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    • 专利摘要:
    The present invention relates to a process for the phospholipidation of imidazoquinolines and oxoadenines. More particularly, the present invention relates to a high efficiency, scalable procedure for the phospholipidation of imidazoquinolines and oxoadenines which obviates the need to isolate unstable phosphoramidite intermediates. This method can be used for the phospholipidation of imidazoquinolines and active oxoadenines on the Toll 7 receptor (TLR7) and active on the Toll 8 receptor (TLR8).
    公开号:BE1024380B1
    申请号:E2016/5915
    申请日:2016-12-12
    公开日:2018-02-12
    发明作者:Helene G. Bazin-Lee；Laura S. Bess；David A. Johnson
    申请人:Glaxosmithkline Biologicals Sa；
    IPC主号:
    专利说明:


    economy
    1024380 Bl
    FPS Economy, SMEs, Middle Classes & Energy Intellectual Property Office
    Date of issue: 12/02/2018
    PATENT
    Priority date: 12/14/2015
    International classification: C07F 9/6558
    Deposit number: BE2016 / 5915
    Filing date: 12/12/2016
    Holder:
    GLAXOSMITHKLINE BIOLOGICALS SA
    1330, RIXENSART
    Belgium
    Inventor:
    BAZIN-LEE Helene G. 59840-3607 HAMILTON United States
    BESS Laura S. 59840-3607 HAMILTON United States
    JOHNSON David A. 59840-3607 HAMILTON United States
    PHOSPHOLIPIDATION OF IMIDAZOQUINOLEINS AND OXOADENINS
    The present invention relates to a process for phospholipidation of imidazoquinolines and oxoadenines. More particularly, the present invention relates to a high-performance, scalable procedure for phospholipidation of imidazoquinolines and oxoadenines which obviates the need to isolate unstable phosphoramidite intermediates. This method can be used for the phospholipidation of imidazoquinolines and oxoadenins active on the Toll 7 type receptor (TLR7) and active on the Toll 8 type receptor (TLR8).
    BELGIAN INVENTION PATENT
    FPS Economy, SMEs, Classes
    Medium & Energy
    Intellectual Property Office
    Publication number: 1024380 Deposit number: BE2016 / 5915
    International Classification: C07F 9/6558 Date of issue: 02/12/2018
    The Minister of the Economy,
    Having regard to the Paris Convention of March 20, 1883 for the Protection of Industrial Property;
    Considering the law of March 28, 1984 on patents for invention, article 22, for patent applications introduced before September 22, 2014;
    Given Title 1 “Patents for invention” of Book XI of the Code of Economic Law, article XI.24, for patent applications introduced from September 22, 2014;
    Having regard to the Royal Decree of 2 December 1986 relating to the request, the issue and the maintenance in force of invention patents, article 28;
    Given the patent application received by the Intellectual Property Office on 12/12/2016.
    Whereas for patent applications falling within the scope of Title 1, Book XI of the Code of Economic Law (hereinafter CDE), in accordance with article XI. 19, §4, paragraph 2, of the CDE, if the patent application has been the subject of a search report mentioning a lack of unity of invention within the meaning of the §ler of article XI.19 cited above and in the event that the applicant does not limit or file a divisional application in accordance with the results of the search report, the granted patent will be limited to the claims for which the search report has been drawn up.
    Stopped :
    First article. - It is issued to
    GLAXOSMITHKLINE BIOLOGICALS SA, Rue de l'Institut 89, 1330 RIXENSART Belgium;
    represented by
    PRONOVEM - Office Van Malderen, Avenue Josse Goffin 158, 1082, BRUXELLES;
    a 20-year Belgian invention patent, subject to payment of the annual fees referred to in article XI.48, §1 of the Code of Economic Law, for: PHOSPHOLIPIDATION OF IMIDAZOQUINOLEINES AND OXOADENINES.
    INVENTOR (S):
    BAZIN-LEE Helene G „c / o GlaxoSmithKline, 553 Old Corvallis Road, 59840-3607, HAMILTON;
    BESS Laura S., c / o GlaxoSmithkline, 553 Old Corvallis Road, 59840-3607, HAMILTON;
    JOHNSON David A., c / o GlaxoSmithKline, 553 Old Corvallis Road, 59840-3607, HAMILTON;
    PRIORITY (S):
    12/14/2015 US 62,266,858;
    DIVISION:
    divided from the basic application: filing date of the basic application:
    Article 2. - This patent is granted without prior examination of the patentability of the invention, without guarantee of the merit of the invention or of the accuracy of the description thereof and at the risk and peril of the applicant (s) ( s).
    Brussels, 02/02/2018, By special delegation:
    BE2016 / 5915
    PHOSPHOLIPIDATION OF IMIDAZOQUINOLEINS AND OXOADENINS
    Statement regarding federally funded research
    This work was partially funded by the National Institute of Allergy and Infectious Diseases (NIAID) under the HHSN272200900036C contract (with Corixa Corporation carrying on business as GlaxoSmithKline Biologicals SA).
    Context of 1 1 invention
    The present invention relates to a process for phospholipidation of imidazoquinolines and oxoadenines. More particularly, the present invention relates to a high yield and adjustable scale method for the phospholipidation of imidazoquinolines and oxoadenines which avoids the need to isolate unstable phosphoramidite intermediates. This method can be used for the phospholipidation of imidazoquinolines and oxoadenins active on the Toll 7 type receptor (TLR7) and active on the Toll 8 type receptor (TLR8).
    Toll-like receptors (TLRs) are a family of more than 10 structurally related receptors on innate immune cells that detect specific components of pathogens common to the major classes of microbial invaders. Activation of these receptors leads to the expression of inflammatory cytokines / chemokines and type I alpha and beta interferons (IFNa / ß) important for
    BE2016 / 5915 effective innate and adaptive immune responses to infectious diseases and cancer.
    In the case of the activation of TLR7 and TLR8, a few different classes of small molecule mimetics of ligands of the natural viral ssRNA rich in uridine and / or guanosine have been identified (Heil et al. Eur. J. Immunol. 2003, 33, 2987-2997, Hemmi et al. Nat. Immunol. 2002, 3, 196-200, Lee et al. Proc. Natl. Acad. Sci. USA 2006, 103, 1828-1833), including analogues oxoadenine (Hirota et al. J. Med. Chem. 2002, 45, 5419; WO 2007/034882 PCT / JP2006 / 318758, Dainippon Sumitomo Pharma Co. Ltd./AstraZeneca Aktiebolag) and 1Himidazo- [4,5- c] quinolines (Gerster et al. J. Med. Chem. 2005, 48, 3481-3491) such as imiquimod, which is approved for topical treatment of certain skin diseases and known to mainly activate TLR7, and resiquimod , The structurally related imidazoquinoline, which potently activates both TLR7 and TLR8 (Miller et al. Drug News Perspect 2008, 21, 69-87).
    Since TLR7 and TLR8 are widely expressed in dendritic cells (CD) and other cells with antigens, TLR7 / 8 agonists and their derivatives may be especially useful as vaccine adjuvants. However, oral and topical preparations of imiquimod and resiquimod and other small molecule TLR7 / 8 agonists may have serious side effects, and clinical trials with some TLR7 / 8 agonists have been suspended compared to security concerns (Horscroft et al. J. Antimicrob. Chemother.
    BE2016 / 5915
    55, 445-451) . In outraged, located in the lysosomal (Lee et al
    2012, 67, 789-801, Strominger, N. L .; Brady, R .;
    Gullikson, G .; Carpenter, D. 0. Brain Res. Bull. 2001, since TLR7 and TLR8 are endosomal compartments / Proc. Natl. Acad. Sei. USA.
    2003, 100, 6646-6651), cellular absorption is a prerequisite for cellular activation by ligands of TLR7 / 8. Thus, there is considerable interest in strategies which will increase the penetration of the TLR7 / 8 ligand into DCs and other immune cells and which will also improve the toxic effects. The conjugation of lipids to nucleoside drugs including TLR7 / 8 agonists (Chan et al. Bioconjugate Chem. 2009, 20, 11941200) is a known strategy to facilitate endocytosis, to amplify oral bioavailability, and to decrease toxic side effects. Such nucleolipids can also be incorporated into liposomes and other biodegradable nanoparticles to help protect the drug from degradation and to further reduce toxicity via a deposition effect (Rosemeyer, H. Chemistry & Biodiversity 2005, 2, 9771063).
    Summary of the invention
    The present invention relates to a process for preparing the compounds of formula (I) and formula (II) which comprises an imidazoquinoline or oxoadenine molecule covalently linked to a phospho group.
    BE2016 / 5915
    Formula (I)
    in which
    R 1 is chosen from H, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl-C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl ~ C 1 -C alkylamino Ce, C 3 -C 8 cycloalkyl-C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkylamino and C 1 -C 6 alkoxy-C 1 -C alkoxy ; C1 to C8 alkyl, C1 to C8 alkylamino, C1 to C8 alkoxy, C 3 to C8 cycloalkyl-C1 to C8 alkyl, C 3 to Cg cycloalkyl-C1 to Cg alkylamino, C 3 to cycloalkyl C1-C6-alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylamino or C1-C6-alkoxy-C1-C6 alkoxy being branched or unbranched and optionally substituted at their ends with a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl, or maleimido group;
    Z is selected from alkyl C 2 to Cg alkenyl and C 2 to C, alkyl, C 2 to Cg alkenyl and C 2 to C being unsubstituted or substituted at their end by a - (O- C 2 to C 6 alkyl) i to 6 _ ;
    A represents
    BE2016 / 5915
    I-fO AWQk
    OFU
    Ms
    /.JA / 4A, A / z
    OR
    Y '' 'in which
    R2 represents H or a linear or branched C4 to C24 alkyl group, optionally unsaturated, or a linear or branched C4 to C24 acyl group, optionally unsaturated;
    R 3 represents a linear or branched C4 to C24 alkyl group, optionally unsaturated, or a linear or branched C4 to C24 acyl group, optionally unsaturated; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
    13, 14, 15, 16, 17, 18, 19 or 20.
    Formula II

    OH (N) in which
    R4 is chosen from C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl-C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl-C 1 -C alkylamino, C 3 -C 8 cycloalkyl-C 1 -C 6 alkoxy, alkoxy
    BE2016 / 5915 C1-C8-C1-C6 alkyl, C1-C8 alkoxy-C1-C6 alkylamino and C1-C6 alkoxy-C1-C6 alkoxy; C1 to C8 alkyl, C1 to C8 alkylamino, C1 to C6 alkoxy, C3 to C8 cycloalkyl-C1 to Cg alkyl, C3 to Cg cycloalkyl-C1 to Cg alkylamino, C3 to Cg cycloalkyl- C1 to C6 alkoxy, C1 to Cg alkoxy-C1 to Cg alkyl, C1 to Cg alkoxy-C1 to Cg alkylamino or C1 to Cg alkoxy-C1 to Cg alkoxy being branched or unbranched and optionally substituted with their end with a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl, or maleimido group;
    d is 0, 1, 2, 3, 4, 5 or 6;
    Het represents a saturated nitrogen heterocycle of four, five, or six members in which
    X, Y = CH or N, and at least one of X and Y represents a nitrogen atom;
    m is 0, 1, 2, 3, 4, 5 or 6;
    A represents

    or in which
    R2 represents H or a linear or branched C4 to C24 alkyl group, optionally unsaturated, or a linear or branched C4 to C24 acyl group, optionally unsaturated;
    BE2016 / 5915
    R 3 represents a linear or branched C4 to C24 alkyl group, optionally unsaturated, or a linear or branched C4 to C24 acyl group, optionally unsaturated; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
    13, 14, 15, 16, 17, 18, 19 or 20.
    As a first aspect, the present invention provides a process for the preparation of compounds of formula (I). The process includes the following steps:
    a) the reaction of a compound of formula (III)
    I - 0¾ —ORs (SH) with a compound of formula (V)
    G PG (V) in which
    PG represents a protective group suitable for protecting a hydroxyl group, including but not limited to cyanoethyl, methyl, ethyl, benzyl and ailyl groups;
    all other variables are as defined above for formula (I);
    to prepare a compound of formula (VI)
    BE2016 / 5915
    RO P N POO CVi) in which 5 R represents

    all other variables are as defined above for formula (I);
    b) the reaction of a compound of formula (VI) with a compound of formula (VII)
    to prepare a compound of formula (IX)
    R O P ö FT <ÎX) OPG
    BE2016 / 5915 in which R represents
    R 'represents
    and all the other variables are as defined above for formula (I);
    c) the oxidation of a compound of formula (IX) and the elimination of the hydroxy-protecting group to obtain a compound of formula (I).
    In another aspect, the present invention provides another process for the preparation of a compound of formula (I). This process includes the following steps:
    a) the reaction of a compound of formula (IV)
    BE2016 / 5915
    £ V>
    with a compound of formula (V)
    NOT
    N P Q PO in which
    PG represents a protective group suitable for protecting a hydroxyl group, including but not limited to cyanoethyl, methyl, ethyl, benzyl and ailyl groups; and all the other variables are as defined above for formula (I);
    to prepare a compound of formula (VI);
    <W ’in which
    BE2016 / 5915
    R represents
    all other variables are as defined above for formula (I);
    b) the reaction of a compound of formula (VI) with a compound of formula (VII)
    to prepare a compound of formula (IX)
    R * O P O P ’QPG (txy in which
    R represents
    BE2016 / 5915
    R 'represents
    all other variables are as defined above for formula (I);
    c) oxidation of a compound of formula (IX) and elimination of the hydroxy-protecting group to obtain a compound of formula (I).
    In a third aspect, the present invention provides a process for the preparation of the compounds of formula (II). The process includes the following steps:
    a) the reaction of a compound of formula (III)
    BE2016 / 5915 with a compound of formula (V)
    N P O PG in which
    PG represents a protective group suitable for protecting a hydroxyl group, including but not limited to cyanoethyl, methyl, ethyl, benzyl and ailyl groups;
    all other variables are as defined above for formula (II);
    to prepare a compound of formula (VI)
    in which R represents
    BE2016 / 5915 all other variables are as defined above for formula (II);
    b) the reaction of a compound of formula (VI) with a compound of formula (VIII) ds
    N '—OH (VHï) to prepare a compound of formula (IX) * in which R represents
    R * represents
    R. O R O
    1 "
    BE2016 / 5915
    all other variables are as defined above for formula (II);
    c) the oxidation of a compound of formula (IX) * and the elimination of the hydroxy-protecting group to obtain a compound of formula (II).
    In a fourth aspect, the present invention provides another process for the preparation of a compound of formula (II). The process comprises the following stages: a) reacting a compound of formula (IV)
    Xv,. · '· X · with a compound of formula (V)' N '
    N P û PG m
    BE2016 / 5915 in which
    PG represents a protective group suitable for protecting a hydroxyl group, including but not limited to cyanoethyl, methyl, ethyl, benzyl and ailyl groups; and all the other variables are as defined above for formula (II);
    to prepare a compound of formula (VI);
    R 1 OPN PQO /
    CW 'in which
    R represents
    all other variables are as defined above for formula (II);
    b) the reaction of a compound of formula (VI) with a compound of formula (VIII)
    BE2016 / 5915
    to prepare a compound of formula (IX) in which R represents z
    R * represents hr ,, Α ^, k
    RÎ ht s ^ H “OH i
    Z X -X. V '—o ~~ <
    BE2016 / 5915 all other variables are as defined above for formula (II);
    c) the oxidation of a compound of formula (IX) * and the elimination of the hydroxy-protecting group to obtain a compound of formula (II).
    Other aspects of the present invention are described in the description of particular embodiments, the examples, and the claims which follow.
    Detailed description of preferred embodiments
    As used herein, "a compound of formula (I)" means a compound of formula (I) or one of its pharmaceutically acceptable salts or solvates. "A compound of formula (II)" means a compound of formula (II) or
    one of his salts pharmaceutically acceptable or solvatesPhone that used here, "a compound of the invention " mean a compound of formula (I) or formula (II) or one of his salts pharmaceutically acceptable or solvatesPhone that used here the term " eventually "
    means that the event (s) described below may / may or may not occur, and includes both an event (s) that occur / occur and events that do not occur.
    Certain compounds of formula (I) or formula (II) can exist in stereoisomeric forms (for example, they can contain one or more asymmetric carbon atoms). Individual stereoisomers (enantiomers and diastereomers) and mixtures of
    BE2016 / 5915 these are included within the scope of the present invention. The present invention also covers the individual isomers of the compounds represented by formula (I) or formula (II) in the form of mixtures with isomers thereof in which one or more chiral centers are reversed.
    Certain compounds of the invention may exist in tautomeric forms. It should be understood that the present invention encompasses all the tautomers of the compounds of the invention whether in the form of individual tautomers or in the form of their mixtures whether or not they are explicitly indicated in the present formulas.
    The suitable pharmaceutically acceptable salts according to the present invention will be readily determined by those skilled in the art and will include, for example, salts prepared from inorganic bases such as lithium hydroxide, sodium hydroxide, hydroxide potassium, lithium carbonate, lithium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, as well as potassium tert-butoxide and organic bases such as diethylamine, lysine, arginine, choline hydroxide, choline bicarbonate, tris (hydroxymethyl) -aminomethane (tromethamine), triethanolamine, diethanolamine, and ethanolamine.
    When used in medicine, the salts of a compound of formula (I) or formula (II) should be pharmaceutically acceptable, but pharmaceutically unacceptable salts may be used
    BE2016 / 5915 conveniently for corresponding or acceptable thereof.
    As used herein, preparing the free base pharmaceutically salts the term "solvate" refers to a crystalline form containing the compound of formula (I) or formula (II) or one of its pharmaceutically acceptable salts and an amount either stoichiometric or non-stoichiometric of a solvent. Solvents, for example, include water (thereby producing hydrates) methanol, ethanol, or acetic acid. Hereinafter, the reference to a compound of formula (I) or of formula (II) is to any physical form of this compound, unless a particular form, a salt or a solvate thereof is specified.
    Processes for preparing the pharmaceutically acceptable salts of the compounds of formula (I) or formula (II) are traditional in the art. See, for example, Burger's Medicinal Chemistry And Drug Discovery 5th Edition, Vol 1: Principles And Practice.
    The compounds of the invention of formula (I) or of formula (II) can be in crystalline or amorphous form. In addition, some of the crystal forms of the compounds of the invention may exist in the form of polymorphs, all of which are included within the scope of the present invention. The most thermodynamically stable polymorphic form or the most thermodynamically stable polymorphic forms of the compounds of the invention is (are) of particular interest.
    BE2016 / 5915
    The polymorphic forms of the compounds of the invention can be characterized and differentiated using a number of traditional analytical techniques including, but not limited to, powder X-ray diffraction (XRPD), infrared spectroscopy ( IR), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (NMR).
    It will be understood from the above that are understood within the scope of the invention, the solvates, isomers and polymorphic forms of the compounds of formula (I) and of formula (II) and their salts .
    A compound of formula (I) or formula (II) can be prepared using the methods illustrated below.
    Diagram 1
    or
    NOT '
    N ~ P O PG (V)
    BE2016 / 5915
    in which
    PG represents a protecting group suitable for protecting hydroxyl group including, but not limited to, cyanoethyl, methyl, ethyl, benzyl and ailyl;
    R represents
    R 'represents
    BE2016 / 5915 all other variables are as defined above for formula (I).
    In general, the process for preparing a compound of formula (I) as illustrated in scheme 1 comprises the following steps:
    a) reacting a compound of formula (III) with a compound of formula (V) to prepare a compound of formula (VI);
    b) reacting a compound of formula (VI) with a compound of formula (VII) to prepare a compound of formula (IX); and
    c) the oxidation of a compound of formula (IX) and the elimination of the hydroxy-protecting group to obtain a compound of formula (I).
    Diagram 2

    BE2016 / 5915
    HR;
    rV'A, -Zx X
    T <·
    NOT
    ON (VH)
    R O R N TOO / Z>)
    NH>
    .......... cy ................ R ”O e OR .............. N. Λ · ... N
    OP'S : ···· ...... Ö -NOT o CW H;> · 0 R O OH
    v) in which
    PG represents a protective group suitable for protecting hydroxyl group including, but not limited to, cyanoethyl, methyl, ethyl, benzyl and ailyl;
    R represents
    <e r € ^ kyiô &
    R 'represents
    BE2016 / 5915
    i * and all other variables are as defined above for formula (I).
    In general, the process for preparing a compound of formula (I) as illustrated in scheme 2 comprises the following steps:
    a) reacting a compound of formula (IV) with a compound of formula (V) to prepare a compound of formula (VI);
    b) reacting a compound of formula (VI) with a compound of formula (VII) to prepare a compound of formula (IX); and
    c) the oxidation of a compound of formula (IX) and the elimination of the hydroxy-protecting group to obtain a compound of formula (I).
    Diagram 3

    N ..... P O R3

    BE2016 / 5915
    NR,
    R 4 jx ~ - roc <ÇR, . “'X .. Y — Where' · ,.
    '···. ···: · i .x ,,,.' “• '.” S.
    RH, (Y "!’ "
    POO
    R ..... Cs ..... p o rÔPG
    W
    Xh'X ..., .-, v
    XW 'WA
    O
    H
    R O A
    ÔH in which
    PG represents a protective group suitable for protecting hydroxyl group including, but not limited to, cyanoethyl, methyl, ethyl, benzyl and ailyl;
    R represents
    R * represents
    Xv -'- N.
    V ~ OH cow z
    -X
    BE2016 / 5915 all other variables are as defined above for formula (II).
    In general, the process for preparing a compound of formula (II) as illustrated in scheme 3 comprises the following steps:
    a) reacting a compound of formula (III) with a compound of formula (V) to prepare a compound of formula (VI); and
    b) reacting a compound of formula (VI) with a compound of formula (VIII) to prepare a compound of formula (IX) *; and
    c) the oxidation of a compound of formula (IX) * and the elimination of the hydroxy-protecting group to obtain a compound of formula (II).
    Diagram 4
    ..... o ..... rc>
    Could /
    hW r * ...... g-p ..... p Fr

    in which
    BE2016 / 5915
    PG represents a protecting group suitable for protecting hydroxyl group including, but not limited to, cyanoethyl, methyl, ethyl, benzyl and ailyl groups;
    R represents
    R * represents
    all other variables are as defined above for formula (II).
    In general, the process for preparing a compound of formula (II) as illustrated in scheme 4 comprises the following steps:
    a) reacting a compound of formula (IV) with a compound of formula (V) to prepare a compound of formula (VI);
    BE2016 / 5915
    b) reacting a compound of formula (VI) with a compound of formula (VIII) to prepare a compound of formula (IX) *;
    c) the oxidation of a compound of formula (IX) * and the elimination of the hydroxy-protecting group to obtain a compound of formula (II).
    More particularly, the compound of formula (VI) or (VI) can be prepared by reacting the compound of formula (III) or (IV) with a compound of formula (V) in the presence of an appropriate phosphoramidite coupling reagent such as as ΙΗ-tetrazole, a substituted tetrazole, dicyano-imidazole, imidazolium triflate or any of these coupling reagents known to those skilled in the art, in an aprotic solvent such as, but not being not limited, methylene chloride, between 0 ° C and room temperature.
    The compound of formula (VI) or (VI), which can be purified by chromatography on silica gel and preferably not isolated or purified, can be reacted directly during its formation with a compound of formula (VII) or ( VIII) in the presence of an appropriate phosphoramidite coupling reagent such as 1Htetrazole, a substituted tetrazole, dicyano-imidazole, imidazolium triflate or any of these coupling reagents known to those skilled in the art, in an aprotic solvent such as, but not limited to, methylene chloride, between 0 ° C and room temperature to prepare compounds of formula (IX), (IX), (IX) * and (IX) *.
    The compound of formula (IX), (IX), (IX) * or (IX) * is converted into a compound of formula (I) or of formula
    BE2016 / 5915 (II) by oxidation using an oxidizing agent for phosphorus such as, but not limited to, chloroperbenzoic acid, hydrogen peroxide,
    Iodine / pyridine / water, or tert-butyl peroxide followed by removal of the protective group using techniques known to those skilled in the art.
    In one embodiment, the compounds of formula (I) or of formula (II) are prepared by:
    (i) the addition of lH-tetrazole (2.1 eq.) in several parts to a solution in methylene chloride of a compound of formula (III) or of formula (IV) (2.0 eq.) followed by the phosphordiamidite reagent of formula (V) (2.1 eq.) and reaction for 30 min to 1 h at room temperature after the last addition of tetrazole, (ii) cooling the reaction mixture to ° C, (iii) the addition of a compound of formula (VII) or (VIII) (1.0 eq.) and imidazolium triflate (1.5 eq.), and reaction at 0 ° C for up to 30 min then at room temperature for 1 hour to 24 hours, and (iv) the subsequent oxidation of a compound of formula (IX), (IX), (IX) * or (IX) * (purified or not) with peroxide tert-butyl (1.5 eq.) followed by deprotection of the protecting group.
    In one embodiment, ΙΗ-tetrazole is added to a compound of formula (III) or formula (IV) in ~ 30 min (for example, 4 parts, for example, one added every ten minutes). As used in this embodiment, ~ 30 min means + or - 10 minutes, 20 to 40 minutes.
    BE2016 / 5915
    In another embodiment, a compound of formula (V) is added and reacted with a compound of formula (III) or a compound of formula (IV), forming a compound of formula (VI) or (VI), to which a compound of formula (VII) or of formula (VIII) is added before the addition of imidazolium triflate.
    In another embodiment, the reaction mixture containing the compound of formula (VI) or (VI) is cooled to 0 ° C. before the addition of a compound of formula (VII) or of formula (VIII).
    In one embodiment, the protecting group is a cyanoethyl group.
    In another embodiment, the deprotection is carried out with triethylamine (TEA).
    In a preferred embodiment, the protecting group is a cyanoethyl group and the deprotection is carried out with triethylamine (TEA).
    In one mode of resorption, the coupling agent used with a compound of formula (III) or of formula
    (IV) and a compound of formula (V) is 2.1 equivalent, the compound of formula (III) or of formula (IV) is at 2.0 equivalents, the compound of formula (V) is at 2.1 equivalents, the compound of formula (seen; i or from formula (VIII) is at 1, 0 equivalent and The agent oxidation for the compound of formula (IX), (IX) , (IX) * or (IX) * is at 1.5 equivalent. In one embodiment, the triflate
    of imidazolium is added with the compound of formula (VII) or the compound of formula (VIII) to the same reaction mixture produced by the reaction of the compound of formula
    BE2016 / 5915 (V) with the compound of formula (III) or the compound of formula (IV).
    The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way, the present invention being defined by the claims.
    In the examples, the following terms have the designated meaning:
    eq. = equivalents;
    ES TOF-MS = electrospray - time-of-flight mass spectroscopy;
    h = time;
    H = hydrogen atom;
    Hz = Hertz; MHz = megaHertz; min = minute;
    M = molar;
    NMR = nuclear magnetic resonance;
    TA = ambient temperature;
    TEA = triethylamine; v = volume.
    Example 1 General procedure for the synthesis of phosphotriester IX
    To a solution of III or IV (2.0 eq.) In anhydrous methylene chloride (0.4 M), N, N, N ', N'-tetra-isopropylphosphordiamidite of 2cyanoethyl V (2) was added. , 1 eq.) At RT. 1H-tetrazole (2.1 eq.) Was then added in four parts over 20 minutes and the reaction mixture was stirred at RT for 1 h. After 1 h, the resulting phosphoramidite VI or VI was formed. The reaction mixture was cooled to 0 ° C and
    BE2016 / 5915 imidazoquinoline VII or oxoadenine VIII (1.0 eq.) And imidazolium triflate triflate (1.5 eq.) Were added. The reaction mixture was allowed to warm to RT. The reaction was usually completed after 1 hour at RT. The resulting phosphite IX, IX, IX * or IX * can be purified at this stage or subsequently oxidized without isolation.
    Example 2 - General procedure for the oxidation of IX
    The phosphotriester IX, IX, IX * or IX * (purified or not) in a solution of methylene chloride was oxidized by the addition of t-butyl hydroperoxide (1.5 eq.) To the reaction mixture and stirring at RT for 30 min. At the end of the oxidation, the reaction mixture was concentrated in vacuo and purified by chromatography on silica gel. The resulting protected phosphotriester was dissolved in acetonitrile (0.06 M). Triethylamine (acetonitrile / TEA, 1 / 0.35, v / v) was added and the reaction mixture was stirred at RT for 6 to 18 hours. After complete deprotection, the reaction mixture was filtered through a Buchner filter and the isolated solid was rinsed with acetonitrile and dried under high vacuum. The reaction mixture can also be purified by chromatography on silica gel.
    Example 3 Synthesis of 4-amino-1- [2- (1,2-di-Qpalmitoyl-sn-glycero-3-phospho) ethyl] -2-n-butyl-1Himidazo [4,5-c] quinoline , Compound
    Ri = n-Bu, Z = (CH 2 ) 2 , n = 0, R 2 = R 3 = n-Ci 5 H 31 CO 'i
    BE2016 / 5915 î
    V TwYtZss' 0., *. î> UîkH $ s * ô H la vils
    é.
    £ v
    Λ C i O
    Χ ™ κ7κχ: χχχχκ ^ ™: ί> ^ <) ^ χκκχκχκχ
    M'6 xj y., .. h • va —fS-Bu
    The phosphotriester IXa was prepared with a yield of 93% by reacting di-O-palmitoyl5 glycerol Ilia with V, this followed by the addition of imidazoquinoline Vila and imidazolium triflate as described in Example 1. IXa was oxidized and deprotected following the procedure described in Example 2 to give the phospholipid imidazoquinoline la with a yield of 71%.
    NMR Χ Η (CDC1 3 / CD 3 OD, 400 MHz): δ 8.23 (bs, 1H), 7.39
    (t, 1H), 7.22 (bs, 1H), 6, 93 (bs, 1H), 5.25 (m, 1H), 4.70 (bs, 2H), . 4, 60 (bs, 2H), 4.42 (dd, 1H), 4.19 (dd, 1H), 4.04 (t, 2H), 3 , 06 (bs, 2H), 2, 32 (m, 4H), 1.96 (m,
    2H) 1.59 (m, 6H), 1.26 (m, 48H), 1.07 (t, 3H), 0.88 (m,
    6H); ES positive TOF-MS, calculated for [M + H] + 915.6340; found 915.6309.
    Example 4 Synthesis of 4-amino-1- [2- (1,2-di-Q2 0 palmitoyl-sn-glycero-3-phospho) ethyl] -2-ethoxymethyllH-imidazo [4,5-c] quinoline , Compound (Ib)
    BE2016 / 5915
    Ri = CH 2 OEt, Z = (CH 2 ) 2 , n = 0, R 2 = R 3 = nC 15 H 31 CO
    · Λ <·· ir <: · . - AT, :; Ç ' Χ ν' · '
    NS 'ς>
    i-XR o dd O 'S> ...
    LXfc m
    , not. N b
    ..3 ib tt
    S: ^ 7 : 7 : 7 : 7 : n <-g : 7 : 7 : .-S77 : 7pKi7 : 7 : 7 : 7 : 7 : 7 : 7 : 77
    ,. / 0 i O
    WHERE ^ Ç-isK · «
    The phosphotriester IXb was prepared with a yield of 99% by reacting di-O-palmitoylglycerol Ilia with V, this followed by the addition of imidazoquinoline Vllb and imidazolium triflate as described in Example 1. IXb was oxidized and deprotected following the procedure described in Example 2 to give the phospholipid imidazoquinoline Ib with a yield of 73%.
    NMR Χ Η (CDC1 3 / CD 3 OD, 400 MHz): δ 8.05 (bs, 1H), 7.29
    (t, 1H), 7.09 (bs, 1H), 6.78 (bs, 1H), 5.11 (m, 1H), 15 4.80 (bs, 4H), 4, 60 (bs, 2H), 4.28 (dd, 1H), 4 , 07 (dd, 1H), 3, 90 (t, 2H), 3 , 54 (dd, 2H), 2, 18 (m, 4H), 1.59 (m, 4H), 1.16 (m, 51H), 0.76 (m, 6H), ES positive TOF-MS,
    calculated for [M + H] + 917.6132; found 917.6162.
    BE2016 / 5915
    Example 5 Synthesis of 4-amino-1- [2- (1,2-di-Qhexadecyl-sn-glycero-3-phospho) ethyl] -2-n-butyl-1Himidazo [4,5-c] quinoline , Compound
    Ri = n-Bu, Z = (CH 2 ) 2 , n = 0, R 2 = R 3 = n-Ci 5 H 31
    SV ά
    HO>
    .. ····· y · N:
    HP 'y V y. P, ίΡΡίΗχ-ί
    PC,
    PC
    ÎXC
    The phosphotriester IXe was prepared with a yield of 97% by reacting di-O-hexadecyl10 glycerol IIIc with V, this followed by the addition of
    Imidazoquinoline Vila and imidazolium triflate as described in Example 1. IXe was oxidized and deprotected using the procedure described in Example 2 to give the phospholipidated imidazoquinoline 1c with a yield of 71% .
    BE2016 / 5915
    RMN Y (CDC1 3 / CD 3 OD, 400
    (t, 1H), 7.18 (bs, 1H) , 6 ,! 4, 60 (bs, 2H), 3.95 (t, 2H), 3, 03 (bs, 2H), 1.94 (m 2H), 1.06 (t, 3H), 0.88 (t, 6H), for [M + H] + 885.659E b t found
    MHz): δ 8.23 (bs, 1H), 7.40 6 (bs, 1H), 4.70 (bs, 2H),
    3.50 (mm, 7H), 4.04 (t, 2H), 1.56 (m, 6H), 1.26 (m, 52H), ES positive TOF-MS, calculated 885.8304.
    Example 6 Synthesis of 4-amino-1- [2- (1,2-di-Qlauroyl-sn-glycero-3-phospho) ethyl] -2-n-butyl-1Himidazo [4,5-c] quinoline , Compound (Id)
    Ri = n-Bu, Z = (CH 2 ) 2 , n = 0, R 2 = R 3 = nC n H 23 CO
    x.
    & AT y-f.MXi
    O ..
    L »
    X
    F * x, j O <0 t "'
    YM! -O
    Phosphotriester IXd was prepared with a yield of 79% by reacting di-O-lauroylglycerol Illd with V, this followed by the addition of imidazoquinoline Vila and imidazolium triflate as described in Example 1. IXd was oxidized and deprotected using the procedure described in
    BE2016 / 5915 Example 2 to give the phospholipid imidazoquinoline Id Id with a yield of 77%.
    NMR X (CDC1 3 / CD 3 OD, 400 MHz): δ 8.09 (bs, 1H), 7.30 (t, 1H), 7.09 (bs, 1H), 6.81 (bs, 1H) , 5.12-5.17 (m, 1H), 4.22-4.76 (m, 4H), 4.31 (dd, 1H), 4.11 (dd, 1H), 3.93 (t , 2H, 1H), 2.93 (bs, 2H), 2.20 (dd, 4H), 1.84 (m, 2H), 1.42-1.49 (m, 6H), 1.15 ( m, 34H), 0.96 (t, 3H), 0.78 (t, 6H), TOF-MS negative ES, calculated for [MH] ~ 801.4931; found 801.4741.
    Example 7 Synthesis of 4-amino-1- [2- (1,2-di-Qmyristoyl-sn-glycero-3-phospho) ethyl] -2-n-butyl-1Himidazo [4,5-c] quinoline , Compound
    Ri = n-Bu, Z = (CH2) 2z n = 0, R2 = R 3 = n-Ci 3 H27CO
    HR X '' d b ....
    è γ
    hhiteYhhhhhhhhhhhhhhhhil
    Xk: M-fe
    ΓΠ. yV * "· Ό ί 'b IX" 4
    R
    The phosphotriester IXe was prepared with a yield of 62% by reacting di-O-myristoylglycerol Ille with V, this followed by the addition of
    Imidazoquinoline Vila and imidazolium triflate
    BE2016 / 5915 as described in Example 1. IXe was oxidized and deprotected following the procedure described in Example 2 to give the phospholipidated imidazoquinoline with a yield of 89%.
    NMR Χ Η (CDC1 3 / CD 3 OD, 400 MHz): δ 8.17 (bs, 1H), 7.39 (bs, 1H), 7.17 (bs, 1H) , 6.91 (bs, 1H), 5.24 (m, 1H), 4.80 (bs, 2H), 4.60 (bs , 2H), 4.41 (dd, 1H), 4.19 (dd, 1H), 4.03 (t, 2H), 2.99 (bs, 2H), 2.30 (m, 4H), 1.94 (bs, 2H), 1.57 (m, 6H), 1.25 (m, 40H), 1.05 (t, • 3H), 0.8 8 (m,
    6H), TOF-MS positive ES, calculated for [M + H] + 857.5558; found 857.5565.
    Example 8 Synthesis of 4-amino-1- [2- (1,2-di-Qoleoyl-sn-glycero-3-phospho) ethyl] -2-n-butyl-1Himidazo [4,5-c] quinoline , Compound (If)
    Rx = n-Bu, (CH 2 ) 7 CH = CH (CH 2 ) 7 ch 3 (CH 2 ) 2 ,
    0,
    R 2 =
    R 3 = • S'h'f γ '' o 'a »
    "
    Ό f!
    iiif "
    hOa- fi i; ·.> & “h O <>
    , h 'y y <»f ij' · · '· C. . x-u y.s; i tc <.S
    6 ......
    fife
    y. :
    ί ;
    H
    ο
    .............: ............ f ....................... .................................................. .
    ο, vX'.fSaCs-st.y · £ .γ> Όΐ>
    y
    The phosphotriester IXf was prepared with a yield of 92 by reacting di-O-oleoylglycerol Illf with V, this followed by the addition of
    BE2016 / 5915
    Imidazoquinoline Vila and imidazolium triflate as described in Example 1. IXf was oxidized and deprotected using the procedure described in Example 2 to give the phospholipidated imidazoquinoline If with a yield of 75% .
    NMR Χ Η (400 MHz, CDC1 3 / CD 3 OD) δ 8.18 (bs, 1H), 7.39 (bs, 1H), 7.18 (bs, 1H), 6.92 (bs, 1H) , 5.33 (m, 4H),
    5.25 (m, 1H), 4.80 (bs, 2H), 4.60 (bs, 2H), 4.41 (dd,
    J = 3.2, 12.0 Hz, 1H), 4.19 (dd, J = 6.4, 12.0 Hz, 1H),
    4.03 (t, J = 6.0 Hz, 2H), 3.01 (bs, 2H), 2.30 (m, 4H),
    1.98 (m, 4H), 1.57 (m, 6H), 1.27 (m, 40H), 1.05 (t, J =
    7.2, 3H), 0.88 (m, 6H); ES negative TOF-MS, calculated for [M-H] ~ 965.6497, found 965.6498.
    Example 9 Synthesis of 4-amino-1- [2-Q- (ethylcholestero-3-phospho) ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinoline, Compound (Ig)
    Ri = n-Bu, Z = (CH 2 ) 2 , n = 1 , tf
    Î.J7 iiWVy .......A / V ....................... .... ............. XJ ......... .............. hi ' x V “ -ΐ i · ............ "........... E ..................,., ... Lives . '> · - ·· <»&»
    . v bu x o ico
    i.Xä
    1JK · '«' h
    not. u
    Phosphotriester IX has been prepared with a yield of 99% by reacting ethyl41
    BE2016 / 5915 cholesterol IVa with V, this followed by the addition of imidazoquinoline Vila and imidazolium triflate as described in example 1. IXa was oxidized and deprotected using the procedure described in Example 2 to give the phospholipid imidazoquinoline Ig with a yield of 44%.
    NMR ! H (400 MHz, CDC1 3 / CD 3 OD) δ 10.17 (bs, 1H), 9, 90 (bs, 0.5 H 0.8.40 (bs, 0.5H), 8.08 (d, 1H), 7.45 (bs, 1H), 7.29 (t, 1H), 7, 02 (t, 1H), 6.86 (d, 1H), 6, 11 (bs, 1H), 10 5.30 (bs, 2H), 4 , 95-4.40 (m, 4H), 4.02 (d, 2H), 3, 68 (t,
    [4,5-c] qurnolerne, Compose (1H) Ri = n-Bu, Z = (CH 2 ) 2 , n = 1
    2H), 3.3-2.8 (m, 3H), 2.36 (d, 1H), 2.18 (t, 1H), 2, ΟΙ, 8 (m, 8H), 1.4-0 , 8 (m, 39H), 0.68 (s, 3H), TOF-MS positive ES, calculated for [M + H] + 777.5084; found 777.6999.
    Example 10 Synthesis of 4-amino-1- [2-Q- (butylcholestero-3-phospho) ethyl] -2-n-butyl-1H-imidazoi .UH
    ........ .......................................... ......
    H:>
    t u ··· i H
    MH · rMA.
    HO
    ML
    BE2016 / 5915
    Z.! !
    ΛΕ C ··: <, A ssssssssssssssTsg • xk>
    LH: H
    Vil "
    ’. (• I g
    '' V> / ns - - SX‘fc>
    t ^ H ^ iili
    oh.
    ,, .j .1 "vù ·," i H
    The phosphotriester 96% yield of cholesterol IVb with V,
    of 5 6 00 · 8.01 (bs, IH), 7.31 IH), 5.32 (m, 2H), -, 2H), , 3.48 (m, 2H), (m, IH), 1, 62 -2.10 -0.95 (m, 9H), 0.68
    IXb was prepared with a butyl reactant followed by the addition of imidazoquinoline Vila and imidazolium triflate as described in Example 1. IXb was oxidized and deprotected using the procedure described in Example 2 to give the phospholipid imidazoquinoline Ih with a yield of 56
    NMR Χ Η (400 MHz, CDC1 3 / CD 3 OD) δ (bs, IH), 7.04 (bs, IH), 6.88 (bs,
    4.82 (bs, 2H), 4.53 (bs, 2H), 3.92 (n 3.2-2.8 (m, 2H), 2.32 (m, 1H), 2.1C (m , 11H), 0.97-1.60 (2m, 9H), 0.86 (s, 3H); ES negative TOF-MS, calculated for [MH]
    803.5240, found 803.5923.
    Example 11 Synthesis of 6-amino-2-butoxy-9- [N- (2 (1,2-di-O-palmitoyl-sn-glycero-3-phosphoramido) ethyl) 4-piperidinylmethyl] -8-hydroxypurine , Compound (lia)
    R = n-butoxy, d = 1, X = CH, Y = N, m = 2, n = 0, R2 = R 3 = n-Ci5H 3 iCO
    BE2016 / 5915
    MO 'Y, xi *
    Ο * * · 'ô
    Viii8
    Mt 'iîl' Y f i
    SXÇ5
    3 ·! ,.
    MC, 0
    ΪΜ ”ί“ Η ”
    ...... s .....
    ο r * fe
    Η bones
    CX
    Ύν 'S ' ïÆisS-i «<5., .. Y« Hsa
    Phosphotriester IX * a was prepared with a yield of 33% by reacting di-O-palmitoylglycerol Ilia with V, this followed by the addition of oxoadenine Villa and imidazolium triflate as described in Example 1. IX * a was oxidized and deprotected following the procedure described in Example 2 to give the phospholipid oxoadenine Ha with a yield of 56%.
    RMN Y (CDC1 3 / CD 3 OD, 400 MHz): δ 5.17 (bs, 1H), 4.32 (dd, 1H), 4.20-4.09 (m, 5H), 3.98 ( br t, 2H), 3.69 (br d, 3H), 3.23 (br s, 1H), 1.86 (br s, 4H), 1.69 (m, 2H), 1.53 (br s, 4H), 1.42 (dd, 2H), 1.20 (m, 48H), 0.91 (t,
    3H), 0.83 (t, 6H), ES negative TOF-MS, calculated for [ΜΗ] - 993.6768; found 993.6782.
    Example 12 Synthesis of 6-amino-2-butoxy-9- [77- (2 (1,2-di-O-oleoyl-sn-glycero-3-phosphoramido) ethyl) -4piperidinylmethyl] -8-hydroxypurine, Compound (Ilb)
    R = n-butoxy, d = 1, X = CH, Y = N, m = 2, n = 0,
    R2 - R 3 (CH 2 ) 7CH = CH (CH 2 ) 7CH 3
    BE2016 / 5915
    ό
    Hi
    Yb f ! Vl &<- ZH '<: ····: .. M ï I -W iW>' h Z iX'fc lllllllll :!
    ΜΖ ... 0 %
    VW sVkH ra ', oo z f'ö'
    AT..
    m.>
    • j Cti ilb
    W i 's l-'q-'Y
    v ... imbbfe.wt;
    Phosphotriester IX * b was prepared in 58% yield by reacting di-O-oleoylglycerol Illf with V, followed by the addition of oxoadenine Villa and imidazolium triflate as described in Example 1. IX * b was oxidized and deprotected following the procedure described in Example 2 to give the phospholipid oxoadenine Ilb with a yield of 73%.
    NMR Χ Η (CDC1 3 / CD 3 OD, 400 MHz): δ 5, 3 (m, 4H), 5.23 (m, 1H), 4.37 (dd, 1H), 4.20 (m, 5H), 4.04 (t, 2H), 3.70 (m, 4H), 3.27 (bs, 2H), 2.74 (m, 2H), 2.30 (m, 5H), 2.00 15 (m, 12H), 1.75 (m, 2H), 1.60 (bs, 4H), 1.4 < 3 (m, 2H), 1.30 (m, 40H), 0.97 (t, 3H), 0.88 (t, 3H), , ES negative TOF-
    MS, calculated for [M-H] “1045.7082; found 1045.2163.
    BE2016 / 5915
    权利要求:
    Claims (11)
    [1]
    1. Process for the preparation of a compound of formula (I) comprising the following steps:
    a) the reaction of a compound of formula (III) in which n is 0, 1, 2, 3, 4
    13, 14, 15, 16, 17, 18, 19
    5, 6, 7, 8, 9, 10, 11, 12 or 20;
    R 2 is H or an alkyl group C 4 -C 2 4 linear or branched, optionally unsaturated, or an acyl group C 4 to C 2 4 linear or branched, optionally unsaturated;
    R 3 represents an alkyl group C4 to C2 4 Linear or branched, optionally unsaturated, or an acyl group C4 to C2 4 Linear or branched, optionally unsaturated;
    with a compound of formula (V)
    CV) in which
    BE2016 / 5915
    PG represents a protective group suitable for protecting a hydroxyl group, including but not limited to cyanoethyl, methyl, ethyl, benzyl and ailyl groups;
    5 to prepare a compound of formula (VI)
    R O R N POQ (Vi) in which 10 R =
    b) reacting a compound of formula (VI) with a compound of formula (VII) in which
    BE2016 / 5915
    Ri is selected from H, alkyl Ci-alkylamino, Ci-Ce alkoxy Ce, cycloalkyl C 3 to Cg-alkyl, C 3 to Ce cycloalkyl, C 3 to Ce ~ alkylamino C 3 to Ce cycloalkyl, C 3 to Cg-alkoxy, C 3 to Ce alkoxy, C 3 to Cg-C 3 to Cg alkoxy, C 3 to Cg-alkylamino, C 3 to Cg alkoxy, C 3 to Cg-C 3 to C6 alkoxy; alkyl C 3 to Cg alkylamino, C 3 to Cg alkoxy, C 3 to Cg cycloalkyl, C 3 to Cg-C 3 to Cg cycloalkyl, C 3 to Cg-alkylamino, C 3 to C cycloalkyl C 3 to Cg-alkoxy, C 3 to Cg alkoxy, C 3 to Cg-C 3 to Cg alkoxy, C 3 to Cg-alkylamino, C 3 to Cg alkoxy or C 3 to Cg C 3 -C 6 alkoxy being branched or unbranched and optionally substituted at their end with a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl, or maleimido group;
    Z is selected from alkyl C 2 to Cg alkenyl and C 2 to C, alkyl, C 2 to Cg alkenyl and C 2 to C being unsubstituted or substituted at their end by a - (O- C 2 to C 6 alkyl) i to 6 _ ;
    to prepare a compound of formula (IX); and
    R O P O R * <ÎX) OPG in which
    PG represents a protective group suitable for protecting a hydroxyl group, including but not limited to cyanoethyl, methyl, ethyl, benzyl and ailyl groups;
    R =
    BE2016 / 5915 in which
    R 1 is chosen from H, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl-C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl ~ C 1 -C alkylamino Ce, C 3 -C 8 cycloalkyl-C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkylamino and C 1 -C 6 alkoxy-C 1 -C alkoxy ; C1 to C8 alkyl, C1 to C8 alkylamino, C1 to C8 alkoxy, C 3 to C8 cycloalkyl-C1 to C8 alkyl, C 3 to Cg cycloalkyl-C1 to Cg alkylamino, C 3 to cycloalkyl C1-C6-alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylamino or C1-C6-alkoxy-C1-C6 alkoxy being branched or unbranched and optionally substituted at their ends with a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl, or maleimido group;
    BE2016 / 5915
    Z is selected from alkyl C 2 to Ce alkenyl and C 2 to Ce alkyl, C 2 to Ce alkenyl and C 2 This being unsubstituted or substituted at their end by a - (O- C 2 to Ce) i to e ~ alkyl;
    C) the oxidation of a compound of formula (IX) and the elimination of the hydroxy-protecting group to obtain a compound of formula (I)
    [2]
    2. Process for the preparation of a compound of formula (I) comprising the following steps:
    a) the reaction of a compound of formula (IV) in which n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, or 20;
    BE2016 / 5915 with a compound of formula (V)
    N- P O PG
    5 in which
    PG represents a protective group suitable for protecting a hydroxyl group, including but not limited to cyanoethyl, methyl, ethyl, benzyl and ailyl groups;
    10 to prepare a compound of formula (VI);
    FT O p N PGO /
    W ’where 15 R =
    BE2016 / 5915
    PG represents a protective group suitable for protecting a hydroxyl group, including but not limited to, cyanoethyl, methyl, ethyl,
    benzyl and allyl; and not worth 0, 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 r b) the reaction of a compound of formula (VI) with
    a compound of formula (VII) in which
    R 1 is chosen from H, C 1 to C 6 alkyl, C 1 to C 6 alkylamino, C 1 to C 6 alkoxy, C 3 to C 8 cycloalkyl-C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl C 1 to C 8 galkylamino, C 3 -C 8 cycloalkyl-C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 8 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkylamino and C 1 -C 6 alkoxy-C 1 -C 6 alkoxy; C1 to C8 alkyl, C1 to C8 alkylamino, C1 to C8 alkoxy, C 3 to C8 cycloalkyl-C1 to C8 alkyl, C 3 to Cg cycloalkyl-C1 to Cg alkylamino, C 3 to cycloalkyl C1-C6-alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylamino or C1-C6-alkoxy-C1-C6 alkoxy being branched or unbranched and optionally substituted at their end with a hydroxyl, amino, thio group,
    BE2016 / 5915 hydrazino, hydrazido, azido, acetylenyl, carboxyl, or maleimido;
    Z is selected from alkyl C 2 to Ce alkenyl and C 2 to Ce alkyl, C 2 to Ce and
    5 C 2 -C alkenyl being unsubstituted or substituted at their ends by a group - (O-C 2 -C 6 alkyl) i to e ~;
    to prepare a compound of formula (IX); and
    R ’O R O R’
    OPO
    W ’where R =
    R '=
    BE2016 / 5915
    c) the oxidation of a compound of formula (IX) and the elimination of the hydroxy-protecting group to obtain a compound of formula (I)
    NK
    -N 'X
    OH
    [3]
    3. Process for the preparation of a compound of formula
    (II) including the following steps: a) the reaction of a compound of formula (III) HO— “(C r C ^ (ky (O) fî - —0¾ CB in which n is 0, 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 r R2 represents H or an alkyl group in C 4 to C24 linear or branched, possibly unsaturated, or a
    C acyl group
    [4]
    4 to C24 linear or branched, possibly unsaturated;
    R3 represents a linear or branched C4 to C24 alkyl group, optionally unsaturated, or a linear or branched C4 to C24 acyl group, optionally unsaturated;
    BE2016 / 5915 with a compound of formula (V)
    N P O PG in which
    PG represents a protective group suitable for protecting a hydroxyl group, including but not limited to cyanoethyl, methyl, ethyl, benzyl and ailyl groups;
    all other variables are as defined above for formula (II);
    to prepare a compound of formula (VI); and in which R represents
    BE2016 / 5915
    b) the reaction of a compound of formula (VI) with a compound of formula (VIII)
    NH>
    <ΟΜ ^ ™ Χ (s. + V-COUn10 <W where d is 0, 1, 2, 3, 4, 5 or 6;
    Het represents a saturated nitrogen heterocycle of four, five, or six members in which
    X, Y = CH or N, and at least one of X and Y represents a nitrogen atom;
    m is 0, 1, 2, 3, 4, 5 or 6;
    to prepare a compound of formula (IX) *; and
    R ....... O ....... R ...... O ...... R * (LX) * ÔPO in which
    R represents
    R * represents
    BE2016 / 5915 "y
    c) the oxidation of a compound of formula (IX) * and the elimination of the hydroxy-protecting group to obtain a compound of formula (II)
    NK
    i II> OH / 'X
    You
    OH * iOX-y
    -0¾
    -0¾
    4. Process for the preparation of a compound of formula (II) comprising the following steps:
    a) the reaction of a compound of formula (IV)
    HO— (CrC ^ ikyiO):
    . "‘ ’Sx d / • Z
    J> ·. »· ...... A .........................„ y * '
    X i X X. X 'ψ · X ·' *
    ZV (IV) in which
    BE2016 / 5915 n is Ο, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
    13, 14, 151, 16, 17, 18, 19, or 20;
    with a compound of formula (V),, -¾, A,
    NOT
    N P O PG in which
    PG represents a protective group suitable for protecting a hydroxyl group, including but not
    Limited thereto, cyanoethyl, methyl, ethyl, benzyl and ailyl;
    to prepare a compound of formula (VI);
    R 'O P N in which R represents
    BE2016 / 5915
    b) the reaction of a compound of formula (VI) with a compound of formula (VIII)
    OH in which d is 0, 1, 2, 3, 4, 5 or 6;
    10 Het represents a saturated nitrogen heterocycle of four, five, or six members in which
    X, Y = CH or N, and at least one of X and Y represents a nitrogen atom;
    m is 0, 1, 2, 3, 4, 5 or 6;
    To prepare a compound of formula (IX) *;
    in which
    BE2016 / 5915
    R represents
    [5]
    5 R * represents
    - / x. „F“ ·> ’Χχί * f
    , ..- ·· * '· -, t
    Oj, -Q | x |
    c) oxidation of a compound of formula (IX) * and elimination of the hydroxy-protecting group to obtain a compound of formula (II)
    W
    > i y-oM rts N ’x'x
    ..... O ..... p .g ..
    -λ yrfejy - j
    014
    ^ .ιΛ
    .....
    5. Method according to any one of claims 1 to 4, in which ΙΗ-tetrazole is added to a compound of formula (III) or of formula (IV).
    BE2016 / 5915
    [6]
    6. Method according to claim 5, in which ΙΗ-tetrazole is added in several parts over 20 to 40 minutes.
    [7]
    7. Method according to any one of claims 1 to 6, in which imidazolium triflate is added with a compound of formula (VII) or (VIII).
    [8]
    8. Method according to any one of claims 1 to 7, in which the coupling agent used with a compound of formula (III) or of formula (IV) and a compound of formula (V) is 2.1 equivalents , the compound of formula (III) or of formula (IV) is at 2.0 equivalents, the compound of formula (V) is at
    2.1 equivalents, the compound of formula (VII) or of formula (VIII) is 1.0 equivalent and the oxidizing agent for the compound of formula (IX), (IX), (IX) * or (IX) * is 1.5 equivalent.
    [9]
    9. Method according to any one of claims 1 to 8, in which imidazolium triflate is added with the compound of formula (VII) or the compound of formula (VIII) to the same reaction mixture produced by the reaction of the compound of formula (V) with the compound of formula (III) or the compound of formula (IV).
    [10]
    10. Process according to any one of the preceding claims, in which the reaction mixture containing the compound of formula (VI) or (VI) is cooled to 0 ° C before the addition of a compound of formula (VII) or formula (VIII).
    [11]
    11. Method according to any one of the preceding claims, in which the group
    BE2016 / 5915 hydroxy-protector is a cyanoethyl group and deprotection is carried out with triethylamine (TEA).
    BE2016 / 5915
    SHORT
    PHOSPHOLIPIDATION OF IMIDAZOQUINOLEINS AND OXOADENINS
    The present invention relates to a process for phospholipidation of imidazoquinolines and oxoadenines More particularly, the present invention relates to a procedure with high efficiency and adjustable scale
    5 for the phospholipidation of imidazoquinolines and oxoadenines which obviates the need to isolate unstable phosphoramidite intermediates. This process can be used for the phospholipidation of imidazoquinolines and active oxoadenines on the
    10 receiver of type Toll 7 (TLR7) and active on the receiver of type Toll 8 (TLR8).
    Number of ia defrsatxte nation ate ^ ôtontami ftc "rtt Office öftR" "wrcipêen ôrî> patents
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    引用文献:
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    US20140323731A1|2008-10-24|2014-10-30|Glaxosmithkline Biologicals S.A.|Lipidated imidazoquinoline derivatives|
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    CN102372711B|2010-08-18|2014-09-17|山东轩竹医药科技有限公司|Imidazo quinoline PI3K and mTOR dual inhibitor|
    US20140242112A1|2012-11-30|2014-08-28|Glaxosmithkline Biologicals S.A.|Novel vaccine|
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    BE1024380B1|2015-12-14|2018-02-12|Glaxosmithkline Biologicals Sa|PHOSPHOLIPIDATION OF IMIDAZOQUINOLINES AND OXOADENINS|BE1024380B1|2015-12-14|2018-02-12|Glaxosmithkline Biologicals Sa|PHOSPHOLIPIDATION OF IMIDAZOQUINOLINES AND OXOADENINS|
    US20210277038A1|2016-09-07|2021-09-09|Glaxosmithkline Biologicals, S.A.|Imidazoquinoline derivatives and their use in therapy|
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    法律状态:
    2018-03-07| FG| Patent granted|Effective date: 20180212 |
    2021-09-03| MM| Lapsed because of non-payment of the annual fee|Effective date: 20201231 |
    优先权:
    申请号 | 申请日 | 专利标题
    US201562266858P| true| 2015-12-14|2015-12-14|
    US62266858|2015-12-14|
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