US 2009/0023666 A1Published application

Modulators of Hypoxia Inducible Factor-1 and Related Uses

AssigneeBTG plc

InventorsGregory Gardiner, Mehran Khodadoust, Hans-Jurgen Hess, Saijat Hussoin, Reimar Bruening

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Abstract

The invention features compounds of formulas I or II: and pharmaceutically acceptable salts and prodrugs thereof, as well methods for modulating the effects of local and systemic hypoxic events using the compounds.

Claims30

Dependent claims

A compound of formulas I or II:

or a pharmaceutically acceptable salt or prodrug thereof, wherein
each of R1, R5, R7, R11, and R12 is, independently, H;
OH, OR1A, or OC(O)R1A, where R1A is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C1-2 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl;
or
each of R3 and R33 is, independently, H, OC(O)NHR3C, OC(O)NR3DR3E, NH2, NHR3F, NR3GR3H, NHC(O)R3I, NHC(O)OR3J, NR3KC(O)OR3L, or NH-Sac, where each of R3C, R3D, R3E, R3F, R3G, R3H, R3I, R3J, R3K, and R3L is, independently, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-4 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl, and Sac is a saccharide;
or
each of R3α and R3β is, independently, H, OR3A or OC(O)R3B and each of R3A and R3B is, independently, C2-4 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl, with the proviso that at least one of R3α and R3β is not H;
or
R3α and R3β together are ═NNR3MR3N, or ═NOR3P, wherein each of R3M, R3N and R3P is, independently, H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl, and with the proviso that at least one of R3α and R3β is not H;
R6 is CH3, CH2OR6A, or CH2OCOR6A, where R6A is H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2— heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl;
R14 is OH, Cl, OR14A, or OC(O)R14A, where R14A is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-4 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl, or R14, R15β, and the carbons they are bonded to together represent an epoxide;
each of R15α and R15β is, independently, H, OH, OR15A, or OC(O)R15A, where R15A is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl, or R15α and R15β together are ═O;
each of R16α and R16β is, independently, H, OH, OR16A, or OC(O)R16A, where R16A is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl, or R16α and R16β together are ═O;
R17β is
where each of R21, R22, R23, R24, R25, R26, R27, R28, R29, and R30 is, independently, H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl;
R17α, is H or OH;
and
R18 is CH3, CH2OR18A, or CH2OCOR18A, where R18A is H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl.

15 more elements

A compound of formulas Ia or IIa:

or a pharmaceutically acceptable salt or prodrug thereof, wherein
each of R1, R5, R7, R11, and R12 is, independently, H;
OH, OR1A, or OC(O)R1A, where R1A is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C1-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl;
R6 is CH3, CH2OR6A, or CH2OCOR6A, where R6A is H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl;
R14 is OH, Cl, OR14A, or OC(O)R14A, where R14A is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl, or R14, R15β, and the carbons they are bonded to together represent an epoxide;
each of R15α and R15β is, independently, H, OH, OR15A, or OC(O)R15A, where R15A is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl, or R15α and R15β together are ═O;
each of R16α and R16β is, independently, H, OH, OR16A, or OC(O)R16A, where R16A is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl, or R16α and R16β together are ═O;
R17β is
where each of R21, R22, R23, R24, R25, R26, R27, R28, R29, and R30 is, independently, H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl;
R17α, is H or OH;
R18 is CH3, CH2OR18A, or CH2OCOR18A, where R18A is H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl;
and
R40 is F, Cl, CF3, NH2, NHR40A, NR41BR40C NHC(O)R40D, NHC(S)R40E, NHC(O)OR4F, NHC(S)OR40G, NHC(O)NHR40H, NHC(S)NHR40I, NHC(O)SR40J, NHC(S)SR40K, or NHS(O)2R40L, and where each of R40A, R40B, R40C, R40D, R40E, R40F, R40G, R40H, R40I, R40J, R40K and R40L is, independently, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl;
or R40B and R40C combine to form a C2 heterocyclyl containing at least one nitrogen atom.

11 more elements

Dependencies are inferred from the claim text.

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