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Epothilone derivatives

  • US RE41,893 E1
  • Filed: 08/11/2009
  • Issued: 10/26/2010
  • Est. Priority Date: 07/08/1997
  • Status: Expired due to Term
First Claim
Patent Images

1. A compound of the formula:

  • embedded imagewherein;

    Q is selected from the group consisting of;

    embedded imageG is selected from the group consisting of alkyl;

    substituted alkyl;

    substituted aryl;

    a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;

    embedded imageand a 1-methyl-2-(substituted R′

    ) ethenyl group, wherein R′

    is a monocyclic group selected from the group consisting of pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2
    -oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl;

    or
    a bicyclic heterocyclic group selected from the group consisting of benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl], furo[2,3-b]pyridinyl, dihydroisoindolyl, dihydroquinazolinyl, 3,4-dihydro-4-oxo-quinazolinyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, and thienothienyl;

    W is O or NR15 NH;

    X is O or H, H;

    Y is selected from the group consisting of O;

    H, OR16;

    OR17, OR17;

    NOR18;

    H,NHOR19;

    H, NR20R21;

    H, H; and

    CHR22;

    wherein OR17, OR17 can be a cyclic ketal;

    Z1 and Z2 are independently CH2;

    B1 and B2 are independently is selected from the group consisting of OR24, OCOR25, and O—

    C(═

    O)—

    NR26R27, and when B1 is OH and Y is OH, H, they can form a six-membered ring ketal or acetal;

    B2 is selected from the group consisting of OH, OCOR25, and O—

    C
    (

    O
    )

    NR
    26R27;

    R1 and R2 are both hydrogen;

    R1, R2, R3, R4, R5, R7, R13, R14, R18, R19, R20, R21, R22, R26 and R27 are selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R1 and R2 are alkyl can be joined to form a cycloalkyl, and when R3 and R4 are alkyl can be joined to form a cycloalkyl;

    R6 is methyl;

    R9, R10, R16, R17, R24, R25 and R31 are selected from the group consisting of H, alkyl, and substituted alkyl;

    R11, R12, R28, R30, R32, and R33 are selected from the group consisting of H;

    alkyl;

    substituted alkyl;

    aryl;

    substituted aryl;

    cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring; and

    a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;

    R8 is hydrogen or methyl;

    R15, R23 and R29 are selected from the group consisting of H;

    alkyl;

    substituted alkyl;

    aryl;

    substituted aryl;

    cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring;

    a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;

    R32C═

    O;

    R33SO2;

    hydroxy;

    O-alkyl or O-substituted alkyl;

    or pharmaceutically acceptable salts thereof, hydrates, or solvates or geometric, optical or stereoisomers thereof;

    with the proviso that compounds wherein W and X are both O; and

    R1, R2 and R7 are H; and

    R3, R4 and R6 are methyl; and

    R8 is H or methyl; and

    G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl; and

    Q is as defined above are the compound[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione is excluded.

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