1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects

a technology of phenyl-3dimethylaminopropane and phenyl-3dimethylaminopropane, which is applied in the direction of phosphorous compound active ingredients, drug compositions, group 5/15 element organic compounds, etc., can solve problems such as a series of side effects

Inactive Publication Date: 2007-04-24
GRUNENTHAL GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]The underlying object of the present invention was to provide substances with an analgesic effect, which are suitable for the treatment of severe pain without giving rise to the side effects which are typical of opioids.

Problems solved by technology

Opioids have been used for many years as analgesics for the treatment of pain, although they give rise to a series of side effects, for example addiction and dependency, respiratory depression, gastrointestinal inhibition and obstipation.

Method used

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  • 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects
  • 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects
  • 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0045]

(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol Hydrochloride(1)

[0046]207.63 g (1.11 mole) 3-bromoanisole dissolved in 400 ml dry tetrahydrofuran were added drop-wise to 26.99 g (1.11 mole) magnesium turnings in 150 ml dry tetrahydrofuran so that the reaction mixture boiled gently. After the addition of 3-bromoanisole was complete the mixture was heated under reflux for one hour and thereafter was cooled to 5-10° C. 128.30 g (0.89 mole) 1-dimethylamino-2-methylpentan-3-one dissolved in 400 ml tetrahydrofuran were added at this temperature. The reaction mixture was allowed to stand overnight and then cooled again to 5-10° C. The Grignard solution was decomposed by the addition of 300 ml of 20% ammonium chloride solution. The reaction mixture was diluted with 400 ml ether, the organic phase was separated off and the aqueous phase was extracted twice with 250 ml ether. The combined organic phases were dried over sodium sulphate. After removing the solvent by dis...

example 2

[0047]

Enantiomers of (1):[0048](−)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol Hydrochloride(−1)

and[0049](+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol Hydrochloride(+1).

[0050]The base was released from (1) with dichloromethane / sodium hydroxide solution. After drying the solution dichloromethane was distilled off under vacuum. The racemate was then separated on the chiral HPLC column. The hydrochlorides, which had a melting point of 150-151° C., were prepared from the enantiomers obtained by reaction with trimethylchlorosilane / water in 2-butanone.

(−1):

[0051]yield: 42% theoretical

[0052][α]DRT=−31.8° (c=0.99; methanol)

(+1):

[0053]yield: 41% theoretical

[0054][α]D=RT+33.0° (c=0.96; methanol)

example 3

[0055]

(2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2-methylpentan-3-ol Hydrochloride (2)

[0056]39 g of crude mixture were prepared analogously to Example 1 from 15 g (105 mmol) 1-dimethylamino-2-methylpentan-3-one, 35.5 g (157 mmole) 4-bromo-1,2-dichlorobenzene and 3.8 g (157 mmole) magnesium turnings. This mixture was introduced on to a 7×40 cm column packed with silica gel and eluted with 4:1 ethyl acetate / methanol. 14.9 g of base were obtained, from which 11.2 g of hydrochloride (2) (31% theoretical) with a melting point of 183-184° C. were obtained with trimethylchlorosilane / water in 2-butanone / diisopropyl ether.

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Abstract

1-phenyl-3-dimethylaminopropane compounds corresponding to the formula I
a method of preparing them, and the use of these substances as analgesic active ingredients in pharmaceutical compositions.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This application is a reissue of U.S. Pat. No. 6,248,737.BACKGROUND OF THE INVENTION[0002]The present invention relates to 1-phenyl-3-dimethylaminopropane compounds, to a method of preparing them, and to the use of these substances as pharmaceutical active ingredients.[0003]The treatment of chronic and non-chronic pain situations is of great importance in medicine. This is reflected in the large number of publications. Thus, for example, 1-naphthyl-3-aminopropane-1-ols with an analgesic-narcotic effect are known from EP 176 049. Secondary and tertiary alcohols with γ-amino groups are described in J. Pharm. Sci. 59, 1038 (1970) and in J. Prakt. Chem. 323, 793 (1981); phenyl-dimethylaminopropanols containing a para-substituted phenyl radical are described in Chem. Abstr. 54, 20963c (1960) and in Chem. Abstr. 63, 6912e (1965). These compounds also possess analgesic properties. In contrast, the 3-dimethylaminopropan-1-ols containing 2-phenyl r...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/535A61K31/135A61K31/138A61K31/215A61K31/27A61K31/34A61K31/343A61P25/04A61P29/00C07C209/68C07C211/27C07C211/29C07C211/30C07C213/00C07C215/30C07C215/54C07C215/62C07C217/62C07C217/66C07C217/72C07C217/74C07C219/06C07C219/22C07C225/10C07C237/40C07C271/58C07C323/32C07C323/36C07D307/79C07D319/18
CPCC07C215/30C07C215/54C07C215/62C07C217/62C07C217/72C07C217/74C07C219/22C07C225/10C07C271/58C07C323/36C07D307/79C07C2601/14A61P25/04A61P29/00A61P29/02
Inventor BUSCHMANN, HELMUTSTRASSBURGER, WOLFGANGFRIDERICHS, ELMAR
Owner GRUNENTHAL GMBH
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