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3-phenoxymethylpyrrolidine compounds

A compound, pyrrolidine technology, used in pain conditions and other ailments to address issues such as limiting efficacy

Inactive Publication Date: 2012-05-23
THERAVANCE BIOPHARMA R&D IP LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Additionally, all therapeutic agents currently used to treat neuropathic pain suffer from various side effects (e.g., nausea, sedation, dizziness, and drowsiness) that may limit their efficacy in some patients (Dworkin et al., supra text, p. 241)

Method used

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Examples

Experimental program
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example

[0217] The following Preparations and Examples are provided to illustrate specific embodiments of the invention. However, unless expressly stated otherwise, these specific examples are not intended to limit the scope of the invention in any way.

[0218] Unless otherwise stated, the following abbreviations have the following meanings, and any other abbreviations used herein that are not defined have their standard meanings:

[0219]

[0220]

[0221] Any other abbreviations used herein and not defined have their generally accepted standard meanings. Unless otherwise noted, all materials such as reagents, starting materials, and solvents were purchased from commercial suppliers (e.g., Sigma-Aldrich, Fluka Riedel-de ), etc.) and were used without further purification.

[0222] In all compounds illustrated in the examples, two chiral centers are indicated by * and ** symbols. When elaborating stereochemistry, the carbon atom indicated by the * symbol is assigned first. ...

example 1

[0231] (S)-3-[(S)-1-(2,4-dichlorophenoxy)propyl]pyrrolidine

[0232]

[0233] 60% NaH in mineral oil (60:40, NaH:mineral oil, 10 mg, 260 μmol) was slowly added to (S)-3-((S)-1 in DMF (680 μL, 8.7 mmol) -Hydroxypropyl)pyrrolidine-1-carboxylic acid tert-butyl ester (50mg, 0.2mmol, 1 equiv). The resulting mixture was stirred at room temperature for 15 minutes. 2,4-Dichloro-1-fluorobenzene (76 μL, 3 equiv) was added and the mixture was heated at 90° C. for 3 hours. MeOH (1 mL) was used to stop the reaction. DMF and MeOH were removed under reduced pressure to obtain the BOC-protected intermediate (S)-3-[(S)-1-(2,4-dichlorophenoxy)propyl]pyrrolidine-1-carboxylic acid tert butyl ester. The protecting group was removed using 1.25M HCl in EtOH (1.7 mL, 2.2 mmol). The mixture was stirred overnight at room temperature. The product was then purified by preparative HPLC to afford the title compound (41.5 mg) as the mono-TFA salt. MS m / z: C 13 h 17 Cl 2 [M+H] of NO + The cal...

example 2

[0237] Compounds 2-1 to 2-75 of formula IIa were prepared as mono-TFA salts according to the procedures set forth in the examples above and substituting appropriate starting materials and reagents:

[0238]

[0239]

[0240]

[0241]

[0242] 1 (S)-3-[(S)-1-(3-chlorophenoxy)propyl]pyrrolidine

[0243] 2 (S)-3-[(S)-1-(4-chlorophenoxy)propyl]pyrrolidine

[0244] 3. (R)-3-[(R)-1-(4-chlorophenoxy)propyl]pyrrolidine

[0245] 4. (S)-3-[(R)-1-(4-chlorophenoxy)propyl]pyrrolidine

[0246] 5. (S)-3-[(S)-1-(4-chloro-3-fluorophenoxy)propyl]pyrrolidine

[0247] 6. (S)-3-[(R)-1-(4-chloro-3-fluorophenoxy)propyl]pyrrolidine

[0248] 7. (S)-3-[(S)-1-(3,4-dichlorophenoxy)propyl]pyrrolidine

[0249] 8. (S)-3-[(R)-1-(3,4-dichlorophenoxy)propyl]pyrrolidine

[0250] 9. (S)-3-[(S)-1-(3-fluorophenoxy)propyl]pyrrolidine

[0251] 10. (S)-3-[(S)-1-(3-chloro-5-fluorophenoxy)propyl]pyrrolidine

[0252] 11. (S)-3-[(R)-1-(3-chloro-5-fluorophenoxy)propyl]pyrrolidine

[0253] 12. (S)-3-[(S...

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PUM

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Abstract

In one aspect, the invention relates to compounds of formula (I): where R1-6 are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds of formula (I) are serotonin and norepinephrine reuptake inhibitors. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

Description

technical field [0001] The present invention relates to 3-phenoxymethylpyrrolidine compounds having serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor activity. The invention also relates to pharmaceutical compositions comprising said compounds, processes and intermediates for preparing said compounds and methods of using said compounds for the treatment of pain conditions such as neuropathic pain and other ailments. Background technique [0002] Pain is an uncomfortable sensory and emotional experience associated with or described in terms of actual or potential tissue damage (International Association for the Study of Pain, Pain Terminology). Chronic pain lasts longer than acute pain or beyond the expected time for injury to heal (American Pain Society "Pain Control in the Primary Care Setting." 2006: 15). Neuropathic pain is pain caused by or resulting from primary damage or dysfunction of the nervous system. Peripheral neuropathic pain occurs when damage or dy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/08A61K31/40A61P25/00A61P29/00
CPCC07D207/08A61K31/40A61P13/00A61P15/12A61P25/00A61P25/02A61P25/04A61P25/08A61P25/14A61P25/16A61P25/18A61P25/24A61P25/28A61P29/00A61P3/02A61P3/04A61P43/00A61P9/00A61P9/02A61P9/08A61K31/4025A61K45/06C07D207/14
Inventor 埃瑞克·L·施坦格兰大介·罗兰·齐藤阿达姆·休斯简·施密特普里西拉·范戴克洛里·琼·帕特森
Owner THERAVANCE BIOPHARMA R&D IP LLC
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