Estrogen receptor modulators and uses thereof
Inventors
Kahraman, Mehmet • Govek, Steven P. • Nagasawa, Johnny Y. • Smith, Nicholas D.
Assignees
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Publication Number
US-8703810-B2
Publication Date
2014-04-22
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 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 patent relates to compounds of Formula (VI), or pharmaceutically acceptable salts thereof, with variable substituents and defined linker groups. Y is selected from O, S, or NR11, X is selected from O, S, CH2, NH, or N(C1-C6alkyl), and m, n, p, and t are restricted to enumerated values. The variables R1, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are selected from broad but explicit substituent classes including halogen, cyano, hydroxy, alkyl, fluoroalkyl, alkoxy, heteroalkyl, aryl, heteroaryl, and carbonyl-containing groups.
The disclosure further specifies that the relevant heterocycle is azetidinyl or pyrrolidinyl, and includes a ring-forming option in which one R8 is taken together with R1, along with the intervening atoms joining R8 to R1, to form a 5-, 6-, or 7-membered ring. The content also presents chromen-6-ol compounds with a chromene core, chiral amine-bearing side chains, and substituted aromatic ring features. Examples include propoxy or ethoxy linkers and substituted aromatic patterns with fluoro, chloro, bromo, difluoro, trifluoromethyl, ethynyl, methylsulfonyl, hydroxy, and methyl substituents.
Claims Coverage
The consolidated claim coverage centers on a compound of Formula (VI), or a pharmaceutically acceptable salt thereof, with broad substituent-variable selections, defined linker selections X and Y, an azetidinyl or pyrrolidinyl heterocycle option, and enumerated parameters m, n, p, and t. It also covers chiral chromen-6-ol compounds with defined stereochemical side chains, aromatic substitution diversity, and pharmaceutically acceptable salts. In total, the provided claim coverage presents 11 inventive features across these independent claims.
Formula (VI) compounds and pharmaceutically acceptable salts
A compound of Formula (VI), or a pharmaceutically acceptable salt thereof.
Variable substituent pattern for R1, R3, R4, R5, and R6
R1 is H, F, C1-C4 alkyl, or C1-C4 fluoroalkyl; R3 is H, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, or C1-C4 fluoroalkyl; each R4, R5, and R6 is independently selected from H, halogen, CN, OH, OR9, SR9, S(=O)R10, S(=O)2R10, C(=O)R10, C(=O)OH, C(=O)OR10, C(=O)NHR10, C(=O)N(R10)2, and substituted or unsubstituted C1-C6 alkyl, fluoroalkyl, fluoroalkoxy, alkoxy, and heteroalkyl.
Azetidinyl or pyrrolidinyl heterocycle option
The compound includes an azetidinyl or pyrrolidinyl option, and R7 is H or C1-C4 alkyl.
Variable R8 selection and ring formation with R1
Each R8 is independently selected from F, Cl, CN, OH, OR9, SR9, S(=O)R10, S(=O)2R10, substituted or unsubstituted C1-C6 alkyl, fluoroalkyl, fluoroalkoxy, alkoxy, and heteroalkyl, or one R8 is taken together with R1 along with the intervening atoms to form a 5-, 6-, or 7-membered ring.
Variable side groups R9 and R10
Each R9 is independently selected from H, C(=O)R10, C(=O)OR10, C(=O)NHR10, substituted or unsubstituted C1-C6 alkyl, heteroalkyl, fluoroalkyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, aryl, heteroaryl, and alkylene-linked variants; each R10 is independently selected from substituted or unsubstituted C1-C6 alkyl, heteroalkyl, fluoroalkyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, aryl, heteroaryl, and alkylene-linked variants.
Defined linker groups X and Y
Y is O, S, or NR11; X is O, S, CH2, NH, or N(C1-C6alkyl); R11 is H, C(=O)R10, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C1-C6 heteroalkyl.
Defined parameter ranges for m, n, p, and t
m is 0, 1, 2, 3 or 4; n is 0, 1, 2, or 3; p is 0, 1, 2, 3 or 4; t is 1, 2, 3 or 4.
Chiral chromen-6-ol scaffold with phenolic substitution
A compound defined as 4-methyl-2H-chromen-6-ol, including 2H-chromen-7-ol alternatives, with phenolic substituents and related hydroxyphenyl positional isomers.
Chiral aryl linkage to (3-methylpyrrolidin-1-yl) side chain
A 4-aryl linkage on the chromene core bearing a chiral 2-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy) arrangement, with alternative ethoxy linker embodiments and stereochemical variants.
Aryl substitution diversity on chromene-attached phenyl groups
The claim enumerates fluoro, chloro, bromo, difluoro, trifluoromethyl, ethynyl, methylsulfonyl, hydroxy positional variants, and methyl-substituted phenyl examples.
Pharmaceutically acceptable salt coverage
The claim explicitly includes pharmaceutically acceptable salts of the listed chiral chromen-6-ol compounds.
The provided claim coverage centers on Formula (VI) compounds with broad substituent and linker definitions, azetidinyl or pyrrolidinyl functionality, and a ring-formation option involving R8 and R1, together with defined parameter ranges. It also covers a separate set of listed chiral chromen-6-ol compounds with defined stereochemical side chains, aromatic substitution diversity, and pharmaceutically acceptable salts.
Stated Advantages
Potential complete or longer-lasting tumor regression in cancer contexts.
Reduced resistance development in cancer contexts.
Reduced tumor invasiveness in cancer contexts.
Diminished estrogen effects.
Potential reduction of ER concentration.
Minimal or no ER agonist activity.
Documented Applications
Treatment, prevention, and/or diagnosis of ER-mediated or estrogen-sensitive diseases, including cancers across multiple tissues.
Treatment, prevention, and/or diagnosis of additional ER-related conditions including endocrine, CNS, cardiovascular, hematological/immune/inflammation, infectious susceptibility, metabolic, neurological, psychiatric, and reproductive disorders.
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