Tetrasubstituted alkene compounds and their use

An alkenyl and enamide technology, applied in organic chemistry, drug combination, antineoplastic drugs, etc., can solve problems such as decreased bone density and increased risk of endometrial cancer

Inactive Publication Date: 2019-09-20
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is an on-target susceptibility associated with these different classes of compounds
For example, tamoxifen has been shown to activate signaling activity in the endometrium leading to an increased risk of clinical endometrial cancer (Fisher et al. (1994) J Natl Cancer Inst. Apr 6; 86 (7):527-37; van Leeuwen et al., (1994) Lancet Feb 19; 343(8895):448-52)
In contrast, since fulvestrant is a pure antagonist, it can lead to decreased bone mineral density in postmenopausal women because ERα activity is critical for osteogenesis

Method used

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  • Tetrasubstituted alkene compounds and their use
  • Tetrasubstituted alkene compounds and their use
  • Tetrasubstituted alkene compounds and their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0226] Non-limiting examples of embodiments of the compounds disclosed herein are provided herein. If there is any discrepancy between the depicted chemical structure of a compound and its chemical name, the depicted chemical structure shall prevail.

[0227] Table 1: Compounds

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

Embodiment 201

[0238]

[0239] General procedure

[0240] The following abbreviations may be used in this document:

[0241] ACN: Acetonitrile

[0242] BOC: tert-butoxycarbonyl

[0243] CAN: Ammonium cerium nitrate

[0244] Conc.: concentrated

[0245] Cs 2 CO 3 : cesium carbonate

[0246] DABCO: 1,4-diazabicyclo[2.2.2]octane

[0247] DCM: dichloromethane

[0248] DHP: dihydropyran

[0249] DIPEA: N,N-Diisopropylethylamine, Hunig's base

[0250] DMA: Dimethylacetamide

[0251] DMF: Dimethylformamide

[0252] DMSO: Dimethylsulfoxide

[0253] DPEphos: (oxydi-2,1-phenylene)bis(diphenylphosphine)

[0254] EDCI·HCl: N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride

[0255] EtOH: ethanol

[0256] EtOAc: ethyl acetate

[0257] Et 3 N: Triethylamine

[0258] Ex.: Example

[0259] h: hours

[0260] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate

[0261] HCl: hydrochloric acid

[0262] HMPA: Hexamethylphosphora...

Embodiment 101

[0292] Example 101: (2E)-N,N-Dimethyl-4-[[2-([5-[(1E)-4,4,4-trifluoro-1-(1H-indole-5- Synthesis of -1-phenylbut-1-en-2-yl]pyridin-2-yl]oxy)ethyl]amino]but-2-enamide (compound 101)

[0293]

[0294] Step 1: Synthesis of 5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indole

[0295]

[0296] Into a 500 mL 3-neck round bottom flask purged and maintained with a nitrogen inert atmosphere was placed 5-bromo-1H-indole (15 g, 76.51 mmol, 1.00 equiv), THF (200 mL). Sodium hydride (4 g, 166.67 mmol, 1.30 equiv) was added portionwise at 0°C after this. Thereto was added SEMCl (14.05 g, 92.01 mmol, 1.10 equiv) dropwise at 0°C with stirring. The resulting solution was stirred at 25°C for 16 hours. The reaction mixture was cooled with a water / ice bath and cooled by adding 50 mL of NH 4 Quenched with Cl (sat aq). The resulting solution was extracted with 3 x 200 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under...

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Abstract

Disclosed herein are compounds, or pharmaceutically acceptable salts thereof, and methods of using the compounds for treating breast cancer by administration to a subject in need thereof a therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof. The breast cancer may be an ER-positive breast cancer and/or the subject in need of treatment may express a mutant ER-alpha protein.

Description

[0001] Cross References to Related Applications [0002] This application claims the priority benefit of Indian Provisional Patent Application No. 201641040208 filed on 24th November 2016. This application is incorporated herein by reference as if fully rewritten herein. Background technique [0003] Breast cancer is the most commonly diagnosed malignancy in women today, with nearly 200,000 / 1.7 million new cases diagnosed each year in the United States / worldwide, respectively. Since approximately 70% of breast tumors are positive for estrogen receptor alpha (ERα), which is a key oncogenic driver in this subset of tumors, several classes of therapies have been developed to antagonize ERα function. Such therapies include 1) selective estrogen receptor down-regulators (SERDs), of which fulvestrant is an example; 2) selective estrogen receptor modulators (SERMs), of which tamoxifen ) is an example; and 3) aromatase inhibitors, which reduce systemic levels of estrogen. These the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08A61P35/00
CPCC07D209/08A61P35/00C07D401/06C07D401/14
Inventor 马克·巴克郝鸣鸿玛那芙·寇波维贾·库莫·涅维奈蒂濮阳晓玲苏珊塔·撒马杰达彼得·盖瑞德·史密斯王渊郑国茱朱平罗纳·海伦·米契尔尼可拉斯·拉森娜塔莉·里乌
Owner EISIA R&D MANAGEMENT CO LTD
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