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Substituted phenylpiperidines with serotoninergic activity and enhanced therapeutic properties

An effective dose and compound technology, applied in the direction of organic active ingredients, medical preparations containing active ingredients, organic chemistry, etc., can solve problems such as increasing the variability of compound formulations

Inactive Publication Date: 2009-02-04
AUSPEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This phenomenon increases interpatient variability in response to compounding

Method used

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  • Substituted phenylpiperidines with serotoninergic activity and enhanced therapeutic properties
  • Substituted phenylpiperidines with serotoninergic activity and enhanced therapeutic properties
  • Substituted phenylpiperidines with serotoninergic activity and enhanced therapeutic properties

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-d2

[0220] Example 1-d 2 -Benzo[1,3]dioxol-5-carbaldehyde (d 2 - piperonal)

[0221]

[0222] To Cs in DMF (60mL) 2 CO 3 (11.6 g, 35.6 mmol) was added 3,4-dihydroxybenzaldehyde (3.30 g, 23.9 mmol). The mixture was evacuated and flushed three times with nitrogen. Then add CD at room temperature 2 Cl 2 (2.29 mL, 26.3 mmol, 99.9% D). The reaction mixture was heated at 110°C for 2 hours, cooled to ambient temperature and partitioned between water and diethyl ether-pentane. The organic layer was washed with water more than 3 times and dried (MgSO 4 ), concentrated to give the desired product d as an off-white solid 2 -Piperonal.

[0223] Yield: 2.21 g (14.5 mmol, 61%, 94% D incorporation at the methylenedioxy group). 1 H-NMR (CDCl 3 ) δppm: 6.06 (s, 0.12H); 6.93 (m, 1H); 7.33 (m, 1H); 7.41 (m, 1H); 9.80 (s, 1H).

Embodiment 2-d2

[0224] Example 2-d 2 -Benzo[1,3]dioxol-5-ol (d 2 -sesamol)

[0225]

[0226] To d in MeOH (20 mL) 2 - Piperonal (2.21 g, 14.5 mmol, 94% D-introduction at the methylenedioxy group) suspension was added H 2 o 2 (2.1 mL, 30% in water). The mixture was dissolved in H in MeOH (4 mL) 2 SO 4 (0.2 mL, concentrated aqueous solution) was treated and stirred at room temperature for 14 hours. The reaction mixture was partitioned between water and ether-pentane. The organic layer was washed more than 5 times with water and dried (MgSO 4 ) and concentrate. The residue was further purified by column chromatography on silica gel (95 g) using 10% EtOAc in hexanes as eluent to give the desired product d as a white solid 2 - Sesamol.

[0227] Yield: 1.12 g (55%, 8.00 mmol, 94% D-incorporation at the methylenedioxy group). 1 H-NMR (CDCl 3) δppm: 5.89 (s, 0.12H); 6.23 (m, 1H); 6.42 (m, 1H); 6.63 (m, 1H).

Embodiment 3

[0228] Example 3-methanesulfonic acid trans-(4R, 3S)-4-(4-fluorophenyl)-1-methyl-piperidin-3-ylmethyl ester

[0229]

[0230] to the anhydrous CH 2 Cl 2 trans-(4R,3S)-[4-(4-fluoro-phenyl)-1-methyl-piperidin-3-yl]-methanol (1.00 g, 4.48 mmol, 3B Medical Systems ) solution by adding Et 3 N (1.5 mL). The mixture was cooled to 0° C. and treated with methanesulfonyl chloride (0.57 mL) and stirred in an ice bath for 0.5 hours, then at room temperature for an additional 1.5 hours. The reaction mixture was filtered through a cotton plug and additional anhydrous CH 2 Cl 2 (10 mL) to wash. The organic layer was washed with diethyl ether (100 mL) and additional CH in a separatory funnel 2 Cl 2 (20mL) diluted and washed 3 times with water (10mL each time), dried (MgSO 4 ), and concentrated to give the desired product trans-(4R,3S)-4-(4-fluorophenyl)-1-methyl-piperidin-3-ylmethyl methanesulfonate.

[0231] Yield: 1.26 g (94%, 4.19 mmol). 1 H-NMR (CDCl 3 )δppm: 1.79-1.90(m, 2...

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PUM

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Abstract

Chemical syntheses and medical uses of novel inhibitors of the uptake of monoamine neurotransmitters and pharmaceutically acceptable salts and prodrugs thereof, for the treatment and / or management of psychotropic disorders, anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive- compulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric disorders, premenstrual dysphoric disorder, social phobia, social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, and / or premature ejaculation are described.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application 60 / 736,581, filed November 14, 2005, entitled "Substituted Phenylpiperidines Having Serotonin-Induced Activity and Enhanced Therapeutic Properties," and filed December 1, 2005, entitled Priority to US provisional application 60 / 741,530 for "Substituted phenylpiperidines having serotonin-derived activity and enhanced therapeutic properties," both of which are incorporated by reference in their entirety. Background of the invention [0003] field of invention [0004] The present invention relates to inhibitors of uptake of monoamine neurotransmitters and their pharmaceutically acceptable salts and prodrugs, their chemical synthesis and the medical use of such compounds for the treatment and / or management of psychotropic disorders , anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obses...

Claims

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Application Information

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IPC IPC(8): C07D405/12A61K31/443A61P25/18
Inventor T·G·甘特S·萨沙
Owner AUSPEX PHARMA INC
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