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6,7-dihydro-5h-benzo[7]annulene derivatives as estrogen receptor modulators

A technology of phenyl and compound, applied in the field of novel substituted 6,7-dihydro-5H-benzo[7]rotene compound

Active Publication Date: 2018-11-23
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although such endocrine therapies greatly contribute to the reduction of breast cancer development, more than one-third of ERα-positive patients exhibit de-novo resistance or develop over time to such existing therapies. resistance

Method used

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  • 6,7-dihydro-5h-benzo[7]annulene derivatives as estrogen receptor modulators
  • 6,7-dihydro-5h-benzo[7]annulene derivatives as estrogen receptor modulators
  • 6,7-dihydro-5h-benzo[7]annulene derivatives as estrogen receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0636] Example 1. 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxyphenyl)-8,9- Dihydro-7H-benzo[7]annulen-3-ol

[0637]

[0638] Method A:

[0639] To 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo [7] To a solution of annulen-2-ol (D2) (80 mg, 173.8 μmol) in dioxane / water (80 / 20; V / V; 4 ml) was added 4-hydroxyphenyl-boronic acid (23.97 mg ,173.77μmol), Cs 2 CO 3 (119.02mg, 364.92μmol) and Pd(dppf)Cl 2 (8.51 mg, 10.43 μmol). The reaction mixture was microwaved at 90 °C for 30 min and purified by column chromatography eluting with a gradient of MeOH / DCM (0% to 10%) to give a solid which was further purified on a strong cation exchange (SCX) column to give 58 mg (71%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(4-hydroxyphenyl)-8, 9-Dihydro-7H-benzo[7]annen-3-ol.

Embodiment 3

[0640] Example 3. 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl)-8 ,9-Dihydro-7H-benzo[7]annulen-3-ol

[0641]

[0642] To 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo [7] Add 5-indolylboronic acid (30.77mg, 191.15μmol), Cs 2 CO 3 (119.02mg, 364.92μmol) and Pd(dppf)Cl 2 (8.51 mg, 10.43 μmol). The reaction mixture was microwaved at 90 °C for 30 min and purified by column chromatography eluting with a gradient of MeOH / DCM (0% to 10%) to give a solid which was further purified on a strong cation exchange (SCX) column to give 12 mg (14%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl) -8,9-Dihydro-7H-benzo[7]annen-3-ol.

Embodiment 4

[0643] Example 4. 6-(2-Chloro-4-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl] -8,9-Dihydro-7H-benzo[7]annulen-3-ol

[0644]

[0645] To 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo [7] Annulen-2-ol (D2) (80 mg, 173.8 μmol) was added to a solution in dioxane / water (80 / 20; V / V; 4 ml) with 2-chloro-4-fluorophenylboronic acid (23.10mg, 132.50μmol), Cs 2 CO 3 (119.02mg, 364.92μmol) and Pd(dppf)Cl 2 (8.51 mg, 10.43 μmol). The reaction mixture was microwaved at 90 °C for 30 min and purified by column chromatography eluting with a gradient of MeOH / DCM (0% to 10%) to give a solid which was further purified on a strong cation exchange (SCX) column to give 50 mg (74%) of 6-(2-chloro-4-fluoro-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxybenzene base]-8,9-dihydro-7H-benzo[7]annen-3-ol.

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Abstract

The present invention relates to compounds of formula (I): wherein R1 and R2 represent hydrogen or deuterium atoms; R3 represents a hydrogen atom or a -COOH, a -OH or a -OPO(OH)2 group; R4 representsa hydrogen atom or a fluorine atom; R5 represents a hydrogen atom or a -OH group; wherein at least one of R3 or R5 is different from a hydrogen atom; when R3 represents a -COOH, -OH or -OPO(OH)2 group, then R5 represents a hydrogen atom; when R5 represents a -OH group, then R3 and R4 represent hydrogen atoms; and R6 is selected from an optionally substituted phenyl, heteroaryl, cycloalkyl or heterocycloalkyl group. The invention also relates to the preparation and to the therapeutic uses of the compounds of formula (I) as inhibitors and degraders of estrogen receptors, useful especially in thetreatment of cancer.

Description

technical field [0001] The present invention relates to novel substituted 6,7-dihydro-5H-benzo[7]annulene compounds, processes for their preparation and their therapeutic use, in particular as antiviral agents via selective antagonism and degradation of estrogen receptors. cancer agent. Background technique [0002] The estrogen receptor (ER) belongs to the steroid / nuclear receptor superfamily, which is involved in the regulation of eukaryotic gene expression, cell proliferation and differentiation in target tissues. There are two forms of ER: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), encoded by the ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors that are activated by the hormone estrogen (the most potent estrogen produced in the body is 17β-estradiol). In the absence of hormones, ER is primarily located in the cytosol of cells. When estrogen binds to ER, ER migrates from the cell's cytosol to the nucleus, fo...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D401/12C07D405/12C07D413/12C07D417/12C07D471/04C07D207/12A61K31/40A61K31/4025A61P35/00
CPCC07D207/12C07D403/12C07D405/12C07D401/12C07D209/08C07F5/025C07F9/572A61P35/00C07B2200/07A61K31/4025A61P5/32A61P13/08A61P15/00A61P15/08A61P19/10A61P29/00A61P35/04A61P43/00C07D413/12C07D417/12C07D471/04C07F7/0812A61K31/4015A61K31/4439A61K31/506C07F5/027
Inventor M·布瓦博拉M·布洛V·塞尔塔尔Y·埃尔-艾哈迈德B·菲洛奇-罗姆雷F·哈利G·麦卡尔特L·舒奥M·塔巴特C·泰瑞尔F·汤普森
Owner SANOFI SA
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