Fluorinated estrogen receptor modulators and uses thereof
Inventors
Smith, Nicholas D. • Govek, Steven P. • Kahraman, Mehmet • Nagasawa, Johnny Y. • Lai, Andiliy G. • Bonnefous, Celine
Assignees
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Publication Number
US-9193714-B2
Publication Date
2015-11-24
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 is directed to a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, with extensive structural variability at R1, R5, R6, R10, R11, and R12, together with indices t, m, and n. R23 is fixed as —CH2F and t is 1. The disclosed scaffold includes chromen-6-ol and 2H-chromen-6-ol embodiments, substituted aromatic and cyclic amine sidechain variants, and fluorinated substituents.
The disclosed compounds include phenyl and difluorophenyl substitution patterns, together with chloro, hydroxy, benzonitrile, fluoromethyl, difluoromethyl, and fluorinated side-chain motifs. Example structures include pyrrolidine, azetidine, and piperidine-related substituents, linked through ether or propoxy motifs. Stereochemistry is emphasized through racemic, (S)-isomer, and (R)-isomer forms, and through defined stereogenic centers in the sidechain portions.
The disclosure further includes a selective estrogen receptor modulator fragment linked to a nitrogen-containing group and broader Formula (V)/(VI) concepts, together with pharmaceutically acceptable salt and solvate embodiments. The compounds are also presented as fluorinated estrogen receptor modulator compounds and as example compounds characterized by NMR and LCMS data. Overall, the core disclosure links the Formula (II) structural framework to defined fluorinated and stereodefined embodiments within a broader chemical space.
Claims Coverage
The claim coverage centers on a Formula (II) compound, or a pharmaceutically acceptable salt or solvate thereof, with fixed R23 as —CH2F and t as 1. The claim set defines broad substituent classes for R1, R5, R6, R10, R11, and R12, and the index limits for m and n. Pharmaceutical composition and method for treating cancer in a mammal claims are also explicitly present.
Formula (II) compound with fixed fluoromethyl substitution
A compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R23 is —CH2F and t is 1.
Substituent scope for R1, R5, R6, R10, R11, and R12
R1 is H, C1-C6 alkyl, or C1-C6 fluoroalkyl; R5 is selected from H, halogen, —CN, —OH, —OR11, —NHR11, —NR11R12, SR11, —S(=O)R12, —S(O)2R12, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, C1-C6 alkoxy, or C1-C6 heteroalkyl; each R6 and each R10 are independently selected from enumerated substituent classes; and each R11 and each R12 are independently selected from enumerated carbonyl, ring system, alkylene-linked, alkyl, heteroalkyl, fluoroalkyl, aryl, and heteroaryl options.
Index constraints for m and n
m is 0, 1, 2, 3, or 4; and n is 0, 1, or 2.
Pharmaceutical composition with specified administration routes
A pharmaceutical composition formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration.
Method for treating cancer in a mammal
A method for treating cancer in a mammal by administering a compound of Formula (II), or a pharmaceutically acceptable salt or solvate, wherein the cancer is breast cancer, cervical cancer, colorectal cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer.
The claimed subject matter is a Formula (II) compound family fixed at R23 = —CH2F and t = 1, with broadly defined substituent selections at multiple positions, defined index ranges, and explicit coverage for pharmaceutical compositions and cancer treatment methods.
Stated Advantages
Tissue-selective pharmacology, including ER antagonist activity in breast and no or minimal agonist activity in uterine cells.
Reduced hERG/QT risk.
Reduced risk related to torsades de pointes.
Reduced access to the hypothalamus and HPO axis.
Reduced ER activation and reduction of ER concentrations, including reduced estrogen binding and reduction of cell-specific ER activation.
Documented Applications
Treatment of cancer in a mammal, including breast cancer, cervical cancer, colorectal cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.
Treatment of ER-relevant cancers and uterine disorders including endometriosis and leiomyoma.
Reducing ER activation and ER concentrations, including reduced estrogen binding and reduction of cell-specific ER activation.
Use in pharmaceutical compositions and medicaments administered by oral, systemic or parenteral, and topical administration.
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