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Aromatic amide compound and preparation method and application thereof

A technology of aromatic amides and compounds, which is applied in a class of aromatic amides and its preparation and use, and can solve the problems of high price, convulsions in patients, and application restrictions

Active Publication Date: 2018-09-21
杨国宏 +2
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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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  • Aromatic amide compound and preparation method and application thereof
  • Aromatic amide compound and preparation method and application thereof
  • Aromatic amide compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] ( S )-5-acetyl-N-(3-(4-cyano-3-trifluoromethyl-phenyl)-amino)-2-hydroxy-2-methyl-3-oxopropyl)-1H -pyrazole-3-carboxamide (C 18 h 16 f 3 N 5 o 4 ) preparation

[0097]

[0098] first step reaction

[0099] Thionyl chloride (2.4 mL, 33.6 mmol) was added dropwise to a solution of (R)-3-bromo-2-hydroxy-2-methylpropionic acid (5.11 g, 28 mmol) in 30 mL of THF , the dropwise temperature is controlled at 0-12°C for 10 minutes. The resulting mixture was stirred under the same conditions for 2 hours. Adjust the internal temperature to about -5°C, slowly add triethylamine (Et 3 N) (5.0ml, 36.4mmol, 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 (4.0 g, 21 mmol) in 40 mL of THF was then added dropwise thereto, and the resulting mixture was stirred at 50° C. for two hours. The reaction solution was cooled to 20 ± 5°C, then water (15 ml, 2...

Embodiment 2

[0118] N-( S )-(3-(4-cyano-3-trifluoromethyl-phenyl)-amino)-2-hydroxy-2-methyl-3-oxopropyl)-5-(1-hydroxyethyl )-1H-pyrazole-3-carboxamide preparation

[0119]

[0120] In a 100mL round bottom flask add ( S )-5-acetyl-N-(3-(4-cyano-3-trifluoromethyl-phenyl)-amino)-2-hydroxy-2-methyl-3-oxopropyl)-1H -Pyrazole-3-carboxamide (0.10 g, 0.2362 mmol), 5 mL of absolute ethanol as a solvent, slowly add a suspension of sodium borohydride (sodium borohydride, 22 mg, 0.5905 mmol) and ethanol to the reaction solution , and then the reaction solution was stirred overnight at room temperature under the protection of argon.

[0121] After confirming the completion of the reaction by thin-layer chromatography, add 0.5mL of water and 1mL of 0.5M HCl, stir briefly, concentrate to dryness by distillation under reduced pressure, then add dichloromethane (20mL) to dissolve, and use NaHCO for the organic phase. 3 It was washed with aqueous solution, brine, dried over magnesium sulfate, filtere...

Embodiment 3

[0125] (S)-N-(3-(4-cyano-3-trifluoromethyl-phenyl)-amino)-2-hydroxy-2-methyl-3-oxopropyl)-5-trifluoro Methyl-1H-pyrazole-3-carboxamide (C 17 h 13 f 6 N 5 o 3 ) preparation

[0126]

[0127] In a 100 mL round bottom flask was added 5-trifluoromethyl-1H pyrazole-3-carboxylic acid (0.23 g, 1.253 mmol), 2.3 mL of anhydrous DMF as a solvent, and then EDCI (0.24 g, 1.567 mmol) , DIPEA (0.27 g, 2.089 mmol) and HOBT (48 mg, 0.3133 mmol), stirred for 20 minutes. Another starting material (S)-3-amino-N-(4-cyano-3-trifluoromethyl-phenyl)-2-hydroxy-2-methylpropanamide (0.30 g, 1.044 mmol) was added at 6.0 mL of a solution in anhydrous DMF, and then the reaction solution was stirred at room temperature for 3 days under the protection of argon.

[0128] After the thin-layer chromatography confirmed that the reaction was complete, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to obtain an oily substance. Silica gel column chro...

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PUM

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Abstract

The invention relates to an aromatic amide compound as shown in general formula I, a preparation method of the aromatic amide compound, a pharmaceutical composition containing the compound as shown ingeneral formula I, a pharmaceutic preparation containing the compound as shown in general formula I, and application of the compound as shown in general formula I in preparation of drugs for treatingdiseases related to androgen. In general formula, definitions of R1, R2, R3, R4, R5, R6, X, Y, Q and n are the same as definitions in specification. The compound as shown in general formula I can becombined to an androgen receptor, and has activities of resisting androgen and degrading the androgen receptor. The compound can be independently used as a composition for treating various diseases related to the androgen such as prostate cancer, benign prostate hyperplasia, breast cancer and bladder cancer, and can further be used for treating diseases such as acnes, hirsutism and alopecia.

Description

technical field [0001] The invention relates to a class of aromatic amide compounds and their preparation methods and their application as medicines. 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 and dih...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/14C07D401/12C07D213/84C07C231/12C07C237/22C07D231/18A61K31/4439A61K31/44A61K31/415A61K31/277A61P35/00A61P17/10A61P17/14A61P17/00A61P5/28
CPCA61P5/28A61P17/00A61P17/10A61P17/14A61P35/00C07B2200/07C07C231/12C07C237/22C07D213/84C07D231/14C07D231/18C07D401/12
Inventor 杨国宏何君泽段美娟
Owner 杨国宏
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