Estrogen receptor modulators and uses thereof
Inventors
Smith, Nicholas D. • Govek, Steven P. • Kahraman, Mehmet • Julien, Jackaline D. • Nagasawa, Johnny Y. • Lai, Andiliy G.
Assignees
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Publication Number
US-9187460-B2
Publication Date
2015-11-17
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 concerns substituted chromen-6-ol and related chromene, coumarin, benzocoumarin, and chroman scaffold compounds defined by Formula (I), Formula (VI), Formula (VII), and Formula (VIII), including pharmaceutically acceptable salts and solvates. The structures use multiple variable substituent groups and ring or linker parameters, including R1 through R12, R23 formed by R2 and R3 with the N atom, and discrete values for t, m, n, and p. The permitted substituents include halogen, CN, OH, alkyl, fluoroalkyl, fluoroalkoxy, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, monocyclic heteroaryl, sulfur-oxo, and carbonyl-containing groups.
The disclosure further describes stereochemically defined chromen-6-ol derivatives with chiral propoxy-linked side chains, including pyrrolidine-, piperidine-, morpholine-, thiomorpholine-, piperazinyl-, diazepan-, azabicyclic-, and other heterocyclic substituents. Specific embodiments include hydroxyphenyl, benzonitrile, methylsulfonyl, trifluoromethylsulfonyl, difluoromethyl, fluoromethyl, methoxy, ethynyl, vinyl, and halogen-substituted aryl variations, together with illustrated chemical structures and analytical characterization. The patent also includes pharmaceutical composition language and therapeutic use language in cancer treatment settings and in ER-mediated or ER-dependent diseases and conditions.
The disclosed formula-based families include fixed or constrained ring and linker selections, including Y and X as O in Formula (VI) and Formula (VII), together with formula-specific limits on t, m, n, and p. Some embodiments are tied to specific dependent refinements and narrowed substituent selections, and one input describes synthetic schemes that construct the chromene core and install amino sidechains.
Claims Coverage
The consolidated claim coverage includes independent claims for Formula (I), Formula (VI), Formula (VII), and Formula (VIII). Across these independent claims, the inventive scope is the defined scaffold plus enumerated substituent-variable constraints, with pharmaceutically acceptable salts and solvates included; the Formula (VI) and Formula (VII) claims additionally fix Y and X as O and specify discrete values for p. Four inventive features are identified.
Formula (I) compound scaffold with defined substituent variables
A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof, with R1 as H or C1-C6 alkyl; R2 and R3 together with the N atom forming R23; R23 selected from Cl, CN, OH, C1-C4 alkyl, C1-C6 fluoroalkyl, C1-C4 alkoxy, or C1-C4 heteroalkyl; t as 0 or 1; R5 selected from halogen, CN, NHR11, NR11R12, SR11, S(=O)R12, S(=O)2R12, and other alkyl, fluoroalkyl, fluoroalkoxy, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, and monocyclic heteroaryl options; and each R6, R9, R10, R11, and R12 independently selected from enumerated sets, with m and n taking discrete values.
Formula (VI) compound scaffold with fixed Y and X as O
A compound of Formula (VI), or a pharmaceutically acceptable salt, or solvate thereof, with R1 as H or C1-C6 alkyl; R2 and R3 together with the N atom forming R23; R23 selected from Cl, CN, OH, C1-C4 alkyl, C1-C6 fluoroalkyl, C1-C4 alkoxy, or C1-C4 heteroalkyl; t as 1; R4 as C1-C4 alkyl; each R6 selected from halogen, CN, OH, OR11, SR11, S(=O)R12, S(=O)2R12, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, C1-C6 alkoxy, and C1-C6 heteroalkyl; R7 as H; each R8 selected from H, halogen, CN, OH, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, and C1-C6 alkoxy; R9, R10, R11, and R12 selected from enumerated sets; Y as O; X as O; m as 1, 2, 3 or 4; n as 0, 1, or 2; and p as 0 or 1.
Formula (VII) compound scaffold with fixed Y and X as O
A compound of Formula (VII), or a pharmaceutically acceptable salt, or solvate thereof, with R1 as H or C1-C6 alkyl; R2 and R3 together with the N atom forming R23; R23 selected from Cl, CN, OH, C1-C4 alkyl, C1-C6 fluoroalkyl, C1-C4 alkoxy, or C1-C4 heteroalkyl; t as 0 or 1; R4 as C1-C4 alkyl; each R6 selected from halogen, CN, OH, OR11, SR11, S(=O)R12, S(=O)2R12, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, C1-C6 alkoxy, and C1-C6 heteroalkyl; R7 as H; each R8 selected from H, halogen, CN, OH, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, and C1-C6 alkoxy; R9, R10, R11, and R12 selected from enumerated sets; Y as O; X as O; m as 1, 2, 3 or 4; n as 0, 1, or 2; and p as 0 or 1.
Formula (VIII) compound scaffold with heterocycloalkyl-forming R2 and R3
A compound of Formula (VIII), or a pharmaceutically acceptable salt, or solvate thereof, with R1 as H or C1-C6 alkyl; R2 and R3 together with the N atom to form R23; R23 selected from Cl, CN, OH, C1-C4 alkyl, C1-C6 fluoroalkyl, C1-C4 alkoxy, or C1-C4 heteroalkyl; t as 0 or 1; R5 selected from halogen or specified substituted functional groups; each R6, R9, R10, R11, and R12 independently selected from enumerated sets; and m as 0, 1, 2, 3 or 4 and n as 0, 1, or 2.
Across the independent claims, the coverage is directed to structurally related substituted chromen-6-ol, chromene, coumarin, benzocoumarin, and chroman compounds defined by formula frameworks and extensive enumerated substituent options. The core claim scope is the scaffold definition itself, with discrete parameter settings and, where applicable, fixed Y and X as O, plus inclusion of pharmaceutically acceptable salts and solvates.
Stated Advantages
Minimal or no ER agonist activity.
Tissue-selective ER activity, including antagonist activity in breast cells and no agonist activity in uterine cells.
Treating cancer in a mammal.
Treating ER-mediated/ER-dependent diseases and conditions.
Providing pharmaceutical compositions for administration in dosage forms including tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, and lotion.
Documented Applications
Treating cancer in a mammal, including breast, ovarian, endometrial, prostate, lung, and uterine cancer.
Treating uterine disorders including leiomyoma and endometriosis.
Pharmaceutical compositions administered in dosage forms including tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, and lotion.
Combination therapy use cases directed to reducing ER activation and reducing ER receptor concentrations, including ER-alpha levels.
A pharmaceutical composition containing the compound of claim 1, or a pharmaceutically acceptable salt, together with at least one pharmaceutically acceptable inactive ingredient.
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