EP0000693B1 - Aminophenoxymethyl-2-morpholine derivatives, the preparation thereof and pharmaceuticals containing them - Google Patents

Description

beschrieben, welche eine Wirkung auf das Zentralnervensystem aufweist.In British Patent 1,260,886, the compound of the formula

described, which has an effect on the central nervous system.

in der

• R₁ ein Wasserstoff- oder Halogenatom oder die Methylgruppe,
• R₂ ein Wasserstoff- oder Halogenatom,
• R₃ ein Wasserstoffatom oder die Nitrogruppe und
• R₄ ein Wasserstoffatom, eine niedere Alkylgruppe, eine Carbalkoxygruppe, die Phenyl- oder Benzylgruppe bedeuten, und deren physiologisch vertägliche Säureadditionssalze mit anorganischen und organischen Säuren ebenfalls wertvolle pharmakologische Eigenschaften aufweisen, nämlich bei einer größeren therapeutischen Breite eine Wirkung auf das Zentralnervensystem, insbesondere. antidepressive, antikonvulsive und/oder sedierend-muskelrelaxierende oder anxiolytische Wirkungen.

It has now been found that the new morpholine derivatives of the formula

in the

• R _{1 represents} a hydrogen or halogen atom or the methyl group,
• R _{2 is} a hydrogen or halogen atom,
• R _{3 is} a hydrogen atom or the nitro group and
• R _{4 represents} a hydrogen atom, a lower alkyl group, a carbalkoxy group, which mean phenyl or benzyl group, and the physiologically acceptable acid addition salts thereof with inorganic and organic acids also have valuable pharmacological properties, namely an effect on the central nervous system, in particular with a greater therapeutic breadth. antidepressant, anticonvulsive and / or sedative muscle relaxant or anxiolytic effects.

Under the term "halogen atom" mentioned in the definition of the radicals R ₁ and R ₂ is in particular a fluorine, chlorine or bromine atom, under the term "lower alkyl group" mentioned in the definition of the radical R ₄ in particular an alkyl group with 1 to 4 Carbon atoms "and by" carbalkoxy group "to understand a carbalkoxy group with a total of 2 to 4 carbon atoms.

• R₁ ein Wasserstoff-, Fluor-, Chlor- oder Bromatom oder die Methylgruppe,
• R₂ ein Wasserstoff-, Fluor-, Chlor- oder Bromatom,
• R₃ ein Wasserstoffatom oder die Nitrogruppe und
• R₄ ein Wasserstoffatom, eine Alkylgruppe mit 1 bis 4 Kohlenstoffatomen, eine Carbalkoxygruppe mit insgesamt 2 bis 4 Kohlenstoffatomen, die Phenyl- oder Benzylgruppe bedeuten, deren physiologisch verträgliche Säureadditionssalze mit anorganischen und organischen Säuren, diese sie enthaltende Arzneimittel und Verfahren zu ihrer Herstellung.

The invention thus primarily relates to the new morpholine derivatives of the above general formula I, in which

• R _{1 is} a hydrogen, fluorine, chlorine or bromine atom or the methyl group,
• R _{2 is} a hydrogen, fluorine, chlorine or bromine atom,
• R _{3 is} a hydrogen atom or the nitro group and
• R _{4 represents} a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a carbalkoxy group having a total of 2 to 4 carbon atoms, the phenyl or benzyl group, the physiologically compatible acid addition salts thereof with inorganic and organic acids, medicaments containing them and processes for their preparation.

For the meanings mentioned in the definition of the radical R ₄ , there is therefore in particular that of the hydrogen atom, the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-bufyl-carbomethoxy- , Carbäthoxy-, carbisopropoxy, carbopropoxy, phenyl or benzyl group into consideration.

• R₁ oder R₂ in 3- oder 5-Stellung ein Bromatom
  und der andere der Reste R₁ oder R₂ in 3- oder 5-Stellung ein Wasserstoff- oder Bromatom,
• R₃ ein Wasserstoffatom und
• R₄ ein Wasserstoffatom, eine Alkylgruppe mit 1 bis 4 Kohlenstoffatomen oder die Carbäthoxygruppe bedeuten.

However, preferred morpholine derivatives of the present invention are the 2-amino and 4-amino compounds of the general formula I above. Particularly preferred compounds of the general formula I mentioned above are those in which one of the radicals

• R ₁ or R ₂ in the 3- or 5-position is a bromine atom
  and the other of the radicals R ₁ or R ₂ in the 3- or 5-position is a hydrogen or bromine atom,
• R _{3 is} a hydrogen atom and
• R _{4 represents} a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or the carbethoxy group.

• a) Reduktion einer Nitroverbindung der Formel
  
  in der
  • R₁, R₂ und R₄ wie eingangs definiert sind.

According to the invention, the new morpholine derivatives of the formula are obtained by the following processes:

• a) Reduction of a nitro compound of the formula
  
  in the
  • R ₁ , R ₂ and R _{4 are} as defined in the introduction.

The reduction is conveniently carried out in a solvent such as methanol, ethanol, water / ethanol, ethyl acetate, glacial acetic acid or water / hydrochloric acid in the presence of an electron donor such as nascent hydrogen, e.g. Zinc / hydrochloric acid or iron / sulfuric acid such as catalytically excited hydrogen, e.g. Hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, palladium / carbon or platinum, or with tin (II) chloride / hydrochloric acid or iron (II) sulfate / sodium hydroxide solution at temperatures between 0 and 100 ° C, but preferably at temperatures between 0 and 80 ° C.

• b) Abspaltung einer Schutzgruppe von einer Verbindung der Formel.
  
  in der
  • R₁ bis R₄ wie eingangs definiert sind und
  • Y eine Schutzgruppe für eine Aminogruppe wie die Benzyl-, Formyl-, Acetyl-, Benzoyl- oder Carbäthoxygruppe darstellt.

If the reduction is carried out with a compound of the general formula II in which R ₁ and / or R _{2 is} a chlorine or bromine atom and / or R _{4 is} the benzyl group, these radicals can be wholly or partly in the reduction with catalytically excited hydrogen be replaced by hydrogen atoms during the reaction.

• b) splitting off a protective group from a compound of the formula.
  
  in the
  • R ₁ to R _{4 are} as defined above and
  • Y represents a protecting group for an amino group such as the benzyl, formyl, acetyl, benzoyl or carbethoxy group.

If the protective group Y is an acyl or carbonic acid ester group, the protective group is split off hydrolytically, preferably in a suitable solvent such as methanol, methanol / water, ethanol, isopropanol or dioxane / water in the presence of an acid such as hydrochloric acid or in the presence of a base such as Sodium hydroxide solution, potassium hydroxide solution or ammonia at temperatures between '50 and 120 ° C, but preferably at the boiling point of the reaction mixture. If a compound of the general formula III R ₄ denotes a carbalkoxy group having 2 to 4 carbon atoms, this is replaced by a hydrogen atom during the hydrolysis.

If the protective group Y is a benzyl group, this protective group is split off hydrogenolytically, preferably in a suitable solvent such as methanol, ethyl acetate or glacial acetic acid, with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel or palladium / carbon at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 50 ° C and at a hydrogen pressure of 1-7 atmospheres. If here in a compound of the general formula III R ₁ and / or R _{2 is} a chlorine or bromine atom and / or R _{4 is} the benzyl group, these can each be replaced by a hydrogen atom during hydrogenolysis.

A compound of general formula I obtained according to the invention, in which R ₃ and R _{4 are} as defined at the outset and R ₁ and / or R _{2 represent} a hydrogen atom, can then, if desired, be converted into a corresponding chlorine or bromine compound of general formula I by halogenation
and / or a compound of the general formula I obtained, in which R _{4 represents} an aralkyl radical such as the benzyl group, can subsequently be converted by means of a halogen-formic acid ester into a compound of general formula I, in which R _{4 represents} a carbalkoxy group, and / or a compound of the general formula I obtained in which R _{4 represents} a carbalkoxy group can then be converted by hydrolysis into a compound of general formula I in which R _{4 represents} a hydrogen atom.

The subsequent halogenation is carried out, for example, with chlorine, bromine, sulfuryl chloride or tribromophenol bromine, preferably in a solvent, for example in 50-100% acetic acid, in chloroform or in methylene chloride, or with phenyl iododichloride in tetrahydrofuran and in the presence of a tertiary organic base such as triethylamine or pyridine , and expediently at Tem temperatures between -20 and 50 ° C carried out. One mole or two moles of halogenating agent or an excess of, for example, up to 10 moles, is preferably used per mole of a compound of the general formula I used, which can be used as base or as a salt, for example as mono- or dihydrochloride however, an excess of up to 10% of the halogenating agent used is used.

The subsequent reaction with a halogen-formic acid ester e.g. with methyl chloroformate, ethyl chloroformate, propyl chloroformate or isopropyl chloroformate, is advantageously carried out in a solvent such as methylene chloride, chloroform, ethylene chloride, toluene or tetrachlorethylene at temperatures between 0 and 120 ° C, but preferably at the boiling point of the solvent used.

The subsequent hydrolysis is preferably carried out in the presence of an acid such as hydrochloric acid or a base such as sodium hydroxide solution or potassium hydroxide solution, advantageously in a suitable solvent such as methanol, methanol / water, ethanol, isopropanol or dioxane / water at temperatures between 50 and 120 ° C., but preferably at Boiling temperature of the reaction mixture carried out.

Furthermore, the compounds of the general formula I obtained according to the invention can, if desired, be converted into their physiologically compatible acid addition salts with one or two equivalents of the acid in question using inorganic or organic acids. For example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid or fumaric acid have proven to be suitable.

The compounds of general formulas II and III used as starting materials are obtained by processes known per se, for example by reacting a corresponding phenol with epichlorohydrin in the presence of sodium or potassium hydroxide; the epoxy derivative thus obtained is converted into the corresponding mornholine derivative by reaction with an appropriate amine and subsequent cyclization with thionyl chloride in dimethylformamide.

As already mentioned at the beginning, the new morpholine derivatives of the general formula and their physiologically compatible acid addition salts with inorganic and organic acids have valuable pharmacological properties, namely an action on the central nervous system, but especially antidepressant, anticonvulsive and / or sedative muscle relaxant or anxiolytic effects.

For example, the connections

• A = 2-(2-Amino-3,5-dibrom-phenoxy-methylen)-morpholin-hydrochlorid,
• B = 2-(4-Amino-3,5-dibrom-phenoxy-methylen)-4-isopropyl-morpholin-hydrochlorid,
• C = 2-(4-Amino-3,5-dibrom-phenoxy-methylen)-morpholin-hydrochlorid,
• D = 2-(2-Amino-3,5-dibrom-phenoxy-methylen)-4-tert.butyl-morpholin-hydrochlorid und
• E = 2-(2-Amino-5-brom-4-chlor-phenoxy-methylen)-4-isopropyl-morpholin-dihydrochlorid im Vergleich zu
• F = 2-(2-Äthoxy-phenoxy-methylen)-morpholin-hydrochlorid

auf ihre biologischen Wirkungen wie folgt untersucht:

• 1. Die antidepressive Wirkung wurde am Modell des Antagonismus gegen die durch Reserpin hervorgerufene Hypothermie bei Mäusen (ASKEW, B. M., Life Sci. 2, 725, 1963) geprüft. Bei 20-26 g schweren männlichen Mäusen wurde durch 3 mg/kg Reserpin s.c. Hypothermie erzeugt. 17 Stunden später wurde die Körpertemperatur mittels eines elektrischen Schlundsondenthermometers gemessen. Anschließend wurden Gruppen von 6-10 Tieren die zu prüfenden Substanzen in der Dosis von 40 mg/kg p.o. verabreicht. Kontrollgruppen erhielten das Lösungsmittel (Aqua dest.). Die Körpertemperaturen wurden 1-4 Stunden nach Substanzverabreichung in stündlichem Abstand gemessen. Zur Auswertung wurden der maximale Wiederansteig der Körpertemperatur der Substanzgruppe mit den Temperaturen der Kontrolltiergruppen verglichen und die Temperaturunterschiede mit dem MANN-WHITNEY-U-Test auf Signifikanz geprüft.
• 2. Die antikonvulsive Wirkung der zu prüfenden Substanzen wurde am Modell der Wirkung gegen den maximalen Elektrokrampf bei Mäusen (SWINYARD, E. A., BROWN, W. C., GOODMAN, L. A., J. Pharmacol. exp. Ther 106, 319, 1952) ermittelt. Dazu wurde bei 10 männlichen, 20-26 g schweren Mäusen ein Krampfzustand mit Wechselstrom (50 mA, 50 Hz, 0,2 sec Dauer) über mit physiologischer Kochsalz-Lösung angefeuchtete, an den Kopf der Tiere gelegte Metallelektroden erzeugt, wobei das Ausbleiben der tonischen Extensorkomponente dieses Krampfes 150 Minuten nach Substanzgabe als antikonvulsive Wirkung gewertet wurde. ED₅₀-Werte wurden als Dosen mit 50%iger Krampfhemmung nach LITCHFIELD und WILCOXON (J. Pharmacol. exp. Ther. 96, 99, 1949) berechnet.
• 3. Die muskelrelaxierend-sedierende Wirkung der zu prüfenden Verbindungen wurde mit der Methode der Beeinflussung des Haltevermögens von Mäusen in rotierenden Drahtzylindern (YOUNG, D. M., LEWIS, A. H., Science 10e, 368, 1947) geprüft. Hierbei wurden bei jeweils 10 weiblichen 20-26 g schweren Mäusen pro Dosis 90-120 Minuten nach oraler Substanzverabreichung die Anzahl der im Versuchsverlauf aus den Zylindern fallenden Tiere festgestellt. EDso-Werte wurden graphisch als die Dosen ermittelt, bei denen sich 50% der Tiere nicht in den Zylindern halten konnten.
• 4. Die angsthemmende Wirkung der Substanzen wurde an 160-190 g schweren, weiblichen Ratten nach dem Verfahren von J. R. VOGEL, B. BEER und D. E. CLODY (Psychopharmacologia (Berl.) 21, 1, 1971) geprüft. Hierbei diente die Anzahl der von durstigen Ratten beim Trinken hingenommenen Elektroschocks als Maß der Angsthemmung. Tiere unter dem Ainfluß angsthemmender Substanzen nehmen mehr Elektroschocks hin als Kontrolltiere. Die zu prüfenden Substanzen wurden den Tieren eine Stunde vor Versuch in der Standarddosis von 10 mg/kg p.o., verabreicht. Die Differenzen in der Anzahl hingenommener Elektroschocks zwischen Substanztieren und Kontrolltieren wurden mit dem MANN-WHITNEY-U-Test auf statistische Signifikanz geprüft. Die mittlere Anzahl der Trinkakte betrug bei den Kontrollgruppen 2,9±0,4 pro Tier.

• A = 2- (2-amino-3,5-dibromophenoxy-methylene) morpholine hydrochloride,
• B = 2- (4-amino-3,5-dibromophenoxy-methylene) -4-isopropyl-morpholine hydrochloride,
• C = 2- (4-amino-3,5-dibromophenoxy-methylene) morpholine hydrochloride,
• D = 2- (2-amino-3,5-dibromophenoxy-methylene) -4-tert.butyl-morpholine hydrochloride and
• E = 2- (2-amino-5-bromo-4-chlorophenoxy-methylene) -4-isopropyl-morpholine-dihydrochloride compared to
• F = 2- (2-ethoxy-phenoxy-methylene) morpholine hydrochloride

examined for their biological effects as follows:

• 1. The antidepressant effect was tested on the model of the antagonism against the hypothermia caused by reserpine in mice (ASKEW, BM, Life Sci. 2, 725, 1963). In 20-26 g male mice, 3 mg / kg reserpine sc caused hypothermia. 17 hours later, the body temperature was measured using an electric gavage thermometer. Subsequently, groups of 6-10 animals were administered the substances to be tested in a dose of 40 mg / kg po. Control groups received the solvent (aqua dest.). Body temperatures were measured every hour 1-4 hours after substance administration. For the evaluation, the maximum rise in the body temperature of the substance group was compared with the temperatures of the control animal groups and the temperature differences were checked for significance using the MANN-WHITNEY-U test.
• 2. The anticonvulsive effect of the substances to be tested was determined on the model of the effect against the maximum electrical spasm in mice (SWINYARD, EA, BROWN, WC, GOODMAN, LA, J. Pharmacol. Exp. Ther 106, 319, 1952). For this purpose, a cramping condition with alternating current (50 mA, 50 Hz, 0.2 sec duration) was generated in 10 male, 20-26 g heavy mice via metal electrodes moistened with physiological saline solution and attached to the head of the animals, the absence of the tonic extensor component of this cramp 150 minutes after administration of the substance was evaluated as an anticonvulsant effect. ED ₅₀ values were calculated as doses with 50% cramp inhibition according to LITCHFIELD and WILCOXON (J. Pharmacol. Exp. Ther. 96, 99, 1949).
• 3. The muscle relaxant-sedative effect of the compounds to be tested was tested using the method of influencing the holding capacity of mice in rotating wire cylinders (YOUNG, DM, LEWIS, AH, Science 10e, 368, 1947). Here, the number of im in 90 female 120-26 g mice per dose 90-120 minutes after oral administration Experimental course determined animals falling from the cylinders. ED 50 values were determined graphically as the doses at which 50% of the animals could not stay in the cylinders.
• 4. The anti-anxiety effect of the substances was tested on 160-190 g female rats by the method of JR VOGEL, B. BEER and DE CLODY (Psychopharmacologia (Berl.) 21, 1, 1971). Here, the number of electric shocks tolerated by thirsty rats when drinking served as a measure of anxiety inhibition. Animals under the influence of anti-anxiety substances take more electric shocks than control animals. The substances to be tested were administered to the animals one hour before the test in the standard dose of 10 mg / kg po. The differences in the number of electric shocks tolerated between substance animals and control animals were checked for statistical significance using the MANN-WHITNEY-U test. The mean number of drinking acts in the control groups was 2.9 ± 0.4 per animal.

• 5. Die toxische Wirkung der zu prüfenden Substanzen wurde
  • a) als LD₅₀-Wert, als Dosis bei der 50% der Tiere nach einmaliger oraler Substanzverabreichung und 14-tägiger Nachbeobachtung starben, nach dem Verfahren von LITCHFIELD und WILCOXON (J. Pharmacol. exp. Ther. 96, 99, 1949) ermittelt. Hierbei wurden pro Dosis 5 weibliche und 5 männliche 20-26 g schwere Mäuse verwendet.
  • b) In orientierenden Toxizitätsprüfungen wurden 5 weiblichen 20-26 g schweren Mäusen die Substanzen mit 200, 500 oder 1,000 mg/kg oral verabreicht und die Tiere 24 Stunden nachbeobachtet:

The following table contains the results of experiments 1 to 4:

• 5. The toxic effects of the substances to be tested were
  • a) as the LD ₅₀ value, as the dose at which 50% of the animals died after a single oral administration of substance and 14 days of follow-up, determined by the method of LITCHFIELD and WILCOXON (J. Pharmacol. exp. Ther. 96, 99, 1949) . 5 female and 5 male 20-26 g heavy mice were used per dose.
  • b) In orientative toxicity tests, 5 female 20-26 g mice were given the substances at 200, 500 or 1,000 mg / kg orally and the animals were followed up for 24 hours:

The morpholine derivatives of the general formula obtained according to the invention and their physiologically tolerated acid addition salts with inorganic and organic acids are therefore suitable in particular for the treatment of depression and anxiety and can be incorporated into the usual pharmaceutical preparation forms such as tablets, dragees, capsules, suppositories, ampoules, suspensions or solutions, optionally in combination with other active substances, for pharmaceutical use. The single dose in humans is expediently 20 to 50 mg.

The following examples are intended to explain the invention in more detail:

EXAMPLE A 1,2-epoxy-3- (2-nitro-phenoxy) propane

A mixture of 318 g of o-nitrophenol, 304 g of epichlorohydrin and 160 g of solid potassium hydroxide in 3 l of water are stirred at room temperature for 16 hours. After this time, the mixture is extracted 3 times with 1000 ml of chloroform. The combined chloroform phase is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo on a rotary evaporator. The oily residue is taken up in 500 ml of isopropanol. After adding 500 ml of petroleum ether, crystallization occurs. The crystals are filtered off and washed with petroleum ether. Melting point: 45-47 ° C.

EXAMPLE B 4-benzyl-2- (2-nitro-phenoxy-methylene) morpholine hydrochloride

70 g of 1,2-epoxy-3- (2-nitro-phenoxy) propane and 57.5 g of benzylaminoethanol are dissolved in 300 ml of chloroform. After evaporating the solvent in vacuo, the mixture is heated at 140 ° C for 3 hours. After this time, it is dissolved in 300 ml of dimethylformamide and this solution is cooled to 0 ° C. At this temperature, 29.6 ml of thionyl chloride are added dropwise with stirring, the mixture is stirred at room temperature for 3 hours and then heated to reflux temperature for 16 hours. After cooling, the mixture is stirred into ice / sodium hydroxide solution, taking care that the pH remains> 7. A precipitate which is difficult to filter precipitates and is extracted three times with 250 ml of chloroform. The combined chloroform phases are washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The remaining residue is column chromatographed over 1 kg of silica gel, a mixture of chloroform / ethyl acetate = 4/1 serving as the eluent. The eluates containing the combined substance are evaporated to dryness in vacuo. The residue is taken up in isopropanol and this solution is acidified with ethereal hydrochloric acid. Crystallization occurs. The crystals which have separated out are filtered off with suction and recrystallized from isopropanol / ether = 1/1. Melting point: 206-208 ° C.

• 4-tert.Butyl-2-(2-nitro-phenoxy-methylen)-morpholin-hydrochlorid Schmelzpunkt: 175-177°C
• 4-Methyl-2-(4-nitro-phenoxy-methylen)-morpholin-hydrochlorid Schmelzpunkt: 216-218°C
• 4-Methyl-2-(2-nitro-phenoxy-methylen)-morpholin Schaum
• 4-Äthyl-2-(4-nitro-phenoxy-methylen)-morpholin-hydrochlorid Schmelzpunkt: 240-242°C
• 4-Isopropyl-2-(4-nitro-phenoxy-methylen)-morpholin-hydrochlorid Schmelzpunkt: 195-197°C
• 2-(4-Nitro-phenoxy-methylen)-4-methyl-morpholin Schmelzpunkt: 105―107°C
• 4-tert.Butyl-2-(4-nitro-phenoxy-methylen)-morpholin-hydrochlorid Schmelzpunkt: 201-203°C
• 4-Isopropyl-2-(2-nitro-phenoxy-methylen)-morpholin-hydrochlorid Schmelzpunkt: 187-189°C
• 4-Benzyl-2-(5-methyl-2-nitro-phenoxy-methylen)-morpholin-hydrochlorid Schmelzpunkt: 192-194°C
• 4-Benzyl-2-(2-nitro-phenoxy-methylen)-morpholin-hydrochlorid Schmelzpunkt: 206-208°C
• 2-(4-Chlor-2-nitro-phenoxy-methylen)-4-isopropyl-morpholin-hydrochlorid Schmelzpunkt: 208-210°C
• 4-Benzyl-2-(4-chlor-2-nitro-phenoxy-methylen)-morpholin-hydrochlorid Schmelzpunkt: 218-220°C
• 2-(2-Chlor-4-nitro-phenoxy-methylen)-4-isopropyl-morpholin-hydrochlorid Schmelzpunkt: 205-206°C
• 4-Benryl-2-(2-chlor-4-nitro-phenoxy-methylen)-morpholin-hydrochlorid Schmelzpunkt: 198-200°C
• 4-Benzyl-2-(5-methyl-2-nitro-phenoxy-methylen)-morpholin-hydrochlorid Schmelzpunkt: 198-200°C
• 4-Benzyl-2-(3-methyl-4-nitro-phenoxy-methylen)-morpholin-hydrochlorid Schmelzpunkt: 217-218°C

The following compounds were prepared analogously to Examples A and B:

• 4-tert-butyl-2- (2-nitro-phenoxy-methylene) -morpholine hydrochloride Melting point: 175-177 ° C
• 4-methyl-2- (4-nitro-phenoxy-methylene) -morpholine hydrochloride Melting point: 216-218 ° C
• 4-methyl-2- (2-nitro-phenoxy-methylene) morpholine foam
• 4-ethyl-2- (4-nitro-phenoxy-methylene) -morpholine hydrochloride Melting point: 240-242 ° C
• 4-isopropyl-2- (4-nitro-phenoxy-methylene) -morpholine hydrochloride Melting point: 195-197 ° C
• 2- (4-nitro-phenoxy-methylene) -4-methyl-morpholine Melting point: 105-107 ° C
• 4-tert-butyl-2- (4-nitro-phenoxy-methylene) -morpholine hydrochloride Melting point: 201-203 ° C
• 4-isopropyl-2- (2-nitro-phenoxy-methylene) -morpholine hydrochloride Melting point: 187-189 ° C
• 4-Benzyl-2- (5-methyl-2-nitro-phenoxymethylene) morpholine hydrochloride Melting point: 192-194 ° C
• 4-Benzyl-2- (2-nitro-phenoxy-methylene) -morpholine hydrochloride Melting point: 206-208 ° C
• 2- (4-chloro-2-nitro-phenoxy-methylene) -4-isopropyl-morpholine hydrochloride Melting point: 208-210 ° C
• 4-Benzyl-2- (4-chloro-2-nitro-phenoxymethylene) morpholine hydrochloride Melting point: 218-220 ° C
• 2- (2-chloro-4-nitro-phenoxy-methylene) -4-isopropyl-morpholine hydrochloride Melting point: 205-206 ° C
• 4-Benryl-2- (2-chloro-4-nitro-phenoxy-methylene) -morpholine hydrochloride Melting point: 198-200 ° C
• 4-Benzyl-2- (5-methyl-2-nitro-phenoxymethylene) morpholine hydrochloride Melting point: 198-200 ° C
• 4-Benzyl-2- (3-methyl-4-nitro-phenoxymethylene) morpholine hydrochloride Melting point: 217-218 ° C

• 4-Carbäthoxy-2-(2-chlor-4-nitro-phenoxy-methylen)-morpholin Schmelzpunkt: 106-108°C
• 4-Carbäthoxy-2-(4-chlor-2-nitro-phenoxy-methylen)-morpholin Schmelzpunkt: 91-93°C
• 4-Carbäthoxy-2-(3-methyl-4-nitro-phenoxy-methylen)-morpholin Schmelzpunkt: 88-91 °C

The following compounds were prepared by reacting the corresponding benzyl compound with carbethoxy chloride (see Example 6):

• 4-carbethoxy-2- (2-chloro-4-nitro-phenoxymethylene) morpholine Melting point: 106-108 ° C
• 4-carbethoxy-2- (4-chloro-2-nitro-phenoxymethylene) morpholine Melting point: 91-93 ° C
• 4-carbethoxy-2- (3-methyl-4-nitro-phenoxymethylene) morpholine Melting point: 88-91 ° C

EXAMPLE C 3- (4 AcetaminophenoxyJ-1,2-epoxypropane

A mixture of 178 g of 4-hydroxyacetanilide, 166 g of epichlorohydrin and 52 g of solid sodium hydroxide in 1.2 l of water is stirred for 20 hours at room temperature. The solid precipitate is filtered off, washed with water and crystallized from isopropanol.

Melting point: 116-1 18 ° C.

EXAMPLE D 2- (4-Acetaminophenoxy-methylene) -4-benzyl-morpholine

51 g of 3- (4-acetaminophenoxy) -1,2-epoxypropane and 37.8 g of benzylaminoethanol are dissolved in 250 ml of chloroform. After evaporating the solvent in vacuo, the mixture is heated at 140 ° C for 3 hours. After this time, it is dissolved in 200 ml of dimethylformamide and this solution is cooled to 0 ° C. At this temperature, 19.6 ml of thionyl chloride are added dropwise with stirring, the mixture is stirred at room temperature for 3 hours and then heated to reflux temperature for 16 hours. After cooling, the mixture is stirred into ice / sodium hydroxide solution, taking care that the pH remains> 7. A precipitate which is difficult to filter precipitates and is extracted three times with 200 ml of chloroform. The combined chloroform phase is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The remaining residue is column chromatographed over 800 g of silica gel, using ethyl acetate as the eluent. The eluates containing the combined substance are evaporated to dryness in vacuo. The residue is taken up in toluene and crystallized by adding petroleum ether. The crystals are filtered off and washed with petroleum ether.

Melting point: 120-122 ° C.

• 2-(4-Acetamino-phenoxy-methylen)-4-benzyl-morpholin-hydrochlorid Schaum
• 2-(2-Acetamino-4-nitro-phenoxy-methylen)-4-benzyl-morpholin Ö1
• 2-(2-Acetamino-4-nitro-phenoxy-methylen)-4-isopropyl-morpholin 01

The following substances were prepared analogously to Examples C and D:

• 2- (4-acetaminophenoxy-methylene) -4-benzyl-morpholine hydrochloride foam
• 2- (2-acetamino-4-nitro-phenoxy-methylene) -4-benzyl-morpholine Ö1
• 2- (2-acetamino-4-nitro-phenoxy-methylene) -4-isopropyl-morpholine 01

EXAMPLE 1 2- (2-Amino phenoxymethylene) morpholine hydrochloride

25 g of 4-benzyl-2- (2-nitro-phenoxy-methylene) -morpholine hydrochloride are dissolved in 450 ml of methanol and, after addition of 2 g of 10% palladium-carbon, hydrogenated at 5 at pressure and at room temperature until the theoretical amount Hydrogen is absorbed. After removing the catalyst, the methanol solution is evaporated to dryness in vacuo, the residue is dissolved in hot ethanol and the solution is mixed with ethereal hydrochloric acid. Crystallization occurs upon standing. The crystals are filtered off and washed with a mixture of ethanol and ether.

Melting point: 126-130 ° C.

EXAMPLE 2 2- (2-Amino-phenoxy-methyleny-4-tert-butyl-morpholine hydrochloride

16 g of 4-tert-butyl-2- (2-nitro-phenoxy-methylene) -morpholine hydrochloride are dissolved in 150 ml of methanol and, after addition of 1 g of 10% palladium-carbon, hydrogenated at 5 at pressure and at room temperature until the theoretical amount of hydrogen is added. After removing the catalyst, the methanol solution is evaporated to dryness in vacuo and the residue is crystallized from ethanol.

Melting point: 224-226 ° C (decomp.).

EXAMPLE 3 4-ethoxycarbonyl-2- (4-amino-2-chlorophenoxy-methyleneJ-morphine hydrochloride

12 g of 4-ethoxycarbonyl-2- (2-chloro-4-nitro-phenoxy-methylene) morpholine are dissolved in 200 ml of ethanol. With cooling with ice and with stirring, 150 ml of conc. Hydrochloric acid and there after 75 g of stannous chloride were added in portions over a period of 1.5 hours with further cooling. When the addition is complete, the mixture is poured onto ice, made alkaline with 10N sodium hydroxide solution and extracted 3 times with 200 ml of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved in isopropanol and the isopropanol solution is acidified with ethereal hydrochloric acid. Crystallization occurs. The crystals which have separated out are filtered off with suction and washed with isopropanol.

Melting point: 116-117 ° C (dec.).

EXAMPLE 4 2- (2-amino-4-nitro-phenoxy-methylene) -4-isopropyl-morpholine-dihydrochloride

17 g of 2- (2-acetamino-4-nitro-phenoxy-methylene) -4-isopropyl-morpholine are dissolved in 200 ml of ethanol and, after adding a solution of 5 g of sodium hydroxide in 50 ml of water, boiled under reflux for 2 hours. The solution is concentrated to remove the alcohol, the residue is partitioned between water and chloroform; the chloroform extract is dried and evaporated to dryness. The residue is dissolved in isopropanol and acidified with ethanolic hydrochloric acid, whereupon 2- (2-amino-4-nitro-phenoxy-methylene) -4-isopropyl-morpholine-dihydrochloride crystallizes out; it is suctioned off, washed with a little isopropanol and dried.

Melting point: 230-233 ° C (decomp.).

EXAMPLE 5 2- (2-amino-3,5-dibromophenoxy methylene) morpholine hydrochloride

9 g of 2- (2-aminophenoxymethylene) morpholine hydrochloride are dissolved in 100 ml of glacial acetic acid. A solution of 3.7 ml of bromine in 20 ml of glacial acetic acid is added dropwise with stirring. When the addition is complete, the mixture is poured into ice water, made alkaline with 10N sodium hydroxide solution and extracted 3 times with 200 ml of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved in ethanol and acidified with ethereal hydrochloric acid. The crystallizing precipitate is filtered off and the ethanol crystallized.

Melting point: 207-209 ° C.

EXAMPLE 6 2- (2-amino-3,5-dibromo-4-nitro-phenoxy-methylene) -4-carbethoxy-morpholine

16 g of 2- (2-amino-3,5-dibromo-4-nitro-phenoxy-methylene) -4-benzyl-morpholine are dissolved in 350 ml of toluene and, after adding 5 ml of carbethoxychloride, boiled under reflux for 4 hours. After standing for about 15 hours at room temperature, the reaction mixture is concentrated in vacuo, the residue is triturated with isopropanol, suction filtered and recrystallized from isopropanol, 2- (2-amino-3,5-dibromo-4-nitro-phenoxy-methylene) -4-carbäthoxy-morpholin vom.

Melting point: 105-107 ° C is obtained.

EXAMPLE 7 2- (4-amino-2-chlorophenoxy methylene) morpholine hydrochloride

9 g of 4-ethoxycarbonyl-2- (4-amino-2-chlorophenoxy-methylene) morpholine hydrochloride are dissolved in 100 ml of methanol. After the addition of 10 g of solid sodium hydroxide, the mixture is heated at the reflux temperature for 3 hours. The solution is then evaporated to dryness in vacuo and the residue is partitioned between water and 100 ml of chloroform. The aqueous phase is extracted twice with 100 ml of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved in isopropanol. The solution is acidified with ethereal hydrochloric acid. The crystallizing precipitate is filtered off and crystallized from ethanol.

Melting point: 271-274 ° C.

EXAMPLE 8 2- (4-aminophenoxymethylene) -4-methylmorpholine hydrochloride

Prepared from 4-methyl-2- (4-nitro-phenoxy-methylene) -morpholine by catalytic hydrogenation as in Example 2.

Melting point: 179-182 ° C.

EXAMPLE 9 2- (2-aminophenoxymethylene) -4-methylmorpholine dihydrochloride

Prepared from 4-methyl-2- (2-nitro-phenoxy-methylenl-morpholine by catalytic hydrogenation as in Example 2.

Melting point: 262-265 ° C (dec.).

EXAMPLE 10 2- (4-aminophenoxymethylene) morpholine dihydrochloride

Prepared from 2- (4-aminophenoxy-methylene) -4-benzyl-morpholine-dihydrochloride by catalytic hydrogenation as in Example 1.

Melting point: 250-254 ° C.

EXAMPLE 11 4-ethyl-2- (4-aminophenoxymethylene) morpholine hydrochloride

Prepared from 4-ethyl-2- (4-nitro-phenoxy-methylene) -morpholine hydrochloride by catalytic hydrogenation as in Example 2.

Melting point: 199-200 ° C.

EXAMPLE 12 2- (4-aminophenoxymethylene) -4-isopropylmorpholine hydrochloride

Prepared from 4-isopropyl-2- (4-nitro-phenoxy-methylene) -morpholine hydrochloride by catalytic hydrogenation as in Example 2.

Melting point: 179-181 ° C.

EXAMPLE 13 2- (4-aminophenoxymethylene) -4 phenylmorpholine hydrochloride

Prepared from 2- (4-nitro-phenoxy-methylene) -4-phenyl-morpholine by catalytic hydrogenation as in Example 2.

Melting point: 210-215 ° C (dec.).

EXAMPLE 14 2- (4-aminophenoxy-methylene) -4-tert-butyl-morphaline hydrochloride

Manufactured from 4-tert-butyl-2- (4-nitro-phenoxy-methylene) -morpholine hydrochloride by catalytic hydrogenation as in Example 2.

Melting point: 155-157 ° C.

EXAMPLE 15 2- (2-aminophenoxymethylene) -4-isopropylmorpholine hydrochloride

Manufactured from 4-isopropyl-2- (2-nitro-phenoxy-methylene) -morpholine hydrochloride by catalytic hydrogenation as in Example 2.

Melting point: 165-167 ° C.

EXAMPLE 16 2- (2-amino-5-methylphenoxymethylene) morpholine

Manufactured from 4-benzyl-2- (5-methyl-2-nitro-phenoxy-methylene) -morpholine hydrochloride by catalytic hydrogenation as in Example 1.

Melting point: 108-110 ° C.

EXAMPLE 17 2- (2-aminophenoxy methylene) -4-benzyl morpholine dihydrochloride

Prepared from 4-benzyl-2- (2-nitro-phenoxy-methylene) -morpholine hydrochloride by reduction with tin-II-chloride analogously to Example 3.

Melting point: 248-253 ° C.

EXAMPLE 18 2- (2-amino-4-chlorophenoxy methylene) -4-isopropyl morpholine dihydrochloride

Prepared from 2- (4-chloro-2-nitro-phenoxy-methylene) -4-isopropyl-morpholine hydrochloride by reduction with tin-II-chloride analogously to Example 3.

Melting point: 248-252 ° C.

EXAMPLE 19 2- (2-amino-4-chlorophenoxy-methylene) -4-benzyl morpholine hydrochloride

Manufactured from 4-benzyl-2- (4-chloro-2-nitro-phenoxy-methylene) -morpholine hydrochloride by reduction with tin-II-chloride analogously to Example 3.

Melting point: 262-266 ° C.

EXAMPLE 20 2- (2-amino-4-chlorophenoxy-methylene) -4-carbethoxy-morpholine

Made from 4-carbethoxy-2- (4-chloro-2-nitro-phenoxy-methylene) -morpholine by reduction with tin-II-chloride analogously to Example 3.

Melting point: 110-112 ° C.

EXAMPLE 21

2- (4-Amino-2-chlorophenoxy-methylene) -4-isopropyl morpholine hydrochloride Made from 2- (2-chloro-4-nitro-phenoxy-methylene) -4-isopropyl morpholine hydrochloride by reduction with Tin-II chloride analogous to Example 3.

• 6,3 -6,8 ppm Multiplett (3 arom. H)
• 5,2 -6,2 ppm Singulett (3H: NH₂ + HCI)
• 3,8 -3,95 ppm Dublett
  
• 1,25-1,35 ppm Dublett
  

Foam, structural evidence by NMR spectrum (CDCl ₃ ):

• 6.3 -6.8 ppm multiplet (3 aromatic H)
• 5.2 -6.2 ppm singlet (3H: NH ₂ + HCI)
• 3.8 -3.95 ppm doublet
  
• 1.25-1.35 ppm doublet
  

EXAMPLE 22 2- (4-amino-2-chlorophenoxy-methylene) -4-benzyl-morpholine hydrochloride

Manufactured from 4-benzyl-2- (2-chloro-4-nitro-phenoxy-methylene) -morpholine hydrochloride by reduction with tin-II-chloride analogously to Example 3.

Melting point: 229 = 230 ° C.

EXAMPLE 23 2- (2-amino-5-methylphenoxymethylene) -4-benzylmorpholine hydrochloride

Prepared from 4-benzyl-2- (5-methyl-2-nitro-phenoxy-methylene) -morpholine hydrochloride by reduction with tin-II-chloride analogously to Example 3.

Melting point: 191-193 ° C.

EXAMPLE 24 2- (4-amino-3-methylphenoxymethylene) -4-benzylmorpholine hydrochloride

Prepared from 4-benzyl-2- (3-methyl-4-nitro-phenoxy-methylene) -morpholine hydrochloride by reduction with tin-II-chloride analogously to Example 3.

Melting point: 172-175 ° C.

EXAMPLE 25 2- (4-amino-3-methyl-phenoxy-methylene) -4-carbethoxy-morpholine hydrochloride

Made from 4-carbethoxy-2- (3-methyl-4-nitro-phenoxy-methylene) -morpholine hydrochloride by reduction with tin-II-chloride analogously to Example 3.

Melting point: 195-198 ° C (dec.).

EXAMPLE 26 2- (2-amino-4-nitro-phenoxy-methylene) -4-benzyl-morpholine-dihydrochloride

Prepared from 2- (2-acetamino-4-nitro-phenoxy-methylene) -4-benzyl-morpholine and sodium hydroxide solution analogous to Example 4.

Melting point: 242-248 ° C (dec.).

EXAMPLE 27 2- (4-aminophenoxymethylene) -4-benzylmorpholine dihydrochloride

Prepared from 2- (4-acetaminophenoxy-methylene) -4-benzyl-morpholine and sodium hydroxide solution analogous to Example 4.

Foam.

EXAMPLE 28 2- (4-amino-3,5-dibromophenoxy-methylene) -4-methyl-morpholine hydrochloride

Prepared from 2- (4-aminophenoxy-methylene) -4-methyl-morpholine hydrochloride and bromine as in Example 5.

Melting point: 211-213 ° C (decomp.).

EXAMPLE 29 2- (2-amino-3,5-dibromophenoxy-methylene) -4-methyl-morpholine hydrochloride

Prepared from 2- (2-aminophenoxy-methylene) -4-methyl-morpholine hydrochloride and bromine as in Example 5.

Melting point: 207-209 ° C.

EXAMPLE 30 2- (4-amino-3,5-dibromophenoxy-methylene) -4-isopropyl-morpholine hydrochloride

Prepared from 2- (4-aminophenoxy-methylene) -4-isopropyl-morpholine hydrochloride and bromine as in Example 5.

Melting point: 178-180 ° C.

EXAMPLE 31 2- (4-amino-3,5-dibromophenoxy methylene) morpholine hydrochloride

Prepared from 2- (4-aminophenoxy-methylene) -morpholine-dihydrochloride and bromine as in Example 5.

Melting point: 183-185 ° C.

EXAMPLE 32 2- (4-amino-3,5-dibromophenoxy-methylene) -4-benzyl-morpholine hydrochloride

Prepared from 2- (4-aminophenoxy-methylene) -4-benzyl-morpholine-dihydrochloride and bromine as in Example 5.

Melting point: 234-236 ° C.

EXAMPLE 33 2- (4-amino-3,5-dibromophenoxy-methylene) -4-tert-butyl-morpholine hydrochloride

Prepared from 2- (4-aminophenoxy-methylene) -4-tert.butyl-morpholine hydrochloride and bromine as in Example 5.

Melting point: 228-230 ° C (decomp.).

EXAMPLE 34 2- (2-amino-3,5-dibromo-phenaxy-methylene) -4-isopropyl-morphaline hydrochloride

Prepared from 2- (2-aminophenoxy-methylene) -4-isopropyl-morpholine hydrochloride and bromine as in Example 5.

Melting point: 115-117 ° C (dec.).

EXAMPLE 35 4-ethyl-2- (2-amino-3,5-dibromo-phenoxy-methylene) morpholine hydrochloride

Prepared from 4-ethyl-2- (2-aminophenoxymethylene) morpholine hydrochloride and bromine analogously to Example 5.

Melting point: 255―257 ° C.

EXAMPLE 36 2- (2-amino-3,5-dibromophenoxy-methylene) -4-benzyl-morpholine hydrochloride

Prepared from 2- (2-aminophenoxy-methylene) -4-benzyl-morpholine-dihyrochloride and bromine as in Example 5.

Melting point: 220-225 ° C.

EXAMPLE 37 2- (2-amino-3,5-dibromophenoxy-methylene) -4-tert-butyl-morpholine hydrochloride

Prepared from 2- (2-aminophenoxy-methylene) -4-tert.butyl-morpholine hydrochloride and bromine as in Example 5.

Melting point: 243-245 ° C (decomp.).

EXAMPLE 38 2- (2-amino-5-bromo-4-chlorophenoxy-methylene) -4-isopropyl-morpholine-dihydrochloride

Manufactured from 2- (2-amino-4-chlorophenoxy-methylene) -4-isopropyl-morpholine-dihydrochloride and bromine as in Example 5.

Melting point: 225-228 ° C (decomp.).

EXAMPLE 39 2- (2-amino-5-bromo-4-chlorophenoxy-methylene) -4-benzyl-morpholine hydrochloride

Prepared from 2- (2-amino-4-chlorophenoxy-methylene) -4-benzyl-morpholine-dihydrochloride and bromine as in Example 5.

Melting point: 235-237 ° C.

EXAMPLE 40 2- (2-amino-5-bromo-4-chlorophenoxy methylene) morpholine

Made from 2- (2-amino-4-chlorophenoxy-methylene) -morpholine-dihydrochloride and bromine as in Example 5.

Melting point: 130-132 ° C.

EXAMPLE 41 2- (4-amino-5-bromo-2-chlorophenoxy-methylene) -4-benzyl-morpholine dihydrochloride

Prepared from 2- (4-amino-2-chlorophenoxy-methylene) -4-benzyl-morpholine hydrochloride and bromine as in Example 5.

Melting point: 182-185 ° C.

EXAMPLE 42 2- (4-amino-5-bromo-2-chlorophenoxy-methylene) -4-isopropyl-morpholine hydrochloride

Prepared from 2- (4-amino-2-chlorophenoxy-methylene) -4-isopropyl-morpholine hydrochloride and bromine as in Example 5.

Foam, structural evidence by NMR spectrum. Solvent CDCIJCD3OD:

EXAMPLE 43 2- (4-amino-5-bromo-2-chlorophenoxy methylene) morpholine hydrochloride

Made from 2- (4-amino-2-chlorophenoxy-methylene) -morpholine-dihydrochloride and bromine as in Example 5.

Melting point: 220-223 ° C.

EXAMPLE 44 2- (2-amino-3-bromo-5-methylphenoxy-methylene) -4-benzyl-morpholine hydrochloride

Prepared from 2- (2-amino-5-methylphenoxymethylene) -4-benzylmorpholine hydrochloride and bromine analogously to Example 5.

Melting point: 223-226 ° C.

EXAMPLE 45 2- (2-amino-3-bromo-5-methylphenoxymethylene) morpholine hydrochloride

Prepared from 2- (2-amino-5-methyl-phenoxy-methylene) -morpholine hydrochloride and bromine as in Example 5.

Melting point: 225-227 ° C.

EXAMPLE 46 2- (2-amino-3-bromo-5-methylphenoxy-methylene) -4-isopropyl-morpholine hydrochloride

Prepared from 2- (2-amino-5-methylphenoxymethylene) -4-isopropylmorpholine and bromine as in Example 5.

Melting point: 205-2070C.

EXAMPLE 47 2- (4-amino-3-bromo-5-methylphenoxymethylene) -4-benzylmorpholine dihydrochloride

Prepared from 2- (4-amino-5-methylphenoxymethylene) -4-benzylmorpholine dihydrochloride and bromine as in Example 5.

Melting point: 241-243 ° C (decomp.).

EXAMPLE 48 2- (2-Amino-3,5-dibromo-4-nitro-phenoxy-methylenl-4-benzyl-morpholine-dihydrochloride

Prepared from 2- (2-amino-4-nitro-phenoxy-methylene) -4-benzyl-morpholine-dihydrochloride and bromine as in Example 5.

Melting point: 122-125 ° C.

EXAMPLE 49 2- (2-amino-3,5-dibromo-4-nitro-phenoxy-methylene) -4-isopropyl-morpholine-dihydrochloride

Prepared from 2- (2-amino-4-nitro-phenoxy-methylene) -4-isopropyl-morpholine-dihydrochloride and bromine as in Example 5.

Melting point: 110-114 ° C.

EXAMPLE 50 2- (2-amino-4-chlorophenoxy methylene) morpholine dihydrochloride

Prepared from 2- (2-amino-4-chlorophenoxy-methylene) -4-carbethoxy-morpholine and sodium hydroxide as in Example 7.

Melting point: 247-251 ° C.

EXAMPLE A 50 mg tablets of 2- (2-amino-3,5-dibromo-phenoxy-methylene) -morpholine hydrochlaride

Composition:

Description:

• Tablet weight: 200 mg
• Diameter: 8 mm, round, biplane, facet on both sides, partial notch on one side

• Wirkstoff, CaHPO₄, Milchzucker und Maisstärke werden mit der wäßrigen PVP-Lösung gleichmäßig befeuchtet. Dann wird die Masse durch 2 mm-Maschenweite gesiebt, im Umlufttrockenschrank bei 50°C getrocknet und erneut gesiebt (1,5 mm-Maschenweite). Nach Zumischen des Schmiermittels wird die Mischung auf einer Tablettiermaschine verpreßt.

Manufacturing:

• Active ingredient, CaHPO ₄ , milk sugar and corn starch are moistened evenly with the aqueous PVP solution. The mass is then sieved through a 2 mm mesh size, dried in a forced-air drying cabinet at 50 ° C. and sieved again (1.5 mm mesh size). After the lubricant has been mixed in, the mixture is compressed on a tabletting machine.

EXAMPLE B Coated tablets containing 20 mg of 2- (2-amino-3,5-dibromo-phenoxy-methylene) -morpholine hydrochloride

Beschreibung:

• Kerndurchmesser: 6 mm, rund, bikonvex, 5 mm Wölbungsradius

Description:

• Core diameter: 6 mm, round, biconvex, 5 mm radius of curvature

• Erfolgt analog Beispiel A.

Core production:

• Is carried out analogously to example A.

• Erfolgt im Dragierkessel mit einer gebräuchlichen Zucker-Dragiersuspension und anschließender Polierung.
• Drageegewicht: 130 mg

Coating:

• Takes place in the coating pan with a customary sugar coating suspension and subsequent polishing.
• Drage weight: 130 mg

EXAMPLE C. 25 mg capsules of 2- (2-amino-3,5-dibromo-phenoxy-methylene) -morpholine hydrochloride

Herstellung:

• Wirkstoff und Hilfsstoffe werden durch ein Sieb von 0,75 mm-Maschenweite gegeben und anschließend gut miteinander vermischt.
• Abfüllung in Hartgelatine-Kapseln der Größe 4.
• Das Füllgewicht wird laufend überprüft.
• Kapselfüllung: 150 mg.

Manufacturing:

• The active substance and auxiliary substances are passed through a sieve with a mesh size of 0.75 mm and then mixed well with one another.
• Filled in size 4 hard gelatin capsules.
• The filling weight is checked continuously.
• Capsule filling: 150 mg.

. EXAMPLE D Salt with 25 mg of 2- (2-amino-3,5-dibromo phenoxy-methylene) morpholine hydrochloride per 15 ml (1 tablespoon)

Herstellungsverfahren:

• Dest. Wasser wird auf 70°C erhitzt. Hierin wird unter Rühren p-Hydroxybenzoesäuremethylester und -propylester sowie Glycerin und Carboxymethylcellulose gelöst. Es wird auf Raumtemperatur abgekühlt und unter Rühren der Wirkstoff zugegeben und gelöst. Nach Zugabe und Lösung des Zuckers, der Sorbitlösung und des Aromas wird zur Entlüftung des Saftes unter Rühren evakuiert.

15 ml Saft enthalten 25 mg Wirksubstanz

Production method:

• Dest. Water is heated to 70 ° C. P-Hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethyl cellulose are dissolved therein with stirring. It is cooled to room temperature and the active ingredient is added and dissolved while stirring. After adding and dissolving the sugar, the sorbitol solution and the aroma, the juice is evacuated with stirring.

15 ml of juice contain 25 mg of active substance

R _{4 is} a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, a carbalkoxy group with a total of 2 to 4 carbon atoms, which mean phenyl or benzyl group, and their physiologically tolerated acid addition salts.

• 3. New 2-amino and 4-amino-phenoxymethyl-2-morpholine derivatives of the formula according to claim 1, in which one of the radicals R ₁ or R ₂ in the 3- or 5-position is a bromine atom and the other of the radicals R ₁ or R ₂ in the 3- or -5-position is a hydrogen or bromine atom,
  • R _{3 is} a hydrogen atom and
  • R _{4 represents} a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or the carbethoxy group, and their physiologically tolerable acid addition salts.
• 4. 2- (2-amino-3,5-dibromophenoxy-methylene) -morpholine and its acid addition salts.
• 5. 2- (4-amino-3,5-dibromophenoxy-methylene) -4-isopropyl-morpholine and its acid addition salts.
• 6. 2- (4-amino-3,5-dibromo-phenoxy-methylene) -morpholine and its acid addition salts.
• 7. 2- (2-amino-3,5-dibromophenoxy-methylene) -4-tert.butyl-morpholine and its acid addition salts.
• 8. Medicament containing a compound according to claim 1 to 7 in addition to one or more inert carriers or diluents.
• 9. Use of a compound according to claim 1 to 7 for the manufacture of a medicament by a non-chemical route for the treatment of depression and anxiety.
• 10. A process for the preparation of aminophenoxymethyl-2-morpholine derivatives according to claim 1 to 7, characterized in that
  • a) a nitro compound of the formula
    
    in the
    • R ₁ , R ₂ and R _{4 are} as defined in the introduction, is reduced or
  • b) a compound of the formula
    
    in the
    • R until R ₄ are defined as above and
    • Y represents a protective group for an amino group such as the benzyl, formyl, acetyl, benzoyl or carbethoxy group, a protective radical is split off hydrolytically or hydrogenolytically and, if desired, a prevention of the general formula in which R ₃ and R _{4 are} as defined at the outset and R , and / or R _{2 represents} a hydrogen atom, is then converted into a corresponding chlorine or bromine compound of the formula I by halogenation,
    • and / or a compound of the formula I in which R _{4 represents} an aralkyl radical is then converted by means of a halogen formate into a compound of the formula in which R _{4 represents} a carbalkoxy group,
    • and / or a compound of the formula I in which R _{4 represents} a carbalkoxy group, is then converted by hydrolysis into a compound of formula I in which R _{4 represents} a hydrogen atom, and / or a compound of the formula in its physiologically tolerated acid addition salts is transferred with inorganic and organic acids.

EXAMPLE E 10 mg ampoules of 2- (2-amino-3,5-dibromophenoxy-methylene) morpholine hydrochloride

Herstellungsbeschreibung:

• Zu einem geeichten Ansatzgefäß aus indifferentem Material wird die Hauptmenge des N₂- gesättigten Ampullenwassers vorgelegt und nacheinander die Puffersubstanzen, die Wirksubstanz und das Natriumchlorid unter Rühren und ständiger N₂-Begasung gelöst. Danach wird mit dem restlichen Ampullenwasser bis zur Eichmarke aufgefüllt und durch Membranfilter sterilfiltriert. Die Abfüllung erfolgt unter Vor- und Nachbegasung mit N₂ in gereinigte und sterilisierte 1 ml-Ampullen aus braunem Glas.

Manufacturing description:

• The majority of the N ₂ - saturated ampoule water is placed in a calibrated batch vessel made of indifferent material and the buffer substances, the active substance and the sodium chloride are dissolved in succession with stirring and constant N ₂ gassing. Then the remaining ampoule water is filled up to the calibration mark and sterile filtered through membrane filters. The filling takes place with pre-and post-gassing with N ₂ in cleaned and sterilized 1 ml ampoules made of brown glass.

EXAMPLE F Suppositories of 50 mg of 2- (2-amino-3,5-dibromo-phenoxy-methylene) -morpholine hydrochloride

Herstellungsbeschreibung:

• In die aus Suppositorienmasse bereitete und auf ca. 40°C temperierte Schmelze wird der gemahlene Wirkstoff unter Rühren eingearbeitet und gleichmäßig verteilt. Die fertige Suppositorienmasse wird bei laufendem Rührwerk in vorgekühlte Formen gegossen; nach dem völligen Erstarren werden die Zäpfchen der Form entnommen.

Manufacturing description:

• The ground active ingredient is incorporated into the melt prepared from suppository mass and heated to about 40 ° C. with stirring and distributed evenly. The finished suppository mass is poured into pre-cooled molds with the agitator running; after complete solidification, the suppositories are removed from the mold.

Suppository weight: 1.7 g.

Claims (10)

1. Aminophenoxymethyl-2-morpholine derivatives of formula

in which

R₁ represents a hydrogen or halogen atom or the methyl group,

R₂ represents a hydrogen or halogen atom,

R₃ represents a hydrogen atom or the nitro group and

R₄ represents a hydrogen atom, a lower alkyl group, a carbalkoxy group, the phenyl or benzyl group, and their physiologically compatible acid addition salts.

2. Aminophenoxymethyl-2-morpholine derivatives of formula I according to claim 1 in which

R₁ represents a hydrogen, fluorine, chlorine or bromine atom or the methyl group,

R₂ represents a hydrogen, fluorine, chlorine or bromine atom,

R₃ represents a hydrogen atom or the nitro group and

R₄ represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, a carbalkoxy group with altogether 2 to 4 carbon atoms, the phenyl or benzyl group, and their physiologically compatible acid addition salts.

3. Novel 2-amino- and 4-amino-phenoxymethyl-2-morpholine derivatives of formula I according to claim 1 in which one of the radicals R₁ or R₂ in 3- or 5-position represents a bromine atom and the other of the radicals R₁ or R₂ in 3- or 5-position represents a hydrogen or bromine atom,

R₃ represents a hydrogen atom and

R₄ represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or the carbethoxy group, and their physiologically compatible acid addition salts.

4. 2-(2-Amino-3,5-dibromo-phenoxy-methylene)-morpholine and its acid solution salts.

5. 2-(4-Amino-3,5-dibromo-phenoxy-methylene)-4-isopropyl-morpholine and its acid addition salts.

6. 2-(4-Amino-3,5-dibromo-phenoxy-methylene)-morpholine and its acid addition salts.

7. 2-(2-Amino-3,5-dibromo-phenoxy-methylene)-4-tert.butyl-morpholine and its acid addition salts.

8. Pharmaceuticals containing a compound according to claims 1 to 7 together with one or more inert carriers or diluting agents.

9. Use of a compound according to claims 1 to 7 for the preparation of a pharmaceutical in a non- chemical way for the treatment of depressions and anxiety conditions.

10. Process for the preparation of aminophenoxymethyl-2-morpholine derivatives according to claims 1 to 7, characterised in that

a) a nitro compound of formula

in which

R₁, R₂ and R₄ are as defined above is reduced or

b) a protective radical is separated by hydrolysis or hydrogenolysis from a compound of formula

in which

R₁ to R₄ are as defined above and

Y represents a protective group for an amino group such as the benzyl, formyl; acetyl, benzoyl or carbethoxy group and, if desired, a compound of formula I in which R₃ and R₄ are as defined above and R₁ and/or R₂ represent a hydrogen atom is subsequently converted by means of a halogenation into a corresponding chlorine or bromine compound of formula I

and/or a compound of formula I in which R₄ represents an aralkyl radical is subsequently converted by means of a haloformate into a compound of formula I in which R₄ represents a carbalkoxy group and/or a compound of formula I in which R₄ represents a carbalkoxy group is subsequently converted by means of hydrolysis into a compound of formula ( in which R₄ represents a hydrogen atom

and/or a compound of formula I is converted into its physiologically compatible acid addition salts with inorganic and organic acids.