ES2524398T3 - Métodos para la preparación de profármacos de fosforoamidato diastereoméricamente puros - Google Patents

Métodos para la preparación de profármacos de fosforoamidato diastereoméricamente puros Download PDF

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ES2524398T3
ES2524398T3 ES11743400.1T ES11743400T ES2524398T3 ES 2524398 T3 ES2524398 T3 ES 2524398T3 ES 11743400 T ES11743400 T ES 11743400T ES 2524398 T3 ES2524398 T3 ES 2524398T3
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alkyl
formula
aryl
compound
carbocyclyl
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Aesop Cho
Scott Alan Wolckenhauer
Michael O'neil Hanrahan Clarke
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Gilead Sciences Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
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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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

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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)
  • Molecular Biology (AREA)
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  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Un método para preparar un compuesto de fórmula Ia o Ib:**Fórmula** o una sal o un ácido farmacéuticamente aceptables del mismo; en las que: cada R1, R2, R7, R22, R23 o R24 es independientemente H, OR11, NR11R12, C(O)NR11R12, -OC(O)NR11R12, C(O)OR11, OC(O)OR11, S(O)nRa, S(O)2NR11R12, N3, CN, halógeno, alquilo (C1-C8), (C3-C8)carbociclilo, carbociclilalquilo (C4-C8), alquenilo (C2-C8), alquinilo (C2-C8) o arilalquilo (C1-C8); 10 o dos cualquiera de R1, R2, R7, R22, R23 o R24 en átomos de carbono adyacentes cuando se toman juntos son -O(CO)O- o -O(CR11R12)O- o cuando se toman junto con los átomos de carbono del anillo al que están unidos forman un doble enlace; cada base es independientemente una base de purina o pirimidina de origen natural o modificada unida al anillo de furanosa a través de un átomo de carbono o nitrógeno; siempre que la base no sea uracilo; cada n es independientemente 0, 1 o 2; cada Ra, R4 o R6 es independientemente alquilo (C1-C8), alquenilo (C2-C8), alquinilo (C2-C8), carbociclilo (C3-C8), carbociclilalquilo (C4-C8), arilalquilo (C1-C8), heterociclilalquilo (C1-C8), arilo (C6-C20), heterociclilo (C2-C20) o heteroarilo; cada Rc o Rd es independientemente H, alquilo (C1-C8), alquenilo (C2-C8), alquinilo (C2-C8), carbociclilo (C3-C8), carbociclilalquilo (C4-C8), arilalquilo (C1-C8), heterociclilalquilo (C1-C8), arilo (C6-C20), heterociclilo (C2-C20) o heteroarilo siempre que Rc y Rd no sean los mismos; cada R5 es independientemente H, alquilo (C1-C8), alquenilo (C2-C8), alquinilo (C2-C8), carbociclilo (C3-C8), carbociclilalquilo (C4-C8), arilalquilo (C1-C8), heterociclilalquilo (C1-C8), arilo (C6-C20), heterociclilo (C2-C20) o 25 heteroarilo; cada R11 o R12 es independientemente H, alquilo (C1-C8), alquenilo (C2-C8), alquinilo (C2-C8), carbociclilo, (C3-C8), carbociclilalquilo (C4-C8), arilalquilo (C1-C8), heterociclilalquilo (C1-C8), arilo (C6-C20), heterociclilo (C2-C20), heteroarilo, -C(>=O)alquilo (C1-C8), -S(O)nalquilo(C1-C8) o R11 y R12 junto con un nitrógeno al que están ambos unidos forman un anillo heterocíclico de 3 a 7 miembros en el que uno cualquiera de los átomos de carbono de dicho anillo heterocíclico puede estar sustituido opcionalmente con -O-, -S(O)n- o -NRa-; y en el que cada alquilo (C1-C8), alquenilo (C2-C8), alquinilo (C2-C8), carbociclilo (C3-C8), carbociclilalquilo, (C4-C8), arilalquilo (C1-C8), heterociclilalquilo (C1-C8), arilo (C6-C20), heterociclilo (C2-C20) o heteroarilo de cada Rc, Rd, R1, R2, R22, R23, R24, R4, R5, R6, R7, R11 o R12 está, independientemente, opcionalmente sustituido con uno o más halo, hidroxi, CN, N3, N(Ra)2, NH(Ra), NH2, NO2, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O)nRa, S(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2, ORa o Ra: comprendiendo dicho método: (a) proporcionar un compuesto de fórmula II **Fórmula** y (b) tratar el compuesto de fórmula II con un compuesto de fórmula IIIa y una base**Fórmula** formando de este modo un compuesto de fórmula Ia o (c) tratar el compuesto de fórmula II con un compuesto de fórmula IIIb y una base formando de este modo un compuesto de fórmula Ib; en la que: cada Ar es un arilo o heteroarilo (C6-C20) en el que dicho (arilo o heteroarilo (C6-C20) está sustituido con uno o más halógeno, NO2, o haloalquilo (C1-C8) y opcionalmente sustituido con uno o más de CN, N3, N(Ra)2, C(O)N(Ra)2, OC(O)N(Ra)2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O)nRa, S(O)2N(Ra)2, ORa o Ra con la condición de que Ar sea diferente de R4, comprendiendo el método además un método de preparación de un compuesto de fórmula IIIa o fórmula IIIb**Fórmula**
ES11743400.1T 2010-07-19 2011-07-19 Métodos para la preparación de profármacos de fosforoamidato diastereoméricamente puros Active ES2524398T3 (es)

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US36562110P 2010-07-19 2010-07-19
US365621P 2010-07-19
PCT/US2011/044581 WO2012012465A1 (en) 2010-07-19 2011-07-19 Methods for the preparation of diasteromerically pure phosphoramidate prodrugs

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US (2) US9090642B2 (es)
EP (2) EP2805960A1 (es)
JP (1) JP5937073B2 (es)
KR (3) KR102108864B1 (es)
CN (1) CN103052646A (es)
AP (1) AP2013006665A0 (es)
AU (1) AU2011282241B2 (es)
BR (1) BR112013001267A2 (es)
CA (1) CA2804375C (es)
CL (1) CL2013000076A1 (es)
CO (1) CO6680607A2 (es)
CR (1) CR20130063A (es)
EA (1) EA025311B1 (es)
EC (1) ECSP13012451A (es)
ES (1) ES2524398T3 (es)
IL (2) IL224045A (es)
MA (1) MA34471B1 (es)
MX (1) MX2013000656A (es)
NZ (1) NZ606141A (es)
PE (1) PE20130807A1 (es)
PT (1) PT2596004E (es)
SG (1) SG186831A1 (es)
WO (1) WO2012012465A1 (es)
ZA (1) ZA201300135B (es)

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