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CH533115A - Process for the preparation of 5-substituted aza-dibenzo-cycloheptenes - Google Patents

Process for the preparation of 5-substituted aza-dibenzo-cycloheptenes

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Publication number
CH533115A
CH533115A CH1316967A CH1316967A CH533115A CH 533115 A CH533115 A CH 533115A CH 1316967 A CH1316967 A CH 1316967A CH 1316967 A CH1316967 A CH 1316967A CH 533115 A CH533115 A CH 533115A
Authority
CH
Switzerland
Prior art keywords
compound
aza
formula
general formula
dibenzo
Prior art date
Application number
CH1316967A
Other languages
German (de)
Inventor
J Villani Frank
Original Assignee
Scherico Ltd
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Priority claimed from US330244A external-priority patent/US3366635A/en
Application filed by Scherico Ltd filed Critical Scherico Ltd
Publication of CH533115A publication Critical patent/CH533115A/en

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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
    • C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • A—HUMAN NECESSITIES
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    • 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
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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
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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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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    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
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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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
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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
    • C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
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    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
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    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

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  • Pyridine Compounds (AREA)

Description

  

  
 



  Verfahren zur Herstellung von 5-substituierten Aza-dibenzo-cycloheptenen
Die Erfindung betrifft ein Verfahren zur Herstellung einer neuen Klasse von Verbindungen der aza-Dibenzocycloheptene.



   Die Endprodukte, die gemäss der Erfindung erhalten werden, sind aza-Dibenzocycloheptenderivate der folgenden allgemeinen Formel I
EMI1.1     
 und deren pharmazeutisch anwendbare Säureadditionssalze.



  Dabei bedeutet die punktierte Linie in Formel I eine fakultative Doppelbindung; A stellt ein Wasserstoffatom oder einen oder mehrere der folgenden Substituenten in den Stellungen 6, 7, 8 und/oder 9 (vorzugsweise 7 und/oder 8) dar: Halogen (vorzugsweise Chlor oder Brom), niedriges Alkyl (vorzugsweise Methyl oder Äthyl), Trifluormethyl, Alkoxy (vorzugsweise Methoxy oder   Äthoxy.,    Hydroxy und Acyloxy (vorzugsweise niedrig-Alkanoyloxy);

  B stellt diejenige Gruppierung von Atomen dar, die erforderlich ist, um zusammen mit den Kohlenstoffatomen, mit denen es verknüpft ist, einen Pyridinring zu bilden; und Z steht für eine der Gruppierungen
EMI1.2     
 wobei   Rt    und   R2    unabhängig voneinander Wasserstoff oder niedriges Alkyl sind oder gemeinsam eine solche Gruppierung bilden, wie sie erfoderlich ist, um zusammen mit dem Stickstoffatom, mit dem sie verknüpft sind, einen fünf- oder sechsgliedrigen heterocyclischen Ring zu ergeben, dessen Ringglieder abgesehen vom vorgenannten Stickstoffatom alle Kohlenstoff sind, ausser einem, welches Kohlenstoff, Sauerstoff oder Stickstoff sein kann.



   Die in dieser Beschreibung verwendete NomenMatur basiert im wesentlichen auf der durch die  Chemical Abstracts  für Dibenzocycloheptene empfohlenen. Für die Bezifferung der Stellungen in dem tricyclischen System dient die folgende   Formel I**    für   5-(ss-Dimethylamino-äthyl)-4-aza-10,1 1- dihydro-5H-dibenzo-[a,d]-cyclohepten,    eines der bevorzugten erfindungsgemässen Endprodukte, als Beispiel:
EMI1.3     

Formel I umfasst die entsprechenden 1-aza-, 2-aza-, 3-azaund 4-aza-Analogen, die alle unter die gegebene Definition von B fallen.

  Als weitere Definition werden solche Verbindun  gen nach Formel I, die in Stellung 5 ein Wasserstoffatom haben, gelegentlich als  gesättigte Verbindungen  und solche, die einen doppelt gebundenen Substituenten in Stellung 5 enthalten, gelegentlich als  ungesättigte Verbindungen  oder als  Alkylidenverbindungen  bezeichnet.



   Der Substituent
EMI2.1     
 umfasst NH2, niedrig-Alkylamino (vorzugsweise Methylamino) und Di-niedrig-alkylamino (vorzugsweise Dimethylamino), Hydroxyalkylamino (z. B.



     ss-Hydroxyäthylamino),    Bis-(hydroxyalkyl)-amino [z. B.   Bis-(ss-hydroxyäthyl)-amino3,    Pyrrolidino, Piperidino, Morpholino und Piperazino, [unter Einschluss substituierter Analoga, wie niedrig-Alkyl-, z. B. 4 -Methylpiperazino, Hydroxy-niedrig-alkyl-, z. B.   4 -(t3-Hydroxyäthyl)-piperazino,    niedrig-Alkanoyloxyalkyl-, z. B.   4 .(p-Acetoxyäthyl)-piperazino,      Hydroxy-niedrig-alkoxyalkyl-,    z. B. 4 -(Hydroxy-niedrig-alkoxy)-piperazino und dergleichen.



   Die Verbindungen der Formel I haben basischen Charakter und bilden Additionssalze mit Säuren. Diese Salze zeigen zum Teil bessere Löslichkeit und eignen sich besser zur Verarbeitung als die freien Basen. Dementsprechend werden die pharmazeutisch anwendbaren Salze der oben erwähnten freien Basen als in die Erfindung eingeschlossen betrachtet. Solche Salze können sich beispielsweise von der Malein-, Salicyl-, Bernstein-, Methylsulfon-, Wein-, Citronen-, Chlorwasserstoff-, Bromwasserstoff-, Schwefel-, Salpeter-, Phosphorsäure und dergleichen ableiten.



   Die Verbindungen der Formel I unter Einschluss der besagten Salze sind durch ihre Antihistamin- und Antiserotoninwirkung sowie ihre antianaphylaktische Wirkung gekennzeichnet und sind bei der Behandlung von allergischen Krankheitserscheinungen wie Urticaria, Heuschnupfen und Pollenüberempfindlichkeit nützlich.



   Innerhalb der Klasse von Verbindungen, die durch Formel I umfasst werden (d. h. den  gesättigten Verbindungen  und den  Alkylidenverbindungen  der 1-aza-, 2-aza-, 3-aza- und 4-aza-Reihe), haben einige grössere therapeutische Nützlichkeit als andere. Obgleich alle diese Verbindungen die oben beschriebenen Eigenschaften besitzen, gibt es eine gewisse Strukturabhängigkeit von Wirksamkeit und Nützlichkeit. Zum Beispiel zeigen die 4-aza-Verbindungen im allgemeinen stärkere Antihistaminwirksamkeit als die anderen Stellungsisomeren, Verbindungen, die eine 3-aza-Gruppierung haben, scheinen ausserdem eine blutdrucksenkende Wirkung zu haben; diejenigen Verbindungen, die in den Stellungen 10 und 11 ungesättigt sind, scheinen etwas weniger wirksam zu sein als ihre gesättigten Analogen.



   Die Verbindungen der Formel I unter Einschluss der besag   fachen    Zubereitungen, die die entsprechende Substanz in Mischung mit einem für enterale oder parenterale Verabreichung geeigneten pharmazeutischen Trägerstoff enthalten, verabreicht werden. Die Zubereitungen können fest sein, wie z. B. Tabletten oder Kapseln, oder sie können flüssig sein, wie z. B. Sirupe, Elixiere, Emulsionen und Injektionslösungen. In den Rezepturen der pharmazeutischen Zubereitungsformen werden im allgemeinen Trägerstoffe wie Wasser, Gelatine, Lactose, Stärken, Magnesiumstearat, Talk, pflanzliche Öle, Benzylalkohole, Gummis, Polyalkylenglykole und Vaseline verwendet.



   Die Dosierung des wirksamen Bestandteils in solchen Zusammensetzungen hängt von der Art und Schwere und den individuellen Merkmalen eines jeden einzelnen Falles ab und wird durch den behandelnden Arzt bestimmt. Im allgemeinen stellt ein Dosierungsspielraum von ungefähr 0,1 bis 15 mg pro kg Körpergewicht und Tag die praktischen Grenzen dar, wobei ein Bereich von ungefähr 0,1 bis 5 mg pro kg Körpergewicht und Tag für die bevorzugte Form der aktiven Ingredienz gilt.



  In seinen bevorzugten Dosierungseinheiten liegt der aktive Bestandteil deshalb üblicherweise in Mengen von ungefähr 5 bis 150 mg vor.



   Erfindungsgemäss werden die Verbindungen der allgemeinen Formel I hergestellt, indem man Verbindungen der allgemeinen Formel   1   
EMI2.2     
 worin die punktierte Linie, A und B die obige Bedeutung haben und Z eine der Gruppierungen
EMI2.3     
 bedeutet, wobei   Rt    und R2 wie oben definiert sind, an der Ketogruppe von Z reduziert und eine durch eine solche Reduktion erhaltene   5(1)-ungesättigte    Verbindung gewünschtenfalls zu der entsprechenden 10(11)- und 5(1)-gesättigten Verbindung hydriert und die durch eine oder beide der voranstehenden Stufen erhaltene Verbindung der Formel I mit Z gleich
EMI2.4     
  gewünschtenfalls einer oder (in beliebiger Reihenfolge) mehreren der folgenden Umsetzungen unterworfen wird:

   i) Hydrierung oder Dehydrierung in Stellung 10(11); ii) reduktive Abspaltung einer oder zweier gegebenenfalls an das Stickstoffatom der Aminogruppe von Z gebundener Benzylgruppen; iii) Umwandlung in ein pharmazeutisch anwendbares Salz durch Reaktion mit der entsprechenden Säure oder mit einem reaktionsfähigen Derivat davon.



   Falls die verwendete Ausgangsverbindung der allgemeinen Formel   1"    leicht reduzierbare Doppelbindungen im Ringsystem oder Substituenten enthält, die erhalten bleiben sollen, so ist es wichtig, die Reduktion an der Ketogruppe selektiv durchzuführen. Dies geschieht vorzugsweise mittels Lithiumalumini umhydrid oder ähnlichen die Amidgruppierung bevorzugt reduzierenden Mitteln.



   Eine gegebenenfalls sich anschliessende Hydrierung von
5(1')- und/oder 10(11)-ungesättigten Produkten gemäss Formel I zu den entsprechenden gesättigten Verbindungen erfolgt vorzugsweise katalytisch, z. B. an einem Palladiumkatalysator.



  Diese Reduktion ist jedoch nicht selektiv. Liegen daher beide genannten Doppelbindungen vor und soll nur eine davon hydriert werden oder enthält das Molekül weitere leicht hydrierbare Bindungen, so kann diese Hydrierung nicht ohne besondere Vorkehrungen (Schutz oder nachfolgende Wiedereinführung der betreffenden Bindungen) vorgenommen werden.



   Eine sich gegebenenfalls anschliessende reduktive Debenzylierung - die dann erfolgt, wenn eine im Endprodukt gewünschte und im gewählten Ausgangsstoff vorgebildete primäre oder sekundäre Aminogruppe vor Durchführung des erfindungsgemässen Verfahrens zu dessen glatterem Ablauf durch Benzylierung geschützt wurde - erfolgt ebenfalls vorzugsweise durch katalytische Hydrierung an Pd/C; sie kann jedoch leicht selektiv durchgeführt werden, indem man die Hydrierung nach Verbrauch des errechneten Wasserstoffvolumens abbricht.



   Die gegebenenfalls sich anschliessende Umwandlung in ein Salz kann nach üblichen Methoden erfolgen.



   Die für die Durchführung des erfindungsgemässen Verfahrens erforderlichen Ausgangsstoffe der Formel I" werden im wesentlichen nach Methoden hergestellt, wie sie für die Synthese ihrer Desaza-analogen, d. h. entsprechender Verbindungen, die einen Benzolring an Stelle des Pyridinringes des tricyclischen Systems der Formel I" enthalten, bekannt sind.



   Ein bevorzugter Weg besteht darin, dass zuerst ein 5-Ketoaza-dibenzocyclohepten (IIA) mit einem Bromessigsäureester (vorzugsweise Bromessigsäureäthylester) in Gegenwart von Zink kondensiert wird (die bekannte Reformatsky-Kondensation), wobei man folgendermassen zu einem Carbalkoxymethyl-Zwischenprodukt III gelangt;
EMI3.1     

In dem voranstehenden Reaktionsschema haben A, B und die punktierte Linie dieselbe Bedeutung wie oben. Die Reaktion wird zweckmässig in einem inerten Lösungsmittel wie Toluol oder Xylol unter Rückfluss ausgeführt, und das Produkt, III, wird daraus nach bekannten Methoden isoliert. Der Ester, III, wird dann einer Dehydratisierung, z. B. durch Erhitzen mit Thionylchlorid, unterworfen und das so erhaltene exocyclisch-ungesättigte Analoge, IV, durch Behandlung mit Säure oder Alkali zur entsprechenden Carbonsäure, V, verseift. 

  Diese wird in ein Amid, VI, übergeführt, indem man zuerst mittels Thionylchlorid das Säurechlorid bildet und anschliessend mit einem Amin   HNRIR-    umsetzt, bei dem   Rt    und R2 wie oben definiert, aber vorzugsweise nicht Wasserstoff sind. Diese Folge von Reaktionen ist in dem folgenden Schema dargestell; der Einfachheit halber wird nur die 5-Stellung des tricyclischen Systems gezeigt:
EMI3.2     
  
EMI4.1     

Reduktion der in Formel VI gezeigten Doppelbindung, z. B.



  durch katalytische Hydrierung an Palladium ergibt die entsprechende gesättigte Verbindung.



   Die im Zusammenhang mit der Herstellung der erfindungsgemäss verwendeten Ausgangsstoffe oben erwähnten Verbindungen der Formel IIA können nach einer Reihe von Verfahren, wie sie beispielsweise in der belgischen Patentschrift Nr.



  647 043 beschrieben worden sind, hergestellt werden.



   Die folgenden Beispiele dienen der Erläuterung der Erfin dung. Beispiel 1 erläutert die Herstellung der erfindungsge   mäss    eingesetzten Ausgangsstoffe gemäss allgemeiner Formel I aus solchen der Formel IIA; und die Beispiele 2 bis 4 erläutern die Herstellung der Endprodukte (I) der Erfindung.



   Beispiel 1    5-Dimethylcarboxamido-methyliden-4-aza- 10,11 -dihydro-   
5H-dibenzo-[a,d]-cyclohepten
A. Zu einer gerührten Mischung von 13 g Zink (20 mesh) und 33,4 g Bromessigsäureäthylester in 400 ml Benzol/Toluol   (1:1) wird tropfenweise eine Lösung von 41,4 g 4-aza- 10,11 -Dihydro-5H-dibenzo-[a,d]-cyclohepten-5 -on    gegeben. Es wird zwei Stunden auf einem Dampfbad erhitzt, dann werden 13 g Zink zugesetzt und das Erhitzen wird vier Stunden lang fortgesetzt. Dann wird abgekühlt,   obige    Essigsäure dazugegeben. und die Phasen werden getrennt. Die wässrige Phase wird mit Benzol extrahiert, und die Benzolfraktionen werden vereinigt.

  Es wird zu einem Rückstand eingedampft und im Vakuum destilliert, und man erhält das    5-Hydroxy-5 -carbäthoxymethyl-4-aza- 10,11 - dihydro-5H-dibenzo-[a,d]-cyclohepten.   



   B. Das Produkt der Stufe A wird dehydratisiert, indem 20 g davon mit 100 ml Essigsäureanhydrid, das 1 bis 2% Schwefelsäure enthält. auf   90-l00'C    erhitzt werden. Nach drei Stunden wird im Vakuum eingedampft, mit Wasser verdünnt, neutralisiert und mit Äther extrahiert. Es wird zu einem Rückstand eingedampft und im Vakuum destilliert, und man erhält das   5-Carbäthoxymethyliden-4-aza- 10,11 1-    dihydro-SH-dibenzo-[a,d]-cyclohepten.



   C. 15 g des Produktes von Stufe B mit einer Mischung aus
15 g Kaliumhydroxyd, 50 ml Wasser und 150 ml Äthanol sechs Stunden lang auf einem Dampfbad unter Rückfluss gekocht. Es wird zu einem Rückstand eingedampft, Wasser hinzugefügt und mit Äther extrahiert. Man neutralisiert die wässrige Phase mit Essigsäure und lässt das Produkt kristalli sieren. Es wird filtriert und aus wässrigem Methanol umkristal lisiert, und man erhält das
5-Carboxymethyliden-4-aza- 10,11    dihydro-5H-dibenzo-[a,d]-cyclohepten.   



   D. 12 g der durch Stufe D erhaltenen Säure werden mit
50 ml Thionylchlorid unter Rückfluss erhitzt. Es wird im
Vakuum eingeengt, dann werden 50 ml Benzol zugegeben und zu einem Rückstand eingedampft. Dieser wird in 150 ml Ben zol aufgenommen, und unter Rühren wird eine Lösung von 9 g
Dimethylamin in Benzol zugegeben. Es wird vier Stunden lang unter Rückflusskühlung und Rühren gekocht und dann in
Wasser gegossen. Es wird mit Natriumcarbonat alkalisch gemacht und mit Benzol extrahiert. Es wird im Vakuum einge dampft, und man erhält das   5-Dimethylcarboxamido-methyliden-4-aza- 10,11 - dihydro -5 H-dibenzo-[a,d]-cyclohepten .   



  Reinigung erfolgt durch Umkristallisation aus Methanol.



   Beispiel 2    5-(ss-Dimethylaminoäthyliden)-4-aza-    10,11 -dihydro
5H-dibenzo-[a,d]-cyclohepten
Eine ätherische Lösung von 10 g des Produkts von Beispiel 1 wird zu einer Suspension von 3 g Lithiumaluminiumhydrid in 250 ml Äther gegeben. Es wird zwei Stunden lang gerührt, dann wird Wasser dazugegeben; die Phasen werden getrennt, die ätherische Phase wird zu einem Rückstand eingedampft, und man erhält   5-Dimethylaminoäthyliden-4-aza-10,1 1-    dihydro-SH-dibenzo-[a,d]-cyclohepten.



  Reinigung erfolgt durch Destillation im Vakuum.



   Typische Vertreter der ungesättigten Verbindungen, die analog Beispiel 2 erhältlich sind, sind im folgenden aufgeführt (dabei wird der Ausdruck     10,11 -Dihydro-5H-dibenzo-[a,d]-    cyclohepten  zu  Dihydrohepten  abgekürzt, der Name des 10,11-ungesättigten Analogen davon zu  Hepten , derart wurde z. B. die Verbindung des Beispiels 2 als    4-aza-5-(3-    Dimethyl-aminoäthyliden-dihydrohepten  bezeichnet:   3-aza-5-(P-Dimethylaminoäthyliden)-dihydrohepten, 3-aza-5-(ss-Pyrrolidinoäthyliden)-dihydrohepten.



  3-aza-5-( P-Dibenzylaminoäthyliden)-dihydrohepten, 3-aza-5-(P-Dimethylaminoäthyliden)-hepten, 3-aza-5-(B-Pyrrolidinoäthyliden)-hepten,
3 -aza-5-(ss-Dibenzylaminoäthyliden)-hepten,    und die 1-aza-. 2-aza- und 4-aza-Analogen der voranstehenden Verbindungen sowie ihre 7-Chlor-, 7-Trifluormethyl-, 8 Methyl-, 9-Methyl-, 8-Chlor-, 7-Brom-, 6-Methoxy- und 7 Methylderivate.



   Beispiel 3    5-(ss-Dimethylaminoäthyl)-4-aza-    10,11 -dihydro    SH-dibenzo-[a,d] -cyclohepten   
In einer Schüttel-Apparatur wird eine Lösung von 6,8 g des Produktes des Beispiels 2 in 100 ml Äthanol in Gegenwart von 0,5 g Platinoxyd mit Wasserstoff unter einem Druck von ungefähr 3,6 Atmosphären hydriert, bis eine äquivalente Menge Wasserstoff aufgenommen worden ist, d. h. für gewöhnlich ungefähr eine Stunde. Es wird filtriert, das Filtrat wird zu einem Rückstand eingeengt und das Produkt durch Vakuumdestillation gereinigt.

 

   Beispiel 4    5-(ss-Dimethylaminoäthyl)-4-aza-10,1 1-dihydro-   
5H-dibenzo-[a,d]-cyclohepten-dimaleat
Zu einer Lösung von 4,2 g   5-(ss-Dimethylaminoäthyl)-4-aza-10, -dihydro- 5H-dibenzo-[a,d]-cyclohepten    in 55 ml Essigsäureäthylester wird eine Lösung von 3,45 g Maleinsäure in Essigsäureäthylester zugegeben. Der entstandene Niederschlag wird abfiltriert und das gewünschte Produkt aus einer Essigsäureäthylester-Methanol-Mischung umkristallisiert, und man erhält das    5-(ss-Dimethylaminoäthyl)-4-aza-10,1 1-dihydro-      SH-dibenzo-[a,d]-cyclohepten-dimaleat; Fp. =   117120CC.    



  
 



  Process for the preparation of 5-substituted aza-dibenzo-cycloheptenes
The invention relates to a process for the preparation of a new class of compounds of the aza-dibenzocycloheptenes.



   The end products obtained according to the invention are aza-dibenzocycloheptene derivatives of the general formula I below
EMI1.1
 and their pharmaceutically acceptable acid addition salts.



  The dotted line in formula I denotes an optional double bond; A represents a hydrogen atom or one or more of the following substituents in positions 6, 7, 8 and / or 9 (preferably 7 and / or 8): halogen (preferably chlorine or bromine), lower alkyl (preferably methyl or ethyl), Trifluoromethyl, alkoxy (preferably methoxy or ethoxy., Hydroxy and acyloxy (preferably lower-alkanoyloxy);

  B represents that grouping of atoms necessary to together with the carbon atoms to which it is attached form a pyridine ring; and Z stands for one of the groupings
EMI1.2
 where Rt and R2, independently of one another, are hydrogen or lower alkyl or together form such a grouping as is necessary in order, together with the nitrogen atom to which they are linked, to give a five- or six-membered heterocyclic ring, the ring members of which apart from the aforementioned Nitrogen atoms are all carbon except one, which can be carbon, oxygen or nitrogen.



   The nomenclature used in this description is essentially based on that recommended by Chemical Abstracts for dibenzocycloheptenes. For the numbering of the positions in the tricyclic system, the following formula I ** is used for 5- (ss-dimethylamino-ethyl) -4-aza-10.1 1- dihydro-5H-dibenzo- [a, d] -cycloheptene, one of the preferred end products according to the invention, as an example:
EMI1.3

Formula I encompasses the corresponding 1-aza, 2-aza, 3-aza, and 4-aza analogs, all of which fall under the definition of B given.

  As a further definition, those compounds according to formula I which have a hydrogen atom in position 5 are sometimes referred to as saturated compounds and those which contain a double bonded substituent in position 5 are sometimes referred to as unsaturated compounds or as alkylidene compounds.



   The substituent
EMI2.1
 includes NH2, lower-alkylamino (preferably methylamino) and di-lower-alkylamino (preferably dimethylamino), hydroxyalkylamino (e.g.



     β-hydroxyethylamino), bis (hydroxyalkyl) amino [e.g. B. bis (ss-hydroxyethyl) -amino3, pyrrolidino, piperidino, morpholino and piperazino, [including substituted analogs such as lower-alkyl, z. B. 4 -methylpiperazino, hydroxy-lower-alkyl- e.g. B. 4 - (t3-hydroxyethyl) piperazino, lower alkanoyloxyalkyl, e.g. B. 4. (p-Acetoxyethyl) -piperazino, hydroxy-lower-alkoxyalkyl-, e.g. B. 4 - (hydroxy-lower alkoxy) piperazino and the like.



   The compounds of the formula I have a basic character and form addition salts with acids. Some of these salts show better solubility and are more suitable for processing than the free bases. Accordingly, the pharmaceutically acceptable salts of the above-mentioned free bases are considered to be included in the invention. Such salts can be derived, for example, from maleic, salicylic, succinic, methyl sulfonic, tartaric, citric, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric acid and the like.



   The compounds of the formula I, including the said salts, are characterized by their antihistamine and antiserotonin effects and their antianaphylactic effects and are useful in the treatment of allergic symptoms such as urticaria, hay fever and pollen hypersensitivity.



   Within the class of compounds encompassed by Formula I (ie, the saturated compounds and the alkylidene compounds of the 1-aza, 2-aza, 3-aza, and 4-aza series), some have greater therapeutic utility than others . While all of these compounds have the properties described above, there is some structural dependence of potency and utility. For example, the 4-aza compounds generally show more antihistamine activity than the other positional isomers; compounds which have a 3-aza moiety also appear to have an antihypertensive effect; those compounds unsaturated in positions 10 and 11 appear to be somewhat less effective than their saturated analogues.



   The compounds of the formula I, including the said preparations which contain the corresponding substance in a mixture with a pharmaceutical carrier suitable for enteral or parenteral administration, are administered. The preparations can be solid, such as. B. tablets or capsules, or they can be liquid, such as. B. syrups, elixirs, emulsions and injection solutions. In the formulations of the pharmaceutical preparation forms, carriers such as water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols and petroleum jelly are generally used.



   The dosage of the active ingredient in such compositions depends on the nature and severity and the individual characteristics of each individual case and is determined by the attending physician. In general, a dosage range of about 0.1 to 15 mg per kg of body weight per day is the practical limit, with a range of about 0.1 to 5 mg per kg of body weight per day for the preferred form of the active ingredient.



  In its preferred dosage units, the active constituent is therefore usually present in amounts of approximately 5 to 150 mg.



   According to the invention, the compounds of general formula I are prepared by adding compounds of general formula 1
EMI2.2
 where the dotted line, A and B have the above meaning and Z one of the groupings
EMI2.3
 where Rt and R2 are as defined above, reduced at the keto group of Z and a 5 (1) -unsaturated compound obtained by such a reduction is hydrogenated, if desired, to the corresponding 10 (11) - and 5 (1) -saturated compound and the compound of formula I obtained by one or both of the preceding steps with Z being the same
EMI2.4
  if desired, one or (in any order) several of the following reactions is subjected:

   i) hydrogenation or dehydrogenation in position 10 (11); ii) reductive cleavage of one or two benzyl groups optionally bonded to the nitrogen atom of the amino group of Z; iii) Conversion into a pharmaceutically acceptable salt by reaction with the corresponding acid or with a reactive derivative thereof.



   If the starting compound of general formula 1 "contains easily reducible double bonds in the ring system or substituents which are to be retained, it is important to carry out the reduction on the keto group selectively. This is preferably done using lithium aluminum hydride or similar agents which preferably reduce the amide group.



   An optionally subsequent hydrogenation of
5 (1 ') - and / or 10 (11) -unsaturated products according to formula I to the corresponding saturated compounds is preferably carried out catalytically, e.g. B. on a palladium catalyst.



  However, this reduction is not selective. If, therefore, both of the double bonds mentioned are present and only one of them is to be hydrogenated or if the molecule contains further easily hydrogenatable bonds, this hydrogenation cannot be carried out without special precautions (protection or subsequent reintroduction of the bonds in question).



   Any subsequent reductive debenzylation - which occurs when a primary or secondary amino group desired in the end product and pre-formed in the selected starting material has been protected by benzylation before the process according to the invention is carried out in order to make it smoother - is likewise preferably carried out by catalytic hydrogenation on Pd / C; however, it can easily be carried out selectively by terminating the hydrogenation after the calculated hydrogen volume has been consumed.



   Any subsequent conversion into a salt can take place by customary methods.



   The starting materials of the formula I "required for carrying out the process according to the invention are essentially prepared by methods such as those used for the synthesis of their desaza-analogues, ie corresponding compounds which contain a benzene ring instead of the pyridine ring of the tricyclic system of the formula I", are known.



   A preferred way is that first a 5-ketoaza-dibenzocycloheptene (IIA) is condensed with a bromoacetic acid ester (preferably ethyl bromoacetate) in the presence of zinc (the known Reformatsky condensation), a carbalkoxymethyl intermediate III being obtained as follows;
EMI3.1

In the above reaction scheme, A, B and the dotted line have the same meanings as above. The reaction is conveniently carried out under reflux in an inert solvent such as toluene or xylene, and the product, III, is isolated therefrom by known methods. The ester, III, is then subjected to dehydration, e.g. B. by heating with thionyl chloride, and the exocyclically unsaturated analog thus obtained, IV, is saponified by treatment with acid or alkali to give the corresponding carboxylic acid, V.

  This is converted into an amide, VI, by first forming the acid chloride using thionyl chloride and then reacting it with an amine HNRIR- in which Rt and R2 are as defined above, but are preferably not hydrogen. This sequence of reactions is shown in the following scheme; for the sake of simplicity, only the 5-position of the tricyclic system is shown:
EMI3.2
  
EMI4.1

Reduction of the double bond shown in Formula VI, e.g. B.



  catalytic hydrogenation on palladium gives the corresponding saturated compound.



   The compounds of the formula IIA mentioned above in connection with the preparation of the starting materials used according to the invention can be prepared by a number of processes, such as those described, for example, in Belgian Patent No.



  647 043 have been described.



   The following examples serve to explain the invention. Example 1 explains the preparation of the starting materials used according to the invention according to general formula I from those of formula IIA; and Examples 2 to 4 illustrate the preparation of the end products (I) of the invention.



   Example 1 5-Dimethylcarboxamido-methylidene-4-aza-10,11 -dihydro-
5H-dibenzo- [a, d] -cycloheptene
A. To a stirred mixture of 13 g of zinc (20 mesh) and 33.4 g of ethyl bromoacetate in 400 ml of benzene / toluene (1: 1), a solution of 41.4 g of 4-aza- 10,11 -Dihydro- is added dropwise 5H-dibenzo- [a, d] -cyclohepten-5-one given. It is heated on a steam bath for two hours, then 13 g of zinc is added and heating is continued for four hours. It is then cooled, and the above acetic acid is added. and the phases are separated. The aqueous phase is extracted with benzene and the benzene fractions are combined.

  It is evaporated to a residue and distilled in vacuo, and the 5-hydroxy-5-carbethoxymethyl-4-aza-10,11-dihydro-5H-dibenzo- [a, d] -cycloheptene is obtained.



   B. The product of step A is dehydrated by adding 20 g of it with 100 ml of acetic anhydride containing 1 to 2% sulfuric acid. be heated to 90-100'C. After three hours, it is evaporated in vacuo, diluted with water, neutralized and extracted with ether. It is evaporated to a residue and distilled in vacuo, and the 5-carbethoxymethylidene-4-aza-10,11-dihydro-SH-dibenzo- [a, d] -cycloheptene is obtained.



   C. 15 g of the product from stage B with a mixture of
15 g of potassium hydroxide, 50 ml of water and 150 ml of ethanol are refluxed on a steam bath for six hours. Evaporate to a residue, add water and extract with ether. The aqueous phase is neutralized with acetic acid and the product is allowed to crystallize. It is filtered and recrystallized from aqueous methanol and this is obtained
5-carboxymethylidene-4-aza-10,11 dihydro-5H-dibenzo- [a, d] -cycloheptene.



   D. 12 g of the acid obtained by step D are with
50 ml of thionyl chloride heated under reflux. It will be in
Concentrated in vacuo, then 50 ml of benzene are added and evaporated to a residue. This is taken up in 150 ml of benzene, and a solution of 9 g is obtained with stirring
Dimethylamine in benzene added. It is refluxed with stirring for four hours and then in
Poured water. It is made alkaline with sodium carbonate and extracted with benzene. It is evaporated in vacuo, and 5-dimethylcarboxamido-methylidene-4-aza-10,11-dihydro -5 H-dibenzo- [a, d] -cycloheptene is obtained.



  Purification is carried out by recrystallization from methanol.



   Example 2 5- (ss-dimethylaminoethylidene) -4-aza-10,11 -dihydro
5H-dibenzo- [a, d] -cycloheptene
An ethereal solution of 10 g of the product from Example 1 is added to a suspension of 3 g of lithium aluminum hydride in 250 ml of ether. It is stirred for two hours, then water is added; the phases are separated, the ethereal phase is evaporated to a residue, and 5-dimethylaminoethylidene-4-aza-10,1-dihydro-SH-dibenzo- [a, d] -cycloheptene is obtained.



  Purification is carried out by distillation in vacuo.



   Typical representatives of the unsaturated compounds that can be obtained analogously to Example 2 are listed below (the expression 10,11 -Dihydro-5H-dibenzo- [a, d] - cyclohepten is abbreviated to dihydrohepten, the name of the 10,11- unsaturated analogs thereof to heptene, for example the compound of Example 2 was designated as 4-aza-5- (3-dimethylaminoethylidene dihydroheptene: 3-aza-5- (P-dimethylaminoethylidene) dihydroheptene, 3- aza-5- (ss-pyrrolidinoethylidene) dihydroheptene.



  3-aza-5- (P-Dibenzylaminoäthyliden) -dihydrohepten, 3-aza-5- (P-Dimethylaminoäthyliden) -hepten, 3-aza-5- (B-Pyrrolidinoäthyliden) -hepten,
3-aza-5- (s-dibenzylaminoethylidene) -heptene, and the 1-aza-. 2-aza and 4-aza analogs of the above compounds and their 7-chloro, 7-trifluoromethyl, 8-methyl, 9-methyl, 8-chloro, 7-bromo, 6-methoxy and 7 Methyl derivatives.



   Example 3 5- (ss-dimethylaminoethyl) -4-aza-10,11 -dihydro SH-dibenzo- [a, d] -cycloheptene
In a shaking apparatus, a solution of 6.8 g of the product of Example 2 in 100 ml of ethanol in the presence of 0.5 g of platinum oxide is hydrogenated with hydrogen under a pressure of approximately 3.6 atmospheres until an equivalent amount of hydrogen has been absorbed is, d. H. usually about an hour. It is filtered, the filtrate is concentrated to a residue and the product is purified by vacuum distillation.

 

   Example 4 5- (ss-dimethylaminoethyl) -4-aza-10.1 1-dihydro-
5H-dibenzo- [a, d] -cycloheptene-dimaleate
To a solution of 4.2 g of 5- (s-dimethylaminoethyl) -4-aza-10, -dihydro-5H-dibenzo- [a, d] -cyclohepten in 55 ml of ethyl acetate, a solution of 3.45 g of maleic acid in Ethyl acetate added. The resulting precipitate is filtered off and the desired product is recrystallized from an ethyl acetate-methanol mixture, and the 5- (s-dimethylaminoethyl) -4-aza-10,1 1-dihydro-SH-dibenzo- [a, d] -cycloheptene dimaleate; Mp = 117120CC.

Claims (1)

PATENTANSPRÜCHE PATENT CLAIMS I. Verfahren zur Herstellung von neuen Verbindungen der allgemeinen Formel I EMI5.1 in der die punktierte Linie eine fakultative Doppelbindung, A ein Wasserstoffatom oder einen oder mehrere der Substituenten Halogen, niedriges Alkyl, Trifluormethyl, Alkoxy, Hydroxy oder Acyloxy in den Stellungen 6, 7, 8 und/oder 9, B eine Atomgruppierung, die zusammen mit den Kohlenstoffatomen, mit denen sie verknüpft ist, einen Pyridinring bildet, und Z eine der Gruppierungen EMI5.2 bedeuten, wobei Rt und R3 unabhängig voneinander Wasserstoff oder eine niedrige Alkylgruppe sind oder gemeinsam eine solche Gruppierung bilden, wie sie erforderlich ist, um zusammen mit dem Stickstoffatom, mit dem sie verknüpft sind, einen fünf- oder sechs-gliedrigen heterocyclischen Ring zu ergeben, I. Process for the preparation of new compounds of the general formula I. EMI5.1 in which the dotted line is an optional double bond, A is a hydrogen atom or one or more of the substituents halogen, lower alkyl, trifluoromethyl, alkoxy, hydroxy or acyloxy in positions 6, 7, 8 and / or 9, B is an atom grouping which together with the carbon atoms to which it is attached forms a pyridine ring, and Z one of the moieties EMI5.2 denote where Rt and R3 are independently hydrogen or a lower alkyl group or together form such a grouping as is necessary in order, together with the nitrogen atom to which they are linked, to give a five- or six-membered heterocyclic ring, dessen Ringglieder abgesehen vom vorgenannten Stickstoffatom alle Kohlenstoff sind, ausser einem, welches Kohlenstoff, Sauerstoff oder Stickstoff sein kann, sowie ihrer pharmazeutisch anwendbaren Säureadditionssalze, dadurch gekennzeichnet, dass eine Verbindung der allgemeinen Formel I' 10 15 30 30 30 35 40 EMI5.3 worin die punktierte Linie, A und B obige Bedeutung haben und Z eine der Gruppierungen EMI5.4 ist, wobei Rt und R2 obige Bedeutung besitzen, an der Ketogruppe von Z' reduziert wird. the ring members of which, apart from the aforementioned nitrogen atom, are all carbon, except for one, which can be carbon, oxygen or nitrogen, as well as their pharmaceutically acceptable acid addition salts, characterized in that a compound of the general formula I '10 15 30 30 30 35 40 EMI5.3 where the dotted line, A and B have the above meaning and Z one of the groupings EMI5.4 is, where Rt and R2 have the above meaning, is reduced at the keto group of Z '. II. Die nach dem Verfahren gemäss Patentanspruch I erhaltenen neuen Verbindungen der Formel I. II. The new compounds of the formula I obtained by the process according to claim I UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass eine so erhaltene 5(1')-ungesättigte Verbindung der Formel I zu einer 5(1')-gesättigten Verbindung hydriert wird. SUBCLAIMS 1. The method according to claim I, characterized in that a 5 (1 ') - unsaturated compound of the formula I obtained in this way is hydrogenated to a 5 (1') - saturated compound. 2. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass eine so erhaltene 10(11)-gesättigte Verbindung det allgemeinen Formel I zu einer 10(11)-gesättigten Verbindung hydriert wird. 2. The method according to claim I, characterized in that a 10 (11) -saturated compound of the general formula I thus obtained is hydrogenated to a 10 (11) -saturated compound. 3. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass eine so erhaltene 10(1 1).gesättigte Verbindung der allgemeinen Formel I zu einer 10(1 1)-ungesättigten Verbindung dehydriert wird. 3. The method according to claim I, characterized in that a 10 (1 1) .saturated compound of the general formula I thus obtained is dehydrated to give a 10 (1 1) -unsaturated compound. 4. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass eine so erhaltene Verbindung der Formel I in ein Säureadditionssalz übergeführt wird. 4. The method according to claim I, characterized in that a compound of the formula I thus obtained is converted into an acid addition salt.
CH1316967A 1963-04-24 1964-04-20 Process for the preparation of 5-substituted aza-dibenzo-cycloheptenes CH533115A (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US27523763A 1963-04-24 1963-04-24
US330244A US3366635A (en) 1963-04-24 1963-12-13 Aza-5h-dibenzo-[a,d]-(cycloheptenes and cycloheptene-5-ones) and the corresponding 10, 11-dihydro derivatives thereof
US330263A US3326924A (en) 1963-04-24 1963-12-13 Novel aza-dibenzo[a, d]-cycloheptene derivatives
CH509564A CH535769A (en) 1963-04-24 1964-04-20 Cpds. of general formulae I and II, and intermediates of general formula III where A = H or one or more of the following:- halogen, lower alkyl, -CF
US42010164A 1964-12-21 1964-12-21
US580169A US3357986A (en) 1963-04-24 1966-09-19 1, 2, 3 or 4, aza,-[5-piperdyl or hydrocarbyl amino]-10, 11 dihydro-5h-dibenzo-[a, d]-cycloheptene

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CH1317067A CH538478A (en) 1963-04-24 1964-04-20 Cpds. of general formulae I and II, and intermediates of general formula III where A = H or one or more of the following:- halogen, lower alkyl, -CF
CH1316867A CH542847A (en) 1963-04-24 1964-04-20 Process for the preparation of 5-substituted azadibenzocycloheptenes

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CH1316867A CH542847A (en) 1963-04-24 1964-04-20 Process for the preparation of 5-substituted azadibenzocycloheptenes

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