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Benzenesulfonyl Compounds and the Use Thereof

Active Publication Date: 2010-03-11
PURDUE PHARMA LP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014]A further aspect of the present invention is to provide a method for treating pain (e.g., acute pain, chronic pain, which includes but is not limited to, neuropathic pain and inflammatory pain, or surgical pain) by administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, prodrug or solvate thereof, to a mammal in need of such treatment. Specifically, the present invention provides a method for preemptive or palliative treatment of pain by administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, prodrug or solvate thereof, to a mammal in need of such treatment.
[0015]A further aspect of the present invention is to provide a method for treating stroke, neuronal damage resulting from head trauma, epilepsy, migraine, a mood disorder, schizophrenia, a neurodegenerative disorder (e.g., Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease), depression, anxiety, a psychosis, hypertension, or cardiac arrhythmia, by administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, prodrug or solvate thereof, to a mammal in need of such treatment.
[0016]A further aspect of the present invention is to provide a pharmaceutical composition useful for treating a disorder responsive to the blockade of calcium ion channels, especially N-type calcium ion channels, said pharmaceutical composition containing an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, prodrug or solvate thereof, in a mixture with one or more pharmaceutically acceptable carriers.
[0017]Also, an aspect of the invention is to provide a method of modulating calcium channels, especially N-type calcium channels, in a mammal, wherein said method comprises administering to the mammal an effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

Problems solved by technology

However, inhibition of cardiac L-type calcium channels can lead to hypotension.

Method used

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  • Benzenesulfonyl Compounds and the Use Thereof
  • Benzenesulfonyl Compounds and the Use Thereof
  • Benzenesulfonyl Compounds and the Use Thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-(4-Fluorophenyl)-2-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-ylamino]acetamide (6)

[0334]

[0335]N-(4-Fluoro-phenyl)-2-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-ylamino]acetamide (6) was prepared as follows. 3-Trifluoromethylphenylsulfonyl chloride (2) (1.7 g, Aldrich) was added to a solution of compound 1 (1.16 g, Aldrich) and triethylamine (TEA, 1 mL) at 0˜5° C. The reaction mixture was stirred and warmed to room temperature over 12 hours and then quenched with water (4 mL), extracted with dichloromethane (DCM, 2×10 mL), and washed with brine (6 mL). The organic layer was concentrated to obtain the crude product 3, which was dissolved in 1,4-dioxane (15 mL) and treated with HCl (4N, 4 mL in 1,4-dioxane, Aldrich) at room temperature for 12 hours. The solvents were removed under vacuum, and the residue was washed with Et2O (2×15 mL) to give compound 4 as HCl-salt (white solid).

[0336]A mixture of compound 4 (160 mg, 1.0 eq), K2CO3 (400 mg), KI (20 mg) and compound 5 ...

example 2

N-(4-Fluorophenyl)-2-[1-(3-trifluoromethylbenzenesulfonyl)-pyrrolidin-3-ylamino]-acetamide (10)

[0337]

[0338]N-(4-Fluorophenyl)-2-[1-(3-trifluoromethylbenzenesulfonyl)-pyrrolidin-3-ylamino]-acetamide (10) was prepared as follows. 3-Trifluoromethylphenylsulfonyl chloride (2) (1.7 g, Aldrich) was added to a solution of compound 7 (1.16 g, Astatech. Inc) and TEA (1 mL) at 0˜5° C. The reaction mixture was stirred and warmed to room temperature over 12 hours and then quenched with water (4 mL), extracted with DCM (2×10 mL), and washed with brine (6 mL). The organic layer was concentrated to obtain the crude product 8, which was dissolved in 1,4-dioxane (15 mL) and treated with HCl (4N, 4 mL in 1,4-dioxane, Aldrich) at room temperature for 12 hours. The solvents were removed under vacuum, and the residue was washed with Et2O (2×15 mL) to give compound 9 as a HCl-salt (white solid).

[0339]A mixture of compound 9 (180 mg, 1.0 eq), K2CO3 (400 mg), KI (20 mg) and compound 5 (70 mg, 0.7 eq, Oakwo...

example 3

2-{Cyclopropyl-[1-(3-trifluoromethylbenzenesulfonyl)-piperidin-4-yl]amino}-N-(4-fluorophenyl)acetamide (14)

[0340]

[0341]2-{Cyclopropyl-[1-(3-trifluoromethylbenzenesulfonyl)piperidin-4-yl]amino}-N-(4-fluorophenyl)acetamide (14) was prepared as follows. A mixture of compound 11 (1.1 g, Oakwood), compound 5 (1.0 g), K2CO3 (2 g), KI (100 mg) and CH3CN (15 mL) was heated and stirred at 40° C. for 72 hours. The reaction mixture was diluted with EtOAc (30 mL), washed with water (10 mL), and brine (10 mL). The organic layer was concentrated and purified by column (silica gel, EtOAc / hexanes 1 / 1) to give compound 12 as a colorless oil. Compound 12 was then dissolved in 10 mL of 1,4-dioxane and treated with 4 mL of HCl (4N in 1,4-dioxane) at room temperature for 12 hours. The solvent was removed under vacuum, the residue was washed with Et2O (2×20 mL), and the solid was collected and dried to give compound 13 as white solid (HCl-salt).

[0342]A mixture of compound 13 (180 mg), TEA (0.5 mL) and co...

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Abstract

The invention relates to pyrrolidinyl, piperidinyl, and hexahydroazepinyl compounds of Formula I: and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein R1, R2, Z and m are defined as set forth in the specification. The invention is also directed to the use compounds of Formula I to treat a disorder responsive to the blockade of calcium channels, and particularly N-type calcium channels. Compounds of the present invention are especially useful for treating pain.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]This invention is in the field of medicinal chemistry. The invention relates to novel pyrrolidinyl, piperidinyl, and hexahydroazepinyl compounds and the use of these compounds as blockers of calcium (Ca2+) channels.[0003]2. Background Art[0004]Calcium ions play fundamental roles in the regulation of many cellular processes. It is therefore essential that their intracellular levels be maintained under strict, yet dynamic control (Davila, H. M., Annals of the New York Academy of Sciences, pp. 102-117 (1999)). Voltage-gated calcium channels (VGCC) serve as one of the important mechanisms for fast calcium influx into the cell. Calcium channels are hetero-oligomeric proteins consisting of a pore-forming subunit (α1), which is able to form functional channels on its own in heterologous expression systems, and a set of auxiliary or regulatory subunits. Calcium channels have been classified based on their pharmacological and / or...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4468C07D211/56C07D207/48C07D223/04A61K31/40A61K31/55A61P25/00A61P9/12A61P25/24A61P25/22G01N33/53
CPCC07D211/96C07D207/48A61P25/00A61P25/22A61P25/24A61P9/12
Inventor KYLE, DONALD J.YAO, JIANGCHAO
Owner PURDUE PHARMA LP
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