EP0000013B1 - 4-phenyl-8-amino-tetrahydroisoquinolines, pharmaceutical compositions containing them and process for preparation of these compositions - Google Patents

4-phenyl-8-amino-tetrahydroisoquinolines, pharmaceutical compositions containing them and process for preparation of these compositions Download PDF

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Publication number
EP0000013B1
EP0000013B1 EP78100025A EP78100025A EP0000013B1 EP 0000013 B1 EP0000013 B1 EP 0000013B1 EP 78100025 A EP78100025 A EP 78100025A EP 78100025 A EP78100025 A EP 78100025A EP 0000013 B1 EP0000013 B1 EP 0000013B1
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acid
amino
phenyl
pharmaceutical compositions
tetrahydroisoquinolines
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French (fr)
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EP0000013A1 (en
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Karl Dr. Schmitt
Irmgard Dr. Hoffmann
Ulrich Dr. Schacht
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Hoechst AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, ***e

Definitions

  • German Patent 1,795,829 describes 4-phenyl-8-amino-tetrahydroisoquinolines of the general formula I. wherein R 1 is hydrogen, a lower alkyl or the benzyl group, R 2 is hydrogen, the methyl group, chlorine or fluorine atoms, R 2 'is hydrogen, methyl, methoxy, hydroxyl or halogen atoms, R 3 and R 4 are hydrogen or a lower alkyl group and R 5 is hydrogen, a chlorine atom or a methoxy group in the 5- or 6-position, known.
  • the invention therefore relates to compounds of the general formula II in which either R 1 is bromine and R 2 is hydrogen or both R 1 and R 2 are chlorine.
  • the new compounds of the general formula II are among others by an increased effect in the serotonin uptake inhibition test compared to the previously known class of compounds. While the previously known compounds of formula 1 (with the exception of compounds of formula II) only inhibit serotonin uptake in higher concentrations, the compounds of formula II bring about an inhibition of serotonin uptake which was not previously possible with the compounds of formula I. could achieve.
  • the inhibition of serotonin uptake manifests itself in an increased emotional mood-enhancing effect and is therefore of considerable importance for therapy.
  • the compounds of formula II are therefore valuable pharmaceuticals which are used for the treatment of depressive states.
  • the compounds of the formula II are prepared by the process of German patent 1,670,694 by cyclization of the corresponding a- [N- (2-aminobenzyl) -N-methylaminomethyl] benzyl alcohols.
  • the compounds of formula II can form salts with either one or two equivalents of an acid.
  • physiologically acceptable acids are suitable for salt formation.
  • suitable inorganic acids are: hydrohalic acids, such as hydrochloric acid and hydrobromic acid, and also sulfuric acid, phosphoric acid and amidosulfonic acid.
  • organic acids which may be mentioned are: formic acid, acetic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, maleic acid, succinic acid, tartaric acid, benzoic acid, salicylic acid, citric acid, acetic acid or oxyethanesulfonic acid.
  • the base is again prepared from the hydrochloride and is isolated with methylene chloride as an oil (18 g).
  • the carbonyl and nitro groups are then hydrogenated one after the other.
  • the carbonyl group gives 15 g of the hydroxy compound with sodium borohydride (5 g in 50 ml methanol to 18 g acetophenone derivative in 250 ml methanol), the nitro group is now hydrogenated with Raney nickel at normal pressure and room temperature.
  • the hydrogen uptake is as calculated, 14 g of a - [N - 2 - aminobenzyl - N - methylamino - methyl] - 3,4 - dichlorobenzyl alcohol are obtained as an oily product.
  • the base is dissolved with maleic acid (3 g for 8 g base) in ethanol with heating.
  • the maleinate that crystallizes on cooling is recrystallized from ethanol.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Psychiatry (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • General Chemical & Material Sciences (AREA)
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Description

Aus der deutschen Patentschrift 1 795 829 sind 4-Phenyl-8-amino-tetrahydroisochinoline der allgemeinen Formel I

Figure imgb0001
worin R1 Wasserstoff, eine niedere Alkyl- oder die Benzylgruppe, R2 Wasserstoff, die Methylgruppe, Chlor- oder Fluoratome, R2' Wasserstoff, Methyl-, Methoxy-, Hydroxygruppen oder Halogenatome, R3 und R4 Wasserstoff oder eine niedere Alkylgruppe und R5 Wasserstoff, ein Chloratom oder eine Methoxygruppe in 5- oder 6-Stellung bedeuten, bekannt.German Patent 1,795,829 describes 4-phenyl-8-amino-tetrahydroisoquinolines of the general formula I.
Figure imgb0001
 wherein R 1 is hydrogen, a lower alkyl or the benzyl group, R 2 is hydrogen, the methyl group, chlorine or fluorine atoms, R 2 'is hydrogen, methyl, methoxy, hydroxyl or halogen atoms, R 3 and R 4 are hydrogen or a lower alkyl group and R 5 is hydrogen, a chlorine atom or a methoxy group in the 5- or 6-position, known.

Es wurde nun überraschenderweise ge-. funden, daß zwei bisher nicht bekannte Verbindungen die vorbekannte Verbindungsklasse der obigen Formel I in ihrer antidepressiven Wirkung erheblich übertreffen.It has now surprisingly been. found that two previously unknown compounds significantly exceed the previously known class of compounds of formula I in their antidepressant activity.

Gegenstand der Auswahlerfindung sind somit Verbindungen der allgemeinen Formel II

Figure imgb0002
in der entweder R1 für Brom und R2 für Wasserstoff stehen oder sowohl R1 als auch R2 Chlor bedeuten.The invention therefore relates to compounds of the general formula II
Figure imgb0002
 in which either R 1 is bromine and R 2 is hydrogen or both R 1 and R 2 are chlorine.

Die neuen Verbindungen der allgemeinen Formel II Zeichnen sich u.a. durch eine gegenüber der vorbekannten Verbindungsklasse verstärkte Wirkung im Serotonin-Aufnahme-Hemmtest aus. Während die vorbekannten Verbindungen der Formel 1 (mit Ausnahme von Verbindungen der Formel Il) erst in höherer Konzentration die Serotonin-Aufnahme hemmen, bewirken die Verbindungen der Formel II eine Serotonin-Aufnahme-Hemmung, wie man sie bisher mit den Verbindungen der Formel I nicht erzielen konnte.The new compounds of the general formula II are among others by an increased effect in the serotonin uptake inhibition test compared to the previously known class of compounds. While the previously known compounds of formula 1 (with the exception of compounds of formula II) only inhibit serotonin uptake in higher concentrations, the compounds of formula II bring about an inhibition of serotonin uptake which was not previously possible with the compounds of formula I. could achieve.

Die Serotonin-Aufnahme-Hemmung äußert sich in einer verstärkten seelischen stimmungsaufhellenden Wirkung und hat daher für die Therapie erhebliche Bedeutung. Die Verbindungen der Formel II sind daher wertvolle Pharmazeutika, die zur Behandlung von depressiven Zuständen verwendet werden.The inhibition of serotonin uptake manifests itself in an increased emotional mood-enhancing effect and is therefore of considerable importance for therapy. The compounds of formula II are therefore valuable pharmaceuticals which are used for the treatment of depressive states.

Die Herstellung der Verbindungen der Formel II erfolgt nach dem Verfahren der deutschen Patentschrift 1 670 694 durch Cyclisierung der entsprechenden a-[N-(2-Aminobenzyl)-N-methylaminomethyl]-benzylalkohole.The compounds of the formula II are prepared by the process of German patent 1,670,694 by cyclization of the corresponding a- [N- (2-aminobenzyl) -N-methylaminomethyl] benzyl alcohols.

Die Verbindungen der Formel II können sowohl mit einem als auch mit zwei Äquivalenten einer Säure Salze bilden. Im Hinblick auf ihre Verwendung als Heilmittel kommen für die Salzbildung physiologisch verträgliche Säuren in Betracht. Als anorganische Säuren kommen beispielsweise in Betracht: Halogenwasserstoffsäuren, wie Chlorwasserstoffsäure und Bromwasserstoffsäure sowie Schwefelsäure, Phosphorsäure und Amidosulfonsäure. Als organische Säuren seien beispielsweise genannt: Ameisensäure, Essigsäure, Propionsäure, Milchsäure, Glykolsäure, Gluconsäure, Maleinsäure, Bernsteinsäure, Weinsäure, Benzoesäure, Salicylsäure, Zitronensäure, Acetursäure oder Oxyäthansulfonsäure.The compounds of formula II can form salts with either one or two equivalents of an acid. With regard to their use as medicinal products, physiologically acceptable acids are suitable for salt formation. Examples of suitable inorganic acids are: hydrohalic acids, such as hydrochloric acid and hydrobromic acid, and also sulfuric acid, phosphoric acid and amidosulfonic acid. Examples of organic acids which may be mentioned are: formic acid, acetic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, maleic acid, succinic acid, tartaric acid, benzoic acid, salicylic acid, citric acid, acetic acid or oxyethanesulfonic acid.

Beispiel 1example 1

50 g 3,4-Dichloracetophenon werden in 300 ml methylenchlorid mit Brom bei Raumtemperatur bromiert. Das so erhaltene ω-Brom-3,4-dichloracetophenon wird direkt verwendet. Zunächst wird die ω-Bromverbindung in 300 ml Äthanol gelöst. Unter Rühren läßt man bei 60°C die Lösung von 42,6 g N-Methyl-2-nitrobenzyl- amin und 33,1 g N - Äthyl - N,N - diisopropyläthylamin in 100 ml Äthanol hinzutropfen. Nun wird noch 1 Stunde bei Raumtemperatur, dann 2 Stunden unter Sieden gerührt, darauf dampft man zur Trockne ein. Den Rückstand löst man in Wasser und Äther; der letztere wird abgetrennt, mit Kaliumcarbonat gretrocknet und abermals eingedampft.50 g of 3,4-dichloroacetophenone are brominated in 300 ml of methylene chloride with bromine at room temperature. The ω-bromo-3,4-dichloroacetophenone thus obtained is used directly. First, the ω-bromine compound is dissolved in 300 ml of ethanol. While stirring, the solution of 42.6 g of N-methyl-2-nitrobenzylamine and 33.1 g of N-ethyl-N, N-diisopropylethylamine in 100 ml of ethanol is added dropwise at 60 ° C. Now it is stirred for 1 hour at room temperature, then for 2 hours with boiling, then evaporated to dryness. The residue is dissolved in water and ether; the latter is separated off, dried with potassium carbonate and evaporated again.

Der Rückstand bildet mit Athanol/Chlorwasserstoff ein Salz, und man erhält 19 g N - (3,4 - Dichlorphenacyl) - N - methyl - 2 - nitro - benzylamin - hydrochlorid, Fp 165°C (Zers.).The residue forms a salt with ethanol / hydrogen chloride, and 19 g of N - (3,4-dichlorophenacyl) - N-methyl-2-nitro-benzylamine hydrochloride, mp 165 ° C. (dec.) Are obtained.

Aus dem Hydrochlorid stellt man wieder die Base her, die mit Methylenchlorid als Öl (18 g) isoliert wird. Carbonylund Nitrogruppe werden nun nacheinander hydriert. Die Carbonylgruppe gibt mit Natrium-borhydrid (5 g in 50 ml Methanol zu 18 g Acetophenonderivat in 250 ml Methanol) 15 g der Hydroxyverbindung, die Nitrogruppe hydriert man nun mit Raney-Nickel bei Normaldruck und Zimmertemperatur. Die Wasserstoffaufnahme ist wie berechnet, man erhält 14 g a - [N - 2 - Aminobenzyl - N - methylamino - methyl] - 3,4 - dichlorbenzylalkohol als öliges Produkt.The base is again prepared from the hydrochloride and is isolated with methylene chloride as an oil (18 g). The carbonyl and nitro groups are then hydrogenated one after the other. The carbonyl group gives 15 g of the hydroxy compound with sodium borohydride (5 g in 50 ml methanol to 18 g acetophenone derivative in 250 ml methanol), the nitro group is now hydrogenated with Raney nickel at normal pressure and room temperature. The hydrogen uptake is as calculated, 14 g of a - [N - 2 - aminobenzyl - N - methylamino - methyl] - 3,4 - dichlorobenzyl alcohol are obtained as an oily product.

Zur Cyclisierung werden 14 g des erhaltenen Öls in 100 ml Methylenchlorid unter Rühren bei 5 bis 10°C in 70 ml Schwefelsäure (conz.), eingetropft. Man rührt eine Stunde bei Raumtemperatur nach und gießt schließlich auf zerstroßenes Eis. Unter weiterer Kühlung wird mit conz. NaOH neutralisiert, wobei das Reaktionsprodukt in öliger Form ausfällt. Man isoliert die Base mit Methylenchlorid und erhält 8 g des Isochinolinderivates als Base.For the cyclization, 14 g of the oil obtained in 100 ml of methylene chloride are added dropwise in 70 ml of sulfuric acid (conc.) At 5 to 10 ° C. with stirring. You stir an hour at room temperature and finally pours on crushed ice. With further cooling, conz. NaOH neutralizes, the reaction product precipitating in an oily form. The base is isolated with methylene chloride and 8 g of the isoquinoline derivative are obtained as the base.

Die Base wird mit Maleinsäure (3 g für 8 g Base) in Äthanol unter Erwärmen gelöst. Das beim Abkühlen kristallisierende Maleinat wird aus Äthanol umkristallisiert.The base is dissolved with maleic acid (3 g for 8 g base) in ethanol with heating. The maleinate that crystallizes on cooling is recrystallized from ethanol.

Man erhält 3,5 g 8 - Amino - 4 - (3,4 - dichlorphenyl) - 2 - methyl - 1,2,3,4 - tetrahydroisochinolin - hydrogenmaleinat vom Schmelzpunkt Fp 180-183°C.3.5 g of 8-amino-4 - (3,4-dichlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline-hydrogen maleate of melting point mp 180-183 ° C. are obtained.

Beispiel 2Example 2

Ausgehend von 4-Bromacetophenon erhält man gemäß der in Beispiel 1 beschriebenen Arbeitsweise das 8-(Amino-4-(4-bromophersyl)-2 - methyl - 1,2,3,4 - tetrahydroisochinolinhydrogenmaleinat, das bei 189-191 °C schmilzt.Starting from 4-bromoacetophenone, 8- (amino-4- (4-bromophersyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline hydrogen maleate, which melts at 189-191 ° C., is obtained according to the procedure described in Example 1 .

Claims (3)

1. 4 - Phenyl - 8 - amino - tetrahydroiso- quinolines of the formula
Figure imgb0004
in which either R1 denotes bromine and R2 denotes hydrogen or R1 as well as R2 denote chlorine, and their salts with physiologically tolerated acids.
2. Pharmaceutical compositions having antidepressive action characterized by a content of a compound as claimed in claim 1.
3. Process for the manufacture of pharmaceutical compositions having antidepressive action, characterized in that a compound as claimed in claim 1, optionally together with usual carriers and/or stabilizers, are brought into a form suitable for therapeutical administration.
EP78100025A 1977-06-01 1978-06-01 4-phenyl-8-amino-tetrahydroisoquinolines, pharmaceutical compositions containing them and process for preparation of these compositions Expired EP0000013B1 (en)

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DE2724610 1977-06-01
DE19772724610 DE2724610A1 (en) 1977-06-01 1977-06-01 4-PHENYL-8-AMINO-TETRAHYDROISOCHINOLINE

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EP0000013B1 true EP0000013B1 (en) 1980-10-15

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US (1) US4185105A (en)
EP (1) EP0000013B1 (en)
JP (1) JPS543078A (en)
AT (1) AT361482B (en)
AU (1) AU517664B2 (en)
CA (1) CA1093079A (en)
DE (2) DE2724610A1 (en)
DK (1) DK242278A (en)
EG (1) EG13777A (en)
ES (1) ES470226A1 (en)
FI (1) FI781717A (en)
HU (1) HU176978B (en)
IL (1) IL54810A0 (en)
IT (1) IT1094899B (en)
NO (1) NO781896L (en)
PT (1) PT68123A (en)
ZA (1) ZA783122B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0120438A1 (en) * 1983-03-25 1984-10-03 Hoechst Aktiengesellschaft Optical antipodes of 8-amino-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline, process for its preparation and pharmaceutical compositions having an anti-depressive action containing it

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4340600A (en) * 1980-05-22 1982-07-20 Smithkline Corporation Renal dilating methods and compositions using 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines
PH19604A (en) * 1982-06-04 1986-05-27 Egyt Gyogyszervegyeszeti Gyar Isoquinoline derivatives and pharmaceutical compositions containing the same
BG45572A1 (en) * 1986-10-23 1989-07-14 Druzhestven N Izsledovatelski Antiulcer means
EP3300756B1 (en) * 2003-06-10 2020-10-07 ResMed Pty Ltd Multiple stage blower and enclosure therefor

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US3384640A (en) * 1966-03-15 1968-05-21 Bristol Myers Co Amino isoquinolinium salts
DE1670694B2 (en) * 1966-05-05 1976-07-22 Hoechst Ag, 6000 Frankfurt METHOD FOR MANUFACTURING TETRAHYDROISOCHINOLINES

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0120438A1 (en) * 1983-03-25 1984-10-03 Hoechst Aktiengesellschaft Optical antipodes of 8-amino-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline, process for its preparation and pharmaceutical compositions having an anti-depressive action containing it

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NO781896L (en) 1978-12-04
EG13777A (en) 1982-03-31
DK242278A (en) 1978-12-02
AU3670578A (en) 1979-12-06
IL54810A0 (en) 1978-07-31
CA1093079A (en) 1981-01-06
ES470226A1 (en) 1979-01-01
ATA395078A (en) 1980-08-15
IT7823996A0 (en) 1978-05-30
US4185105A (en) 1980-01-22
JPS543078A (en) 1979-01-11
FI781717A (en) 1978-12-02
DE2724610A1 (en) 1978-12-14
DE2860212D1 (en) 1981-01-22
ZA783122B (en) 1979-06-27
PT68123A (en) 1978-06-01
AU517664B2 (en) 1981-08-20
HU176978B (en) 1981-06-28
IT1094899B (en) 1985-08-10
AT361482B (en) 1981-03-10
EP0000013A1 (en) 1978-12-20

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