AT337181B - PROCESS FOR THE PREPARATION OF NEW 4- (4-PIPERIDYLIDEN) -4H-BENZO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN DERIVATES AND THEIR ACID ADDITIONAL SALTS - Google Patents
PROCESS FOR THE PREPARATION OF NEW 4- (4-PIPERIDYLIDEN) -4H-BENZO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN DERIVATES AND THEIR ACID ADDITIONAL SALTSInfo
- Publication number
- AT337181B AT337181B AT685675A AT685675A AT337181B AT 337181 B AT337181 B AT 337181B AT 685675 A AT685675 A AT 685675A AT 685675 A AT685675 A AT 685675A AT 337181 B AT337181 B AT 337181B
- Authority
- AT
- Austria
- Prior art keywords
- benzo
- cyclohepta
- thiophen
- compounds
- preparation
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims description 9
- 150000003839 salts Chemical class 0.000 title claims description 9
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 4
- DIHAEJKTJPVECJ-UHFFFAOYSA-N 4-benzo[1,2]cyclohepta[3,4-b]thiophen-10-ylidenepiperidine Chemical compound C1CNCCC1=C1C2=CC=CC=C2C=CC2=C1C=CS2 DIHAEJKTJPVECJ-UHFFFAOYSA-N 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 19
- 150000002367 halogens Chemical group 0.000 claims description 9
- 229910052736 halogen Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 125000005059 halophenyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 230000001558 histaminolytic effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- -1 1-benzyl-4-piperidylidene Chemical group 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 231100000820 toxicity test Toxicity 0.000 description 3
- JQZAEUFPPSRDOP-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1 JQZAEUFPPSRDOP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 230000001078 anti-cholinergic effect Effects 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- LJRKFCOGIJPEHN-UHFFFAOYSA-N 10-piperidin-4-ylidene-4h-benzo[1,2]cyclohepta[3,4-b]thiophen-5-one Chemical compound C12=CC=CC=C2C(=O)CC=2SC=CC=2C1=C1CCNCC1 LJRKFCOGIJPEHN-UHFFFAOYSA-N 0.000 description 1
- ZUZJVPBIRPJYMV-UHFFFAOYSA-N 2-(1-benzylpiperidin-4-ylidene)-6-thiatricyclo[8.4.0.03,7]tetradeca-1(14),3(7),4,10,12-pentaen-8-one Chemical compound C(C1=CC=CC=C1)N1CCC(CC1)=C1C2=C(CC(C=3SC=CC31)=O)C=CC=C2 ZUZJVPBIRPJYMV-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- GERPMJPJRJGAGL-UHFFFAOYSA-N C1CN(CCC1=C2C3=C(C(=O)CC4=CC=CC=C42)SC=C3)CC5=CC=C(C=C5)Cl Chemical compound C1CN(CCC1=C2C3=C(C(=O)CC4=CC=CC=C42)SC=C3)CC5=CC=C(C=C5)Cl GERPMJPJRJGAGL-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- IYSYPCSSDZBWHN-UHFFFAOYSA-N Nor-ketotifen Chemical compound C1=2C=CSC=2C(=O)CC2=CC=CC=C2C1=C1CCNCC1 IYSYPCSSDZBWHN-UHFFFAOYSA-N 0.000 description 1
- DDIJNWXOWAUDBQ-UHFFFAOYSA-N O=C(CC1=C2C=CC(Cl)=C1)C(SC=C1)=C1C2=C(CC1)CCN1C(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound O=C(CC1=C2C=CC(Cl)=C1)C(SC=C1)=C1C2=C(CC1)CCN1C(C1=CC=CC=C1)C1=CC=CC=C1 DDIJNWXOWAUDBQ-UHFFFAOYSA-N 0.000 description 1
- BPJWPQMWJVBHKC-UHFFFAOYSA-N O=C(CC1=C2C=CS1)C(C=CC=C1)=C1C2=C1CCN(CC(C=C2)=CC=C2Cl)CC1 Chemical compound O=C(CC1=C2C=CS1)C(C=CC=C1)=C1C2=C1CCN(CC(C=C2)=CC=C2Cl)CC1 BPJWPQMWJVBHKC-UHFFFAOYSA-N 0.000 description 1
- 206010040108 Serotonin syndrome Diseases 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- ZDVDCDLBOLSVGM-UHFFFAOYSA-N [chloro(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(Cl)C1=CC=CC=C1 ZDVDCDLBOLSVGM-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000007788 liquid Substances 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
- 238000004452 microanalysis Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
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Die Erfindung betrifft ein Verfahren zur Herstellung neuer 4-(4-Piperidyliden)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-Derivate der Formel
EMI1.1
worin Rt für Wasserstoff oder einen in 6-oder 7-Stellung ständigen Halogen- oder niederen Alkoxyrest steht, die Oxogruppe 9--oder 10-ständig ist, E für Wasserstoff oder Halogen steht und Rg Wasserstoff, Phenyl oder Halogenphenyl bedeutet, und ihrer Säureadditionssalze.
Stellt das Symbol 1\ Halogen dar, so steht es insbesondere für Chlor oder Brom.
Stellt R1 eine niedere Alkoxygruppe dar, so enthält diese insbesondere 1 bis 4 Kohlenstoffatome.
Stellt R2 Halogen dar, so steht es insbesondere für Fluor, Chlor oder Brom.
Als Halogen-Substituente für den PhenylrestRg sind auch insbesondere Fluor, Chlor und Brom geeignet.
Erfindungsgemäss gelangt man zu den Verbindungen der Formel (I) und ihren Säureadditionssalzen, indem man Verbindungen der Formel
EMI1.2
worin 1\ obige Bedeutung besitzt und die Oxogruppe 9-oder 10-ständig ist, mit Verbindungen der Formel
EMI1.3
worin R2 und R3 obige Bedeutung besitzen und Hal für Halogen steht, umsetzt und gewünschtenfalls die so erhaltenen Verbindungen der Formel (t) in ihre Säureadditionssalze überführt.
Aus den freien Basen lassen sich in bekannter Weise Säureadditionssalze herstellen und umgekehrt.
Die Umsetzung der Verbindungen der Formel (H) mit den Verbindungen der Formel (hui) erfolgt beispielsweise in einem unter den Reaktionsbedingungen inerten organischen Lösungsmittel und vorzugsweise in
<Desc/Clms Page number 2>
Gegenwart eines alkalischen Kondensationsmittels wie Natrium- oder Kaliumcarbonat. Die Anwendung eines stark polaren Lösungsmittels wie Hexamethylphosphorsäuretriamid, Dimethylsulfoxyd, Dimethylformamid usw. ist von VorteiL
Praktisch werden die Verbindungen der Formel (in) als Chlorid oder Bromid eingesetzt. Die Reaktions- temperatur wird vorteilhafterweise niedrig, zwischen Raumtemperatur und etwa 600C, gehalten.
Die Verbindungen der Formel (1) und ihre pharmakologisch verträglichen Säureadditionssalze sind in der Literatur bisher noch nicht beschrieben worden. Sie zeichnen sich durch pharmakodynamische Eigen- schaften aus und können daher als Heilmittel verwendet werden.
So zeichnen sie sich durch histaminolytische Eigenschaften aus, wie aus den Resultaten im HistaminToxizitätstest am Meerschweinchen hervorgeht. Die histaminolytische Wirkung der 10-Keto-Verbindun- gen der Formel (1) ist spezifisch, da bei diesen mit Hilfe des Serotonin-Toxizitätstests und des Acetylcholin- Toxizitätstests am Meerschweinchen keine signifikanten serotonin-antagonistischen und anticholinergen Eigen- schaften festgestellt werden können. Diese Verbindungen sind als spezifische Histaminolytika zu charakteri- sieren.
Die 9-Keto-Verbindungen der Formel (I) weisen über ihre histaminolytischen Eigenschaften hinaus auch noch serotonin-antagonistische und anticholinerge Eigenschaften auf. Sie sind auf Grund dieser Eigenschaften als Antaminika zu bewerten.
Die erfindungsgemässen Verbindungen können bei allergischen Affektionen verschiedenster Genese eingesetzt werden.
Die zu verwendenden Dosen variieren naturgemäss je nach der Art der verwendeten Substanz, der Administration und des zu behandelnden Zustandes ; diese Dosen können nötigenfalls in 2 bis 3 Anteilen oder auch alsRetardform verabreicht werden. Die Tagesdosis liegt bei etwa 0, 5 bis 20mg. Für orale Applikationen enthalten die Teildosen etwa 0, 15 bis 10 mg der neuen Verbindungen neben festen oderflüssigenTrägersubstan- zen oder Verdünnungsmitteln.
Als Heilmittel können die Verbindungen der Formel (I) bzw. ihre physiologisch verträglichen Säureadditionssalze allein oder in geeigneter Arzneiform mit pharmakologisch indifferenten Hilfsstoffen verabreicht werden.
Soweit die Herstellung der Ausgangsverbindungen nicht beschrieben wird, sind diese bekannt oder nach an sich bekannten Verfahren bzw. analog zu den hier beschriebenen oder analog zu an sich bekannten Verfahren herstellbar.
In den nachfolgenden Beispielen, die die Erfindung näher erläutern, ihren Umfang aber in keiner Weise einschränken sollen, erfolgen alle Temperaturangaben in Celsiusgraden und sind unkorrigiert.
Beispiele 1 : 4- (1-Benzyl-4-piperidyliden)-4H-benzo [4, 5] cyclohepta [1, 2-b]thiophen-10 (9H)-on
EMI2.1
wasserfrei werden in 120 cm3 Hexamethylphosphorsäuretriamid vorgelegt und bei 250 mit 6 g Benzylchlorid versetzt. Nach 18-stündigem Rühren bei Raumtemperatur wird noch während 1 h bei 500 geriihrt.
Anschliessend verdünnt man die Reaktionsmischung mit 1000 cm3 Wasser und extrahiert die Base mit 500 cm Benzol. Die Benzollösung wird eingeengt und der Rückstand aus Isopropanol umkristallisiert. Auf diese Weise wird die reine 4- (1-Benzyl-4-piperidyliden)-4H-benzo [4, 5] cyclohepta [l, 2-b]thiophen-10 (9H)-on-Base erhalten, welche bei 136 bis 1380 schmilzt. Die Mikroanalyse stimmt auf die Formel CHNOS.
Beispiel 2 : 4- (1-p-Chlorbenzyl-4-piperidyliden)-4H-benzo [4, 5] cyclohepta [1, 2-b]thiophen-10 (9H)-on
5, 17 g 4- (4-Piperidyliden)-4H-benzo [4, 5] eyclohepta [1, 2-b]thiophen-10 (9H)-on-Baseund 5, 56 g Soda wasserfrei werden in 60 cm3 Hexamethylphosphorsäuretriamid vorgelegt und bei 20 bis 250 mit 3, 38 g p-Chlorbenzylchlorid versetzt. Nach IS-stündigem Rühren bei Raumtemperatur wird die Reaktionsmischung mit 500 cm3 Wasser verdünnt und die Base mit 350 cm3 Benzol extrahiert. Die Benzollösung wird eingeengt und der Rückstand in 30 cm3 Äthanol absolut gelöst. Diese Lösung wird mit äthanolischer Salzsäure schwach sauer gestellt und das auskristallisierte Hydrochlorid nach dem Stehenlassen über Nacht bei 0 bis 50 abfil- triert.
Das rohe Hydrochlorid wird aus 85%igem Äthanol umkristallisiert. Auf diese Weise wird das reine
EMI2.2
Zum Gemisch von 1, 8 g wasserfreiem Natriumcarbonat und 3, 0 g 4- (4-piperidyliden) -4H-benzo[4, 5] cyclohepta[1, 2-b]thiophen-10 (9H) -on in 15 ml N, N- Dimethylformamid lässt man 2, 8 ml Chlordiphenylmethan bei Raumtemperatur zutropfen, rührt das Reaktionsgemisch 4, 5 h bei 700, kühlt es auf Raumtemperatur ab und giesst es auf 200 ml Wasser. Das erhaltene Produkt wird mit Äther ausgezogen, der Extrakt mitWasser und mit Kochsalzlösung neutral gewaschen, über Natriumsulfat getrocknet und eingedampft.
Der Rückstand wird durch 50 g basisches Kieselgel mit Methylenchlorid chromatographiert und die als Hauptfraktion isolierte Titelverbindung aus Äther-Hexan kristallisiert (Smp. 205 bis 207 ).
<Desc/Clms Page number 3>
B e i sp i el 4 : 7-Chlor-4- (1-diphenylmethyl-4-piperidyliden)-4H-benzo [4, 5] cyclohepta[1, 2-b] thiophen- - 10 (9H)-on
EMI3.1
analog zu Beispiel 3, ausgehend von 7-Chlor-4- (4-piperidyliden)-4H-benzo [4, 5hepta[1,2-b]thiophen-10(9H)-on und Benzylchlorid und erhält die Titelverbindung (Smp. des Hydrogen- fumarats der Titelverbindung 224 bis 226 [Zers. J-aus Äthanol). t Beispiele : 4- (1-p-Chlorbenzyl-4-piperidyliden)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H)-on
Man verfährt analog zu Beispiel 3, ausgehend von 4-(4-Piperidyliden)-4H-benzo[4,5]cyclohepta[1,2-b] thiophen-9 (10H)-on und p-Chlorbenzylchlorid und erhält die Titelverbindung (Öl).
Physikalische Charakterisierung : CO-Band bei 1660 n (Nujol) ; Rf 0, 7 (auf neutralem Aluminium- oxyd ; Methylenchlorid) ; Rf 0,77 (auf basischem Kieselgel ; Benzol/Äthanol/Ammoniak 84/15/1).
<Desc / Clms Page number 1>
The invention relates to a process for the preparation of new 4- (4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophene derivatives of the formula
EMI1.1
where Rt is hydrogen or a halogen or lower alkoxy radical in the 6 or 7 position, the oxo group is 9 or 10, E is hydrogen or halogen and Rg is hydrogen, phenyl or halophenyl, and their acid addition salts .
If the symbol 1 represents halogen, it stands in particular for chlorine or bromine.
If R1 represents a lower alkoxy group, this contains in particular 1 to 4 carbon atoms.
If R2 represents halogen, it particularly represents fluorine, chlorine or bromine.
Fluorine, chlorine and bromine are also particularly suitable as halogen substituents for the phenyl radical Rg.
According to the invention, the compounds of the formula (I) and their acid addition salts are obtained by adding compounds of the formula
EMI1.2
wherein 1 \ has the above meaning and the oxo group is 9 or 10 position, with compounds of the formula
EMI1.3
in which R2 and R3 have the above meanings and Hal is halogen, and, if desired, converts the compounds of the formula (t) thus obtained into their acid addition salts.
Acid addition salts can be prepared from the free bases in a known manner and vice versa.
The reaction of the compounds of the formula (H) with the compounds of the formula (hui) takes place, for example, in an organic solvent which is inert under the reaction conditions and preferably in
<Desc / Clms Page number 2>
Presence of an alkaline condensing agent such as sodium or potassium carbonate. The use of a strongly polar solvent such as hexamethylphosphoric acid triamide, dimethyl sulfoxide, dimethylformamide, etc. is advantageous
In practice, the compounds of the formula (in) are used as chloride or bromide. The reaction temperature is advantageously kept low, between room temperature and about 60.degree.
The compounds of the formula (1) and their pharmacologically acceptable acid addition salts have not yet been described in the literature. They are characterized by pharmacodynamic properties and can therefore be used as remedies.
They are characterized by histaminolytic properties, as can be seen from the results of the histamine toxicity test on guinea pigs. The histaminolytic effect of the 10-keto compounds of the formula (1) is specific, since no significant serotonin-antagonistic and anticholinergic properties can be determined with the serotonin toxicity test and the acetylcholine toxicity test on guinea pigs. These compounds can be characterized as specific histaminolytics.
In addition to their histaminolytic properties, the 9-keto compounds of the formula (I) also have serotonin-antagonistic and anticholinergic properties. Due to these properties, they are to be assessed as antaminics.
The compounds according to the invention can be used in allergic diseases of the most varied of origins.
The doses to be used naturally vary depending on the type of substance used, the administration and the condition to be treated; these doses can be administered in 2 to 3 portions, if necessary, or as a retard form. The daily dose is around 0.5 to 20 mg. For oral administration, the partial doses contain about 0.15 to 10 mg of the new compounds in addition to solid or liquid carrier substances or diluents.
The compounds of the formula (I) or their physiologically tolerable acid addition salts can be administered as medicaments alone or in a suitable pharmaceutical form with pharmacologically inert auxiliaries.
If the preparation of the starting compounds is not described, they are known or can be prepared by processes known per se or analogously to those described here or analogously to processes known per se.
In the following examples, which explain the invention in more detail but are not intended to restrict its scope in any way, all temperatures are given in degrees Celsius and are uncorrected.
Examples 1: 4- (1-Benzyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophen-10 (9H) -one
EMI2.1
anhydrous are introduced into 120 cm3 of hexamethylphosphoric triamide and 6 g of benzyl chloride are added at 250 cm. After stirring for 18 hours at room temperature, the mixture is stirred at 500 for a further 1 hour.
The reaction mixture is then diluted with 1000 cm 3 of water and the base is extracted with 500 cm of benzene. The benzene solution is concentrated and the residue is recrystallized from isopropanol. In this way, the pure 4- (1-benzyl-4-piperidylidene) -4H-benzo [4, 5] cyclohepta [l, 2-b] thiophen-10 (9H) -one base is obtained, which is available at 136 to 1380 melts. The microanalysis matches the formula CHNOS.
Example 2: 4- (1-p-Chlorobenzyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophen-10 (9H) -one
5.17 g of 4- (4-piperidylidene) -4H-benzo [4, 5] eyclohepta [1, 2-b] thiophen-10 (9H) -one base and 5.56 g of anhydrous soda are placed in 60 cm3 of hexamethylphosphoric triamide and at 20 to 250 with 3.38 g of p-chlorobenzyl chloride. After stirring at room temperature for 15 hours, the reaction mixture is diluted with 500 cm3 of water and the base is extracted with 350 cm3 of benzene. The benzene solution is concentrated and the residue is dissolved in 30 cm3 of absolute ethanol. This solution is made slightly acidic with ethanolic hydrochloric acid and the hydrochloride which has crystallized out is filtered off after standing at 0 to 50 overnight.
The crude hydrochloride is recrystallized from 85% ethanol. In this way the pure becomes
EMI2.2
To the mixture of 1.8 g of anhydrous sodium carbonate and 3.0 g of 4- (4-piperidylidene) -4H-benzo [4, 5] cyclohepta [1, 2-b] thiophen-10 (9H) -one in 15 ml of N 2.8 ml of chlorodiphenylmethane are added dropwise at room temperature, N-dimethylformamide, the reaction mixture is stirred for 4.5 h at 700, cooled to room temperature and poured into 200 ml of water. The product obtained is extracted with ether, the extract washed neutral with water and with sodium chloride solution, dried over sodium sulphate and evaporated.
The residue is chromatographed through 50 g of basic silica gel with methylene chloride and the title compound isolated as the main fraction is crystallized from ether-hexane (melting point 205 to 207).
<Desc / Clms Page number 3>
Example 4: 7-Chloro-4- (1-diphenylmethyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophen- - 10 (9H) -one
EMI3.1
analogous to Example 3, starting from 7-chloro-4- (4-piperidylidene) -4H-benzo [4,5hepta [1,2-b] thiophen-10 (9H) -one and benzyl chloride and receives the title compound (mp. of the hydrogen fumarate of the title compound 224 to 226 [decomp. J-from ethanol). Examples: 4- (1-p-chlorobenzyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophen-9 (10H) -one
The procedure is analogous to Example 3, starting from 4- (4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophen-9 (10H) -one and p-chlorobenzyl chloride, and the title compound is obtained ( Oil).
Physical characterization: CO band at 1660 n (Nujol); Rf 0.7 (on neutral aluminum oxide; methylene chloride); Rf 0.77 (on basic silica gel; benzene / ethanol / ammonia 84/15/1).
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT685675A AT337181B (en) | 1972-01-24 | 1975-09-05 | PROCESS FOR THE PREPARATION OF NEW 4- (4-PIPERIDYLIDEN) -4H-BENZO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN DERIVATES AND THEIR ACID ADDITIONAL SALTS |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH98672A CH569012A5 (en) | 1972-01-24 | 1972-01-24 | 4-piperidylidene benzocycloheptathiophenes - - antihistamines and serotonin and acetyl choline inhibitors |
| AT73479A ATA47973A (en) | 1972-01-24 | 1973-01-22 | PROCESS FOR THE PREPARATION OF NEW 4- (4-PIPERIDYLIDEN) -4H-BENZO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN DERIVATES AND THEIR ACID ADDITIONAL SALTS |
| AT685675A AT337181B (en) | 1972-01-24 | 1975-09-05 | PROCESS FOR THE PREPARATION OF NEW 4- (4-PIPERIDYLIDEN) -4H-BENZO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN DERIVATES AND THEIR ACID ADDITIONAL SALTS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| ATA685675A ATA685675A (en) | 1976-10-15 |
| AT337181B true AT337181B (en) | 1977-06-10 |
Family
ID=27146351
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AT685675A AT337181B (en) | 1972-01-24 | 1975-09-05 | PROCESS FOR THE PREPARATION OF NEW 4- (4-PIPERIDYLIDEN) -4H-BENZO (4,5) CYCLOHEPTA (1,2-B) THIOPHEN DERIVATES AND THEIR ACID ADDITIONAL SALTS |
Country Status (1)
| Country | Link |
|---|---|
| AT (1) | AT337181B (en) |
-
1975
- 1975-09-05 AT AT685675A patent/AT337181B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| ATA685675A (en) | 1976-10-15 |
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