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CH626066A5 - Process for the preparation of the pure Z isomer of 3-(4-bromophenyl)-N-methyl-3-(3-pyridyl)-allylamine - Google Patents

Process for the preparation of the pure Z isomer of 3-(4-bromophenyl)-N-methyl-3-(3-pyridyl)-allylamine Download PDF

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Publication number
CH626066A5
CH626066A5 CH9479A CH9479A CH626066A5 CH 626066 A5 CH626066 A5 CH 626066A5 CH 9479 A CH9479 A CH 9479A CH 9479 A CH9479 A CH 9479A CH 626066 A5 CH626066 A5 CH 626066A5
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formula
compound
isomer
pure
acid addition
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CH9479A
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German (de)
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Per Arvid Emil Carlsson
Bernt Sigfrid Emanuel Carnmalm
Svante Bertil Ross
Carl Bengt Johan Ulff
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Astra Laekemedel Ab
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles

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Abstract

The pure Z isomer of 3-(4-bromophenyl)-N-methyl-3-(3-pyridyl)-allylamine of the formula (I) <IMAGE> or one of its pharmaceutically acceptable acid addition salts is a highly selective inhibitor of the neuronal uptake of 5-hydroxytryptamine and can be used as antidepressants or neuroleptics. The said Z isomer is prepared by hydrolysing a compound of the formula (VII) <IMAGE> in which Z is an acyl group derived from a carboxylic acid or an organic sulphonyl group, to give a compound of the formula (I), and recrystallising the resulting mixture of stereoisomers, in the form of one of its acid addition salts, several times from a solvent in which the E and Z isomers display a considerably different solubility, and isolating the pure Z isomer. The compound of the formula (VII) is obtained by dehydration of the compound of the formula (VI): <IMAGE>

Description

Die Erfindung betrifft ein Verfahren zur Herstellung des reinen Z-Isomers von 3-(4-Bromphenyl)-N-methyl-3-(3-pyri-dyl)-allylamin. The invention relates to a process for the preparation of the pure Z isomer of 3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) allylamine.

Depressive Störungen bzw. Erkrankungen wurden bisher 25 mit mehr oder weniger Erfolg mit verschiedenen Verbindungen behandelt. Antidepressive Mittel, die die weitest verbreitete klinische Anwendung gefunden haben, sind die tri-cyclischen tertiären Amine Imipramin, das die folgende Formel aufweist: Depressive disorders or illnesses have so far been treated with different compounds with more or less success. Antidepressants that have found widespread clinical use are the tri-cyclic tertiary amines imipramine, which has the following formula:

30 30th

35 35

ch2ch2ch2-n. ch2ch2ch2-n.

:h. :H.

-ch. -ch.

40 40

und Amitriptylin mit der Formel: and amitriptyline with the formula:

45 45

(VI) (VI)

ch2ch2n(ch3)-z worin Z wie im Patentanspruch 1 definiert ist, zu einer Verbindung der Formel (VII) dehydratisiert wird, worauf die Verbindung der Formel (VII) nach dem Verfahren gemäss Patentanspruch 1 zum reinen Z-Isomeren der Verbindung der Formel (I), gegebenenfalls zu einem pharmazeutisch zulässigen Säureadditionssalz, weiter umgesetzt wird. ch2ch2n (ch3) -z wherein Z is dehydrated to a compound of formula (VII) as defined in claim 1, whereupon the compound of formula (VII) by the process according to claim 1 to pure Z isomer of the compound of formula ( I), optionally to a pharmaceutically acceptable acid addition salt, is further implemented.

3. Verfahren gemäss Patentansprach 1, dadurch gekennzeichnet, dass das pharmazeutisch zulässige Säureadditionssalz, das Hydrobromid, Hydrochlorid, Phosphat, Sulfat, Sulfamat, Lactat, Acetat, Citrat, Tartrat, Malat oder Maleat, ist. 3. The method according to claim 1, characterized in that the pharmaceutically acceptable acid addition salt is the hydrobromide, hydrochloride, phosphate, sulfate, sulfamate, lactate, acetate, citrate, tartrate, malate or maleate.

4. Verfahren gemäss Patentanspruch 2, dadurch gekennzeichnet, dass das pharmazeutisch zulässige Säureadditions- 4. The method according to claim 2, characterized in that the pharmaceutically acceptable acid addition

55 Sekundäre Amine, wie Desipramin, das die Strukturformel 55 Secondary amines, such as desipramine, which is the structural formula

60 60

65 65

ch2ch2ch2-n. ch2ch2ch2-n.

h H

"ch. "ch.

hat und Nortriptylin, das die Formel and nortriptyline, which has the formula

3 3rd

626066 626066

CHCH2CH2Nv hat, werden in etwas geringerem Ausmass angewendet. Diese Substanzen haben jedoch für die therapeutische Anwendung unerwünschte Nebenwirkungen, wie beispielsweise Orthostatismus, anticholinergische Wirkungen und hauptsächlich insbesondere bei Verabreichung in grossen Dosen an ältere Patienten eine arrhythmogene Wirkung, d.h. es entwickelt sich eine Herzarrhythmie. Darüber hinaus zeigen sämtliche erwähnten Substanzen den Nachteil, dass die antidepressive Wirkung erst nach einigen Wochen Behandlung beginnt. Ferner ist aus der Literatur bekannt, dass bestimmte 1,1-Diphe-nyl-3-aminopropene-(l) wie beispielsweise die Verbindung CHCH2CH2Nv is used to a somewhat lesser extent. However, these substances have undesirable side effects for therapeutic use, such as orthostatism, anticholinergic effects and, especially when administered in large doses to elderly patients, have an arrhythmogenic effect, i.e. a cardiac arrhythmia develops. In addition, all of the substances mentioned have the disadvantage that the antidepressant effect only begins after a few weeks of treatment. It is also known from the literature that certain 1,1-diphenyl-3-aminopropene- (1) such as the compound

-ch. -ch.

c=chch2nv xh. c = chch2nv xh.

eine antidepressive Wirkung zeigen, vgl. J. Med. Chem. 14, 161-4 (1971). show an antidepressant effect, cf. J. Med. Chem. 14, 161-4 (1971).

Verbindungen der Formel chch2ch2n Compounds of the formula chch2ch2n

worin X Chlor oder Brom und R Wasserstoff oder Methyl bedeuten, weisen antidepressive Wirkung auf, wie in der US-PS 3 423 510 beschrieben ist; diese Verbindungen haben jedoch ausserdem eine starke Antihistaminwirkung. Aus der Literatur ist ausserdem bekannt, dass eine Verbindung der Formel wherein X is chlorine or bromine and R is hydrogen or methyl have antidepressant activity as described in US Pat. No. 3,423,510; however, these compounds also have strong antihistamine activity. It is also known from the literature that a compound of the formula

c=chch2n c = chch2n

bei Tierversuchen eine antidepressive Wirkung aufwies, vgl. BE-PS 781 105. had an antidepressant effect in animal experiments, cf. BE-PS 781 105.

In der klinischen Praxis werden verschiedene Typen depressiver Erkrankungen beobachtet. Depressive Patienten sprechen in verschiedener Weise auf die zahlreichen klinisch verwendeten Antidepressiva an. Viele dieser Substanzen hem-5 men die Noradrenalinaufnahme in den Neuronen, und einige hemmen zusätzlich die 5-Hydroxytryptaminaufnahme. Es wird angenommen, dass Hemmung der 5-Hydroxytryptaminaufnahme der Mechanismus ist, der die Eigenschaft der Stimmungsanhebung bewirkt, der bei einigen dieser Antidepressiva io beobachtet wird. Zusätzlich zu den absoluten Werten für die Hemmung der Aufnahme von 5-Hydroxytryptamin oder Noradrenalin ist die Selektivität gegenüber der Aufnahme einer dieser beiden Amine von grossem Interesse. Various types of depressive disorders are observed in clinical practice. Depressed patients respond in various ways to the numerous clinically used antidepressants. Many of these substances inhibit noradrenaline uptake in the neurons, and some additionally inhibit 5-hydroxytryptamine uptake. Inhibition of 5-hydroxytryptamine uptake is believed to be the mechanism that brings about the mood enhancing property seen with some of these antidepressants. In addition to the absolute values for the inhibition of the uptake of 5-hydroxytryptamine or noradrenaline, the selectivity for the uptake of one of these two amines is of great interest.

Das erfindungsgemässe Verfahren zur Herstellung des 15 reinen Z-Isomers von 3-(4-BromphenyI)-N-methyl-3-(3-pyri-dyl)-allylamin der Formel (I) ist in den vorangehenden Patentansprüchen 1 und 2 charakterisiert. The process according to the invention for the preparation of the pure Z isomer of 3- (4-bromophenyI) -N-methyl-3- (3-pyridyl) allylamine of the formula (I) is characterized in the preceding patent claims 1 and 2.

Da die in der Verbindung der Formel I vorhandene Doppelbindung die freie Rotation verhindert, kann die Verbin-2o dung in verschiedenen stereoisomeren Formen, d.h. in Form von cis-trans-Isomeren, auftreten. Nach der IUPAC-Nomen-klatur (J. Org. Chem. 35, 2849-2867, September 1970) werden diese Formen als E-Form und Z-Form bezeichnet. Since the double bond present in the compound of formula I prevents free rotation, the compound can be formed in various stereoisomeric forms, i.e. in the form of cis-trans isomers. According to the IUPAC nomenclature (J. Org. Chem. 35, 2849-2867, September 1970) these forms are referred to as the E-form and Z-form.

Die erfindungsgemäss erhaltene Verbindung kann in Form 25 einer freien Base oder in Form eines Salzes mit nicht-toxischen Säuren angewendet werden. Einige charakteristische Beispiele für diese Salze sind das Hydrobromid, Hydrochlorid, Phosphat, Sulfat, Sulfamat, Lactat, Acetat, Citrat, Tartrat, Malat und Maleat. The compound obtained according to the invention can be used in the form of a free base or in the form of a salt with non-toxic acids. Some characteristic examples of these salts are the hydrobromide, hydrochloride, phosphate, sulfate, sulfamate, lactate, acetate, citrate, tartrate, malate and maleate.

30 30th

b) Pharmazeutische Präparate b) Pharmaceutical preparations

Bei der klinischen Anwendung werden die erfindungsgemäss erhältlichen Verbindungen normalerweise oral, rektal oder durch Injektion in Form von pharmazeutischen Präpara-35 ten, die die wirksame Verbindung entweder als freie Base oder als pharmazeutisch zulässiges, nicht toxisches Säureadditionssalz, z.B. eines der oben vorgeschlagenen, zusammen mit einem pharmazeutisch zulässigen Trägerstoff enthalten, angewendet. Demgemäss beziehen sich alle Ausdrücke, die die 40 neue erfindungsgemäss erhältliche Verbindung betreffen, sowohl auf die freie Aminbase als auch auf die Säureadditionssalze der freien Base, falls der Zusammenhang, in dem diese Ausdrücke gebraucht werden, z.B. in den spezifischen Beispielen, nicht mit dieser breiten Bedeutung im Widerspruch 45 stehen. Der Trägerstoff kann ein festes, halbfestes oder flüssiges Verdünnungsmittel oder eine Kapsel sein. Üblicherweise macht die wirksame Substanz 0,1 bis 95 Gew.-% aus. Bei Präparaten zur Injektion macht die wirksame Substanz vorzugsweise 0,5 bis 20 Gew.-% und bei Präparaten für orale 50 Verabreichung vorzugsweise 2 bis 50 Gew.-% des Präparats aus. In clinical use, the compounds obtainable according to the invention are normally administered orally, rectally or by injection in the form of pharmaceutical preparations which contain the active compound either as a free base or as a pharmaceutically acceptable, non-toxic acid addition salt, e.g. one of the above proposed, together with a pharmaceutically acceptable carrier. Accordingly, all terms relating to the 40 new compound obtainable according to the invention relate to both the free amine base and the acid addition salts of the free base, if the context in which these terms are used, e.g. in the specific examples, do not conflict with this broad meaning 45. The carrier can be a solid, semi-solid or liquid diluent or a capsule. The active substance usually makes up 0.1 to 95% by weight. In the case of preparations for injection, the active substance is preferably 0.5 to 20% by weight and in the case of preparations for oral administration it is preferably 2 to 50% by weight of the preparation.

Zur Herstellung von pharmazeutischen Präparaten, die eine erfindungsgemäss erhältliche Verbindung in Einheits-dosierungsformen für orale Verabreichung enthalten, kann 55 die ausgewählte Verbindung mit einem festen, pulverförmi-gen Trägerstoff vermischt werden, beispielsweise mit Lactose, Sacharose, Sorbit, Mannit, Stärke, wie beispielsweise Kartoffelstärke, Maisstärke oder Amylopectin, Cellulosederivaten oder Gelatine sowie mit einem Gleitmittel, z.B. Magnesium-60 stearat, Calciumstearat oder Polyäthylenglykolwachsen, und dann zu Tabletten gepresst werden. Falls Dragées gewünscht werden, können die wie oben beschrieben hergestellten Kerne mit einer konzentrierten Zuckerlösung, die beispielsweise Gummi arabicum, Gelatine, Talk oder Titandioxyd enthält, 65 überzogen werden. Wahlweise können die Tabletten mit einem Lack, der in einem leicht flüchtigen organischen Lösungsmittel oder einem Gemisch solcher Lösungsmittel gelöst ist, überzogen werden. Diesen Überzügen können Färb- To produce pharmaceutical preparations which contain a compound according to the invention in unit dosage forms for oral administration, the selected compound can be mixed with a solid, powdery carrier, for example with lactose, sucrose, sorbitol, mannitol, starch, such as, for example Potato starch, corn starch or amylopectin, cellulose derivatives or gelatin and with a lubricant, e.g. Magnesium 60 stearate, calcium stearate or polyethylene glycol wax, and then pressed into tablets. If dragées are desired, the kernels prepared as described above can be coated with a concentrated sugar solution, which contains, for example, gum arabic, gelatin, talc or titanium dioxide. The tablets can optionally be coated with a varnish dissolved in a volatile organic solvent or a mixture of such solvents. These coatings can

626066 626066

4 4th

stoffe zugesetzt werden, um die leichte Unterscheidung zwischen Tabletten mit verschiedenen wirksamen Substanzen oder unterschiedlichen Mengen an wirksamer Substanz zu ermöglichen. substances are added to enable easy distinction between tablets with different active substances or different amounts of active substance.

Das erfindungsgemässe Verfahren wird durch das folgende 5 Beispiel erläutert: The process according to the invention is illustrated by the following 5 examples:

Beispiel example

Herstellung des reinen Z-Isomeren von 3-(4-Bromphenyl)--N-methyl-3-(3-pyridyl)-allylamin der Formeln Preparation of the pure Z isomer of 3- (4-bromophenyl) - N-methyl-3- (3-pyridyl) allylamine of the formulas

10 10th

CH3NCH2 CH3NCH2

COCF. COCF.

CHoNCH^ CHoNCH ^

I 2 I 2

h H

(a) (a)

Zu einer Lösung von 0,4 g (0,001 Mole) der Verbindung (A) in 100 ml Äthanol wurden 0,2 ml (0,002 Mol) einer 10 m NaOH-Lösung gegeben. Die Lösung wurde dann 1,5 Stunden lang bei Raumtemperatur gerührt. Nun wurden der Lösung 0,38 g (0,003 Mol) Oxalsäure-dihydrat in 100 ml Isopropanol zugegeben. Es fiel das kristalline Oxalat aus. Durch Rekristallisation aus 5 ml 95%igem Methanol wurden 0,3 g der Titelverbindung erhalten. Dies entspricht einer Ausbeute von 76%. 0.2 ml (0.002 mol) of a 10 M NaOH solution was added to a solution of 0.4 g (0.001 mol) of compound (A) in 100 ml of ethanol. The solution was then stirred at room temperature for 1.5 hours. Now 0.38 g (0.003 mol) of oxalic acid dihydrate in 100 ml of isopropanol were added to the solution. The crystalline oxalate precipitated out. By recrystallization from 5 ml of 95% methanol, 0.3 g of the title compound was obtained. This corresponds to a yield of 76%.

Schmelzpunkt: 165 bis 175°C. Melting point: 165 to 175 ° C.

Durch weitere Rekristallisation gemäss dem Patentanspruch 1 wurden schliesslich 0,2 g des reinen Z-Isomeren in Form seines Oxalats mit einem Schmelzpunkt von 204 bis 206°C erhalten. By further recrystallization according to claim 1, 0.2 g of the pure Z isomer was finally obtained in the form of its oxalate with a melting point of 204 to 206 ° C.

Die Ausgangsverbindung des Beispiels wurde gemäss folgender Methode erhalten: The starting compound of the example was obtained according to the following method:

35 35

40 40

45 45

Cl-CH Cl-CH

Das Natriumsalz des Methyltrifluoracetamids wurde durch Rühren einer Mischung von 0,06 g (0,002 Mol) einer 80%-igen Natriumhydroxidlösung und 0,25 g (0,002 Mol) CF3-CONHCH3 in 10 ml Dimethylformaldehydäther 1:1 unter Stickstoffatmosphäre bei Raumtemperatur erhalten. Eine Lö- The sodium salt of methyl trifluoroacetamide was obtained by stirring a mixture of 0.06 g (0.002 mol) of an 80% sodium hydroxide solution and 0.25 g (0.002 mol) of CF3-CONHCH3 in 10 ml of dimethylformaldehyde ether 1: 1 under a nitrogen atmosphere at room temperature. A lion

CH3NCH2 CH3NCH2

cocf. cocf.

(a) (a)

sung von 0,61 g (0,002 Mol) 3-(4-Bromphenyl)-3-(3-pyridyI>-65 -allylchlorid in 5 ml des gleichen Lösungsmittels wurden zur obigen Lösung gegeben. Die Reaktionslösung wurde nun 2 Stunden lang bei Raumtemperatur gerührt und dann langsam mit Wasser versetzt. Nun wurde die Reaktionslösung Solution of 0.61 g (0.002 mol) of 3- (4-bromophenyl) -3- (3-pyridyl> -65-allyl chloride in 5 ml of the same solvent was added to the above solution. The reaction solution was then at room temperature for 2 hours stirred and then slowly added water, and the reaction solution

5 5

626066 626066

mit Äther extrahiert. Die kombinierten Ätherphasen wurden mit 0,5 M Salzsäure ausgeschüttelt und die abgetrennten wässrigen Phasen leicht alkalisch gemacht. Diese Phasen wurden nun mit Methylenchlorid extrahiert. Die Extrakte wurden getrocknet und das Lösungsmittel daraus mittels Verdampfen entfernt. Man erhielt 0,5 g N-Methyl-N-trifluor-acetyl-3-(4-bromphenyl)-3-(3-pyridyl)-propenylamin, das in öliger Form vorlag. extracted with ether. The combined ether phases were shaken out with 0.5 M hydrochloric acid and the separated aqueous phases were made slightly alkaline. These phases were then extracted with methylene chloride. The extracts were dried and the solvent removed therefrom by evaporation. 0.5 g of N-methyl-N-trifluoroacetyl-3- (4-bromophenyl) -3- (3-pyridyl) propenylamine was obtained, which was in an oily form.

Es ist mit experimentellen Mitteln nicht möglich, Depressionen bei Versuchstieren zu erzeugen. Um eine mögliche antidepressive Wirkung der neuen Substanzen bestimmen zu können, muss man seine Zuflucht zu biochemisch-pharmako-logischen Testmethoden nehmen. Eine solche Methode, die einen guten Hinweis auf mögliche antidepressive Wirkungen der Testsubstanzen zu geben scheint, ist in Europ. J. Phar-macol. 17, 107, 1972, beschrieben. It is not possible to produce depression in experimental animals using experimental means. In order to determine a possible antidepressant effect of the new substances, one has to take refuge in biochemical-pharmacological test methods. One such method, which seems to give a good indication of possible antidepressant effects of the test substances, is in Europ. J. Phar-macol. 17, 107, 1972.

Diese Methode besteht in der Messung der Abnahme der Aufnahme von 14C-5-Hydroxytryptamin (14C-5-HT) und sH-Noradrenalin (3H-NA) in Gehirnschnitten von Mäusen nach der in-vivo- und in-vitro-Verabreichung der Testsubstanzen. This method consists in measuring the decrease in the intake of 14C-5-hydroxytryptamine (14C-5-HT) and sH-norepinephrine (3H-NA) in brain sections of mice after the in vivo and in vitro administration of the test substances .

Inhibierung der Aufnahme von "•C-5-HT und 3H-NA Inhibition of uptake of "• C-5-HT and 3H-NA

in vitro und in vivo Die Testsubstanzen wurden Stunde, bevor die Tiere getötet wurden, intraperitoneal verabreicht. Das Mittelhirn 5 wurde herausgenommen, in Scheiben geschnitten und in einer Mischung inkubiert, die aus 0,2 nMol 14C-5-HT, 0,2 nMol 3H-NA und 11 fiMol Glucose in 2 ml Krebs-Henseleit-Puf-fer, pH 7,4 pro 100 mg Gehirnscheiben bestand. Die Inkubationszeit betrug 5 Minuten, wobei die Präinkubationszeit io vor der Zugabe der markierten Amine 5 Minuten betrug. Die Scheiben wurden in Soluene ® gelöst, und die aufgenommene Menge an radioaktiven Aminen wurde durch Flüssig-szintillation bestimmt. Die Dosis, die 50% Abnahme der aktiven Aufnahme (ED50) vom 14C-5-HT und 3H-NA bewirkt, 15 wurde aus den Dosis/Reaktion-Kurven graphisch bestimmt. «Aktive Aufnahme» ist definiert als der Teil der radioaktiven Aufnahme, der durch eine hohe Konzentration von Kokain inhibiert wird. in vitro and in vivo The test substances were administered intraperitoneally one hour before the animals were killed. The midbrain 5 was removed, sliced and incubated in a mixture consisting of 0.2 nmol 14C-5-HT, 0.2 nmol 3H-NA and 11 μmol glucose in 2 ml Krebs-Henseleit buffer, pH 7.4 per 100 mg brain slices. The incubation time was 5 minutes, the preincubation time io before the addition of the labeled amines was 5 minutes. The disks were dissolved in Soluene ® and the amount of radioactive amines taken up was determined by liquid scintillation. The dose that causes a 50% decrease in active uptake (ED50) of 14C-5-HT and 3H-NA was determined graphically from the dose / response curves. “Active uptake” is defined as the part of the radioactive uptake that is inhibited by a high concentration of cocaine.

Bei der in-vitro-Methode wurden Scheiben von Mäusemit-20 telhirn 5 Minuten lang mit einer Lösung der zu testenden Verbindung präinkubiert und dann wie oben beschrieben inkubiert. In the in vitro method, slices of mouse brain were preincubated with a solution of the compound to be tested for 5 minutes and then incubated as described above.

Inhibierung der N euronal-Auf nähme von 5-Hydroxytryptamin und Noradrenalin durch Scheiben von Mäusehirn Inhibition of the neuronal uptake of 5-hydroxytryptamine and noradrenaline by slice of mouse brain

TABELLE TABLE

Verbindung Aufnahme von 14C-5-HT Aufnahme von 3H-NA Compound uptake of 14C-5-HT uptake of 3H-NA

in vitro1 in Vivo in. vitro in Vivo in vitro1 in Vivo in. vitro in Vivo

R Isomer Salz ECbo ED50 EC50 ED50 R Isomer salt ECbo ED50 EC50 ED50

[xM [xMol/kg i.p. pM [xMol/kgi.p. [xM [xMol / kg i.p. pM [xMol / kgi.p.

Erfindungsgemäss erhältliche Available according to the invention

Verbindungen links

Bekannte Verbindungen Known connections

H H

Mischung mixture

Oxalat Oxalate

0,5 0.5

32 32

1) 1)

1) 1)

H H

Z Z.

Oxalat Oxalate

0,5 0.5

18 18th

2,5 2.5

102 102

H H

Z Z

Hydrochlorid Hydrochloride

0,1 0.1

15,2 15.2

1,5 1.5

>1012> > 1012>

H H

E E

Oxalat Oxalate

2,5 2.5

102 102

0,8 0.8

25 25th

ch3. ch3.

Z Z

Hydrochlorid Hydrochloride

1,7 1.7

49 49

24,4 24.4

> 98 > 98

ch3, ch3,

E E

Oxalat Oxalate

6,1 6.1

>98 > 98

6,1 6.1

25 25th

Imipramin Imipramine

Hydrochlorid Hydrochloride

0,3 0.3

125 125

0,08 0.08

63 63

nicht getestet not tested

2> 38% Inhibition (gemessen bei der Dosis 101 [iMol/kg i..p.) 2> 38% inhibition (measured at the dose 101 [iMol / kg i..p.)

55 55

Wie aus der Tabelle ersichtlich ist, sind die erfindungsgemäss erhältlichen Verbindungen wirksame Inhibitoren der Neuronalaufnahme von 5-Hydroxytryptamin und Noradrenalin. Die erfindungsgemäss erhältliche Z-Form der Verbindung 60 der Formel (I) zeigt eine stärkere Hemmwirkung auf die Aufnahme von 5-HT in vivo als irgendeine der versuchten bekannten Verbindungen. As can be seen from the table, the compounds obtainable according to the invention are effective inhibitors of the neuronal uptake of 5-hydroxytryptamine and noradrenaline. The Z-form of compound 60 of formula (I) obtainable according to the invention shows a stronger inhibitory effect on the uptake of 5-HT in vivo than any of the known compounds attempted.

Die erfindungsgemäss erhältliche Z-Form der Verbindung der Formel (I), untersucht in Form des Hydrochlorids, ist ein 65 wirksamer Inhibitor der Aufnahme von 5-HT in vitro als irgendeine der bekannten Verbindungen. (Es wird angenommen, dass der Unterschied, der zwischen dem Oxalat und dem Hydrochlorid beobachtet wird, auf die Tatsache zurück- The Z-form of the compound of formula (I) obtainable according to the invention, examined in the form of the hydrochloride, is an effective inhibitor of the uptake of 5-HT in vitro as any of the known compounds. (It is believed that the difference observed between the oxalate and the hydrochloride is due to the fact

626066 626066

zuführen ist, dass das Hydrochlorid aus dem Oxalat hergestellt wurde, wobei ein reineres Z-Isomer erhalten wurde.) Die E-Form der erfindungsgemäss erhältlichen Verbindung inhibiert in erster Linie die Aufnahme von Noradrenalin. Die offenbarte Inhibierung der Neuronalaufnahme von 5-Hy- The hydrochloride was prepared from the oxalate, a purer Z-isomer being obtained.) The E-form of the compound obtainable according to the invention primarily inhibits the uptake of noradrenaline. The disclosed inhibition of 5-Hy neuronal uptake

droxytryptamin und Noradrenalin kann den erfindungsgemäss erhältlichen Verbindungen Wert als antidepressive Mittel verleihen. In gleicher Weise können die erfindungsgemäss erhältlichen Verbindungen als Mittel zur Behebung von 5 Angstzuständen (Neuroleptika) wertvoll sein. Droxytryptamine and norepinephrine can give the compounds obtainable according to the invention value as antidepressants. In the same way, the compounds obtainable according to the invention can be valuable as a remedy for 5 anxiety states (neuroleptics).

v v

Claims (5)

626066 626066 2 2nd PATENTANSPRÜCHE 1. Verfahren zur Herstellung des reinen Z-Isomers von 3-(4-Bromphenyl)-N-methyl-3-(3-pyridyl)-allylamin der Formel (I) 1. A process for the preparation of the pure Z isomer of 3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) allylamine of the formula (I) (I) (I) oder eines pharmazeutisch zulässigen Säureadditionssalzes davon als stark selektiver Inhibitor für die Neuronalaufnahme von 5-Hydroxytryptamin, dadurch gekennzeichnet, dass eine Verbindung der Formel (VII) or a pharmaceutically acceptable acid addition salt thereof as a highly selective inhibitor for the neuronal uptake of 5-hydroxytryptamine, characterized in that a compound of the formula (VII) salz, das Hydrobromid, Hydrochlorid, Phosphat, Sulfat, Sulfamat, Lactat, Acetat, Citrat, Tartrat, Malat oder Maleat, ist. salt which is hydrobromide, hydrochloride, phosphate, sulfate, sulfamate, lactate, acetate, citrate, tartrate, malate or maleate. 5. Verfahren gemäss Patentanspruch 2, dadurch gekenn- 5. The method according to claim 2, characterized in 5 zeichnet, dass eine Verbindung der Formel (VI), worin Z die 5 shows that a compound of formula (VI), wherein Z is the Acetyl-, eine Benzoyl-, Methansulfonyl-, Benzoylmethan-sulfonyl- oder Toluolsulfonylgruppe ist, eingesetzt wird. Acetyl, a benzoyl, methanesulfonyl, benzoylmethanesulfonyl or toluenesulfonyl group is used. 6. Nach dem Verfahren gemäss Patentanspruch 1 hergestelltes reines Z-Isomer von 3-(4-Bromphenyl)-N-methyl-3- 6. Pure Z isomer of 3- (4-bromophenyl) -N-methyl-3- prepared by the process according to claim 1 lo -(3-pyridyl)-allylamin der Formel (I) sowie pharmazeutisch zulässige Säureadditionssalze davon. lo - (3-pyridyl) allylamine of the formula (I) and pharmaceutically acceptable acid addition salts thereof. 7. Nach dem Verfahren gemäss Patentanspruch 2 hergestelltes reines Z-Isomer von 3-(4-Bromphenyl)-N-methyl-3-(3--pyridyl)-allylamin der Formel (I) sowie pharmazeutisch zu- 7. Pure Z-isomer of 3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) -allylamine of the formula (I) prepared by the process according to claim 2 and pharmaceutically 15 lässige Säureadditionssalze davon. 15 casual acid addition salts thereof. (VII) (VII) chch2nch3~z worin Z eine von einer Carbonsäure abgeleitete Acy>-gruppe oder eine Sulfonylgruppe bedeutet, zu einer Verbindung der Formel (I) hydrolysiert wird und dass ein so erhaltenes Stereoisomerengemisch in Form eines seiner Säureaddi-ticnssalze mehrere Male aus einem Lösungsmittel, in dem die E- und Z-Isomeren eine erheblich unterschiedliche Löslichkeit aufweisen, umkristallisiert wird und dass das reine Z-Isomer der Verbindung der Formel (I) isoliert wird, wobei die so erhaltene Verbindung bei Bedarf noch zu einem pharmazeutisch zulässigen Säureadditionssalz umgesetzt wird. chch2nch3 ~ z wherein Z represents an acy> group derived from a carboxylic acid or a sulfonyl group, is hydrolyzed to a compound of formula (I) and that a stereoisomer mixture thus obtained in the form of one of its acid additive salts is repeated several times from a solvent in which the E and Z isomers have a significantly different solubility, is recrystallized and that the pure Z isomer of the compound of the formula (I) is isolated, the compound thus obtained being converted to a pharmaceutically acceptable acid addition salt if necessary. 2. Verfahren zur Herstellung des reinen Z-Isomers der Verbindung der Formel (I) oder eines pharmazeutisch zulässigen Säureadditionssalzes davon, dadurch gekennzeichnet, dass eine Verbindung der Formel (VI) 2. A process for the preparation of the pure Z isomer of the compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof, characterized in that a compound of the formula (VI) 20 20th
CH9479A 1974-11-21 1979-01-05 Process for the preparation of the pure Z isomer of 3-(4-bromophenyl)-N-methyl-3-(3-pyridyl)-allylamine CH626066A5 (en)

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CH9279A CH615665A5 (en) 1974-11-21 1979-01-05 Process for the preparation of the Z-isomer of 3-(4-bromophenyl)-N-methyl-3-(3-pyridyl)allylamine
CH9379A CH626065A5 (en) 1974-11-21 1979-01-05 Process for the preparation of the pure Z isomer of 3-(4-bromophenyl)-N-methyl-3-(3-pyridyl)-allylamine
CH9479A CH626066A5 (en) 1974-11-21 1979-01-05 Process for the preparation of the pure Z isomer of 3-(4-bromophenyl)-N-methyl-3-(3-pyridyl)-allylamine

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