DE1795830B2 - 1,2,3,4-TETRAHYDRO-2-METHYL-4-PHENYL-8-AMINO-ISOCHINOLINE - Google Patents
1,2,3,4-TETRAHYDRO-2-METHYL-4-PHENYL-8-AMINO-ISOCHINOLINEInfo
- Publication number
- DE1795830B2 DE1795830B2 DE19661795830 DE1795830A DE1795830B2 DE 1795830 B2 DE1795830 B2 DE 1795830B2 DE 19661795830 DE19661795830 DE 19661795830 DE 1795830 A DE1795830 A DE 1795830A DE 1795830 B2 DE1795830 B2 DE 1795830B2
- Authority
- DE
- Germany
- Prior art keywords
- acid
- phenyl
- tetrahydro
- amino
- methyl
- 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
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
»owie dessen Salze mit pharmazeutisch unbedenklichen Säuren.“Like its salts with pharmaceutically safe ones Acids.
Diese Verbindung wird z. B. dadurch hergestellt, daß man N-(2Aminobenzyl)-l-phenyl-2-methylamino-Sthanol-(l) der FormelThis connection is z. B. produced by N- (2Aminobenzyl) -l-phenyl-2-methylamino-sthanol- (l) the formula
NH,NH,
NaBH4 NaBH 4
soso
(H)(H)
NH,NH,
mit einem sauren Cyelisierungsmittel, z. B. Schwefelsäure, cyclisiert und gegebenenfalls anschließend ein erhaltenes Salz in die freie Base überrührt oder die erhaltene freie Base mit einer physiologisch verträglichen Säure in ihr Salz überführt.with an acidic cyclizing agent, e.g. B. sulfuric acid, cyclized and optionally then a salt obtained is stirred into the free base or the free base obtained is converted into its salt with a physiologically acceptable acid.
HOCHHIGH
CH,CH,
NCH,NCH,
[ CH,
NH,[CH,
NH,
Die Verbindung der Formel I besitzt 2 Stickstoffatome unterschiedlicher Basizität: sie 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: Halogen-The compound of the formula I has 2 nitrogen atoms of different basicity: they can both form salts with one as well as with two equivalents of an acid. In terms of its use as a Medicinal products can be used for salt formation with physiologically compatible acids. As inorganic Acids come into consideration, for example: halogen
Vasserstoffsäuren, wie Chlorwasserstoffsäure und Bromwasserstoffsäure, sowie Schwefelsäure, Phosphoriäure und Amidosulfonsäure. Als organische Säuren jeien beispielsweise genannt: Ameisensäure, Essigfäure, Propionsäure, Milchsäure, Glykolsäure, GIufonsäure, Maleinsäure, Bernsteinsäure, Weinsäure, Benzoesäure, Salicylsäure, Zitronensäure, Acetursäure ©der Oxyäthansulfonsäure.Hydrogen acids such as hydrochloric acid and Hydrobromic acid, as well as sulfuric acid, phosphoric acid and sulfamic acid. Examples of organic acids are: formic acid, acetic acid, Propionic acid, lactic acid, glycolic acid, glufonic acid, Maleic acid, succinic acid, tartaric acid, benzoic acid, salicylic acid, citric acid, aceturic acid © of oxyethanesulfonic acid.
Für therapeutische Zwecke werden im allgemeinen die Salze mit 1 Äquivalent Säure bevorzugt, da diese in der Regel den günstigeren pH-Wert aufweisen.For therapeutic purposes, the salts with 1 equivalent of acid are generally preferred because these usually have the more favorable pH value.
Die erfindungsgemäße Verbindung ist ein wertvolles Pharmazeutikum mit insbesondere zentral anregender und thymoleptischer Wirkung.The compound according to the invention is a valuable pharmaceutical with, in particular, central stimulating and thymoleptic effect.
Dies ist insofern überraschend, als bisher Verbindungen des Tetrahydro-isochinolin-Typs mit antidepressiver Wirkung nicht bekannt waren, also eine neue Verbindungsklasse für Antidepressiva erschlossen worden ist. Bereits hierin liegt ein bedeutender technischer Fortschritt.This is surprising insofar as compounds of the tetrahydroisoquinoline type with an antidepressant effect were not previously known, that is to say one new class of compounds for antidepressants has been tapped. Here already lies an important technical aspect Progress.
Die erfindungsgemäße Verbindung ist außerdem dem bekannten Antidepressivum Imipramin überlegen. The compound according to the invention is also superior to the known antidepressant imipramine.
Die zentralanregende Wirkung wurde u. a. (I) durch ■Messung der Bewegungsaktivität unvorbehandelter Tiere nachgewiesen (Methode: L. Th er, Dtsch. Apoth.-Ztg. 1953, Seite 292), oder (2) durch Umkehr «der durch Tetrabenazin ausgelösten depressiven Wirkung an der Maus (Methode in Anlehnung an F. S u 1-zer, J. Watts und B. B. Brodie. Fed. Proc. 19. 268 [I960]; Ann. N. Y. Acad. Sei. 96. 279 [1962]).The centrally stimulating effect was inter alia. (I) by ■ measuring the movement activity untreated Animals detected (method: L. Th er, Dtsch. Apoth.-Ztg. 1953, page 292), or (2) by reversing «The depressive effect caused by tetrabenazine on the mouse (method based on F. S u 1-zer, J. Watts and B. B. Brodie. Fed. Proc. 19th 268 [1960]; Ann. N. Y. Acad. May be. 96, 279 [1962]).
Bei der 1. Methode beträgt z. B. die Grenzdosis Tür die Mobilitätssteigerung an de Maus 1 bis 2.5 mg kg i.v.; das bekannte Handelsprodukt ist bei diesem Test völlig unwirksam.In the 1st method z. B. the limit dose door the increase in mobility at de mouse 1 to 2.5 mg kg i.v .; the well-known commercial product is completely ineffective in this test.
Der Effekt bei der 2. Methode wurde mit 5 mg kg per os verabreichtem l,2,3,4-Tetrahydro-2-methyl-4-phenyl-8-aminp-isochinolin-hydrochlorid erzielt, bei Imipramin sind dagegen mehr als 20 mg/kg erfcrderlich. Die thymoleptischc Wirkungskomponente kommt ebenfalls in dem Antagonismus gegen die durch Reserpin hervorgerufene Katatonie und die Ptosis des Oberlides bei Ratten zum Ausdruck. Bei subkutaner Applikation beheben 5 mg/kg der erfindungsgemäßen Verbindung die Ptosis und löschen die Tetrabenazin-Katatonie aus.The effect of the second method was demonstrated with 1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-amine-isoquinoline hydrochloride administered per os with 5 mg kg achieved, with imipramine, however, more than 20 mg / kg are required. The thymoleptic active component also comes in the antagonism against the Reserpine-induced catatonia and ptosis of the upper eyelid in rats. at Subcutaneous administration, 5 mg / kg of the compound according to the invention eliminate the ptosis and delete it the tetrabenazine catatonia.
Die DL50 (Maus i.v.) beträgt bei der erfindungsgemäßen Verbindung 90 mg/kg, bei Imipramin 54 mg/kg.The DL 50 (mouse iv) is 90 mg / kg for the compound according to the invention and 54 mg / kg for imipramine.
Die Lösung von 25,6 g N-(2-Amino-benzyl)-l-phenyl-2-methyiamino-äthanol-(l)(hergeste!it durch Umsetzung von u-Bromacetophenon mit (2-Nitro-The solution of 25.6 g of N- (2-amino-benzyl) -l-phenyl-2-methyiamino-ethanol- (l) (hergeste! It by reacting u-bromoacetophenone with (2-nitro-
benzylT-methylamin in Alkohol, anschließende Hydrierung der Nitrogruppe mit Nickel auf Kieselgur bei Zimmertemperatur und Reduktion der C O-Gruppe mit Natriumborhydrid, wobei die Verbindung als Rohprodukt in öliger Form anfällt und als solchesbenzylT-methylamine in alcohol, subsequent hydrogenation the nitro group with nickel on kieselguhr at room temperature and reduction of the C O group with sodium borohydride, the compound being obtained as a crude product in oily form and as such
eingesetzt wird) in 100 ml Methylenchlorid wird bei 10—15 in 125 ml Schwefelsäure eintropfen gelassen. Nach kurzem Stehen wird das Reaktionsgemisch auf Eis gegossen und mit Natronlauge alkalisch gemacht. Durch Ausschütteln mit Methylenchlorid erhält man 23,8 g 1,2,3,4 - Tetrahydro - 2 - methyl - 4 - phenyl-8-amino-isochinolin. Die rohe Base wird in 60 ml Äthanol gelöst und mit einer Lösung aus 11.6g Maleinsäure in 20 ml Äthanol versetzt. Man erhält 28.6 g des Maleinates vom Zersetzungspunkt 199 bis 20Γ (aus 50%igem wäßrigen Äthanol).is used) in 100 ml of methylene chloride is added dropwise at 10-15 in 125 ml of sulfuric acid. After standing for a short time, the reaction mixture is poured onto ice and made alkaline with sodium hydroxide solution. Shaking out with methylene chloride gives 23.8 g of 1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-amino-isoquinoline. The crude base is dissolved in 60 ml of ethanol and a solution of 11.6g Maleic acid is added to 20 ml of ethanol. 28.6 g of the maleate are obtained from the decomposition point 199 to 20Γ (from 50% aqueous ethanol).
Claims (1)
NHCH3 + CH,\
NHCH 3 + CH,
NCH3 CH,
NCH 3
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19661795830 DE1795830B2 (en) | 1966-08-12 | 1966-08-12 | 1,2,3,4-TETRAHYDRO-2-METHYL-4-PHENYL-8-AMINO-ISOCHINOLINE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19661795830 DE1795830B2 (en) | 1966-08-12 | 1966-08-12 | 1,2,3,4-TETRAHYDRO-2-METHYL-4-PHENYL-8-AMINO-ISOCHINOLINE |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1795830A1 DE1795830A1 (en) | 1975-12-18 |
| DE1795830B2 true DE1795830B2 (en) | 1976-10-14 |
| DE1795830C3 DE1795830C3 (en) | 1977-08-25 |
Family
ID=5708299
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19661795830 Granted DE1795830B2 (en) | 1966-08-12 | 1966-08-12 | 1,2,3,4-TETRAHYDRO-2-METHYL-4-PHENYL-8-AMINO-ISOCHINOLINE |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1795830B2 (en) |
Cited By (1)
| 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 |
-
1966
- 1966-08-12 DE DE19661795830 patent/DE1795830B2/en active Granted
Cited By (1)
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| DE1795830A1 (en) | 1975-12-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C3 | Grant after two publication steps (3rd publication) | ||
| E77 | Valid patent as to the heymanns-index 1977 |