Anti-cancer nuclear hormone receptor-targeting compounds

A technology for compounds, mixtures, applied in, solvates, U.S. Provisional Application No. 2019, 62/, hydrates, isotope enrichment filed on November 13, 2019, capable of solving problems such as damage

Pending Publication Date: 2021-12-17
诺维逊生物股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This requires dosing holidays and/or dose reductions in clinical p

Method used

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  • Anti-cancer nuclear hormone receptor-targeting compounds
  • Anti-cancer nuclear hormone receptor-targeting compounds
  • Anti-cancer nuclear hormone receptor-targeting compounds

Examples

Experimental program
Comparison scheme
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Embodiment

[0572] The present disclosure is further illustrated by the following examples. The following examples are non-limiting and merely represent various aspects of the disclosure. Solid and dotted wedges within the structures disclosed herein illustrate relative stereochemistry, and absolute stereochemistry is only depicted when explicitly stated or described.

[0573] Compounds having the structure of any compound, formula, or any subformula described herein can be synthesized using standard synthetic techniques known to those of skill in the art. Compounds of the present disclosure can be synthesized using the general methods described or the general synthetic procedures illustrated in the Synthetic Examples.

[0574] When it is desired to obtain a specific enantiomer of a compound, this can be achieved from the corresponding enantiomeric mixture using conventional procedures applicable to the separation or resolution of enantiomers. Thus, for example, diastereomeric derivativ...

Embodiment S-1

[0624] Example S-1. Preparation of (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-((8S,9R)-5-fluoro-9-( 1-methyl-1H-1,2,4-triazol-5-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de ]phthalazin-8-yl)phenoxy)-2-hydroxyl-2-methylpropionamide (compound 1.1a)

[0625]

[0626] Step 1: Preparation of (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide

[0627] To a solution of (R)-3-bromo-2-hydroxy-2-methylpropionic acid (1.50 g, 3.79 mmol) in DMA (15 mL) was added thionyl chloride (1.50 g, 3.79 mmol) dropwise at 0 °C and The mixture was stirred at this temperature for 3 h. Then a solution of 4-amino-2-(trifluoromethyl)benzonitrile (0.84 g, 4.5 mmol, 1.2 equiv) in DMA (5 mL) was added to the mixture, and the mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC. Upon completion, the mixture was concentrated under reduced pressure. The combined organic layers were washed with saturated NaHCO 3 solution (50mL), water (5...

Embodiment S-2

[0630] Example S-2. Preparation of (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-((8R,9S)-5-fluoro-9-( 1-methyl-1H-1,2,4-triazol-5-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de ]phthalazin-8-yl)phenoxy)-2-hydroxyl-2-methylpropionamide (compound 1.1b)

[0631]

[0632] To (8R,9S)-5-fluoro-8-(4-hydroxyphenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8 at 0°C , To a stirred solution of 9-dihydro-pyrido[4,3,2-de]phthalazin-3(7H)-one (100 mg, 0.26 mmol) in DMF (5 mL) was added sodium cyanide (60% suspension in mineral oil; 20.8 mg, 0.52 mmol), followed by (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl Propionamide (0.44 g, 0.31 mmol, 2 equiv) and the resulting mixture was heated at 90 °C for 16 h. The reaction was monitored by TLC and LCMS. Upon completion, the reaction was quenched with ice-cold water and extracted with EtOAc (50 mL), the organic layer was washed with water (50 mL), brine (50 mL), washed with Na 2 SO 4 Dried, filtered and concentrated u...

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Abstract

The disclosure relates to anti-cancer compounds derived from nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation.

Description

[0001] Cross References to Related Applications [0002] This application asserts U.S. Provisional Application No. 62 / 847,854 filed May 14, 2019 under 35 U.S.C. § 119(e), U.S. Provisional Application No. 2019, 62 / 935,069 filed Nov. 13, 2019, Nov. 20, 2019 No. 62 / 938,218, filed on 11 May, each of which is hereby incorporated by reference in its entirety. Background technique [0003] The present disclosure relates to anticancer compounds derived from nuclear steroid receptor binding agents, to products containing the same, and to methods of use and preparation thereof. [0004] PARP inhibitors are pharmacological agents that prevent DNA repair, cause cell death, and thus inhibit tumor growth. This mechanism of preventing cell growth caused significant antitumor activity in tumors with mutations in BRCA1, BRCA2, and PALB2, since these proteins are important for the repair of double-strand DNA breaks through the homologous recombination repair (HRR) pathway. Normal cells, whic...

Claims

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Application Information

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IPC IPC(8): A61K45/06C07D401/14
CPCA61K31/4985A61K31/5377C07D401/14A61K31/52A61K31/498C07D403/12C07D401/12A61K31/519C07D471/04A61K31/438C07D471/06A61K31/4745A61K31/502A61K31/55A61K31/5025A61K9/0053A61K47/55A61K47/6877A61K47/545A61K45/06A61P35/00C07D401/10C07D237/30
Inventor D·黄范明山S·查克拉瓦蒂陈霁昀J·坎卡纳拉J·D·佩蒂格鲁A·巴德A·K·纳亚克
Owner 诺维逊生物股份有限公司
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