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Anti-cancer nuclear hormone receptor-targeting compounds

A compound, nuclear receptor technology, applied in the field of anti-cancer compounds derived from nuclear receptor binding agents, can solve problems such as damage

Pending Publication Date: 2021-03-26
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 practice, which compromises the ability to achieve maximum efficacy

Method used

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Examples

Experimental program
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example

[0668] 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.

[0669] Compounds as disclosed herein, or compounds of any formula or 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 synthetic procedures illustrated in the Synthetic Examples of General Methods 1-5.

[0670] 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 derivatives may be p...

example S-1

[0705] Example S-1. Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine- 1-yl)-2-fluoro-N-(6-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzyl Acyl)piperazin-1-yl)-6-oxoylhexyl)benzamide (compound 1.1)

[0706]

[0707] Step 1: Preparation of (Z)-2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzonitrile

[0708] Dimethyl phosphonate 3-oxo-1,3-dihydroisobenzofuran-1-yl ester (10 g, 41.3 mmol) and 2-fluoro-5-formylbenzonitrile ( To a stirred solution of 6.15 g, 41.3 mmol) in THF (50 mL) was slowly added triethylamine (5.76 mL, 41.3 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC. After the reaction was complete, water (200 mL) was added, and the resulting precipitate was filtered through a Büchner funnel. The obtained product was washed with water (50 mL), hexane (50 mL), diethyl ether (30 mL), and dried under vacuum to obtain (Z)-2-fluoro-5-((3-o...

example S-2

[0723] Example S-2. Preparation of 4-(3-(4-(6-(((5S, 8R, 9S, 10S, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-hexadecyl Hydrogen-1H-cyclopenta[a]phenanthrene-17-yl)oxy)hexanoyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (compound 1.2)

[0724]

[0725] Step 1: Preparation of (5S, 8R, 9S, 10S, 13S, 14S, 17S)-10,13-Dimethylhexadecanohydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3] Dioxolane]-17-ol

[0726] To (5S, 8R, 9S, 10S, 13S, 14S, 17S)-17-hydroxyl-10,13-dimethyltetrahydro-1H-cyclopenta[a]phenanthrene-3(2H)- To a stirred solution of the ketone (3 g, 10.3 mmol) in benzene (100 mL) was added PTSA (0.982 g, 5.1 mmol, 0.5 equiv) followed by ethylene glycol (2.88 g, 51.61 mmol, 5 equiv). The resulting mixture was heated to 120° C. for 16 hours using a Dean-Stark apparatus. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (200 mL), and extracted with EtOAc (350 mL). The organic layer was washed with sa...

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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 claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application 62 / 671,382, filed May 14, 2018, which is hereby incorporated by reference in its entirety. Background technique [0003] The present disclosure relates to anticancer compounds derived from nuclear receptor binding agents, such as 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, which do not divide as quickly as tumors and do not carry mutated BRCA1 or BRCA2...

Claims

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Application Information

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IPC IPC(8): A61K45/06A61K47/54A61K47/55C07D401/14
CPCA61P35/00C07D401/14C07D403/10C07D403/14C07D413/14C07D417/14C07D451/02C07D471/04C07D487/04C07D491/048C07D498/04C07D519/00C07J43/003A61K45/06A61K47/55A61K47/554A61K47/545C07D403/12C07D237/32A61K9/0053
Inventor 范明山S·查克拉瓦蒂陈霁昀J·坎卡纳拉A·巴德A·K·纳亚克D·黄
Owner 诺维逊生物股份有限公司
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