EP0000013A1 - 4-Phenyl-8-amino-tetrahydroisochinoline, diese enthaltende pharmazeutische Präparate und Verfahren zur Herstellung dieser Präparate - Google Patents
4-Phenyl-8-amino-tetrahydroisochinoline, diese enthaltende pharmazeutische Präparate und Verfahren zur Herstellung dieser Präparate 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
- preparation
- 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
- 238000000034 method Methods 0.000 title claims abstract description 5
- WXPTXMBRTPQBEN-UHFFFAOYSA-N 4-phenyl-1,2,3,4-tetrahydroisoquinolin-8-amine Chemical class C1NCC=2C(N)=CC=CC=2C1C1=CC=CC=C1 WXPTXMBRTPQBEN-UHFFFAOYSA-N 0.000 title claims abstract description 4
- 238000002360 preparation method Methods 0.000 title claims abstract 4
- 239000000203 mixture Substances 0.000 title description 2
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000007513 acids Chemical class 0.000 claims abstract description 4
- 239000000460 chlorine Substances 0.000 claims abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 15
- 230000001430 anti-depressive effect Effects 0.000 claims description 3
- 239000012050 conventional carrier Substances 0.000 claims 1
- 230000003001 depressive effect Effects 0.000 claims 1
- 239000003381 stabilizer Substances 0.000 claims 1
- 208000020401 Depressive disease Diseases 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- -1 methoxy, hydroxyl Chemical group 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000008517 inhibition of serotonin uptake Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000013275 serotonin uptake Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- FDAPQPBDNFNJOF-BTJKTKAUSA-N (z)-but-2-enedioic acid;4-(3,4-dichlorophenyl)-2-methyl-3,4-dihydro-1h-isoquinolin-8-amine Chemical compound OC(=O)\C=C/C(O)=O.C12=CC=CC(N)=C2CN(C)CC1C1=CC=C(Cl)C(Cl)=C1 FDAPQPBDNFNJOF-BTJKTKAUSA-N 0.000 description 1
- 0 *C(C1CI(*)C2)=CC=CC1C2c1ccc(*)c(*)c1 Chemical compound *C(C1CI(*)C2)=CC=CC1C2c1ccc(*)c(*)c1 0.000 description 1
- VCSDWVZFKKJKAI-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-2-[methyl-[(2-nitrophenyl)methyl]amino]ethanone;hydrochloride Chemical compound Cl.C=1C=CC=C([N+]([O-])=O)C=1CN(C)CC(=O)C1=CC=C(Cl)C(Cl)=C1 VCSDWVZFKKJKAI-UHFFFAOYSA-N 0.000 description 1
- WBPAOUHWPONFEQ-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C(Cl)=C1 WBPAOUHWPONFEQ-UHFFFAOYSA-N 0.000 description 1
- WYECURVXVYPVAT-UHFFFAOYSA-N 1-(4-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Br)C=C1 WYECURVXVYPVAT-UHFFFAOYSA-N 0.000 description 1
- WGILVXQNSFDASI-UHFFFAOYSA-N 2-nitro-n-methylbenzylamine Chemical compound CNCC1=CC=CC=C1[N+]([O-])=O WGILVXQNSFDASI-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 101100387923 Caenorhabditis elegans dos-1 gene Proteins 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000008062 acetophenones Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960004698 dichlorobenzyl alcohol Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
4-Phenyl-8-amino-tetrahydroisochinoline der Formel
in der entweder R1 für Brom und Rz für Wasserstoff stehen oder sowohl R, 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.
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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.).
- 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.
- 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.
- 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.
- 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.
- 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.
Claims (4)
1. 4-Phenyl-8-amino-tetrahydroisochinoline der Formel
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.
2. Pharmazeutische Präparate mit antidepressiver Wirkung gekennzeichnet durch einen Gehalt an Verbindungen nach Anspruch 1.
3. Verfahren zur Herstellung von pharamzeutischen Präparaten mit antidepressiver Wirkung, dadurch gekennzeichnet, daß man eine Verbindung nach Anspruch 1, gegebenenfalls mit üblichen Trägerstoffen und/oder Stabilisatoren in eine pharmazeutisch verträgliche Anwendungsform bringt.
4. Verwendung von Verbindungen nach Anspruch 1 bei der Bekämpfung von depressiven Zuständen.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2724610 | 1977-06-01 | ||
| DE19772724610 DE2724610A1 (de) | 1977-06-01 | 1977-06-01 | 4-phenyl-8-amino-tetrahydroisochinoline |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0000013A1 true EP0000013A1 (de) | 1978-12-20 |
| EP0000013B1 EP0000013B1 (de) | 1980-10-15 |
Family
ID=6010350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP78100025A Expired EP0000013B1 (de) | 1977-06-01 | 1978-06-01 | 4-Phenyl-8-amino-tetrahydroisochinoline, diese enthaltende pharmazeutische Präparate und Verfahren zur Herstellung dieser Präparate |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4185105A (de) |
| EP (1) | EP0000013B1 (de) |
| JP (1) | JPS543078A (de) |
| AT (1) | AT361482B (de) |
| AU (1) | AU517664B2 (de) |
| CA (1) | CA1093079A (de) |
| DE (2) | DE2724610A1 (de) |
| DK (1) | DK242278A (de) |
| EG (1) | EG13777A (de) |
| ES (1) | ES470226A1 (de) |
| FI (1) | FI781717A7 (de) |
| HU (1) | HU176978B (de) |
| IL (1) | IL54810A0 (de) |
| IT (1) | IT1094899B (de) |
| NO (1) | NO781896L (de) |
| PT (1) | PT68123A (de) |
| ZA (1) | ZA783122B (de) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT384806B (de) * | 1982-06-04 | 1988-01-11 | Egyt Gyogyszervegyeszeti Gyar | Verfahren zur herstellung von neuen 4-aryl-2-methyl-1,2,3,4-tetrahydro-isochinolinderivaten und deren salzen |
| 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 (de) * | 1983-03-25 | 1984-09-27 | Hoechst Ag, 6230 Frankfurt | Optische antipoden von 8-amino-4-phenyl-1,2,3,4-tetrahydroisochinolin, verfahren zu ihrer herstellung und sie enthaltende arzneimittel mit antidepressiver wirkung |
| 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 (de) * | 1966-05-05 | 1976-07-22 | Hoechst Ag, 6000 Frankfurt | Verfahren zur herstellung von tetrahydroisochinolinen |
-
1977
- 1977-06-01 DE DE19772724610 patent/DE2724610A1/de not_active Withdrawn
-
1978
- 1978-05-26 ES ES470226A patent/ES470226A1/es not_active Expired
- 1978-05-29 EG EG343/78A patent/EG13777A/xx active
- 1978-05-30 IL IL54810A patent/IL54810A0/xx unknown
- 1978-05-30 FI FI781717A patent/FI781717A7/fi not_active Application Discontinuation
- 1978-05-30 US US05/910,781 patent/US4185105A/en not_active Expired - Lifetime
- 1978-05-30 IT IT23996/78A patent/IT1094899B/it active
- 1978-05-30 ZA ZA00783122A patent/ZA783122B/xx unknown
- 1978-05-31 DK DK242278A patent/DK242278A/da not_active Application Discontinuation
- 1978-05-31 AT AT395078A patent/AT361482B/de not_active IP Right Cessation
- 1978-05-31 PT PT68123A patent/PT68123A/pt unknown
- 1978-05-31 CA CA304,518A patent/CA1093079A/en not_active Expired
- 1978-05-31 AU AU36705/78A patent/AU517664B2/en not_active Expired
- 1978-05-31 HU HU78HO2078A patent/HU176978B/hu unknown
- 1978-05-31 NO NO78781896A patent/NO781896L/no unknown
- 1978-06-01 JP JP6499278A patent/JPS543078A/ja active Pending
- 1978-06-01 EP EP78100025A patent/EP0000013B1/de not_active Expired
- 1978-06-01 DE DE7878100025T patent/DE2860212D1/de not_active Expired
Non-Patent Citations (1)
| Title |
|---|
| Keine Entgegenhaltungen * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT384806B (de) * | 1982-06-04 | 1988-01-11 | Egyt Gyogyszervegyeszeti Gyar | Verfahren zur herstellung von neuen 4-aryl-2-methyl-1,2,3,4-tetrahydro-isochinolinderivaten und deren salzen |
| AU2011202113B2 (en) * | 2003-06-10 | 2012-03-15 | Resmed Limited | Multiple Stage Blower and Enclosure Therefor |
Also Published As
| Publication number | Publication date |
|---|---|
| AU517664B2 (en) | 1981-08-20 |
| JPS543078A (en) | 1979-01-11 |
| IL54810A0 (en) | 1978-07-31 |
| ES470226A1 (es) | 1979-01-01 |
| PT68123A (en) | 1978-06-01 |
| HU176978B (hu) | 1981-06-28 |
| AU3670578A (en) | 1979-12-06 |
| FI781717A7 (fi) | 1978-12-02 |
| CA1093079A (en) | 1981-01-06 |
| DK242278A (da) | 1978-12-02 |
| DE2724610A1 (de) | 1978-12-14 |
| AT361482B (de) | 1981-03-10 |
| US4185105A (en) | 1980-01-22 |
| NO781896L (no) | 1978-12-04 |
| IT1094899B (it) | 1985-08-10 |
| EG13777A (en) | 1982-03-31 |
| DE2860212D1 (en) | 1981-01-22 |
| ATA395078A (de) | 1980-08-15 |
| IT7823996A0 (it) | 1978-05-30 |
| EP0000013B1 (de) | 1980-10-15 |
| ZA783122B (en) | 1979-06-27 |
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