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Propionamide derivatives useful as androgen receptor modulators

A halogen, compound technology, applied in the field of tissue-selective androgen receptor modulators, pharmaceutical compositions containing such compounds, therapeutic active compounds for androgen receptor-dependent disorders, and pharmaceutically acceptable salts and esters thereof

Inactive Publication Date: 2006-08-02
ORION CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Various attempts have been made to overcome these deficiencies of steroid androgens as therapeutic agents with only limited success

Method used

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  • Propionamide derivatives useful as androgen receptor modulators
  • Propionamide derivatives useful as androgen receptor modulators
  • Propionamide derivatives useful as androgen receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Example 1. (Method A)

[0106] 3-(4-Acetamidophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-propionamide

[0107] a) 2-methyl-N-(3-methyl-4-nitrophenyl)acrylamide

[0108] 3-Methyl-4-nitroaniline (2.0 g, 13 mmol) in N,N-dimethylacetamide (DMAC) (6 ml) was added dropwise to cold methacryloyl chloride (2.0 ml, 20.7 mmol) while maintaining the temperature of the reaction mixture at 0-5 °C. The solution was allowed to warm to room temperature and the mixture was stirred overnight. The mixture was poured into water (70ml) and extracted with ethyl acetate (4x40ml). The organic phase was saturated with Na 2 CO 3 (3×20ml) and water (1×50ml), washed with Na 2 SO 4 Dry and evaporate. The crude yield was 4.17 g (with DMA, theoretical yield 2.9 g), which was used without further purification.

[0109] 1 H NMR (DMSO-d 6 ): 1.97(3H,s), 2.55(3H,s), 5.62(1H,m), 5.96(1H,m), 7.80(2H,m), 8.05(1H,m), 10.22(1H,s) .

[0110] b) 2-Methyloxirane-2-carboxylic acid (3-methyl...

Embodiment 2

[0117] 3-(4-Acetamido-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-propionamide a}N-(2- Fluoro-4-hydroxyphenyl)acetamide

[0118] Acetic anhydride (1.3ml, 13.8mmol) was added dropwise to a solution of 4-amino-3-fluorophenol (1.0g, 7.9mmol) in acetic acid (25ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, water (2ml) was added and stirring was continued at room temperature for 30 minutes. The mixture was evaporated in vacuo. Crude yield 1.3 g (100%) was used without further purification.

[0119] 1 H NMR (DMSO-d 6 ): 2.00 (3H, s), 6.50-6.68 (2H, m), 7.39 (1H, m), 9.39 (1H, s), 9.72 (1H, s).

[0120] b) 3-(4-acetylamino-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-propionamide

[0121] This compound was synthesized following the procedure described in Example 1c. With N-(2-fluoro-4-hydroxyphenyl)acetamide (0.5g, 3.0mmol) and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide (0.6 ...

Embodiment 3

[0123] Example 3. (Method B)

[0124] (2S)-3-(4-Acetamidophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-propionamide

[0125] a) (2R)-1-(2-methacryloyl)pyrrolidine-2-carboxylic acid

[0126] D-proline (5 g, 43.4 mmol) was dissolved in 2M NaOH (26 ml) and cooled in an ice bath, and the solution was diluted with acetone (26 ml). A solution of methacryloyl chloride (6.3ml, 65.1mmol) in acetone (26ml) and 2M NaOH solution (34ml) were added simultaneously to the solution of D-proline over 1 hour. After the addition was complete, the resulting mixture was stirred at room temperature for 3 hours. The mixture was evaporated at 40°C, extracted with diethyl ether (2 x 40ml) and acidified to pH 2 with concentrated HCl. The resulting mixture was extracted with ethyl acetate (3×50ml), washed with Na 2 SO 4 Dry and evaporate. Yield 11.5 g (8.0 g theoretical), the crude was used without further purification.

[0127] b) (3R,8aR)-3-bromomethyl-3-methyltetrahydropyrrolo[2,1-c][1...

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Abstract

Compounds of formula (I) wherein R1 to R4, X and A are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds of formula (I) possess utility as tissue-selective androgen receptor modulators (SARM) and are useful in hormonal therapy, e.g. in the treatment or prevention of male hypogonadism and age-related conditions such as andropause.

Description

technical field [0001] The present invention relates to therapeutically active compounds, pharmaceutically acceptable salts and esters thereof, and pharmaceutical compositions containing such compounds for the treatment of nuclear receptors, in particular steroid vectors, especially androgen receptor (AR)-dependent disorders. Specifically, the present invention discloses novel non-steroidal N-propionanilide compounds, which can be used as tissue selective androgen receptor modulators (SARMs). The compounds of the present invention possess AR agonist activity and are useful in hormone therapy, in particular for the treatment or prevention of conditions such as male hypogonadism and age-related conditions such as andropause. Background of the invention [0002] Nuclear hormone receptors constitute a family of ligand-inducible transcription factors, members of which are involved in a variety of physiological and developmental functions. In the last 20 years, more than 60 struc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/24C07C255/58C07D213/68A61K31/395A61K31/277A61K31/167A61P5/26A61P15/16
Inventor J·拉蒂莱宁A·莫伊拉宁O·特尔梅坎加斯A·卡尔亚莱宁P·胡赫塔拉G·沃尔法特P·卡里奥
Owner ORION CORPORATION
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