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-8455534-B2
Publication Date
2013-06-04
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 relates to administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, to a mammal. The compounds are defined by a structural Formula (I) with substituent variables including Z, R2, W, and additional groups R3, R4, R5, R6, R7, R9, and R10, together with integer parameters m, n, and p. The scaffold is described as an indazole (1H-indazol-5-yl) core combined with substituted ethyl acrylate/acrylic acid derivatives, including (E)- and (Z)-configured compounds and pharmaceutically acceptable salt forms.
The claimed therapeutic use focuses on alleviating at least one symptom of a disease or condition in a mammal or arresting the development of the disease or condition. One aspect specifies breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, bone cancer, colorectal cancer, cervical cancer, or lung cancer, while another specifies leiomyoma, uterine leiomyoma, or endometriosis. The document also names multiple stereodefined examples and related analogs within the Formula (I) chemical space.
Claims Coverage
Two independent claims are identified. Both recite administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, to a mammal to alleviate symptoms or arrest development of a specified disease or condition, with the main inventive scope defined by the Formula (I) substituent framework and integer parameters. The disease/condition scope differs between the two claims: one covers specified cancers, and the other covers leiomyoma, uterine leiomyoma, and endometriosis.
Administering Formula (I) to mammal with specified cancers
A method of alleviating at least one symptom of a disease or condition in a mammal or arresting the development of a disease or condition in a mammal, wherein the disease or condition is breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, bone cancer, colorectal cancer, cervical cancer, or lung cancer, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, or N-oxide thereof.
Formula (I) substituent-variable definition for the therapeutic compound
A compound of Formula (I) defined such that Z is —OH or —OR10; R2 is C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 deuteroalkyl, C3-C6 cycloalkyl, or —C1-C4 alkylene-W; W is hydroxy, halogen, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or C3-C6 cycloalkyl; each R3 is independently halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl; each R4 is independently halogen, —CN, —OR9, —S(=O)2R10, C1-C4 alkyl, C1-C4 fluoroalkyl, or C1-C4 heteroalkyl; each R5 is independently halogen, —CN, —OR9, —S(=O)2R10, C1-C4 alkyl, C1-C4 fluoroalkyl, or C1-C4 heteroalkyl; R6 is H, C1-C4 alkyl, or halogen; R7 is H, C1-C4 alkyl, or halogen; R9 is H, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl; R10 is C1-C6 alkyl; and m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, or 2.
Administering Formula (I) to mammal with leiomyoma/uterine leiomyoma/endometriosis
A method of alleviating at least one symptom of a disease or condition in a mammal or arresting the development of a disease or condition in a mammal, wherein the disease or condition is leiomyoma, uterine leiomyoma, or endometriosis, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, or N-oxide thereof.
Across the independent claims, the inventive concept is the therapeutic administration of compounds of Formula (I), including pharmaceutically acceptable salts and N-oxides, to alleviate symptoms or arrest development of specified cancers or leiomyoma/uterine leiomyoma/endometriosis. The chemical coverage is expressed by the Formula (I) substituent definitions and integer parameters, with the disease/condition scope separated into the two independent claims.
Stated Advantages
Alleviating at least one symptom of a disease or condition in a mammal.
Arresting the development of a disease or condition in a mammal.
Diminishes estrogen effects.
May function as estrogen receptor degraders with minimal or none agonist activity.
Documented Applications
Breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, bone cancer, colorectal cancer, cervical cancer, or lung cancer by alleviating at least one symptom or arresting development in a mammal.
Leiomyoma, uterine leiomyoma, or endometriosis by alleviating at least one symptom or arresting development in a mammal.
Biological evaluation using an ERE-driven MCF-7 reporter and assessments including breast and ovarian cancer cell viability and ER-α SP1 in-cell western.
Xenograft assays, including a tamoxifen-resistant model.
Pharmaceutical compositions and clinical trial-related embodiments.
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