Large-scale synthesis of selective androgen receptor modulators

An androgen receptor and selective technology, which is applied in the field of large-scale synthesis of selective androgen receptor modulators, can solve the problems of low yield and unsuitability for large-scale preparation, and achieve high yield

Inactive Publication Date: 2010-12-08
UNIV OF TENNESSEE RES FOUND
View PDF5 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the methods disclosed in these references are not suitable for large-scale preparations because one or more steps lead to mixed products and thus involve purifications that ultimately lead to reduced yields

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Large-scale synthesis of selective androgen receptor modulators
  • Large-scale synthesis of selective androgen receptor modulators
  • Large-scale synthesis of selective androgen receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0091] Accordingly, in one embodiment, the present invention provides a synthetic method for the preparation of the SARM compounds described herein, which involves a purification step comprising crystallization of the SARM product from a mixture of non-toxic organic solvents and water. In one embodiment, the non-toxic organic solvent is ethanol. In a particular embodiment, the crystallization step comprises mixing an alcoholic solution containing the SARM compound and water to crystallize the SARM compound. In another embodiment, the method further comprises the step of collecting the SARM compound by filtration.

[0092] The method of the present invention is suitable for large-scale preparations, since all steps give high-purity compounds, thus avoiding complicated purification processes which ultimately reduce yields. Accordingly, the present invention provides a method for the synthesis of non-steroidal agonist compounds, which is applicable to industrial large-scale synt...

Embodiment 1

[0270] Embodiment 1: the synthesis of compound (1)

[0271] Compound (1) was synthesized according to the description below and the scheme of Scheme 1.

[0272]

[0273] Route 1

[0274] (2R)-1-methacryloylpyrrolidine-2-carboxylic acid (R-129). Dissolve D-proline (R-128, 14.93 g, 0.13 mol) in 71 mL of 2N NaOH and place in an ice bath Cool in medium; the basic solution obtained was diluted with acetone (71 mL). A solution of methacryloyl chloride 127 (13.56 g, 0.13 mol) in acetone (71 mL) and 2N NaOH solution (71 mL) were added simultaneously to an aqueous D-proline solution in an ice bath over 40 minutes. During the addition of methacryloyl chloride, the pH of the mixture was maintained at 10-11°C. After stirring (3 hours, room temperature), the mixture was evaporated under vacuum at a temperature of 35-45°C to remove acetone. The resulting solution was washed with ether and acidified to pH 2 with concentrated HCI. The acidic mixture was saturated with NaCl and extract...

Embodiment 2

[0282] Large-Scale Synthesis of Compound (1)

[0283]Compound (1) (3-[4-(acetylamino)phenoxy]-2-hydroxy-2-methyl-N-[3-trifluoromethyl-4-nitro-phenyl]-propionamide) is a member of the oxolutamide family of androgen receptor agonists and is a non-steroidal selective androgen receptor modulator (SARM). In vitro, it binds to the androgen receptor with high affinity (Ki=7.5±0.5nM). In vivo, it is a partial agonist of the androgen receptor and causes strong anabolic and weak androgenic effects. Compound (1) has no other known endocrine activity.

[0284]

[0285] Compound (2) was synthesized according to the following synthetic steps:

[0286] Step 1 - Synthesis of (2R)-1-methacryloylpyrrolidine-2-carboxylic acid (R-129)

[0287]

[0288] route 2

[0289] A 72 L flask with mechanical stirrer and inlet for inert atmosphere was mounted in a cooling bath. Place the flask under argon and add 5000 g (43.4 mol) D-proline (ICN Lot #7150E, > 99%), 11.9 L 4N NaOH and 12 L acetone...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
melting pointaaaaaaaaaa
melting pointaaaaaaaaaa
Login to view more

Abstract

The present invention relates to a synthetic process for the preparation of a novel class of androgen receptor targeting agents (ARTA) which demonstrate androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. The agents define a new subclass of compounds which are selective androgen receptor modulators (SARM) which are useful for a) male contraception; b) treatment ofa variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, and alterations in mood and cognition; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity and endometriosis, d) treatment and / or prevention of chronic muscular wasting; e) decreasing the incidence of, halting or causing a regression of prostate cancer; f) oral androgen replacement; g) preventing and / or treating dry eye conditions; h) treatment and / or prevention of begnin prostate hyperplasia (BPH); I) inducing apoptosis in a cancer cell; j) treatment and / or prevention of cancers of female sexual organs such as breast cancer, uterine cancer and ovarian cancer; and / or other clinical therapeutic and / or diagnostic areas. The process of the present invention is suitable for large-scale preparation, since all of the steps give rise to highly pure compounds, thus avoiding complicated purification procedures which ultimately lower the yield. Thus the present invention provides methods for the synthesis of non-steroidal agonist compounds, that can be used for industrial large-scale synthesis, and that provide highly pure products in high yield.

Description

technical field [0001] The present invention relates to a synthetic process for the preparation of a new class of androgen receptor targeting agents (ARTAs), which exhibit androgenic and anabolic activity of non-steroidal ligands of the androgen receptor. This agent defines a new subclass of compounds that are selective androgen receptor modulators (SARMs) for use in a) contraception in men; b) in the treatment of a variety of hormone-related conditions, such as those associated with decreased androgen in aging men (ADAM) related conditions such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, age-related muscular atrophy, osteopenia, osteoporosis, Mood and cognitive changes; c) Treatment of conditions associated with androgen deficiency in women (ADIF) such as sexual dysfunction, decreased libido, hypogonadism, senile muscular atrophy, osteopenia, osteoporosis, cognition and mood Alter...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/00C07C235/24C07C231/12
CPCC07C231/12A61P13/08A61P15/00A61P15/10A61P17/14A61P19/10A61P21/00A61P25/24A61P3/04A61P35/00A61P5/26A61P7/06C07C235/24
Inventor 米切尔·S·斯坦纳纪沃·冲詹姆斯·多尔顿杜安·D·米勒卡伦·A·韦韦尔卡
Owner UNIV OF TENNESSEE RES FOUND
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap