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EP0000693B1 - Dérivés d'aminophénoxyméthyl-2-morpholine, procédé pour leur préparation et médicaments les contenant - Google Patents

Dérivés d'aminophénoxyméthyl-2-morpholine, procédé pour leur préparation et médicaments les contenant Download PDF

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Publication number
EP0000693B1
EP0000693B1 EP78100205A EP78100205A EP0000693B1 EP 0000693 B1 EP0000693 B1 EP 0000693B1 EP 78100205 A EP78100205 A EP 78100205A EP 78100205 A EP78100205 A EP 78100205A EP 0000693 B1 EP0000693 B1 EP 0000693B1
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EP
European Patent Office
Prior art keywords
methylene
morpholine
amino
group
phenoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP78100205A
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German (de)
English (en)
Other versions
EP0000693A1 (fr
Inventor
Helmut Dr.Dipl.-Chem. Pieper
Klaus Dr. Dipl.-Chem. Noll
Gerd Dr. Dipl.-Chem. Krüger
Johannes Dr. Dipl.-Chem. Keck
Joachim Dr. Kähling
Harald Dr. Ziegler
Helmut Ballhause
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Dr Karl Thomae GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
Publication of EP0000693A1 publication Critical patent/EP0000693A1/fr
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Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds

Definitions

  • halogen atom mentioned in the definition of the radicals R 1 and R 2 is in particular a fluorine, chlorine or bromine atom
  • 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.
  • 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.
  • 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.
  • a solvent such as methanol, ethanol, water / ethanol, ethyl acetate, glacial acetic acid or water / hydrochloric acid
  • an electron donor such as nascent hydrogen, e.g. Zinc /
  • 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.
  • 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.
  • 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.
  • a hydrogenation catalyst such as Raney nickel or palladium / carbon
  • 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.
  • 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.
  • 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.
  • an acid such as hydrochloric acid or a base such as sodium hydroxide solution or potassium hydroxide solution
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the combined chloroform phases are washed with water, dried over sodium sulfate and evaporated to dryness in vacuo.
  • 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 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.
  • Example 5 Made from 2- (4-amino-2-chlorophenoxy-methylene) -morpholine-dihydrochloride and bromine as in Example 5.
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Claims (10)

1. Dérivés d'aminophénoxyméthyl-2-morpholine de formule:
Figure imgb0020
dans laquelle:
- R1 représente un atome d'hydrogène ou d'halogène ou le groupe méthyle,
- R2 représente un atome d'hydrogène ou d'halogène,
- R3 représente un atome d'hydrogène ou le groupe nitro et
- R4 représente un atome d'hydrogène, un groupe alcoyle inférieur, un groupe carbalcoxy, le groupe phényle ou benzyle, et leurs sels d'addition avec des acides physiologiquement supportables.
2. Dérivés d'aminophénoxyméthyl-2-morpholine de formule I selon la revendication 1, dans laquelle:
- R1 représente un atome d'hydrogène, de fluor, de chlore ou de brome ou le groupe méthyle,
- R2 représente un atome d'hydrogène, de fluor, de chlore ou de brome,
- R3 représente un atome d'hydrogène ou le groupe nitro et
- R4 représente un atome d'hydrogène, un groupe alcoyle comprenant 1 à 4 atomes de carbone, un groupe carbalcoxy avec en tout 2 à 4 atomes de carbone, le groupe phényle ou benzyle, et leurs sels d'addition avec des acides physiologiquement supportables.
3. Nouveaux dérivés de 1-amino et 4-amino-phénoxyméthyl-2-morpholine de formule I selon la revendication 1, dans laquelle l'un des radicaux R1 ou R2 en position 3 ou 5 représente un atome de brome et l'autre des radicaux R1 ou R2 en position 3 ou 5 représente un atome d'hydrogène ou de brome,
- R3 représente un atome d'hydrogène et
- R4 représente un atome d'hydrogène, un groupe alcoyle comprenant 1 à 4 atomes de carbone ou le groupe carbéthoxy, et leurs sels d'addition avec des acides physiologiquement supportables.
4. La 2-(2-amino-3,5-dibromo-phénoxy-méthylène)-morpholine et ses sels d'addition avec des acides.
5. La 2-(4-amino-3,5-dibromo-phénoxy-méthylène)-4-isopropyl-morpholine et ses sels d'addition avec des acides.
6. La 2-(4-amino-3,5-dibromo-phénoxy-méthylène)-morpholine et ses sels d'addition avec des acides.
7. La 2-(2-amino-3,5-dibromo-phénoxy-méthylène)-4-tert.butyl-morpholine et ses sels d'addition avec des acides.
8. Médicament renfermant un composé selon l'une des revendications 1 à 7 en présence d'un ou de plusieurs excipients inertes ou d'agents de dilution.
9. Utilisation d'un composé selon l'une des revendications 1 à 7 pour préparer, selon une voie non chimique, un médicament pour le traitement des dépressions et des états d'anxiété.
10. Procédé de préparation des dérivés d'aminophénoxyméthyl-2-morpholine selon l'une des revendications 1 à 7, caractérisé en ce que:
a) on réduit un composé nitré de formule:
Figure imgb0021
dans laquelle:
- R1, R2 et R4 sont définis comme précédemment, ou
b) à partir d'un composé de formule:
Figure imgb0022
 dans laquelle:
- R1 à R4 sont définis comme précédemment et
- Y représente un groupe protecteur pour un groupe amino tel que le groupe benzyle, formyle, acétyle, benzoyle ou carbéthoxy,
on élimine hydrolytiquement ou hydrogénolytiquement un groupe protecteur et si on le désire on transforme un composé de formule dans laquelle R3 et R4 sont définis comme précédemment et R,
et/ou R2 représentent un atome d'hydrogène, subséquemment au moyen d'une halogénation en un composé chloré ou bromé correspondant de formule I,
et/ou on transforme un composé de formule I dans laquelle R4 représente un radical aralcoyle, subséquemment au moyen d'un ester halogénoformique, en un composé de formule I dans laquelle R4 représente un groupe carbalcoxy,
et/ou on transforme un composé de formule dans laquelle R4 représente un groupe carbalcoxy, subséquemment au moyen d'une hydrolyse en un composé de formule dans laquelle R4 représente un atome d'hydrogène,
et/ou on transforme un composé de formule 1 en ses sels d'addition physiologiquement supportables avec des acides minéraux et organiques.
EP78100205A 1977-06-27 1978-06-21 Dérivés d'aminophénoxyméthyl-2-morpholine, procédé pour leur préparation et médicaments les contenant Expired EP0000693B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2728898 1977-06-27
DE19772728898 DE2728898A1 (de) 1977-06-27 1977-06-27 Neue morpholinderivate

Publications (2)

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EP0000693A1 EP0000693A1 (fr) 1979-02-21
EP0000693B1 true EP0000693B1 (fr) 1980-07-23

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EP78100205A Expired EP0000693B1 (fr) 1977-06-27 1978-06-21 Dérivés d'aminophénoxyméthyl-2-morpholine, procédé pour leur préparation et médicaments les contenant

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DE (2) DE2728898A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2575158B1 (fr) * 1984-12-20 1987-10-02 Pf Medicament Arylalcoyloxymethyl-2 morpholines, leur preparation et leur application en tant que medicaments utiles dans le traitement des troubles du systeme nerveux central
WO1993015052A1 (fr) * 1992-01-28 1993-08-05 Smithkline Beecham Plc Composes utilises comme antagonistes des canaux calciques
GB9226111D0 (en) * 1992-12-15 1993-02-10 Smithkline Beecham Plc Madicaments
ATE287878T1 (de) 1996-08-23 2005-02-15 Neurosearch As Disubstituierte morpholin-, oxazepin- oder thiazepinderivate, deren herstellung und verwendung als dopamin-d4-rezeptorantagonisten
US7294637B2 (en) 2000-09-11 2007-11-13 Sepracor, Inc. Method of treating addiction or dependence using a ligand for a monamine receptor or transporter
WO2002022572A2 (fr) 2000-09-11 2002-03-21 Sepracor, Inc. Ligands pour les recepteurs de monoamine et transporteurs, et procedes d'utilisation de ces derniers

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3876769A (en) * 1967-11-24 1975-04-08 Ici Ltd Morpholine derivatives in the treatment of depression

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EP0000693A1 (fr) 1979-02-21
DE2860067D1 (en) 1980-11-13

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