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Use of R (+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-flurophenyl)-ethyl]-4- piperidinemethanol for the treatment of sleep disorders and process for making pharmaceutical composition

a technology of dimethylphenyl and r (+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-flurophenyl)-ethyl)-ethyl)-4-piperidinemethanol, which is applied in the direction of drug compositions, heterocyclic compound active ingredients, biocide, etc., can solve the adverse effects of benzodiazepines such as daytime sedation, cognitive impairment, and reduced motor

Inactive Publication Date: 2005-12-08
AVENTIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention is a method for treating sleep disorders by administering a therapeutic amount of a specific substance called R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol or a pharmaceutically acceptable salt thereof. This substance can be used to treat insomnia, obstructive sleep apnea, and other conditions such as schizophrenia, fibromyalgia, and depressive disorders. The invention also includes the use of monotherapy to treat sleep disorders and other conditions."

Problems solved by technology

The most common class of medications for treating insomnia are the benzodiazepines, but the adverse effect profile of benzodiazepines include daytime sedation, diminished motor coordination, and cognitive impairments.
Excessive daytime sleepiness is also a major complication.
Currently, the therapies used to treat obstructive sleep apnea include weight loss for the obese patient, nasal-continuous positive airway pressure (a facemask used at night which produces a positive pressure within the upper airway), pharyngeal surgery and the administration of a variety of pharmacologic agents which have not been proven to be entirely successful.

Method used

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  • Use of R (+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-flurophenyl)-ethyl]-4- piperidinemethanol for the treatment of sleep disorders and process for making pharmaceutical composition
  • Use of R (+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-flurophenyl)-ethyl]-4- piperidinemethanol for the treatment of sleep disorders and process for making pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0037] Example 1, Steps A-D, demonstrates the preparation of the starting material (±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, structure 1.

A) 1-[2-(4-Fluorophenyl)ethyl]-4-piperidinecarboxamide

[0038] A solution of isonipectoamide (10.9 g, 85.0 mmol), 2-(4-fluorophenyl)ethyl Bromide (15.7 g, 77.3 mmol), and K2CO3 (2.3 g, 167 mmol) was prepared in DMF (280 mL) and stirred under argon at 90-95° C. overnight. The cooled solution was concentrated to a white oily solid. The solid was partitioned between water and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed 2× with water, dried (MgSO4), filtered, and evaporated to an oily solid. The solid was recrystallized from EtOAc to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxamide as a white powder, m.p. 177-178° C. (decomp.). Anal. Calcd. for C14H19FN2O: C, 67.18; H, 7.65: N, 11.19. Found: C, 67.25; H, 7.67; N, 11.13.

B) 4-Cyan...

example 2

[0042] Example 2, Steps A-F, demonstrate an alternative manner of preparing (±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, structure 1.

A) 1-(1,1-Dimethylethyl)-1,4-piperidinedicarboxylic acid

[0043] To isonipecotic acid (107.5 g, 832 mmol) stirred in 1N NaOH (40 g NaOH in 900 mL H2O) and tert-butanol (1800 mL) was added di-tert-butyl dicarbonate (200 g, 916 mmol) in portions. After stirring overnight, the solution was concentrated and the resulting water layer was extracted 3× with ether. The combined organic layers were washed with water, brine, dried (MgSO4), filtered, and evaporated to a white solid, which was recrystallized from EtOAc / hexane (300 mL / 200 mL) to afford 1-(1,1-dimethylethyl)-1,4-piperidinedicarboxylic acid as white needles, m.p. 147-149° C.

B) 4-(N-methoxy-N-methylcarboxamido)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester

[0044] To a stirred solution of 1-(1,1-dimethylethy)-1,4-piperidinedicarboxylic acid (50.0 g, 218 mmol) in ...

example 3

[0050] This example demonstrates the preparation of the compound of Formula-I.

Preparation of (+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol

A) Preparation of Diastereomers

[0051] A solution of 3.90 g (10.4 mmol) of (±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, 1.74 g (10.4 mmol) of S-(+)-α-methoxyphenylacetic acid, 2.15 g (10.4 mmol) of 1,3-dicyclohexylcarbodiimide and 0.1 g of 4-dimethylaminopyridine in chloroform (75 mL) was refluxed for 17 hours, allowing to cool to room temperature and filtered. The filtrate was concentrated and chromatographed on a silica gel column eluting with ethyl acetate / hexane (1:1) to afford two diastereomers, Rf=0.1 and 0.2 (TLC EtOAc / hexane, 1:1). Intermediate fractions were re-chromatographed to give additional material. Those fractions with Rf=0.2 were combined to give a single diastereomeric ester, (+,+)-(2,3-dimethoxyphenyl)[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]methyl-α-methoxybenz...

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Abstract

A process for making a pharmaceutical composition for treating a variety of sleep disorders comprising an effective amount of R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol or a pharmaceutically acceptable salt thereof is disclosed and claimed.

Description

CROSS REFERENCE TO RELATED CASES [0001] This application is a continuation of U.S. application Ser. No. 10 / 609,751, filed, Jun. 30, 2003, now allowed, which is a continuation of U.S. application Ser. No. 09 / 886,424, filed, Jun. 21, 2001, now U.S. Pat. No. 6,613,779 B2, issued Sep. 2, 2003, which is a continuation of U.S. application Ser. No. 09 / 382,932, filed, Aug. 25, 1999, now U.S. Pat. No. 6,277,864 B1, issued Aug. 21, 2001, which claims the benefit of U.S. Provisional Application No. 60 / 155,214, filed, Aug. 28, 1998; all of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION [0002] The present invention relates to the method of manufacturing a pharmaceutical composition comprising the R-(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol or a pharmaceutically acceptable salt thereof for the treatment of sleep disorders (insomnia and obstructive sleep apnea). BACKGROUND OF THE INVENTION [0003] The compound, R-(+)-α-(2,3-dim...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/445
CPCA61K31/445A61P25/20
Inventor MONDADORI, CESARSORENSEN, STEPHEN M.HITCHCOCK, JANICE M.
Owner AVENTIS PHARMA INC