CH615665A5 - Process for the preparation of the Z-isomer of 3-(4-bromophenyl)-N-methyl-3-(3-pyridyl)allylamine - Google Patents
Process for the preparation of the Z-isomer of 3-(4-bromophenyl)-N-methyl-3-(3-pyridyl)allylamine Download PDFInfo
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- CH615665A5 CH615665A5 CH9279A CH9279A CH615665A5 CH 615665 A5 CH615665 A5 CH 615665A5 CH 9279 A CH9279 A CH 9279A CH 9279 A CH9279 A CH 9279A CH 615665 A5 CH615665 A5 CH 615665A5
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- 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
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Abstract
Description
Die Erfindung betrifft Verfahren zur Herstellung des Z-Isomers von 3-(4-Bromphenyl)-N-methyl-3-(3-pyridyl)-25 allylamin. The invention relates to processes for the preparation of the Z isomer of 3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) -25 allylamine.
Depressive Störungen bzw. Erkrankungen wurden bisher mit mehr oder weniger Erfolg mit verschiedenen Verbindungen behandelt. Antidepressive Mittel, die die weitestverbrei-tete klinische Anwendung gefunden haben, sind die tricycli-30 sehen tertiären Amine Imipramin, das die folgende Formel aufweist: Depressive disorders and illnesses have been treated with different compounds with more or less success. Antidepressants that have found widespread clinical use are the tricycli-30 see tertiary amines imipramine, which has the following formula:
35 35
ch2ch2ch2-n; ch2ch2ch2-n;
40 und Amitriptylin mit der Formel: 40 and amitriptyline with the formula:
""ch. "" ch.
Ï Ï
chch0ch->- n, chch0ch -> - n,
,ch. , ch.
:h. :H.
50 50
Sekundäre Amine, wie Desipramin, das die Strukturformel Secondary amines, such as desipramine, which is the structural formula
55 55
n I n I
ch2CH2ch2:Nn ch2CH2ch2: Nn
60 hat und Nortriptylin, das die Formel 60 and nortriptyline, which has the formula
65 65
,h ,H
"CH. "CH.
3 3rd
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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 l,l-Diphenyl-3-aminopro-pene-(l), wie beispielsweise die Verbindung has been used to a somewhat lesser extent. However, these substances have undesirable side effects for therapeutic use, such as, for example, orthostatism, anticholinergic effects and, especially when administered in large doses to elderly patients, have an arrhythmogenic effect, i.e. H. 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 l, l-diphenyl-3-aminopro-pene- (l), such as the compound
Hemmung der Aufnahme von 5-Hydroxytryptamin oder Noradrenalin ist die Selektivität gegenüber der Aufnahme einer dieser beiden Amine von grossem Interesse. Inhibiting the uptake of 5-hydroxytryptamine or norepinephrine is of great interest in selectivity over the uptake of either of these two amines.
Aufgabe der vorliegenden Erfindung ist ein Verfahren zur s Herstellung neuer Verbindungen mit guter antidepressiver Wirksamkeit. Die neue Verbindung soll ausserdem nur geringe Nebenwirkungen, insbesondere arrhythmogenische Wirkungen, aufweisen und therapeutische Wirkung gegen Angstzustände haben. The object of the present invention is a process for the production of new compounds with good antidepressant activity. The new compound should also have only minor side effects, especially arrhythmogenic effects, and have therapeutic effects against anxiety.
io Überraschenderweise wurde nunmehr gefunden, dass das Z-Isomer der Verbindung der Formel (I) Surprisingly, it has now been found that the Z isomer of the compound of the formula (I)
c=chch2nv c = chch2nv
'ch- 'ch-
xh. 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).
Verbindung der Formel chch2ch2n Compound 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 ochch2n bei Tierversuchen eine antidepressive Wirkung aufwies, vgl. BE-PS 781 105. 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 ochch2n 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 hemmen die Noradrenalinaufnahme in den Neuronen, und einige hemmen zusätzlich die 5-Hydroxytryptaminaufnahme. Es wird angenommen, dass Hemmungen der 5-Hydroxytryptaminaufnahme der Mechanismus ist, der die Eigenschaft der Stimmungsanhebung bewirkt, der bei einigen dieser Antidepressiva beobachtet wird. Zusätzlich zu den absoluten Werten für die 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 causes the mood enhancement property seen with some of these antidepressants. In addition to the absolute values for the
15 15
20 20th
sowie pharmazeutisch zulässige Salze dieser Verbindung die 25 genannten Bedingungen erfüllen. and pharmaceutically acceptable salts of this compound meet the 25 conditions mentioned.
Die erfindungsgemässen Verfahren zur Herstellung des Z-Isomers von 3-(4-Bromphenyl)-N-methyl-3-(3-pyridyl)-allylamin sind in den Patentansprüchen 1 und 2 definiert. The processes according to the invention for the preparation of the Z-isomer of 3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) -allylamine are defined in patent claims 1 and 2.
Da die in der Verbindung der Formel I vorhandene Dop-30 pelbindung die freie Rotation verhindert, kann die Verbindung in verschiedenen stereoisomeren Formen, d. h. in Form von cis-trans-Isomeren, auftreten. Nach der IUPAC-Nomenklatur (J. Org. Chem. 35, 2849—2867, September 1970) werden diese Formen als E-Form und Z-Form bezeichnet. Die Ver-35 bindung kann therapeutisch als ein Gemisch der geometrischen Isomeren oder in der reinen E- bzw. Z-Form angewendet werden. Since the Dop-30 pel bond present in the compound of formula I prevents free rotation, the compound can exist in various stereoisomeric forms, i.e. H. 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. The compound can be used therapeutically as a mixture of the geometric isomers or in the pure E or Z form.
Die erfindungsgemäss erhaltene Verbindung kann in Form einer freien Base oder in Form eines Salzes mit nichttoxischen 40 Säuren angewendet werden. Einige charakteristische Beispiele für diese Salze sind das Hydrobromid, Hydrochlorid, Phosphat, Sulfat, Sulfamat, Lactat, Acetat, Citrat, Tartrat, Malat und Meleat. 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 meleate.
Bei der klinischen Anwendung werden die erfindungsge-45 mäss erhältlichen Verbindungen normalerweise oral, rektal oder durch Injektion in Form von pharmazeutischen Präparaten, die die wirksame Verbindung entweder als freie Base oder als pharmazeutisch zulässiges, nichttoxisches Säureadditionssalz, z. B. eines der oben vorgeschlagenen, zusammen mit so einem pharmazeutisch zulässigen Trägerstoff enthalten, angewendet. Demgemäss beziehen sich alle Ausdrücke, die die neue erfindungsgemäss erhältliche Verbindung betreffen, sowohl auf die freie Aminbase als auch auf die Säureadditionssalze der freien Base, falls der Zusammenhang, in dem diese 55 Ausdrücke gebraucht werden, z. B. in den spezifischen Beispielen, nicht mit dieser breiten Bedeutung im Widerspruch 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 präpa-60 raten zur Injektion macht die wirksame Substanz vorzugsweise 0,5 bis 20 Gew.% und bei Präparaten für orale 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. B. one of the above, together with such a pharmaceutically acceptable carrier. Accordingly, all terms relating to the new compound obtainable according to the invention relate both to the free amine base and to the acid addition salts of the free base, if the context in which these 55 terms are used, e.g. B. in the specific examples, do not contradict this broad meaning. 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 prepa-60 rates for injection, the active substance preferably makes up 0.5 to 20% by weight and in the case of preparations for oral administration preferably 2 to 50% by weight of the preparation.
Zur Herstellung von pharmazeutischen Präparaten, die eine erfindungsgemäss erhältliche Verbindung in Einheitsdosie-65 rungsformen für orale Verabreichung enthalten, kann die ausgewählte Verbindung mit einem festen, pulverförmigen Trägerstoff vermischt werden, beispielsweise mit Lactose, Saccharose, Sorbit, Mannit, Stärke, wie beispielsweise Kartoffelstärke, For the preparation of 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.
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Maisstärke oder Amylopectin, Cellulosederivaten oder Gelatine sowie mit einem Gleitmittel, z. B. Magnesiumstearat, Cal-ciumstearat 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, 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 Farbstoffe zugesetzt werden, um die leichte Unterscheidung zwischen Tabletten mit Corn starch or amylopectin, cellulose derivatives or gelatin and with a lubricant, e.g. As magnesium stearate, calcium stearate or polyethylene glycol waxes, and then pressed into tablets. If dragées are desired, the cores 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. Dyes can be added to these coatings to make it easy to distinguish between tablets
Br Br
Dehydratation und Einführung einer austretenden Gruppe Y Dehydration and introduction of a leaving group Y
> IV > IV
verschiedenen wirksamen Substanzen oder unterschiedlichen Mengen an wirksamer Substanz zu ermöglichen. to enable different active substances or different amounts of active substance.
Geeignete tägliche Dosen der erfindungsgemäss erhältlichen Verbindungen zur Behandlung sind 25 bis 250 mg bei 5 peroraler Verabreichung, vorzugsweise 50 bis 150 mg, und 5 bis 50 mg bei parenteraler Verabreichung, vorzugsweise 10 bis 30 mg. Ein Präparat in Einheitsdosierungsform für orale Verabreichung kann 10 bis 50 mg, vorzugsweise 10 bis 25 mg, an wirksamer Substanz pro Dosis enthalten. Suitable daily doses of the compounds obtainable according to the invention for treatment are 25 to 250 mg for 5 oral administration, preferably 50 to 150 mg, and 5 to 50 mg for parenteral administration, preferably 10 to 30 mg. A unit dosage form preparation for oral administration may contain 10 to 50 mg, preferably 10 to 25 mg, of active substance per dose.
io Die zur Durchführung des erfindungsgemässen Verfahrens erforderliche Ausgangsverbindung (IV) kann nach dem folgenden Reaktionsschema hergestellt werden: The starting compound (IV) required to carry out the process according to the invention can be prepared according to the following reaction scheme:
Im Reaktionsschema hat Y die oben angegebene Bedeutung, und R1 bedeutet eine Alkylgruppe mit 1 bis 5 C-Atomen. In the reaction scheme, Y has the meaning given above and R1 denotes an alkyl group with 1 to 5 carbon atoms.
Die Reduktion in der ersten Stufe wird vorzugsweise unter Verwendung von Lithiumaluminiumhydrid, LiAlH4, durchgeführt. Die letzte Stufe wird vorzugsweise unter Verwendung von Phosphortribromid, PBr3, ausgeführt, was bedeutet, dass die austretende Gruppe Y Brom ist. The reduction in the first stage is preferably carried out using lithium aluminum hydride, LiAlH4. The last stage is preferably carried out using phosphorus tribromide, PBr3, which means that the leaving group Y is bromine.
30 30th
Dasselbe Ausgangsmaterial der Formel IV, worin die austretende Gruppe Y1 ein Halogen, vorzugsweise Chlor, Brom oder Jod, ist, kann auch nach dem folgenden Reaktionsschema erhalten werden: The same starting material of the formula IV, in which the leaving group Y1 is a halogen, preferably chlorine, bromine or iodine, can also be obtained according to the following reaction scheme:
Br Br
-> ->
CHCH. CHCH.
Allylhalogenierung » Allyl halogenation »
CHCH2Y CHCH2Y
Die Allylhalogenierung wird vorzugsweise mit einem ge- 55 Im folgenden wird anhand eines Beispiels eine bevorzugte eigneten Halogenierungsmittel, wie beispielsweise ein Halo- Ausführungsform der Erfindung in Form zweier Verfahren gensuccinimid, durchgeführt. näher erläutert. The allyl halogenation is preferably carried out using a preferred halogenating agent, for example a halo embodiment of the invention in the form of two methods, gensuccinimide. explained in more detail.
Beispiel r 1) Example r 1)
CH2CH2OH CH2CH2OH
PBr. PBr.
2) 2)
-> ->
nh2ch3 nh2ch3
xr xr
CHCH2NHCH^ CHCH2NHCH ^
5 5
615 665 615 665
7,2 g (0,023 Mol) l-(4-Bromphenyl)-l-(3-pyridyl)-l,3-propandiol wurden in 70 ml trockenem Aceton gelöst. Durch die Lösung wurde Bromwasserstoff geleitet, und das Lösungsmittel wurde im Vakuum verdampft. Zu dem Rückstand wurden 50 ml Methylenchlorid und 6,4 g (0,047 Mol) Phosphor- 5 tribromid gegeben, und die Mischung wurde 14 Stunden lang unter Rückflusskühlung zum Sieden erhitzt, auf Eis gegossen und mit Natriumcarbonat alkalisch gemacht. Zu der organischen Phase wurden 50 ml Methanol gegeben, und die Lösung wurde bei 30° C im Vakuum auf 30 ml eingedampft. Die Lö- io sung wurde in einem Autoklav mit 14 g (0,47 Mol) Monomethylamin 15 Std. lang auf 110° C erhitzt. Nach dem Abkühlen wurde das Lösungsmittel verdampft, und der Rückstand wurde in 25 ml Äther und 25 ml Wasser gelöst. Der pH-Wert der Mischung wurde mit Ammoniak auf 9,0 eingestellt, und is die Schichten wurden getrennt. Zu der ätherischen Schicht wurde eine weitere Menge Wasser gegeben, und der pH-Wert wurde mit Salzsäure auf 2,1 eingestellt. Die wässrige Phase wurde mit Aktivkohle behandelt, mit Ammoniak alkalisch gemacht und dann mit Äther extrahiert. Die organische Phase 20 wurde mit Natriumsulfat getrocknet und im Vakuum eingedampft. Die zurückbleibende Base wurde in 40 ml Äther gelöst und in einem Eisbad gekühlt. Es wurde tropfenweise eine Lösung von Chlorwasserstoffsäure in Äther zugegeben, wobei ein schwach gelber Niederschlag erhalten wurde. Der Nieder- 25 schlag wurde abfiltriert, mit Äther gewaschen und im Vakuum getrocknet. Es wurde das Hydrochlorid von 3-(4-Bromphe-nyl)-N-methyl-3-(3-pyridyl)-allylamin erhalten; Ausbeute 43%; F. 138-144° C. 7.2 g (0.023 mol) of l- (4-bromophenyl) -1- (3-pyridyl) -1, 3-propanediol were dissolved in 70 ml of dry acetone. Hydrogen bromide was bubbled through the solution and the solvent was evaporated in vacuo. To the residue were added 50 ml of methylene chloride and 6.4 g (0.047 mol) of phosphorus 5-tribromide, and the mixture was boiled under reflux for 14 hours, poured onto ice and made alkaline with sodium carbonate. 50 ml of methanol were added to the organic phase and the solution was evaporated to 30 ml at 30 ° C. in vacuo. The solution was heated in an autoclave with 14 g (0.47 mol) of monomethylamine at 110 ° C. for 15 hours. After cooling, the solvent was evaporated and the residue was dissolved in 25 ml of ether and 25 ml of water. The pH of the mixture was adjusted to 9.0 with ammonia and the layers were separated. A further amount of water was added to the ethereal layer and the pH was adjusted to 2.1 with hydrochloric acid. The aqueous phase was treated with activated carbon, made alkaline with ammonia and then extracted with ether. The organic phase 20 was dried with sodium sulfate and evaporated in vacuo. The remaining base was dissolved in 40 ml of ether and cooled in an ice bath. A solution of hydrochloric acid in ether was added dropwise to give a pale yellow precipitate. The precipitate was filtered off, washed with ether and dried in vacuo. The hydrochloride of 3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) allylamine was obtained; Yield 43%; F. 138-144 ° C.
Das Stereoisomerengemisch der Formel (I) wird nun in 30 Form seines Oxalates dreimal aus Äthanol umkristallisiert, wodurch das reine Z-Isomer der Verbindung von Formel (I) erhalten wird. The stereoisomer mixture of the formula (I) is then recrystallized three times from ethanol in the form of its oxalate, whereby the pure Z isomer of the compound of formula (I) is obtained.
Anstelle des oben beschriebenen Verfahrens kann die Ausgangsverbindung der Formel (IV) zuerst in das reine Z-Isomer 35 übergeführt und dann erst mit Monomethylamin umgesetzt werden. Zum Erhalt des Z-Isomers wird die Verbindung der Formel (IV) in das Oxalat übergeführt und dieses weiter einmal aus einer Mischung gleicher Volumina von Methanol und Instead of the process described above, the starting compound of the formula (IV) can first be converted into the pure Z isomer 35 and only then reacted with monomethylamine. To obtain the Z isomer, the compound of the formula (IV) is converted into the oxalate and this is repeated once more from a mixture of equal volumes of methanol and
Isopropylalkohol und einmal aus reinem Methanol umkristallisiert. Es wird dabei eine bei 160 bis 162° C schmelzende Substanz erhalten. Das NMR-Spektrum zeigt, dass es das Z-Isomer ist. Isopropyl alcohol and recrystallized once from pure methanol. A substance melting at 160 to 162 ° C. is obtained. The NMR spectrum shows that it is the Z isomer.
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. Pharma-col. 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. Pharma-col. 17, 107, 1972.
Diese Methode besteht in der Messung der Abnahme der Aufnahme von 14C-5-Hydroxytryptamin (14C-5-HT) und 3H-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 3H-norepinephrine (3H-NA) in brain sections of mice after the in vivo and in vitro administration of the test substances .
Inhibierung der Aufnahme von 14C-5-HT und 3H-NA in vitro und in vivo Inhibition of 14C-5-HT and 3H-NA uptake in vitro and in vivo
Die Testsubstanzen wurden V2 Stunde bevor die Tiere getötet wurden intraperitoneal verabreicht. Das Mittelhirn 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 «Mol Glucose in 2 ml Krebs-Henseleit-Puffer, pH 7,4 pro 100 mg Gehirnscheiben bestand. Die Inkubationszeit betrug 5 Minuten, wobei die Präinkubationszeit vor der Zugabe der markierten Amine 5 Minuten betrug. Die Scheiben wurden in Soluene® gelöst, und die aufgenommene Menge an radioaktiven Aminen wurde durch Flüssigszintillation bestimmt. Die Dosis, die 50% Abnahme der aktiven Aufnahme (EDS0) von 14C-5-HT und 3H-NA bewirkt, 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. The test substances were administered intraperitoneally V2 hours before the animals were killed. The midbrain was removed, sliced and incubated in a mixture consisting of 0.2 nmol 14C-5-HT, 0.2 nmol 3H-NA and 11 mol glucose in 2 ml Krebs-Henseleit buffer, pH 7, 4 per 100 mg brain slices. The incubation time was 5 minutes, the pre-incubation time 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 caused a 50% decrease in active uptake (EDS0) 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 ***e.
Bei der in-vitro-Methode wurden Scheiben von Mäuse-mittelhirn 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 midbrain were preincubated with a solution of the compound to be tested for 5 minutes and then incubated as described above.
Tabelle table
Inhibierung der Neuronal-Aufnahme von 5-Hydroxytryptamin und Noradrenalin durch Scheiben von Mäusehirn Inhibition of neuronal uptake of 5-hydroxytryptamine and norepinephrine by slice of mouse brain
Verbindung Aufnahme von 14C-5-HT Aufnahme von 3H-NA Compound uptake of 14C-5-HT uptake of 3H-NA
R R
Isomer isomer
Salz in vitro in vivo in vitro in vivo Salt in vitro in vivo in vitro in vivo
ECS0 ECS0
ed50 ed50
ecs0 ecs0
ed50 ed50
fiWl fiWl
^Mol/kg i.p. ^ Mol / kg i.p.
/(Mol/kg i / (Mol / kg i
Erfindungs Invention
H H
Mischung mixture
Oxalat Oxalate
0,5 0.5
32 32
_i _i
_i gemäss _i according to
H H
Z Z
Oxalat Oxalate
0,5 0.5
18 18th
2,5 2.5
102 102
erhältliche available
H H
Z Z
Hydrochlorid Hydrochloride
0,1 0.1
15,2 15.2
1,5 1.5
<1012 <1012
Verbindungen links
H H
E E
Oxalat Oxalate
2,5 2.5
102 102
0,8 0.8
25 25th
Bekannte ch3 Known ch3
Z Z
Hydrochlorid Hydrochloride
1,7 1.7
49 49
24,4 24.4
>98 > 98
Verbindungen ch3 Connections 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
1 nicht getestet 1 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.)
615 665 615 665
6 6
Wie aus der Tabelle ersichtlich ist, sind die erfindungsgemäss erhältlichen Verbindungen wirksame Inhibitoren der Neuronalaufnahme von 5-Hydroxytryptamin und Noradreana-lin. Die Z-Form der erfindungsgemäss erhältlichen Verbindung 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 noradreana-lin. The Z-form of the compound 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 Z-Form der erfindungsgemäss erhältlichen Verbindung, untersucht in Form des Hydrochlorids, ist ferner ein wirksamerer 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 The Z-form of the compound obtainable according to the invention, examined in the form of the hydrochloride, is also a more effective inhibitor of the uptake of 5-HT in vitro than any of the known compounds. (It is believed that the difference between the oxalate and the
Hydrochlorid beobachtet wird, auf die Tatsache zurückzuführen ist, dass das Hydrochlorid aus dem Oxalat hergestellt wurde, wobei ein reineres Z-Isomer erhalten wurde.) Die E-Form der erfindungsgemäss erhältlichen Verbindung inhi-5 biert in erster Linie die Aufnahme von Noradrenalin. Die offenbarte Inhibierung der Neuronalaufnahme von 5-Hydroxytryptamin und Noradrenalin kann den erfindungsgemäss erhältlichen Verbindungen Wert als antidepressive Mittel verleihen. In gleicher Weise können die erfindungsgemäss erhält-10 liehen Verbindungen als Mittel zur Behebung von Angstzuständen (Neuroleptika) wertvoll sein. Hydrochloride is observed, is due to the fact that the hydrochloride was prepared from the oxalate, whereby a purer Z-isomer was obtained.) The E-form of the compound obtainable according to the invention primarily inhibits the uptake of noradrenaline. The disclosed inhibition of the neuronal uptake of 5-hydroxytryptamine and norepinephrine can confer value on the compounds obtainable according to the invention as antidepressant agents. In the same way, the compounds obtained according to the invention can be valuable as a means of eliminating anxiety (neuroleptics).
Claims (7)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE7414622A SE388854B (en) | 1974-11-21 | 1974-11-21 | PROCEDURE FOR THE PREPARATION OF PHENYLPYRIDYLAMINE DERIVATIVES |
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Family
ID=20322772
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1512975A CH614937A5 (en) | 1974-11-21 | 1975-11-21 | 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 |
| 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 |
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| CH1512975A CH614937A5 (en) | 1974-11-21 | 1975-11-21 | 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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| BE (1) | BE835802A (en) |
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| DD (1) | DD122528A5 (en) |
| DE (1) | DE2550005A1 (en) |
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| FI (1) | FI61484C (en) |
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| SE409860B (en) * | 1977-07-04 | 1979-09-10 | Astra Laekemedel Ab | A NEW INTERMEDIATE PRODUCT FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRIDINE COMPOUNDS |
| DE2857020A1 (en) * | 1977-07-04 | 1981-01-08 | Astra Laekemedel Ab | A NOVEL INTERMEDIATE FOR PREPARATION OF THERAPEUTICALLY ACTIVE PYRIDINE COMPOUNDS |
| SE7909514L (en) | 1979-11-16 | 1981-05-17 | Astra Laekemedel Ab | NEW HALOPHENYL-PYRIDYL-ALLYLAMINE DERIVATIVES |
| US4312368A (en) * | 1980-02-20 | 1982-01-26 | Philip Morris, Incorporated | Smoking compositions |
| US5148817A (en) * | 1980-11-07 | 1992-09-22 | Philip Morris Incorporated | Smoking compositions |
| CA1150269A (en) * | 1980-11-14 | 1983-07-19 | Carl B. J. Ulff | Process for preparing 3-(4-bromophenyl)-3-(3-pyridyl)-allylamines |
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