CH534123A - Tricyclic amines - anti-depressants sedatives - Google Patents
Tricyclic amines - anti-depressants sedativesInfo
- Publication number
- CH534123A CH534123A CH887969A CH887969A CH534123A CH 534123 A CH534123 A CH 534123A CH 887969 A CH887969 A CH 887969A CH 887969 A CH887969 A CH 887969A CH 534123 A CH534123 A CH 534123A
- Authority
- CH
- Switzerland
- Prior art keywords
- chlorine
- formula
- fluorine
- hydrogen
- atom
- Prior art date
Links
- 150000001412 amines Chemical class 0.000 title claims abstract description 8
- 239000000935 antidepressant agent Substances 0.000 title abstract description 3
- 229940005513 antidepressants Drugs 0.000 title abstract description 3
- 239000000932 sedative agent Substances 0.000 title abstract description 3
- 230000001430 anti-depressive effect Effects 0.000 title description 3
- 229940125723 sedative agent Drugs 0.000 title 1
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 22
- 239000000460 chlorine Substances 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- 229910052731 fluorine Chemical group 0.000 claims abstract description 15
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000011737 fluorine Chemical group 0.000 claims abstract description 9
- 125000005843 halogen group Chemical group 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 5
- -1 dimethylaminopropylmagnesium halide Chemical class 0.000 claims description 4
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 4
- 239000007858 starting material Substances 0.000 claims 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 abstract description 2
- 239000005977 Ethylene Substances 0.000 abstract description 2
- 150000007513 acids Chemical class 0.000 abstract description 2
- 230000003444 anaesthetic effect Effects 0.000 abstract description 2
- 230000001624 sedative effect Effects 0.000 abstract description 2
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 abstract 1
- 230000002908 adrenolytic effect Effects 0.000 abstract 1
- 230000001387 anti-histamine Effects 0.000 abstract 1
- 239000000739 antihistaminic agent Substances 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 230000003533 narcotic effect Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- MDSXOOMPQIMETH-UHFFFAOYSA-N 3-(5,7-dichloro-2-tricyclo[9.4.0.03,8]pentadeca-1(15),3(8),4,6,11,13-hexaenyl)-N,N-dimethylpropan-1-amine Chemical compound ClC1=CC(=CC=2C(C3=C(CCC21)C=CC=C3)CCCN(C)C)Cl MDSXOOMPQIMETH-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
- NYYRRBOMNHUCLB-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCCl NYYRRBOMNHUCLB-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- QPJORFLSOJAUNL-UHFFFAOYSA-N dibenzo[a,d][7]annulene Chemical compound C1=CC2=CC=CC=C2CC2=CC=CC=C21 QPJORFLSOJAUNL-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- NGPAITITALWALP-UHFFFAOYSA-M magnesium;n,n-dimethylpropan-1-amine;chloride Chemical compound [Mg+2].[Cl-].CN(C)CC[CH2-] NGPAITITALWALP-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Method for the preparation of tricyclic amines of the general formula (I) and salts thereof with pharmaceutically acceptable acids. where R1 = hydrogen or methyl, R = chlorine or fluorine, R2 and R3 hydrogen, chlorine or fluorine, X = ethylene or vinylene group, the latter opt. substd. by a halogen atom. The exocyclic double bond of the centre ring may be opt. hydrogenated. The compounds are antidepressants, narcotic potentiators, adrenolytic, sedative, antihistamine and local anaesthetic active.
Description
5H-Dibenzo[a,d]cycloheptene und 10,1 1-Dinydro-SH- dibenzo[a,d]cycloheptene mit einer basischen Seitenkette in Stellung sind bereits als antidepressiv wirkende Psychopharmaka bekannt, z. B. 10,11 -Dihydro-5-(3 -dimethylamino- propyliden)-5H-dibenzo[a,d]cyclohepten und 10,1 1-Dihydro- 5-(3 -methylaminopropyliden)-5H-dibenzo[a,d]cyclohepten.
Gegenstand des Hauptpatentes Nr. 486 416 ist ein Verfahren zur Herstellung von tricyclischen Aminen der Formel
EMI1.1
in der X eine Äthylengruppe oder eine gegebenenfalls durch ein Halogenatom substituierte Vinylengruppe bedeutet, die im aromatischen Teil durch Chlor oder Fluor substituiert sind, wobei ein bzw. der Substituent in 1-Stellung steht, und von Salzen dieser Verbindungen. Diese tricyclischen Amine, die sich von den bekannten Vertretern der betreffenden Substanzgruppe durch die Anwesenheit eines Chlor- oder Fluoratoms in 1-Stellung unterscheiden, zeichnen sich durch eine beträchtlich erhöhte antidepressive Wirkung und stark verminderte Toxizität aus. Als besonders vorteilhaft ist die fehlende oder nur geringfügige anticholinergische Wirkung zu erwähnen. Die Verbindungen der Formel Ia zeichnen sich ausserdem durch vielfältige Wirkungen auf das Nervensystem aus.
So sind narkosepotenzierende, andrenolytische, sedative, antihistaminartige und lokalanästhetische Wirkungen festgestellt worden.
Es wurde nun gefunden, dass tricyclische Amine der Formel Ia, welche ausser dem Chlor- bzw. Fluoratom in 1-Stellung zusätzlich durch Chlor bzw. Fluor in den aromatischen Kernen substituiert sind, und zwar Verbindungen der Formel
EMI1.2
in der R ein Chlor- oder Fluoratom, X eine Äthylengruppe oder eine gegebenenfalls durch ein Halogenatom substituierte Vinylengruppe und R2 und R3 je ein Wasserstoff-, Chlor- oder Fluoratom bedeuten, wobei mindestens einer der Reste R2 und R3 Chlor oder Fluor darstellt, sowie Salze dieser Verbindungen ebensolche Eigenschaften wie die Verbindungen der oben stehenden Formel Ia besitzen.
In der obigen Formel I bedeutet R bevorzugt ein Chloratom. Bevorzugte Gruppen von Verbindungen der Formel I sind diejenigen, in der R2 ein Chloratom in 3-Stellung und R3 Wasserstoff bedeuten, sowie auch Verbindungen der Formel I, in der R2 Wasserstoff und R3 ein Chloratom in 9-Stellung darstellen. X ist vorzugsweise eine unsubstituierte Äthylen- oder Vinylengruppe, kann aber auch eine durch ein Halogenatom, insbesondere ein Chlor- oder Bromatom, substituierte Vinylengruppe darstellen. Ein besonders interessanter Vertreter von Verbindungen der Formel I ist: 1,3 -Dichlor-10, 11-dihydro-5-(3-dimethylaminopropyl)-5H dibenzoLa,d]cyclohepten.
Die Verbindungen der Formel I können in gleicher Weise wie die oben stehenden Verbindungen der Formel Ia hergestellt werden, gemäss dem Verfahren vom Hauptpatent Nr. 486 416. Das vorliegende Patent betrifft ein Verfahren zur Herstellung von tricyclischen Aminen der Formel I sowie von Salzen dieser Verbindungen. Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man eine Verbindung der Formel
EMI1.3
in der R, R2, R3 undX die oben gegebene Bedeutung haben und W ein Halogenatom bedeutet, mit einem Dimethylaminopropylmagnesiumhalogenid umsetzt. In beliebiger Reihenfolge können einerseits die Isomeren aus dem erhaltenen Isomerengemisch isoliert und anderseits kann eine erhaltene Base in ein Säureadditionssalz überführt werden.
Die erfindungsgemässe Umsetzung ist besonders geeignet für die Darstellung von solchen exocyclisch gesättigten Verbindungen der Formel I, die eine Doppelbindung in 10,11 Stellung tragen. Nach einer bevorzugten Ausführungsform wird eine Verbindung der Formel II, in der W Chlor darstellt, entweder in fester, fein pulverisierter Form oder in einem indifferenten organischen Lösungsmittel, wie z. B. in absolutem Äther, Benzol, Tetrahydrofuran, in eine Suspension von Dimethylaminopropylmagnesiumchlorid in einem der vorstehend genannten, indifferenten Lösungsmittel eingetragen. Die Umsetzung wird zweckmässig bei einer Temperatur zwischen Raumtemperatur und dem Siedepunkt des Reaktionsgemisches vorgenommen. Nach beendeter Umsetzung wird das Reaktionsprodukt der Hydrolyse unterworfen, bevorzugt unter praktisch neutralen Bedingungen, z. B. durch Behandeln mit wässriger Ammoniumchloridlösung.
Das Ausgangshalogenid der Formel II kann nach an sich bekannten Methoden, z. B. durch Reduktion des entsprechenden tricyclischen 5-Ketons und anschliessende Halogenierung der entstandenen 5-Hydroxy-Verbindung, gewonnen werden.
Diese tricyclischen 5-Ketone sind nach an sich bekannten Methoden erhältlich, wobei jedoch zu beachten ist, dass die Einführung eines Halogenatoms in 10 (bzw. 11)-Stellung von 1-Chlor (oder Fluor)-5H-dibenzo[a,d]cyclohepten-5-on bevorzugt unter Zugabe des entsprechenden Halogens mit gleichzeitiger Belichtung erfolgt. Das resultierende 1-Chlor (oder Fluor)-10, 1 1-dihalogen-10,1 1-dihydro-5H-dibenzo- [a,d]cyclohepten-5-on spaltet nach Zugabe von Alkali ein Molekül Halogenwasserstoff ab, wobei ein 1-Chlor (oder Fluor)-10 (bzw. 1 1)-halogen-5H-dibenzo[a,d]cyclohepten-5- on entsteht.
Erhaltene, unsymmetrisch substituierte Verbindungen und deren Salze liegen als Racemate vor. Sie können in ihre optischen Isomeren in an sich bekannter Weise, z. B. durch Umsetzung mit optisch aktiven Säuren, wie Weinsäure oder Camphersulfonsäure, und anschliessende Kristallisation, aufgetrennt werden.
Die Erfindung erfasst, wie gesagt, auch die Herstellung der Säureadditionssalze der tricyclischen Amine der Formel I.
Solche Salze sind beispielsweise diejenigen mit organischen Säuren, wie Oxalsäure, Zitronensäure, Essigsäure, Milchsäure, Maleinsäure und Weinsäure, oder mit anorganischen Säuren, wie Chlorwasserstoffsäure, Bromwasserstoffsäure oder Schwefelsäure.
Die Verfahrensprodukte können als Heilmittel in Form pharmazeutischer Präparate Verwendung finden, welche sie oder ihre Salze in Mischung mit einem für die enterale oder parenterale Applikation geeigneten pharmazeutischen, organischen oder anorganischen inerten Trägermaterial enthalten.
Die pharmazeutischen Präparate können in fester oder in flüssiger Form vorliegen. Gegebenenfalls enthalten sie Hilfsstoffe, wie Konservierungs-, Stabilisierungs, Netz- oder Emulgiermittel, Salze zur Veränderung des osmotischen Druckes oder Puffer. Sie können auch noch andere therapeutisch wertvolle Stoffe enthalten.
Beispiel
Analog zu Beispiel 1 vom Hauptpatent Nr. 486 416 gewinnt man durch Einsatz von 1,3,5-Trichlor-10,11-dihydro 5H-dibenzora,d]cyclohepten und Dimethylaminopropylchlorid 1,3-Dichlor-10,1 1-dihydro-5-(3-dimethylaminopro- pyl)-5H-dibenzo[a,d]cyclohepten. Das entsprechende Hydrochlorid ist hygroskopisch und schmilzt bei 168-169 C.
5H-dibenzo [a, d] cycloheptene and 10,1 1-dinydro-SH-dibenzo [a, d] cycloheptene with a basic side chain in position are already known as antidepressant psychotropic drugs, z. B. 10,11-dihydro-5- (3-dimethylaminopropylidene) -5H-dibenzo [a, d] cycloheptene and 10,1 1-dihydro-5- (3-methylaminopropylidene) -5H-dibenzo [a, d ] cycloheptene.
The subject of the main patent no. 486 416 is a process for the preparation of tricyclic amines of the formula
EMI1.1
in which X denotes an ethylene group or a vinylene group optionally substituted by a halogen atom, which are substituted in the aromatic part by chlorine or fluorine, one or the substituent being in the 1-position, and salts of these compounds. These tricyclic amines, which differ from the known representatives of the substance group in question by the presence of a chlorine or fluorine atom in the 1-position, are distinguished by a considerably increased antidepressant effect and greatly reduced toxicity. The lack of or only a slight anticholinergic effect should be mentioned as particularly advantageous. The compounds of the formula Ia are also distinguished by a wide range of effects on the nervous system.
Anesthesia-potentiating, andrenolytic, sedative, antihistamine-like and local anesthetic effects have been found.
It has now been found that tricyclic amines of the formula Ia which, in addition to the chlorine or fluorine atom in the 1-position, are additionally substituted by chlorine or fluorine in the aromatic nuclei, namely compounds of the formula
EMI1.2
in which R is a chlorine or fluorine atom, X is an ethylene group or a vinylene group optionally substituted by a halogen atom and R2 and R3 are each a hydrogen, chlorine or fluorine atom, at least one of the radicals R2 and R3 being chlorine or fluorine, and salts of these compounds have the same properties as the compounds of the above formula Ia.
In the above formula I, R preferably denotes a chlorine atom. Preferred groups of compounds of the formula I are those in which R2 is a chlorine atom in the 3-position and R3 is hydrogen, and also compounds of the formula I in which R2 is hydrogen and R3 is a chlorine atom in the 9-position. X is preferably an unsubstituted ethylene or vinylene group, but can also represent a vinylene group substituted by a halogen atom, in particular a chlorine or bromine atom. A particularly interesting representative of compounds of the formula I is: 1,3-dichloro-10,11-dihydro-5- (3-dimethylaminopropyl) -5H dibenzoLa, d] cycloheptene.
The compounds of the formula I can be prepared in the same way as the above compounds of the formula Ia, according to the process from main patent no. 486,416. The present patent relates to a process for the preparation of tricyclic amines of the formula I and salts of these compounds. The inventive method is characterized in that a compound of the formula
EMI1.3
in which R, R2, R3 and X have the meaning given above and W is a halogen atom, reacted with a dimethylaminopropyl magnesium halide. In any order, on the one hand, the isomers can be isolated from the isomer mixture obtained and, on the other hand, a base obtained can be converted into an acid addition salt.
The reaction according to the invention is particularly suitable for the preparation of those exocyclically saturated compounds of the formula I which have a double bond in the 10, 11 position. According to a preferred embodiment, a compound of formula II in which W is chlorine, either in solid, finely powdered form or in an inert organic solvent, such as. B. in absolute ether, benzene, tetrahydrofuran, registered in a suspension of dimethylaminopropylmagnesium chloride in one of the above-mentioned inert solvents. The reaction is expediently carried out at a temperature between room temperature and the boiling point of the reaction mixture. After the reaction has ended, the reaction product is subjected to hydrolysis, preferably under practically neutral conditions, e.g. B. by treatment with aqueous ammonium chloride solution.
The starting halide of the formula II can be prepared by methods known per se, e.g. B. by reduction of the corresponding tricyclic 5-ketone and subsequent halogenation of the resulting 5-hydroxy compound can be obtained.
These tricyclic 5-ketones can be obtained by methods known per se, although it should be noted that the introduction of a halogen atom in the 10 (or 11) position of 1-chloro (or fluorine) -5H-dibenzo [a, d] cyclohepten-5-one is preferably carried out with the addition of the appropriate halogen with simultaneous exposure. The resulting 1-chlorine (or fluorine) -10, 1 1-dihalo-10,1 1-dihydro-5H-dibenzo- [a, d] cyclohepten-5-one splits off one molecule of hydrogen halide after adding alkali, with one 1-chloro (or fluorine) -10 (or 11) -halogen-5H-dibenzo [a, d] cyclohepten-5-one is formed.
Unsymmetrically substituted compounds obtained and their salts are present as racemates. They can be converted into their optical isomers in a manner known per se, for. B. by reaction with optically active acids, such as tartaric acid or camphorsulfonic acid, and subsequent crystallization, separated.
As said, the invention also covers the preparation of the acid addition salts of the tricyclic amines of the formula I.
Such salts are, for example, those with organic acids such as oxalic acid, citric acid, acetic acid, lactic acid, maleic acid and tartaric acid, or with inorganic acids such as hydrochloric acid, hydrobromic acid or sulfuric acid.
The products of the process can be used as medicaments in the form of pharmaceutical preparations which contain them or their salts in a mixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration.
The pharmaceutical preparations can be in solid or liquid form. They may contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.
example
Analogously to Example 1 of the main patent no. 486 416, 1,3-dichloro-10,11-dihydro-5H-dibenzora, d] cycloheptene and dimethylaminopropyl chloride give 1,3-dichloro-10,11-dihydro- 5- (3-dimethylaminopropyl) -5H-dibenzo [a, d] cycloheptene. The corresponding hydrochloride is hygroscopic and melts at 168-169 C.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH887969A CH534123A (en) | 1966-11-08 | 1967-09-19 | Tricyclic amines - anti-depressants sedatives |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH887269A CH486416A (en) | 1966-11-08 | 1966-11-08 | Process for the preparation of tricyclic amines |
| CH1614466A CH484044A (en) | 1966-11-08 | 1966-11-08 | Process for the preparation of tricyclic amines |
| CH887969A CH534123A (en) | 1966-11-08 | 1967-09-19 | Tricyclic amines - anti-depressants sedatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH534123A true CH534123A (en) | 1973-02-28 |
Family
ID=25703879
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH887969A CH534123A (en) | 1966-11-08 | 1967-09-19 | Tricyclic amines - anti-depressants sedatives |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH534123A (en) |
-
1967
- 1967-09-19 CH CH887969A patent/CH534123A/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |