EP0000013A1 - 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 PDFInfo
- Publication number
- EP0000013A1 EP0000013A1 EP78100025A EP78100025A EP0000013A1 EP 0000013 A1 EP0000013 A1 EP 0000013A1 EP 78100025 A EP78100025 A EP 78100025A EP 78100025 A EP78100025 A EP 78100025A EP 0000013 A1 EP0000013 A1 EP 0000013A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amino
- acid
- tetrahydroisoquinolines
- phenyl
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 *C(C1CI(*)C2)=CC=CC1C2c1ccc(*)c(*)c1 Chemical compound *C(C1CI(*)C2)=CC=CC1C2c1ccc(*)c(*)c1 0.000 description 1
Classifications
-
- 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, cocaine
Definitions
- DOS 1 795 829 are 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.
- 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
- 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 characterized inter alia by by an increased effect in the serotonin uptake inhibition test compared to the previously known class of compounds. While the previously known compounds of the formula I (with the exception of compounds of the formula II) only inhibit serotonin uptake in higher concentrations, the compounds of the formula II bring about an inhibition of serotonin uptake which was not previously possible with the compounds of the 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 N- (2-aminobenzyl) - ⁇ -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 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 in succession.
- 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 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)
- Medicinal Chemistry (AREA)
- Psychiatry (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
4-Phenyl-8-amino-tetrahydroisochinoline der Formel <IMAGE> in der entweder R1 für Brom und R2 für Wasserstoff stehen oder sowohl R1 als auch R2 Chlor bedeuten und deren Salze mit physiologisch unbedenklichen Säuren, daraus hergestellte pharmazeutische Präparate, Verfahren zur Herstellung dieser Präparate und ihre Verwendung zur Behandlung von depressiven Zuständen.4-phenyl-8-amino-tetrahydroisoquinolines of the formula <IMAGE> in which either R1 is bromine and R2 is hydrogen or both R1 and R2 are chlorine and their salts with physiologically acceptable acids, pharmaceutical preparations made therefrom, processes for producing them Preparations and their use for the treatment of depressive conditions.
Description
Aus der deutschen Patentschrift ... (DOS 1 795 829) sind 4-Phenyl-8-amino-tetrahydroisochinoline der allgemeinen Formel I
Es wurde nun überraschenderweise gefunden, 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
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 I (mit Ausnahme von Verbindungen der Formel II) 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 characterized inter alia by by an increased effect in the serotonin uptake inhibition test compared to the previously known class of compounds. While the previously known compounds of the formula I (with the exception of compounds of the formula II) only inhibit serotonin uptake in higher concentrations, the compounds of the formula II bring about an inhibition of serotonin uptake which was not previously possible with the compounds of the 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 N-(2-Aminobenzyl) -α-methylaminomethyl-benzylalkohole.The compounds of the formula II are prepared by the process of German patent 1,670,694 by cyclization of the corresponding N- (2-aminobenzyl) -α-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 genahnt: 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. in the 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. The following may be mentioned as organic acids: 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.
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 42,6g N-Methyl-2-nitrobenzylamin und 33,1 g N-Älthyl-N,N-diisopropyläthyl- amin 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 getrocknet 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 Äthanol/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 are obtained, mp 165 ° C. (dec.).
Aus dem Hydrochlorid stellt man wieder die Base her, die mit Methylenchlorid als öl (18 g) isoliert wird. Carbonyl-und 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 N-2-Aminobenzyl-α-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 in succession. 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 N-2-aminobenzyl-α-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 zerstoßenes 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.) With stirring at 5 to 10 ° C. The mixture is stirred for one hour at room temperature and finally poured onto 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. Da.s 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, melting at mp 180 ° -183 ° C., are obtained.
Ausgehend von 4-Bromacetophenon erhält man gemäß der in Beispiel 1 beschriebenen Arbeitsweise das 8-Amino-4-(4-bromphenyl)-2-methyl-1,2,3,4-tetrahydroisochinolin-hydrogen- maleinat, das bei 189-191°C schmilzt.Starting from 4-bromoacetophenone, 8-amino-4- (4-bromophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline hydrogen maleate, which is 189-191, is obtained according to the procedure described in Example 1 ° C melts.
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772724610 DE2724610A1 (en) | 1977-06-01 | 1977-06-01 | 4-PHENYL-8-AMINO-TETRAHYDROISOCHINOLINE |
| DE2724610 | 1977-06-01 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0000013A1 true EP0000013A1 (en) | 1978-12-20 |
| EP0000013B1 EP0000013B1 (en) | 1980-10-15 |
Family
ID=6010350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP78100025A Expired EP0000013B1 (en) | 1977-06-01 | 1978-06-01 | 4-phenyl-8-amino-tetrahydroisoquinolines, pharmaceutical compositions containing them and process for preparation of these compositions |
Country Status (17)
| Country | Link |
|---|---|
| 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 (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT384806B (en) * | 1982-06-04 | 1988-01-11 | Egyt Gyogyszervegyeszeti Gyar | METHOD FOR PRODUCING NEW 4-ARYL-2-METHYL-1,2,3,4-TETRAHYDRO-ISOCHINOLINE DERIVATIVES AND THE SALTS THEREOF |
| AU2011202113B2 (en) * | 2003-06-10 | 2012-03-15 | Resmed Limited | Multiple Stage Blower and Enclosure Therefor |
Families Citing this family (3)
| 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 |
| DE3310878A1 (en) * | 1983-03-25 | 1984-09-27 | Hoechst Ag, 6230 Frankfurt | OPTICAL ANTIPODES OF 8-AMINO-4-PHENYL-1,2,3,4-TETRAHYDROISOCHINOLINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING ITS ANTIDEPRESSIVE EFFECT |
| BG45572A1 (en) * | 1986-10-23 | 1989-07-14 | Druzhestven N Izsledovatelski | Antiulcer means |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
1977
- 1977-06-01 DE DE19772724610 patent/DE2724610A1/en not_active Withdrawn
-
1978
- 1978-05-26 ES ES470226A patent/ES470226A1/en not_active Expired
- 1978-05-29 EG EG343/78A patent/EG13777A/en active
- 1978-05-30 IL IL54810A patent/IL54810A0/en unknown
- 1978-05-30 US US05/910,781 patent/US4185105A/en not_active Expired - Lifetime
- 1978-05-30 FI FI781717A patent/FI781717A/en not_active Application Discontinuation
- 1978-05-30 IT IT23996/78A patent/IT1094899B/en active
- 1978-05-30 ZA ZA00783122A patent/ZA783122B/en unknown
- 1978-05-31 NO NO78781896A patent/NO781896L/en unknown
- 1978-05-31 DK DK242278A patent/DK242278A/en not_active Application Discontinuation
- 1978-05-31 PT PT68123A patent/PT68123A/en unknown
- 1978-05-31 AU AU36705/78A patent/AU517664B2/en not_active Expired
- 1978-05-31 AT AT395078A patent/AT361482B/en not_active IP Right Cessation
- 1978-05-31 CA CA304,518A patent/CA1093079A/en not_active Expired
- 1978-05-31 HU HU78HO2078A patent/HU176978B/en unknown
- 1978-06-01 DE DE7878100025T patent/DE2860212D1/en not_active Expired
- 1978-06-01 JP JP6499278A patent/JPS543078A/en active Pending
- 1978-06-01 EP EP78100025A patent/EP0000013B1/en not_active Expired
Non-Patent Citations (1)
| Title |
|---|
| Keine Entgegenhaltungen * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT384806B (en) * | 1982-06-04 | 1988-01-11 | Egyt Gyogyszervegyeszeti Gyar | METHOD FOR PRODUCING NEW 4-ARYL-2-METHYL-1,2,3,4-TETRAHYDRO-ISOCHINOLINE DERIVATIVES AND THE SALTS THEREOF |
| AU2011202113B2 (en) * | 2003-06-10 | 2012-03-15 | Resmed Limited | Multiple Stage Blower and Enclosure Therefor |
Also Published As
| Publication number | Publication date |
|---|---|
| ES470226A1 (en) | 1979-01-01 |
| IL54810A0 (en) | 1978-07-31 |
| DK242278A (en) | 1978-12-02 |
| CA1093079A (en) | 1981-01-06 |
| NO781896L (en) | 1978-12-04 |
| JPS543078A (en) | 1979-01-11 |
| DE2860212D1 (en) | 1981-01-22 |
| AT361482B (en) | 1981-03-10 |
| AU517664B2 (en) | 1981-08-20 |
| PT68123A (en) | 1978-06-01 |
| EG13777A (en) | 1982-03-31 |
| AU3670578A (en) | 1979-12-06 |
| US4185105A (en) | 1980-01-22 |
| EP0000013B1 (en) | 1980-10-15 |
| HU176978B (en) | 1981-06-28 |
| IT7823996A0 (en) | 1978-05-30 |
| DE2724610A1 (en) | 1978-12-14 |
| FI781717A (en) | 1978-12-02 |
| ZA783122B (en) | 1979-06-27 |
| ATA395078A (en) | 1980-08-15 |
| IT1094899B (en) | 1985-08-10 |
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