07-31
EP2655398A4 (en) 2015-06-17
HUE028918T2 (en) 2017-01-30
EP2655398A2 (en) 2013-10-30
CA2819510A1 (en) 2012-06-28
US20130345423A1 (en) 2013-12-26
JP2014513663A (ja) 2014-06-05
SG191269A1 (en) 2013-07-31

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