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N-aromatic amide compound and preparation method and application thereof

An aromatic amide and compound technology, which is applied to N-aromatic amide compounds and the fields of their preparation and use, can solve the problems of convulsions of patients, high price, application limitation and the like

Active Publication Date: 2020-04-07
SHENZHEN EDK PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The downside is that it is expensive and can also develop hormone-resistant prostate cancer
In addition, enzalutamide was found to cause side effects of convulsions in patients during treatment, so its application is limited

Method used

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  • N-aromatic amide compound and preparation method and application thereof
  • N-aromatic amide compound and preparation method and application thereof
  • N-aromatic amide compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] N-(4-cyano-3-trifluoromethyl)phenyl-2-[4-fluoro-6-(4-fluorophenyl)-1H-indol-1-yl]-2-methylpropane Preparation of amides

[0087]

[0088] first step reaction

[0089] Thionyl chloride (2.62 mL, 35.93 mmol, 1.2 eq) was added dropwise to a solution of 2-bromo-2-methylpropionic acid (5.00 g, 29.94 mmol) in 30 mL of dry tetrahydrofuran (THF) , The temperature during the dropwise addition is controlled at 0-12°C, and the time is 10 minutes. The resulting mixture was stirred under the same conditions for 2 hours. The internal temperature was adjusted to about -5°C, and triethylammonia (Et 3 N) (5.42ml, 38.92mmol, 1.3eq), the internal temperature was lower than 12°C during the addition. Stir for 20 minutes under the same reaction conditions. A solution of 4-cyano-3-trifluoromethyl-aniline (5.57 g, 29.94 mmol) in 30 mL of anhydrous tetrahydrofuran was then added dropwise thereto, and the resulting mixture was stirred at 50° C. for two hours. After the thin layer chroma...

Embodiment 2

[0100] Preparation of N-(4-cyano-3-trifluoromethyl)phenyl-2-(5-fluoro-6-phenyl-1H-indol-1-yl)-2-methylpropionamide

[0101]

[0102] first step reaction

[0103] With embodiment 1.

[0104] second step reaction

[0105] 6-Bromo-5-fluoro-1H-indole (1.00 g, 4.672 mmol) was added to tetrakis(triphenylphosphine)palladium [Pd(PPh 3 ) 4 ] (0.54 g, 0.4672 mmol) in a suspension of 20 ml of ethylene glycol dimethyl ether (DME), stirred at room temperature for 15 minutes under the protection of argon. A solution of phenylboronic acid (0.57 g, 4.672 mmol) in 2.5 mL of ethanol was added to the above reaction solution, and the resulting mixture was stirred under the same conditions for 10 minutes. Potassium carbonate (0.97 g, 7.008 mmol) in 2.0 mL of water was then added to the above reaction solution. The resulting reaction mixture was heated to reflux for 2-3 hours under the protection of argon. After the reaction was confirmed by thin layer chromatography, brine (20 ml) and eth...

Embodiment 3

[0112] Preparation of N-(4-cyano-3-trifluoromethyl)phenyl-2-(5-fluoro-1H-indol-1-yl)-2-methylpropionamide

[0113]

[0114] In a 100 mL round bottom flask was added 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.20 g, 0.5968 mmol), 5-fluoro-1H -Indole (0.16 g, 1.1963 mmol), cuprous bromide dimethyl sulfide (12.3 mg, 0.05868 mmol), triphenylphosphine (15.7 mg, 0.05968 mmol), sodium hydroxide (23.9 mg, 0.5968 mmol), 10 mL of anhydrous toluene as solvent. The resulting mixture was heated to 50 °C and stirred under argon protection for 12 hours. After thin-layer chromatography confirmed that the reaction was complete, the reaction solution was cooled to 20 ± 5 ° C, then water (30 ml) and ethyl acetate (30 ml) were added, the liquids were separated after brief stirring, and the organic phase was washed with brine (20 ml). Dried over magnesium sulfate, filtered and the organic phase was drained to give an oily substance. Separation by silica gel column chr...

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Abstract

The invention relates to N-aromatic amide compounds represented by general formulas (I) and (II), a preparation method thereof, a pharmaceutical composition and a pharmaceutical preparation containingthe compound represented by the general formula (I) or (II), and applications of the compounds represented by the general formulas (I) and (II) in preparation of drugs used for treating androgen-related diseases. The definitions of R1, R2, R3, R4, R5, R6, W1, W2, W3, W4 and W5 in the general formulas are the same as those in the specifications. The compounds of the general formulas (I) and (II) are capable of binding to androgen receptors, have activity against androgens and degrade androgen receptors. The compound can be used for treating various androgen-related diseases such as prostate cancer, benign prostatic hyperplasia, breast cancer, bladder cancer, ovarian cancer and the like alone or as a composition, and can also be used for treating diseases such as acnes, hirsutism, alopeciaand the like.

Description

technical field [0001] The present invention relates to a class of N-aromatic amide compounds and their preparation methods and pharmaceutical applications. The compounds have the effect of resisting androgen and degrading androgen receptors, and can be used for prostate cancer, benign prostatic hyperplasia, breast cancer, bladder cancer, and acne , hirsutism, hair loss and other androgen-related disease treatment. Background technique [0002] The androgen receptor belongs to the nuclear receptor family and is a receptor for ligand-induced nuclear transcription factors. The androgen receptor is an important cell regulatory protein that plays an important role in a series of physiological processes through endogenous androgens, including the development and maintenance of male secondary sexual characteristics, including muscle and bone mass, Male hair, prostate growth, sperm development, etc. Endogenous steroidal androgens, known as male sex hormones, include testosterone ...

Claims

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Application Information

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IPC IPC(8): C07D209/08C07D231/16C07D231/12C07D231/14C07D401/12A61K31/404A61K31/415A61K31/4439A61P35/00A61P17/14A61P17/10
CPCC07D209/08C07D231/16C07D231/12C07D231/14C07D401/12A61P35/00A61P17/14A61P17/10A61K31/415A61P5/28A61K9/0019A61K47/26A61K9/2054A61K9/2059A61K9/2013A61K9/2009A61K31/404A61K31/4439A61K9/2018A61K47/10C07D209/18C07D209/42
Inventor 杨国宏于丽俊何君泽段美娟
Owner SHENZHEN EDK PHARM TECH CO LTD
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