Therapeutically active compounds and their methods of use
Inventors
Konteatis, Zenon • Popovici-Muller, Janeta • Travins, Jeremy • Zahler, Robert • Cai, Zhenwei • Zhou, Ding
Assignees
PHARMARESOURCES (SHANGHAI) CO Ltd • Servier Pharmaceuticals LLC
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Publication Number
US-11844758-B2
Publication Date
2023-12-19
Expiration Date
Abstract
Provided are compounds useful for treating cancer and methods of treating cancer comprising administering to a subject in need thereof a compound described herein.
Core Innovation
The invention relates to a method for treating a glioma characterized by the presence of an isocitrate dehydrogenase 1 (IDH1) mutation by administering to a patient in need thereof a therapeutically effective amount of a compound having Formula (Ia), or a pharmaceutically acceptable salt or hydrate thereof. The compounds are defined by selection of ring A from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, with ring A optionally substituted with up to two substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, NH-S(O)2-(C1-C4 alkyl), S(O)2NH(C1-C4 alkyl), S(O)2-(C1-C4 alkyl), C1-C4 alkoxy, NH(C1-C4 alkyl), OH, OCF3, CN, NH2, C(O)NH2, C(O)NH(C1-C4 alkyl), C(O)-N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH. The structural definition further specifies variable selections for R1, R2, R3, R4, R5, R6, R7, and R8, including optional substitutions on alkyl or alkylene moieties and terminal methyl replacements.
The compound definition includes multiple provisos that exclude certain combinations of N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) depending on the identity and substitution pattern of ring A. These exclusions apply to optionally substituted pyridyl, optionally substituted heteroaryl selected from the listed heteroaryl groups, optionally substituted 1-pyrazolyl, optionally substituted phenyl, and substituted 1-pyrazolyl, thereby narrowing the permitted Formula (Ia) embodiments.
The provided material also includes pharmaceutical composition embodiments comprising the compound and one or more pharmaceutically acceptable excipients, as well as dependent refinements specifying IDH1 R132H or IDH1 R132C mutation variants. The document further describes an unmet need for inhibitors of mutant IDH1 and/or mutant IDH2 and their alpha-hydroxyglutarate neoactivity, and states that the compounds are intended to inhibit mutant IDH1/IDH2 in the context of cancers characterized by mutant IDH1/IDH2.
Claims Coverage
The independent claims cover treatment of glioma characterized by an IDH1 mutation through administration of therapeutically effective amounts of Formula (Ia) compounds, a Formula-defined compound variant, and a pharmaceutical composition containing the compound with pharmaceutically acceptable excipients. The Formula (Ia) claim includes ring A selection and substitution limits, defined R-group selections, terminal methyl replacement options, and ring-A-dependent exclusion rules for N-substituent patterns.
Treating IDH1-mutant glioma with Formula (Ia) compounds
A method for treating a glioma characterized by the presence of an isocitrate dehydrogenase 1 (IDH1) mutation comprising administering to a patient in need thereof a therapeutically effective amount of a compound having Formula (Ia) or a pharmaceutically acceptable salt or hydrate thereof.
Ring A selection with optional substitution limits
Ring A is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, and ring A is optionally substituted with up to two substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, NH-S(O)2-(C1-C4 alkyl), S(O)2NH(C1-C4 alkyl), S(O)2-(C1-C4 alkyl), C1-C4 alkoxy, NH(C1-C4 alkyl), OH, OCF3, CN, NH2, C(O)NH2, C(O)NH(C1-C4 alkyl), C(O)-N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH.
R-group substituent definitions and terminal methyl replacements
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 alkyl, and CN, with optional substitution on the alkyl moieties; R2 and R5 are each independently selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, with optional substitution by OH, O(C1-C4 alkyl), CO2H, or halo, and terminal methyl moieties in R2 and R5 are optionally replaced with CH2OH, CF3, CH2F, CH2Cl, C(O)CH3, C(O)CF3, CN, or CO2H; and R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl.
Conditional exclusion constraints based on ring A and N-substitution patterns
Provided provisos exclude certain paired N-substituted configurations depending on whether A is an optionally substituted pyridyl, a listed heteroaryl, optionally substituted 1-pyrazolyl, optionally substituted phenyl, or substituted 1-pyrazolyl, including cases where specific combinations are not both present or are otherwise excluded.
Pharmaceutical composition with excipients
A method for treating a glioma characterized by the presence of an IDH1 mutation by administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the compound and one or more pharmaceutically acceptable excipients, or a pharmaceutically acceptable salt or hydrate thereof.
Overall, the claim coverage is directed to treatment of IDH1-mutant glioma by administering a therapeutically effective amount of defined compounds or a pharmaceutical composition including such compounds. The most detailed coverage is for Formula (Ia), where ring A selection, substituent-variable definitions, and conditional exclusions define the inventive compound class.
Stated Advantages
Addresses an unmet need for inhibitors of mutant IDH1/IDH2 and their alpha-hydroxyglutarate neoactivity.
Documented Applications
Treating a glioma characterized by the presence of an isocitrate dehydrogenase 1 (IDH1) mutation by administering a therapeutically effective amount of a compound having Formula (Ia) or a pharmaceutically acceptable salt or hydrate thereof.
Treating a glioma characterized by an IDH1 mutation by administering a therapeutically effective amount of a pharmaceutical composition comprising the compound and one or more pharmaceutically acceptable excipients.
Treating a glioma characterized by the presence of an IDH1 R132H or IDH1 R132C mutation.
Treating cancers characterized by mutant IDH1/IDH2.
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