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EP0000154B1 - New benz(f)isoindolines, their preparation and medicaments containing them - Google Patents

New benz(f)isoindolines, their preparation and medicaments containing them Download PDF

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Publication number
EP0000154B1
EP0000154B1 EP78100169A EP78100169A EP0000154B1 EP 0000154 B1 EP0000154 B1 EP 0000154B1 EP 78100169 A EP78100169 A EP 78100169A EP 78100169 A EP78100169 A EP 78100169A EP 0000154 B1 EP0000154 B1 EP 0000154B1
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Prior art keywords
formula
compounds
alkyl
acid addition
und
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EP78100169A
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German (de)
French (fr)
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EP0000154A1 (en
Inventor
Roland Dr. Achini
Wolfgang Dr. Oppolzer
Emil Dr. Pfenninger
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Sandoz AG
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Sandoz AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles

Definitions

  • R 2 as an alkyl group is especially ethyl or methyl, very particularly methyl.
  • R 2 and R 3 are independently hydrogen or methyl.
  • the compounds of the formula Ia are obtained wherein R3 is alkyl with 1-2 C atoms, and their acid addition salts, by compounds of the formula II dehydrated and, if desired, the compounds of formula la obtained are converted into their acid addition salts.
  • This dehydration can be carried out by methods known per se, for example in the presence of a mineral acid such as hydrochloric acid or a strong organic acid such as trifluoroacetic acid or with acetic anhydride, thionyl chloride or phosphorus oxychloride, if appropriate at elevated temperature, for example at the boiling point of the reaction mixture.
  • R s CO group is preferably cleaved off by acidic or basic hydrolysis.
  • the basic hydrolysis can be carried out, for example, with the aid of a 1 to about 5N solution of an alkali metal hydroxide, such as sodium or potassium hydroxide.
  • a suitable solvent is, for example, a lower alkanol; methanol and ethanol in particular are suitable.
  • R 5 C0 stands for an easily removable acyl group, for example the trifluoroacetyl group or the benzyloxycarbonyl group
  • the hydrolysis can take place at room temperature or slightly elevated temperature.
  • the hydrolysis is then complete after about 1/2 to about 2 hours.
  • R 5 C0 stands for a less easily removable acyl group, for example for the ethoxycarbonyl group, the procedure is advantageously carried out with heating, preferably at the reflux temperature of the reaction mixture.
  • the reaction then takes about 10 to 20 hours.
  • the acidic hydrolysis can be carried out, for example, with the aid of 2N hydrochloric acid, advantageously at elevated temperature, preferably at the reflux temperature of the reaction mixture.
  • Z represents an R 4 SO 2 group
  • this group can be used under reductive conditions - analogously to known methods - for example with sodium dihydro-bis (2-methoxy-ethoxy) aluminate, or hydrolytically, for example with phenol in 40% Hydrobromic acid / acetic acid.
  • the compounds of the formula I obtained according to the invention may be in the form of the free bases or their acid addition salts.
  • the free bases can be converted into their acid addition salts in a manner known per se and vice versa.
  • the compounds of the formula I according to the invention form acid addition salts with inorganic acids such as hydrochloric acid or with organic acids such as maleic acid.
  • the starting compounds of formula III can, for example, by thermal cycloaddition of a compound of formula Xa or Xb be preserved.
  • This thermal cyclization can take place in an inert organic solvent, preferably with a high boiling point, for example dichlorobenzene. It is useful to work in the absence of oxygen at 160 to 190 ° C.
  • the compounds of the formulas Xa and Xb can be obtained, for example, by using a compound of the formula XI with a compound of formula Xlla or the formula Xllb alkylated, for example in the presence of NaH in hexamethylphosphoric triamide.
  • the compounds of formula I and their pharmacologically acceptable acid addition salts are distinguished by interesting pharmacodynamic properties and can therefore be used as medicines.
  • the compounds show special anti-aggressive properties.
  • the anti-aggressive effects are shown in animal experiments, for example on mice, in a dampening of the aggressive behavior caused by isolation.
  • the substances can be used to treat aggressive arousal states, for example to dampen the aggressive behavior of psychopaths and feeble-minded people.
  • the daily dose to be used is approximately 1 to 30 mg. If necessary, this dose can be administered in two to two portions or as a slow-release form. For example, for oral applications, the partial doses of about 0.25 to 15 mg of the compounds of the formula in addition to solid or liquid carriers.
  • the substances in higher doses also have central damping properties.
  • the central damping effects are shown in animal experiments e.g. on mice when measuring motor activity in the climbing test. Due to their central depressant effects, the substances can be used in psychiatry to treat arousal.
  • the daily dose to be used is approximately 10 to 200 mg. If necessary, this dose can be administered in two to four portions or as a slow-release form.
  • the partial doses of about 2.5 to 100 mg of the compounds of the formula I in addition to solid or liquid carriers.
  • the invention also relates to medicaments which contain a compound of the formula I.
  • These remedies for example a solution or a tablet, can be prepared by known methods using the customary auxiliaries and carriers.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Die Erfindung betrifft neue Verbindungen der Formel I

Figure imgb0001
worin

  • R1 für Wasserstoff, Fluor, Chlor, Brom, Alkyl mit 1-4 C-Atomen,
  • R2 für Wasserstoff oder Alkyl mit 1-4 C-Atomen und
  • R3 für Wasserstoff oder Alkyl mit 1-2 C-Atomen

stehen, und ihre Säureadditionssalze sowie Verfahren zu ihrer Herstellung.The invention relates to new compounds of formula I.
Figure imgb0001
 wherein
  • R 1 for hydrogen, fluorine, chlorine, bromine, alkyl with 1-4 C atoms,
  • R 2 for hydrogen or alkyl with 1-4 C atoms and
  • R 3 for hydrogen or alkyl with 1-2 C atoms

stand, and their acid addition salts and processes for their preparation.

In der obigen Formel steht R2 als Alkylgruppe besonders für Aethyl oder Methyl, ganz besonders für Methyl. Vorzugsweise bedeuten R2 und R3 unabhängig voneinander Wasserstoff oder Methyl.In the above formula, R 2 as an alkyl group is especially ethyl or methyl, very particularly methyl. Preferably R 2 and R 3 are independently hydrogen or methyl.

Erfindungsgemäss gelangt man zu den Verbindungen der Formel la

Figure imgb0002
worin R3 für Alkyl mit 1-2 C-Atomen steht, und ihren Säureadditionssalzen, indem man Verbindungen der Formel II
Figure imgb0003
dehydratisiert und gewünschtenfalls die erhaltenen Verbindungen der Formel la in ihre Säureadditionssalze überführt. Diese Dehydratisierung kann nach an sich bekannten Methoden, z.B. in Gegenwart einer Mineralsäure wie Salzsäure oder einer starken organischen Säure wie Trifluoressigsäure oder mit Essigsäureanhydrid, Thionylchlorid oder Phosphoroxychlorid, gegebenenfalls bei erhöhter Temperatur, z.B. bei Siedetemperatur des Reaktionsgemisches, durchgeführt werden.According to the invention, the compounds of the formula Ia are obtained
Figure imgb0002
 wherein R3 is alkyl with 1-2 C atoms, and their acid addition salts, by compounds of the formula II
Figure imgb0003
 dehydrated and, if desired, the compounds of formula la obtained are converted into their acid addition salts. This dehydration can be carried out by methods known per se, for example in the presence of a mineral acid such as hydrochloric acid or a strong organic acid such as trifluoroacetic acid or with acetic anhydride, thionyl chloride or phosphorus oxychloride, if appropriate at elevated temperature, for example at the boiling point of the reaction mixture.

Erfindungsgemäss gelangt man zu den Verbindungen der Formel Ib

Figure imgb0004
und ihren Säureadditionssalzen, indem man aus Verbindungen der Formel III
Figure imgb0005
worin Z für eine abspaltbare Acylgruppe steht, diese Schutzgruppe entfernt und gewünschtenfalls die erhaltenen Verbindungen der Formel Ib in ihre Säureadditionssalze überführt.

  • Z bedeutet vorzugsweise eine R4SO2- oder RsCO-Gruppe,
    worin
  • R4 für Alkyl mit 1-4 C-Atomen, Phenyl oder p-Tolyl und
  • R5 für Wasserstoff, Alkyl mit 1-4 C-Atomen, CF3, Phenyl, Alkoxy mit 1-4 C-Atomen, Phenoxy oder Benzyloxy
    stehen.
According to the invention, the compounds of formula Ib are obtained
Figure imgb0004
 and their acid addition salts by preparing compounds of formula III
Figure imgb0005
 in which Z stands for an acyl group which can be split off, removes this protective group and, if desired, converts the compounds of the formula Ib obtained into their acid addition salts.
  • Z preferably denotes an R 4 SO 2 or R s CO group,
    wherein
  • R 4 for alkyl with 1-4 C atoms, phenyl or p-tolyl and
  • R 5 for hydrogen, alkyl with 1-4 C atoms, CF 3 , phenyl, alkoxy with 1-4 C atoms, phenoxy or benzyloxy
    stand.

Die erfindungsgemässe Abspaltung der Gruppe Z aus den Verbindungen der Formel III kann nach an sich bekannten Methoden durchgeführt werden.The cleavage of group Z according to the invention from the compounds of the formula III can be carried out by methods known per se.

Die Abspaltung einer RsCO-Gruppe erfolgt vorzugsweise durch saure oder basische Hydrolyse.An R s CO group is preferably cleaved off by acidic or basic hydrolysis.

Die basische Hydrolyse kann z.B. mit Hilfe einer 1- bis etwa 5N-Lösung eines Alkalimetallhydroxids wie Natrium-oder Kaliumhydroxid durchgeführt werden. Ein geeignetes Lösungsmittel ist z.B. ein niederes Alkanol; insbesondere Methanol und Aethanol sind geeignet. Steht R5C0 für eine leicht abspaltbare Acylgruppe, z.B. die Trifluoracetylgruppe oder die Benzyloxycarbonylgruppe, so kann die Hydrolyse bei Raumtemperatur bzw. leicht erhöhter Temperatur erfolgen. Die Hydrolyse ist dann nach etwa 1/2 bis etwa 2 Stunden vollendet. Steht R5C0 für eine weniger leicht abspaltbare Acylgruppe, z.B. für die Aethoxycarbonylgruppe, so arbeitet man zweckmässig unter Erwärmung, vorzugsweise unter Rückflusstemperatur des Reaktionsgemisches. Die Reaktion dauert dann etwa 10 bis 20 Stunden. Die saure Hydrolyse kann beispielsweise mit Hilfe von 2N Chlorwasserstoffsäure, zweckmässig bei erhöhter Temperatur, vorzugsweise bei Rückflusstemperatur des Reaktionsgemisches erfolgen. Steht Z für eine R4SO2-Gruppe, so kann diese Gruppe unter reduktiven Bedingungen - analog zu bekannten Methoden -, beispielsweise mit Natriumdihydro-bis-(2-methoxy- äthoxy)-aluminat, oder hydrolytisch, beispielsweise mit Phenol in 40% Bromwasserstoffsäure/Essigsäure, gespalten werden.The basic hydrolysis can be carried out, for example, with the aid of a 1 to about 5N solution of an alkali metal hydroxide, such as sodium or potassium hydroxide. A suitable solvent is, for example, a lower alkanol; methanol and ethanol in particular are suitable. If R 5 C0 stands for an easily removable acyl group, for example the trifluoroacetyl group or the benzyloxycarbonyl group, the hydrolysis can take place at room temperature or slightly elevated temperature. The hydrolysis is then complete after about 1/2 to about 2 hours. If R 5 C0 stands for a less easily removable acyl group, for example for the ethoxycarbonyl group, the procedure is advantageously carried out with heating, preferably at the reflux temperature of the reaction mixture. The reaction then takes about 10 to 20 hours. The acidic hydrolysis can be carried out, for example, with the aid of 2N hydrochloric acid, advantageously at elevated temperature, preferably at the reflux temperature of the reaction mixture. If Z represents an R 4 SO 2 group, this group can be used under reductive conditions - analogously to known methods - for example with sodium dihydro-bis (2-methoxy-ethoxy) aluminate, or hydrolytically, for example with phenol in 40% Hydrobromic acid / acetic acid.

Die erfindungsgemäss erhaltenen Verbindungen der Formel I können in Form der freien Basen oder ihrer Säureadditionssalze vorliegen.The compounds of the formula I obtained according to the invention may be in the form of the free bases or their acid addition salts.

Die freien Basen können auf an sich bekannte Weise in ihre Säureadditionssalze überführt werden und umgekehrt. So können die erfindungsgemässen Verbindungen der Formel I z.B. mit anorganischen Säuren wie Chlorwasserstoffsäure oder mit organischen Säuren wie Maleinsäure Säureadditionssalze bilden.The free bases can be converted into their acid addition salts in a manner known per se and vice versa. For example, the compounds of the formula I according to the invention form acid addition salts with inorganic acids such as hydrochloric acid or with organic acids such as maleic acid.

Die Ausgangsverbindungen der Formel II können beispielsweise wie folgt erhalten werden:

  • a) Alkylierung eines Amins der Formel IV
    Figure imgb0006
    mit einem Cinnamylhalogenid der Formel V
    Figure imgb0007
    in Gegenwart einer Base, z.B. NaOH, oder in einem Ueberschuss des Amins der Formel IV. Die Alkylierung in Gegenwart von NaOH erfolgt vorzugsweise in einem Wasser-Methylenchlorid-Gemisch unter Zusatz eines Phasentransferkatalysators wie Benzyl-tri-(n-butyl)-ammoniumbromid.
  • b) Cyclisierung der erhaltenen Verbindung der Formel VI
    Figure imgb0008
    mit einer Base, z.B. NaH in Hexamethylphosphorsäuretriamid oder Na0C2H5 in Dimethylformamid, zu einer Verbindung der Formel VII
    Figure imgb0009
  • c) Hydrolyse und Cyclisierung der Verbindung der Formel VII in Gegenwart einer Säure wie z.B. Polyphosphorsäure zu einer Verbindung der Formel VIII
    Figure imgb0010
  • d) 1) falls R2 für Wasserstoff steht: Reduktion des Ketons der Formel VIII zu dem Alkohol der Formel IXa
    Figure imgb0011
    z.B. mit komplexen Metallhydriden wie LiAIH4 oder NaBH4 in einem geeigneten Lösungsmittel wie z.B. Aether oder Tetrahydrofuran bzw. Aethanol;
  • 2) falls R2 für Alkyl steht: Umsetzung mit einer metallorganischen Verbindung, z.B. R2MgHal oder RLi, worin R2 eine Alkylgruppe mit 1-4 C-Atomen bedeutet, und anschliessende Hydrolyse zu dem Alkohol der Formel IXb
    Figure imgb0012
The starting compounds of the formula II can be obtained, for example, as follows:
  • a) Alkylation of an amine of formula IV
    Figure imgb0006
     with a cinnamyl halide of formula V
    Figure imgb0007
     in the presence of a base, for example NaOH, or in an excess of the amine of the formula IV. The alkylation in the presence of NaOH is preferably carried out in a water / methylene chloride mixture with the addition of a phase transfer catalyst such as benzyl-tri- (n-butyl) ammonium bromide.
  • b) cyclization of the compound of formula VI obtained
    Figure imgb0008
     with a base, for example NaH in hexamethylphosphoric triamide or Na0C 2 H 5 in dimethylformamide, to give a compound of the formula VII
    Figure imgb0009
  • c) hydrolysis and cyclization of the compound of formula VII in the presence of an acid such as polyphosphoric acid to a compound of formula VIII
    Figure imgb0010
  • d) 1) if R 2 is hydrogen: reduction of the ketone of the formula VIII to the alcohol of the formula IXa
    Figure imgb0011
     eg with complex metal hydrides such as LiAIH 4 or NaBH 4 in a suitable solvent such as ether or tetrahydrofuran or ethanol;
  • 2) if R 2 is alkyl: reaction with an organometallic compound, for example R2MgHal or RLi, in which R2 is an alkyl group with 1-4 C atoms, and subsequent hydrolysis to the alcohol of the formula IXb
    Figure imgb0012

Die Verbindungen der Formeln IV und V sind bekannt oder können nach an sich bekannten Methoden hergestellt werden.The compounds of the formulas IV and V are known or can be prepared by methods known per se.

Die Ausgangsverbindungen der Formel III können z.B. durch thermische Cycloaddition einer Verbindung der Formel Xa

Figure imgb0013
oder Xb
Figure imgb0014
erhalten werden.The starting compounds of formula III can, for example, by thermal cycloaddition of a compound of formula Xa
Figure imgb0013
 or Xb
Figure imgb0014
 be preserved.

Diese thermische Cyclisierung kann in einem inerten organischen Lösungsmittel mit vorzugsweise hohem Siedepunkt, beispielsweise Dichlorbenzol, erfolgen. Man arbeitet zweckmässig unter Sauerstoffausschluss bei 160 bis 190°C.This thermal cyclization can take place in an inert organic solvent, preferably with a high boiling point, for example dichlorobenzene. It is useful to work in the absence of oxygen at 160 to 190 ° C.

Zu den Verbindungen der Formeln Xa und Xb gelangt man z.B., indem man eine Verbindung der Formel XI

Figure imgb0015
mit einer Verbindung der Formel Xlla
Figure imgb0016
bzw. der Formel Xllb
Figure imgb0017
alkyliert, z.B. in Gegenwart von NaH in Hexamethylphosphorsäuretriamid.The compounds of the formulas Xa and Xb can be obtained, for example, by using a compound of the formula XI
Figure imgb0015
 with a compound of formula Xlla
Figure imgb0016
 or the formula Xllb
Figure imgb0017
 alkylated, for example in the presence of NaH in hexamethylphosphoric triamide.

Die Verbindungen der Formeln XI, Xlla und Xllb sind bekannt oder nach an sich bekannten Methoden herstellbar.The compounds of the formulas XI, Xlla and Xllb are known or can be prepared by methods known per se.

Die Verbindungen der Formel I und ihre pharmakologisch verträglichen Säureadditionssalze zeichnen sich durch interessante pharmakodynamische Eigenschaften aus und können daher als Heilmittel verwendet werden. Insbesondere zeigen die Verbindungen antiaggressive Eigenschaften. Die antiaggressiven Wirkungen zeigen sich im Tierversuch z.B. an Mäusen in einer Dämpfung des durch Isolation bedingten aggressiven Verhaltens.The compounds of formula I and their pharmacologically acceptable acid addition salts are distinguished by interesting pharmacodynamic properties and can therefore be used as medicines. Ins the compounds show special anti-aggressive properties. The anti-aggressive effects are shown in animal experiments, for example on mice, in a dampening of the aggressive behavior caused by isolation.

Aufgrund ihrer aggressionshemmenden Eigenschaften können die Substanzen zur Behandlung von aggressiven Erregungszuständen, beispielsweise zur Dämpfung von aggressivem Verhalten von Psychopathen und Schwachsinnigen, Verwendung finden. Die zu verwendende Tagesdosis liegt bei etwa 1 bis 30 mg. Diese Dosis kann nötigenfalls in zwei bis zier Anteilen oder auch als Retardform verabreicht werden. So enthalten z.B. für orale Applikationen die Teildosen etwa 0,25 bis 15 mg der Verbindungen der Formel neben festen oder flüssigen Trägersubstanzen.Due to their anti-corrosive properties, the substances can be used to treat aggressive arousal states, for example to dampen the aggressive behavior of psychopaths and feeble-minded people. The daily dose to be used is approximately 1 to 30 mg. If necessary, this dose can be administered in two to two portions or as a slow-release form. For example, for oral applications, the partial doses of about 0.25 to 15 mg of the compounds of the formula in addition to solid or liquid carriers.

Ausserdem besitzen die Substanzen in höheren Dosen auch zentraldämpfende Eigenschaften. Die zentraldämpfenden Wirkungen zeigen sich im Tierversuch z.B. an Mäusen bei der Messung der motorischen Aktivität im Klettertest. Aufgrund ihrer zentraldämpfenden Wirkungen können die Substanzen in der Psychiatrie zur Behandlung von Erregungszuständen Verwendung finden. Die zu verwendende Tagesdosis liegt bei etwa 10 bis 200 mg. Diese Dosis kann nötigenfalls in zwei bis vier Anteilen oder auch als Retardform verabreicht werden. So enthalten z.B. für orale Applikationen die Teildosen etwa 2,5 bis 100 mg der Verbindungen der Formel I neben festen oder flüssigen Trägersubstanzen.In addition, the substances in higher doses also have central damping properties. The central damping effects are shown in animal experiments e.g. on mice when measuring motor activity in the climbing test. Due to their central depressant effects, the substances can be used in psychiatry to treat arousal. The daily dose to be used is approximately 10 to 200 mg. If necessary, this dose can be administered in two to four portions or as a slow-release form. For example, for oral applications, the partial doses of about 2.5 to 100 mg of the compounds of the formula I in addition to solid or liquid carriers.

Die Erfindung betrifft auch Heilmittel, die eine Verbindung der Formel I enthalten. Diese Heilmittel, beispielsweise eine Lösung ode eine Tablette, können nach bekannten Methoden, unter Verwendung der üblichen Hilfsund Trägerstoffe, hergestellt werden.The invention also relates to medicaments which contain a compound of the formula I. These remedies, for example a solution or a tablet, can be prepared by known methods using the customary auxiliaries and carriers.

In den nachfolgenden Beispielen erfolgen alle Temperaturangaben in Celsiusgraden.In the following examples, all temperatures are given in degrees Celsius.

Beispiel 1example 1 6 - Chlor - 9,9a - dihydro - 2,4 - dimethyl- benz(f)isoindolin - hydrochlorid6 - chlorine - 9.9a - dihydro - 2,4 - dimethylbenz (f) isoindoline - hydrochloride

Eine Lösung von 14 g 6 - Chlor - 3a,4,9,9a - tetrahydro - 2,4 - dimethyl- benz[f]isoindolin - 4 - ol in 140 ml Trifluoressigsäure wird eine Stunde bei Raumtemperatur gerührt und anschliessend eingedampft. Der Rückstand wird in eiskalte wässrige Natronlauge aufgenommen, mit Methylenchlorid extrahiert, die organische Phase über Natriumsulfat getrocknet und eingedampft. Durch Kristallisation des Rückstandes aus methanolischer Salzsäure-Aether erhält man die Titelverbindung; Smp. 253-255°.A solution of 14 g of 6-chloro-3a, 4,9,9a-tetrahydro-2,4-dimethyl-benz [f] isoindolin-4-ol in 140 ml of trifluoroacetic acid is stirred for one hour at room temperature and then evaporated. The residue is taken up in ice-cold aqueous sodium hydroxide solution, extracted with methylene chloride, the organic phase dried over sodium sulfate and evaporated. The title compound is obtained by crystallization of the residue from methanolic hydrochloric acid ether; Mp 253-255 °.

Analog erhält man unter Verwendung der entsprechenden Ausgangsverbindungen:Analogously, using the corresponding starting compounds, one obtains:

Beispiel 2Example 2 9,9a - Dihydro - 2 - methylbenz[f]isoindolin - hydrochlorid9,9a - dihydro - 2 - methylbenz [f] isoindoline hydrochloride

Smp. 219-229 (Zers.)M.p. 219-229 (dec.)

Beispiel 3Example 3 9,9a - Dihydro - 2,4 - dimethylbenz[f]isoindolin - hydrogenfumarat9,9a - dihydro - 2,4 - dimethylbenz [f] isoindoline - hydrogen fumarate

Smp. 205-206°M.p. 205-206 °

Beispiel 4Example 4 6 - Chlor - 9,9a - dihydro 2 - methyl- benz[f]isoindolin - hydrogenfumarat6 - chlorine - 9.9a - dihydro 2 - methylbenz [f] isoindoline - hydrogen fumarate

Smp. 211-212°M.p. 211-212 °

Beispiel 5Example 5 2 - Aethyl - 9,9a - dihydro - 4 - methyl- benz[f]isoindolin - hydrochlorid2-ethyl-9.9a-dihydro-4-methyl-benz [f] isoindoline-hydrochloride

Smp. 237-239° (Zers.)Mp 237-239 ° (dec.)

Beispiel 6Example 6 9,9a - Dihydro - 8 - methoxy - 2 - methyl- benz[f]isoindolin - hydrogenfumarat9.9a - dihydro - 8 - methoxy - 2 - methylbenz [f] isoindoline - hydrogen fumarate

Smp. 185-187 (Zers.)M.p. 185-187 (dec.)

Die im Beispiel 1 verwendete Ausgangsverbindung kann auf folgende Weise hergestellt werden:

  • a) Zu einem Gemisch von 42 g 3 - Methylamino - propionitril und 8,9 g Benzyl - tri - (n - butyl)ammoniumbromid in 1 Liter Methylenchlorid und 500 ml 2N Natronlauge wird unter Rühren in einer Stickstoffatmosphäre bei Raumtemperatur eine Lösung von 116 g p-Chlorcinnamylbromid in 500 ml Methylenchlorid getropft und die Emulsion 65 Stunden bei Raumtemperatur gerührt. Die organische Phase wird abgetrennt, mit Wasser gewaschen, über Natriumsulfat getrocknet und eingedampft. Man erhält 3 - [N - (p - Chlorcinnamyl) - methylamino]propionitril; Smp. des Hydrogenoxalots 143°.
  • b) Zu einer Suspension von 36 g Natriumhydrid (80% in Mineralöl) in 2 Hexamethylphosphorsäuretriamid (HMPT) werden bei 0-5° unter Rühren und in einer Stickstoffatmosphäre innert 1¼ Stunden 252 g 3 - [N - (p - Chlorcinnamyl) - methylamino]propionitril in 1 Liter HMPT getropft und das Gemisch bei Raumtemperatur 16 Stunden gerührt. Dann wird das Gemisch unter Eiskühlung mit Wasser versetzt, mit Aether extrahiert, die organische Phase mit Wasser gewaschen, über Natriumsulfat getrocknet und eingedampft. Man erhält 4 - (p - Chlorbenzyl) - 1 - methylpyrrolidin - 3 - carbonitril; Smp. des Hydrogenoxalats 170-172°.
  • c) Zu 500 g Polyphosphorsäure werden bei 50° 25 ml Wasser, dann 50 g 4 - (p - Chlorbenzyl) - 1 - methylpyrrolidin - 3 - carbonitril getropft und das Gemisch 1 Stunde bei 125°, dann 2t Stunden bei 160° gerührt. Das abgekühlte Gemisch wird dann mit Eis und 1 Liter 50%-iger Natronlauge versetzt und mit Essigsäureäthylester extrahiert. Die organische Phase wird mit Wasser gewaschen, über Natriumsulfat getrocknet und eingedampft. Man erhält 6 - Chlor - 3a,4,9,9a - tetrahydro - 2 - methylbenz[f]isoindolin - 4 - on; Smp. des Hydrogenmaleinats 148 bis 150°.
  • d) Zu 170 ml einer ca. 5%-igen Lösung von Methyllithium in Aether wird bei Raumtemperatur unter Rühren in einer Stickstoffatmosphäre eine Lösung von 43 g 6 - Chlor - 3a,4,9,9a - tetrahydro - 2 - methylbenz[f]-isoindolin - 4 - on in 430 ml Tetrahydrofuran getropft, das Gemisch 5½ Stunden bei Raumtemperatur gerührt, dann mit gesättigter wässriger Ammonchloridlösung und Wasser versetzt und mit Methylenchlorid extrahiert. Die organische Phase wird über Natriumsulfat getrocknet und eingedampft. Beim Kristallisieren des Rückstandes aus Aether - Petroläther erhält man 6 - Chlor - 3a,4,9,9a - tetrahydro - 2,4 - dimethylbenz[f]isoindolin - 4 - ol; Smp. 125 bis 130°.
The starting compound used in Example 1 can be prepared in the following way:
  • a) A solution of 116 g is added to a mixture of 42 g of 3-methylamino-propionitrile and 8.9 g of benzyl-tri - (n-butyl) ammonium bromide in 1 liter of methylene chloride and 500 ml of 2N sodium hydroxide solution with stirring in a nitrogen atmosphere at room temperature p-Chlorcinnamyl bromide was added dropwise in 500 ml of methylene chloride and the emulsion was stirred at room temperature for 65 hours. The organic phase is separated off, washed with water, dried over sodium sulfate and evaporated. 3 - [N - (p - Chlorcinnamyl) methylamino] propionitrile is obtained; Mp of the hydrogen oxalot 143 °.
  • b) To a suspension of 36 g of sodium hydride (80% in mineral oil) in 2 hexamethylphosphoric triamide (HMPT) at 0-5 ° with stirring and in a nitrogen atmosphere within 25 minutes 252 g of 3 - [N - (p - chlorcinnamyl) - methylamino ] propionitrile added dropwise in 1 liter of HMPT and the mixture was stirred at room temperature for 16 hours. Water is then added to the mixture while cooling with ice, the mixture is extracted with ether, the organic phase is washed with water, dried over sodium sulfate and evaporated. 4 - (p-Chlorobenzyl) -1-methylpyrrolidine-3-carbonitrile is obtained; Mp of the hydrogen oxalate 170-172 °.
  • c) 25 ml of water, then 50 g of 4 - (p-chlorobenzyl) -1-methylpyrrolidine-3-carbonitrile are added dropwise to 500 g of polyphosphoric acid at 50 ° and the mixture is stirred at 125 ° for 1 hour and then at 160 ° for 2 hours. The cooled mixture is then mixed with ice and 1 liter of 50% sodium hydroxide solution and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated. 6 - chlorine - 3a, 4,9,9a - tetrahydro - 2 - are obtained methylbenz [f] isoindolin - 4 - one; Mp of the hydrogen maleinate 148 to 150 °.
  • d) A solution of 43 g of 6-chloro-3a, 4,9,9a-tetrahydro-2-methylbenz [f] is added to 170 ml of an approximately 5% solution of methyl lithium in ether at room temperature with stirring in a nitrogen atmosphere. -isoindolin - 4 - one dropped in 430 ml of tetrahydrofuran, the mixture was stirred for 5½ hours at room temperature, then mixed with saturated aqueous ammonium chloride solution and water and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated. When the residue is crystallized from ether / petroleum ether, 6-chloro-3a, 4,9,9a-tetrahydro-2,4-dimethylbenz [f] isoindolin-4-ol is obtained; Mp 125 to 130 °.

Die für die Verbindung des Beispiels 4 benötigte Ausgangsverbindung kann folgendermassen hergestellt werden:

  • e) Eine Lösung von 10 g 6 - Chlor - 3a,4,9,9a - tetrahydro - 2 - methyl- benz[f]isoindolin - 4 - on in 100 ml Aethanol wird bei 0-5° mit 1,6 g Natriumborhydrid in 20 ml Aethanol versetzt, 1 Stunde bei Raumtemperatur weitergerührt und dann mit Wasser versetzt und eingedampft. Der Rückstand wird in 10%-iger Weinsäure aufgenommen, die wässrige Phase mit Aether extrahiert, mit 2N Natronlauge gestellt und mit Essigsäureäthylester extrahiert. Die Essigesterphase wird über Natriumsulfat getrocknet und eingedampft. Durch Krstallisation des Rückstandes aus Methylenchlorid - Pentan erhält man 6 - Chlor - 3a,4,9,9a - tetrahydro - 2 - methyl- benz[f]isoindolin - 4 - ol; Smp. 178-182°.
The starting compound required for the connection of Example 4 can be produced as follows:
  • e) A solution of 10 g of 6-chloro-3a, 4,9,9a-tetrahydro-2-methyl-benz [f] isoindolin-4-one in 100 ml of ethanol is at 0-5 ° with 1.6 g of sodium borohydride added in 20 ml of ethanol, stirring was continued for 1 hour at room temperature and then mixed with water and evaporated. The residue is taken up in 10% tartaric acid, the aqueous phase extracted with ether, made up with 2N sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate phase is dried over sodium sulfate and evaporated. Crystallization of the residue from methylene chloride - pentane gives 6 - chloro - 3a, 4,9,9a - tetrahydro - 2 - methylbenz [f] isoindolin - 4 - ol; M.p. 178-182 °.

Beispiel 7Example 7 9,9a - Dihydrobenz[f]isoindolin - hydrochlorid9,9a - dihydrobenz [f] isoindoline hydrochloride

Ein Gemisch von 10 g 9,9a - Dihydro- benz[f]isoindolin - 2 - trifluoracetamid und 50 ml 3N Kaliumhydroxid in Methanol wird 16 Stunden bei Raumtemperatur stehen gelassen, die Lösung eingedampft, der Rückstand in Wasser aufgenommen und mit Aether extrahiert. Die Aetherphase wird über Natriumsulfat getrocknet und eingedampft. Der Rückstand wird mit methanolischer Salzsäure eingedampft und aus Methanol-Aether kristallisiert. Man erhält die Titelverbindung vom Smp. 240-2480 (Zers.).A mixture of 10 g of 9.9a-dihydrobenz [f] isoindoline-2-trifluoroacetamide and 50 ml of 3N potassium hydroxide in methanol is left to stand at room temperature for 16 hours, the solution is evaporated, the residue is taken up in water and extracted with ether. The ether phase is dried over sodium sulfate and evaporated. The residue is evaporated with methanolic hydrochloric acid and crystallized from methanol ether. The title compound of mp 240-248 0 (decomp.) Is obtained.

Analog erhält man unter Verwendung der entsprechenden Ausgangsverbindungen:Analogously, using the corresponding starting compounds, one obtains:

Beispiel 8Example 8 9,9a - Dihydro - 4 - methylbenz[f]isoindolin - hydrogenfumarat9,9a - dihydro - 4 - methylbenz [f] isoindoline - hydrogen fumarate

Smp. 224-2260 M.p. 224-226 0

Beispiel 9Example 9 9,9a - Dihydro - 6 - methylbenz[f]isoindolin9,9a - dihydro - 6 - methylbenz [f] isoindoline

Smp. 116-118°M.p. 116-118 °

Das im Beispiel 6 verwendete 9,9a - Dihydrobenz[f]isoindolin - 2 - trifluoracetamid kann auf folgende Art hergestellt werden:

  • a) Zu einer Suspension von 27 g Natriumhydrid in 400 ml Hexamethylphosphorsäuretriamid (HMPT) wird unter Eiskühlung und Rühren in einer Stickstoffatmosphäre eine Lösung von 250 g N-Cinnamyltrifluoracetamid in 1 Liter HMPT getropft. Nach Beendigung der Gasentwicklung wird eine Lösung von 130 g 1,3 - Dichlorpropen und 1 g Natriumjodid in 1 Liter HMPT zugetropft und das Gemisch 16 Stunden bei Raumtemperatur gerührt. Dann wird das Reaktionsgemisch auf Wasser gegossen und mit Aether extrahiert. Die über Natriumsulfat getrocknete Aetherlösung wird eingedampft und der ölige Rückstand mit Toluol an 3,5 kg Kieselgel chromatographiert. Man erhält N - (3 - Chlor - 2 - propenyl) - N - cinnamyltrifluoracetamid als Oel.
  • b) Eine Lösung von 267 g N - (3 - Chlor - 2 - propenyl) - N - cinnamyltrifluoracetamid in 5,5 Liter o-Dichlorbenzol wird 30 Stunden in einer Argonatmosphäre am Rückfluss zum Sieden erhitzt und anschliessend eingedampft. Der Rückstand wird mit Toluol an 6 kg Kieselgel chromatographiert. Nach Umkristallisation aus Methylenchlorid-Aether erhält man 9,9a - Dihydrobenz[f]isoindolin - 2 - trifluoracetamid vom Smp. 150-155°.
The 9,9a-dihydrobenz [f] isoindoline-2-trifluoroacetamide used in Example 6 can be prepared in the following way:
  • a) A solution of 250 g of N-cinnamyltrifluoroacetamide in 1 liter of HMPT is added dropwise to a suspension of 27 g of sodium hydride in 400 ml of hexamethylphosphoric triamide (HMPT) with ice cooling and stirring in a nitrogen atmosphere. After the evolution of gas has ceased, a solution of 130 g of 1,3-dichloropropene and 1 g of sodium iodide in 1 liter of HMPT is added dropwise and the mixture is stirred at room temperature for 16 hours. Then the reaction mixture is poured onto water and extracted with ether. The ether solution, dried over sodium sulfate, is evaporated and the oily residue is chromatographed with toluene on 3.5 kg of silica gel. N - (3 - chloro - 2 - propenyl) - N - cinnamyltrifluoroacetamide is obtained as an oil.
  • b) A solution of 267 g of N - (3 - chloro - 2 - propenyl) - N - cinnamyltrifluoroacetamide in 5.5 liters of o-dichlorobenzene is heated to reflux in an argon atmosphere for 30 hours and then evaporated. The residue is chromatographed on 6 kg of silica gel using toluene. After recrystallization from methylene chloride ether, 9.9a-dihydrobenz [f] isoindoline-2-trifluoroacetamide of mp 150-155 ° is obtained.

Claims (10)

1. New compounds of formula I
Figure imgb0026
wherein
R1 is hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms.
R2 is hydrogen or alkyl of 1 to 4 carbon atoms, and
R3 is hydrogen or alkyl of 1 or 2 carbon atoms, and their acid addition salts.
2. Processes for the production of compounds of formula I, and their acid addition salts, as defined in claim 1, characterized in that
a) the production of compounds of formula la
Figure imgb0027
wherein R3 is alkyl of 1 or 2 carbon atoms, compounds of formula II
Figure imgb0028
are dehydrated or
b) for production of compounds of formula Ib
Figure imgb0029
the protecting group is removed from compounds of formula III
Figure imgb0030
wherein Z is a removable acyl group, and if desired the resultant compounds of formula la or Ib are converted into acid addition salt form.
3. Compounds of formula la, as defined in claim 1,
Figure imgb0031
wherein
R1 and R2 are as defined in claim 1, and
R'3 is alkyl of 1 or 2 carbon atoms,

and their acid addition salts.
4. Compounds of formula Ib as defined in claim 1
Figure imgb0032
wherein
R1 and R2 are as defined in claim 1

and their acid addition salts.
5. The compound 9,9a - dihydro - 2,4 - dimethylbenz[f]isoindoline according to claim 1, and its acid addition salts.
6. A medicament containing a compound of any one of the claims 1, 3, 4 and 5.
7. A compound according to any one of claims 1, 3, 4 and 5 for use as a medicament.
8. A compound according to any one of claims 1, 3, 4 and 5 for use in the treatment of aggressive excitation conditions.
9. A compound according to any one of claims 1, 3, 4 and 5 for use in the treatment of excitation conditions.
EP78100169A 1977-06-28 1978-06-15 New benz(f)isoindolines, their preparation and medicaments containing them Expired EP0000154B1 (en)

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DK136420B (en) * 1972-09-29 1977-10-10 Sandoz Ag Analogous process for the preparation of isoindoline compounds.
US4014899A (en) * 1973-10-29 1977-03-29 Ciba-Geigy Corporation 5,6-Benzoisoindolines
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