Melitracen pharmaceutical composition with high security

A kind of technology of melitracen and composition, applied in the field of melitracen pharmaceutical composition, can solve the problem of no antipsychotic effect and the like

Inactive Publication Date: 2014-06-25
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, in vivo and in vitro tests have shown that flupentixol melitracen tablets have a certain antagonistic effect on histamine receptors, and also have analgesic and anticonvulsant effects, but have no antipsychotic effects

Method used

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  • Melitracen pharmaceutical composition with high security
  • Melitracen pharmaceutical composition with high security
  • Melitracen pharmaceutical composition with high security

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The preparation method of embodiment 1. compound Lu6-038

[0050] (1) Preparation of 10,10-dimethylanthrone

[0051] Add 13g (0.063mol) of 9,9-dimethyl-9,10-dihydroanthrone and 130mL of glacial acetic acid into the reaction flask, heat to 55~58°C, dissolve 10g (0.1mol) of chromium trioxide in 450mL Add glacial acetic acid solution (50%) dropwise to the reaction bottle, then react at 55~58°C for 4 hours, remove the solvent by rotary evaporation, add 130mL of water to the residue, stir and heat slightly to completely disperse the solid, Add 130 mL of water, stir for 10 min, filter, wash with water, extract the solid with dichloromethane, wash the organic layer with water, dry, and concentrate to dryness, and recrystallize the residue with ethanol-water (3:1) to obtain 10.2 g of white needle-like crystals, which are set aside .

[0052] (2) Preparation of 10,10-dimethyl-9γ-dimethylaminopropyl-9-anthracenol

[0053] Add 1.35g (0.056mol) of magnesium chips, 50mL of anhy...

Embodiment 2

[0054] Embodiment 2. Preparation of compound Lu0-023

[0055] Add 1.35g (0.056mol) of magnesium chips, 50mL of anhydrous tetrahydrofuran and 3 grains of iodine into the reaction flask, heat slightly, add 10.20g (0.084mol) of N-methyl-3-chloropropylamine, heat up and reflux for 2.5h, and cool to Room temperature; add 8.3g (0.038mol) of 10,10-dimethylanthrone to the above solution, stir at room temperature for 30min, add 45mL of water, separate the organic phase and the aqueous phase, extract with 35mL of dichloromethane, combine the organic phase, Dry over magnesium sulfate and concentrate to dryness to obtain 10.3 g of 3-[10,10-dimethyl-9(10H)-anthracene]-N-methylpropylamine, namely compound Lu0-023. Yield 85.3%, mp 82~85°.

Embodiment 3

[0057] The preparation method and synthetic process of melitracen hydrochloride are shown in figure 2 .

[0058] Add 10g (0.032mol) 10,10-dimethyl-9γ-dimethylaminopropyl-9-anthracenol, 23.5mL dichloromethane and 6.7mL concentrated hydrochloric acid into the reaction flask, heat to reflux for 2h, and cool to room temperature , extracted three times with water and dichloromethane, adjusted the pH of the aqueous layer to 8~9 with sodium hydroxide, extracted with dichloromethane, dried the dichloromethane layer with anhydrous sodium sulfate, concentrated and evaporated to dryness to obtain the free base of melitracen compound, it was dissolved in acetone, concentrated hydrochloric acid was added dropwise, and concentrated to dryness to obtain 7.3g melitracen. Yield 77.9%, mp 246~248°.

[0059] Elemental analysis (C 21 h 25 N·HCl)

[0060] Measured value % (theoretical value, %): C77.08 (76.92), H8.02 (7.99), N4.33 (4.27), C l 10.75 (10.81). MS-ESIm / z:292[M + H] + .

[0...

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Abstract

The invention provides a meilitracen pharmaceutical composition with high security. The meilitracen pharmaceutical composition comprises meilitracen, no more than 0.1% of a compound shown as formula I and no more than 0.1% of a compound shown as formula II. The meilitracen pharmaceutical composition provided by the invention also comprises a certain amount of flupentixol. Commercially available flupentixol and meilitracen tablets may cause adverse effects such as anxiety, dysphoria and agitation which may be related to intermediate and byproduct which are formed in a synthesis process of meilitracen. The intermediate and byproduct are the compounds shown as the formula I and the formula II. The invention provides a method for separation, purification and identification of the compounds shown as the formula I and the formula II. Liquid chromatography is prepared by adding a certain amount of cyclodextrin in a silica gel column, to separate and identify the compounds successfully. The invention provides a preparation method for the compounds shown as the formula I and the formula II. The content of substances causing the adverse effects is greatly reduced in the pharmaceutical composition provided by the invention, so that the drug has higher security and efficacy.

Description

technical field [0001] The invention belongs to the field of nervous system drugs, in particular to a melitracen pharmaceutical composition with high safety. Background technique [0002] Melitracen is a tricyclic antidepressant with the chemical name 3-[10,10-dimethyl-9(10H)-anthracenylidene]-N,N-dimethylpropylamine. [0003] [0004] Melitracen can inhibit the reuptake of norepinephrine and serotonin in the presynaptic membrane, and thus increase the content of monoamine transmitters in the synaptic cleft. [0005] Melitracen and flupentixol form a drug combination, flupentixol melitracen tablets, trade name Deanxit (Deanxit), produced by H. Lundbeck A / S (H. Lundbeck Co., Ltd.) . It is used to treat diseases such as neurasthenia, gastrointestinal neurosis, senile depression and menopausal syndrome. [0006] Flupenthixol is a thioxanthene antipsychotic with different pharmacological effects according to different doses. Large doses of flupentixol mainly antagonize th...

Claims

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Application Information

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IPC IPC(8): A61K31/496A61K31/135A61P25/22A61P25/24A61P25/18
Inventor F.E.奥尔森
Owner H LUNDBECK AS
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