Estrogen receptor modulators and uses thereof
Inventors
Smith, Nicholas D. • Kahraman, Mehmet • Govek, Steven P. • Nagasawa, Johnny Y. • Lai, Andiliy G. • Julien, Jackaline D. • Bonnefous, Celine
Assignees
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Publication Number
US-8299112-B2
Publication Date
2012-10-30
Expiration Date
Abstract
Described herein are compounds that are estrogen receptor modulators. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.
Core Innovation
The invention provides compounds of Formula (I) and pharmaceutically acceptable salts, or N-oxides thereof, with broad substituent variability defined by Z, R2, W, and additional R-group variables R3, R4, R5, R6, R7, R9, and R10 together with indices m, n, and p. The disclosed scope covers indazole-containing acrylic acid and ethyl acrylate species, including (E)/(Z) isomeric forms, stereoisomers, R/S forms, atropisomers, prodrugs, polymorphs, and amorphous forms. Specific named examples are provided as concrete members of the Formula (I) space.
The core structural program is illustrated by specific (E)-configured indazole-containing ethyl acrylate/acrylic acid derivatives bearing substituted phenyl motifs and other variable groups such as cyclopropyl, cyclobutyl, chloro, fluoro, methoxy, hydroxy, and trifluoromethoxy substituents. The disclosure combines a broad Formula (I) scaffold with explicit chemical examples and related forms, while also mentioning pharmaceutical composition and therapeutic use language.
The document also describes pharmaceutical-related language associated with the compound family, including pharmaceutical compositions, routes of administration, dosage forms, and combination therapy language. Example compounds and intermediates are characterized by analytical data such as 1H NMR and LCMS.
Claims Coverage
The consolidated claim coverage centers on one independent Formula (I) compound claim with pharmaceutically acceptable salt or N-oxide coverage, plus dependent claims that refine substituent and index scope and extend to pharmaceutical compositions, administration routes, dosage forms, and specific named (E)/(Z) indazole-containing ethyl acrylate/acrylic acid examples. In total, the recurring inventive features are the Formula (I) substitution framework, salt/N-oxide coverage, pharmaceutical composition embodiments, and explicit example compounds.
Formula (I) indazole-containing compound with variable substituents and indices
A compound of Formula (I), or a pharmaceutically acceptable salt, or N-oxide thereof, wherein Z is —OH or —OR9; R2 is C1-C4 alkyl, C1-C4-fluoroalkyl, C1-C4-deuteroalkyl, C3-C6 cycloalkyl, or —C1-C4alkylene-W; W is hydroxy, halogen, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or C3-C6 cycloalkyl; each R3, R4, and R5 is independently selected from the specified halogen, CN, OR9, S(=O)2R10, alkyl, fluoroalkyl, or heteroalkyl options; R6 and R7 are H, alkyl, or halogen; R9 is H, C1-C6 alkyl, C1-C6-fluoroalkyl, or C3-C6 cycloalkyl; R10 is C1-C6 alkyl; and m, n, and p are within the specified integer ranges.
Pharmaceutically acceptable salt and N-oxide forms
The claimed compound scope explicitly includes pharmaceutically acceptable salts and N-oxides of the Formula (I) compounds.
Pharmaceutical composition including the Formula (I) compound
A pharmaceutical composition that includes the compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide of that compound.
Pharmaceutical composition formulated for specified administration routes
A pharmaceutical composition formulated for one or more administration routes including intravenous injection, subcutaneous injection, oral administration, or topical administration.
Pharmaceutical composition in specified dosage forms
A pharmaceutical composition formulated in tablets, pills, capsules, and various liquid or semi-solid forms.
Specific indazole-containing (E)/(Z) ethyl acrylate/acrylic acid examples
Named (E) or (Z) indazole-containing ethyl acrylate/acrylic acid compounds, including explicit example structures, together with pharmaceutically acceptable salts or N-oxides thereof.
Claim coverage is anchored by a broad Formula (I) indazole-containing compound definition with extensive substituent variability and index ranges, explicitly including salt and N-oxide forms. The dependent claims add pharmaceutical composition embodiments, specified administration routes and dosage forms, and explicit named (E)/(Z) indazole-containing ethyl acrylate/acrylic acid examples.
Stated Advantages
Diminish estrogen effects via ER binding and/or by reducing ER levels.
Estrogen receptor degraders (SERDs) and ER antagonists with minimal or no ER agonist activity.
Improved anticancer activity, including longer-lasting tumor regression, reduced resistance, and reduced invasiveness.
Tissue-selective pharmacology, including antagonist activity in breast cells with minimal agonism in uterine cells.
Documented Applications
Use directed to ER-related diseases and conditions across multiple tissues.
Treatment use case for hormone-dependent metastatic breast cancer after anti-estrogen therapy [procedural detail omitted for safety].
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