CH473146A - Process for the preparation of new 4H-Benzo (4,5) cyclohepta (1,2-b) thiophene derivatives - Google Patents
Process for the preparation of new 4H-Benzo (4,5) cyclohepta (1,2-b) thiophene derivativesInfo
- Publication number
- CH473146A CH473146A CH1519165A CH1519165A CH473146A CH 473146 A CH473146 A CH 473146A CH 1519165 A CH1519165 A CH 1519165A CH 1519165 A CH1519165 A CH 1519165A CH 473146 A CH473146 A CH 473146A
- Authority
- CH
- Switzerland
- Prior art keywords
- benzo
- cyclohepta
- solution
- general formula
- thiophene
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 5
- MHGBFEJHQLAUQM-UHFFFAOYSA-N 10h-benzo[1,2]cyclohepta[3,4-b]thiophene Chemical class C1=CC2=CC=CC=C2CC2=C1SC=C2 MHGBFEJHQLAUQM-UHFFFAOYSA-N 0.000 title claims description 4
- -1 chloroformic acid ester Chemical class 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- NFHHBIGYIAIGFH-UHFFFAOYSA-N 2h-cyclohepta[b]thiophene Chemical compound C1=CC=CC2=CCSC2=C1 NFHHBIGYIAIGFH-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000000155 melt Substances 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- HDCACTWAHGBVJH-UHFFFAOYSA-N 4-(5,10-dihydro-4h-benzo[1,2]cyclohepta[3,4-b]thiophen-10-yl)-1-methylpiperidine Chemical compound C1CN(C)CCC1C1C2=CC=CC=C2CCC2=C1C=CS2 HDCACTWAHGBVJH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000002044 hexane fraction Substances 0.000 description 2
- 230000001558 histaminolytic effect Effects 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-M oxalate(1-) Chemical compound OC(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-M 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- UVBDWPINMVQVHC-UHFFFAOYSA-N 4-(4,5-dihydrobenzo[1,2]cyclohepta[3,4-b]thiophen-10-ylidene)piperidine Chemical compound C1CNCCC1=C1C2=CC=CC=C2CCC2=C1C=CS2 UVBDWPINMVQVHC-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- WVYWICLMDOOCFB-UHFFFAOYSA-N 4-methyl-2-pentanol Chemical compound CC(C)CC(C)O WVYWICLMDOOCFB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000012545 Psychophysiologic disease Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 239000004133 Sodium thiosulphate Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical class OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- XEYWLZRKUJKDSJ-UHFFFAOYSA-N ethyl 4-(4,5-dihydrobenzo[1,2]cyclohepta[3,4-b]thiophen-10-ylidene)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=CC=CC=C2CCC2=C1C=CS2 XEYWLZRKUJKDSJ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- ZDYUUBIMAGBMPY-UHFFFAOYSA-N oxalic acid;hydrate Chemical compound O.OC(=O)C(O)=O ZDYUUBIMAGBMPY-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
- C07D333/80—Seven-membered rings
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2/00—Processes of polymerisation
- C08F2/38—Polymerisation using regulators, e.g. chain terminating agents, e.g. telomerisation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Verfahren zur Herstellung von neuen 4H-Benzo [4,5 ]cyclohepta [1 ,2-b ]thiophen-Derivaten
Die vorliegende Erfindung betritt ein Verfahren zur Herstellung von neuen 4H-Benzo[4,5]cyclohepta- [1 ,2-b]thiophen-Derlvaten der allgemeinen Formel I und ihren Säureadditionssalzen, worin Z die Gruppie rung-CH°CHr bedeutet und die beiden X für Wasserstoff stehen oder zusammen eine weitere Bindung bilden oder Z die Gruppierung -CH=CH- be- deutet und die beiden X zusammen eine weitere Bindung bilden.
Erfindungsgemäss gelangt man zu den neuen Verbindungen der allgemeinen Formel I und ihren Säureadditionssalzen, indem man eine Verbindung der all gemeinen Formel II, worin Z und X obige Bedeutung besitzen, mit einem Chiorameisensäureester der allgemeinen Formel III, worin R eine niedere Alkyl- oder Aralkylgruppe bedeutet, umsetzt, die entstandene Verbindung der allgemeinen Formel IV einer Hydrolyse unterwirft und die erhaltene Verbindung der allgemeinen Formel I gegebenenfalls in ihre Säureadditions- salze überführt.
Die Ausführung des Verfahrens gestaltet sich beispielsweise wie folgt:
Die Lösung eines Chlorameisensäureesters, wie z. B.
Chlorameisensäureäthylester oder Chlorameisensäurebenzylester, in einem indifferenten organischen wasserfreien Lösungsmittel, vorzugsweise Benzol, Toluol, Tetrachlorkohlenstoff oder Tetrahydrofuran, wird mit der im gleichen Lösungsmittel gelösten Verbindung der Formel II bei Raumtemperatur versetzt. Zur Vervollständigung der Reaktion erhitzt man das Gemisch noch 1 bis 3 Stunden zum Sieden am Rückfluss oder lässt das Reaktionsgemisch mehrere Stunden bei Raumtemperatur stehen. Die als Zwischenprodukt erhaltene Verbindung der Formel IV wird nach bekannten Methoden isoliert und gereinigt.
In der nächsten Verfahrensstufe wird die Alkoxy carbonyl- oder Aralkoxycarbonylgruppe hydrolytisch durch ein Wasserstoffatom ersetzt. Man verfährt dabei z. B. in der Weise, dass man die Verbindung in einem niederen Alkanol, vorzugsweise n-Butanol, mit einem Alkalihydroxyd, z. B. Kaliumhydroxyd, mehrere Stunden erhitzt.
Die Abspaltung des Alkoxycarbonyl- oder Aralkoxycarbonylrestes gelingt indessen auch in saurem Medium, z. B. mit 48 % igem Bromwasserstoff. Die erhaltene Verbindung wird in bekannter Weise aus dem Reaktionsgemisch isoliert und durch Kristallisation oder durch Überführung in ein geeignetes Salz gereinigt. Solche Salze sind beispielsweise die Hydrochloride, Hydrobromide, Phosphate, Sulfate, Acetate, Malonate, Fumarate, Oxalate, Maleinate, Tartrate, Malate, Hexahydrobenzoate, Benzolsulfonate oder p-Toluolsulfonate.
Das als Ausgangsprodukt verwendete
4-(1-Methyl-4-piperidyl)-9,10-dihydro-4H benzo[4,5]cyclohepta[ 1 2-bithiophen ist neu. Es kann folgendermassen hergestellt werden: Die Lösung eines 4-(I-Methyl-4-piperidyliden)- oder 4-Hydroxy-4-(1-methyl-4-piperidyl)-9, 10-dihydro- 4H-benzo[4,5]cyclohepta[1 ,2-b]thiophens in Eisessig wird mit rotem Phosphor und Jodwasserstoffsäure während 1¸ Stunden unter Rückfluss erhitzt. Nach Filtration des Reaktionsgemisches und Eindampfen des Filtrates wird der Rückstand in Gegenwart von Alkalien, z. B. 20% iger Natronlauge, in einem organischen Lösungsmittel, vorzugsweise Methylenchlorid, aufgenommen.
Aus der organischen Phase wird Jod mittels Natriumthiosulfat entfernt, und das gewünschte Endprodukt dann in bekannter Weise isoliert und vorzugsweise durch Überführung in ein geeignetes Salz gereinigt.
Die Verbindungen der Formel I besitzen im in vitround in vivo-Test ausgeprägte histaminolytische, anticholinergische und serotoninantagonistische Wirkungen, wobei das 4-(4-Piperidyliden)-9, 1 lOdihydro-4H-benzo- [4, 5] cyclohepta ,2-b]tbiophen besonders durch seine histaminolytische Wirkung hervortritt. Daneben besitzen sie mässige antidepressive und sedative Eigenschaften.
Sie können als Antihistaminika bzw. Antiallergika gegen über Allergosen verschiedenster Genese, wie z. B.
Urticaria, Rhinitis allergika, Überempfindlichkeitsreaktionen oder Asthma bronchiale, in der Therapie Verwendung finden. In der Psychiatrie können die Verbindungen zur Behandlung psychotischer Erkrankungen, wie Depressionen, psychosomatische Störungen usw., angewandt werden. Sie werden vorzugsweise in Form ihrer physiologisch verträglichen, wasserlöslichen Salze verabreicht.
Die Verbindungen können als Arzneimittel allein oder in entsprechenden Arzneiformen für enterale oder parenterale Verabreichung verwendet werden. Zwecks Herstellung geeigneter Arzneiformen werden diese mit anorganischen oder organischen, pharmakologisch indiffe- renten Hilfsstoffen verarbeitet. Als Hilfsstoffe werden verwendet, z. B. für Tabletten und Dragées: Milchzucker, Stärke, Talk, Stearinsäure usw.; für Injektionspräparate: Wasser, Alkohole, Glycerin, pflanzliche Öle und dergleichen; für Suppositorien: natürliche oder gehärtete Öle und Wachse u. a. mehr. Zudem können die Zubereitungen geeignete Konservierungs-, Stabilisierungs-, Netzmittel, Lösungsvermittler, Süss- und Farbstoffe, Aromantien usw. enthalten.
In den nachfolgenden Beispielen, welche die Ausführung des Verfahrens erläutern, den Umfang der Erfindung aber in keiner Weise einschränken sollen, erfolgen alle Temperaturangaben in Celsiusgraden und sind nicht korrigiert.
Beispiel 1 4-(4-Piperidyliden)-9, 1 dihydro-
4H-benzo[4,5]cyclohepta[1,2-b]thiophen a) Zu einer Lösung von 12,4 g Chlorameisensäure äthylester in 50 ml abs. Benzol lässt man innerhalb 1 Stunde eine Lösung von 11,5 g
4-(1-Methyl-4-piperidyliden)-9,10-dihydro 4H-benzo[4,Sjcyclohepta[ 1 ,2]thiophen in 50 ml abs. Benzol zutropfen. Anschliessend erhitzt man die Reaktionslösung unter Rühren noch 2 Stunden zum Sieden, wäscht sie nach dem Abkühlen dreimal mit In Salzsäure, dann noch zweimal mit Wasser und trocknet sie über Natriumsulfat. Nach Abdampfen des Lösungsmittels wird der Rückstand aus einer Hexanfraktion mit Sdp. 67 bis 690 umkristallisiert.
Das reine 4-(1-Äthoxycarbonyl-4-piperidyliden)-9,10 dihydro-4H-benzo [4, 5] cyclohepta 1 ,2-b]thiophen schmilzt bei 116 bis 1170. b) Man erhitzt eine Lösung von 10,0 g
4-(1-Äthoxycarbonyl-4-piperidyliden)-9,10 dihydro-4H-benzo[4,5]cyclohepta[1,2-b] thiophen in 180 ml 48 % iger Bromwasserstoffsäure während 30 Minuten in einer Stickstoffatmosphäre zum Sieden.
Die noch heisse Lösung giesst man in 1500 ml Eiswasser ein und stellt die erhaltene Lösung mit Natronlauge alkalisch. Nach mehrmaligem Ausschütteln. mit Methylenchlorid wäscht man die vereinigten organischen Extrakte mit Wasser und trocknet sie über Natriumsulfat. Anschliessend dampft man das Lösungsmittel ab und kristallisiert den Rückstand aus Aceton um. Das 4-(4-Piperidyliden)-9, 10-dihydro-4H-benzo- [4,5]cyclohepta[1,2-b]thiophen schmilzt bei 130 bis 1310.
Hydrochlorid: Die äthanolische Lösung der Base wird mit der berechneten Menge äthanolischer Chlor wasserstofflösung verletzt, das ausgefallene Hydrochlorid abfiltriert und aus Methanol/Äthanol umkristallisiert. Smp. 306 bis 3080 (Zers.).
Beispiel 2
4-(4-Piperidyliden)-4H-benzo[4,5]cyclohepta [1,2-b]thiophen a) Gemäss der in Beispiel la angegebenen Vorschrift wird aus 17,0 g Chlorameisensäureäthylester und 15,0 g
4-(1-Methyl-4-piperidyliden)-4H-benzo [4,5]cyclohepta[1,2-b]thiophen in 250 ml abs. Benzol das
4-(1-Äthoxycarbonyl-4-piperidyliden)-4H-benzo [4,5]cyclohepta[1,2-b]thiophen vom Smp. 137 bis 1380 (aus Hexanfraktion) hergestellt. b) Man erhitzt in einer Stickstoffatmosphäre und unter Rühren eine Lösung von 7,0 g
4-(1-Äthoxycarbonyl-4-piperidyliden)-4H-benzo [4,5]cyclohepta[1,2-b]thiophen und 8,0 g Kaliumhydroxyd in 100 ml Methylisobutylcarbinol während 3 Stunden auf 1400. Nach dem Abkühlen wäscht man die erhaltene Lösung fünfmal mit Wasser, trocknet sie über Magnesiumsulfat und dampft das Lösungsmittel unter vermindertem Druck ab.
Das 4-(4-Piperidyliden)-4H-benzo[4,5]cyclohepta- [1 ,2-b]thiophen schmilzt bei 149 bis 1510 nach Umkristallisieren aus Aceton.
Hydrochlorid: Eine äthanolische Lösung der reinen Base versetzt man mit der berechneten Menge äthanolischer Chlorwasserstofflösung und kühlt die Lösung ab. Das ausgefallene, analysenreine Hydrochlorid schmilzt bei 309 bis 3100 (Zers.).
Beispiel 3
4-(4-Piperidyl)-9, 1 0ihydro-4H-benzo[4,5 ]- cyclohepta[ 1 2-bithiophen
Zu einer Lösung von 12,6 g Chlorameisensäureäthyl- ester in 50 ml absolutem Benzol lässt man innerhalb 1 Stunde eine Lösung von 11,5 g
4-(1-Methyl-4-piperidyl)-9,10-dihydro-4H-benzo [4,5]cyclohepta[1,2-b]thiophen (Smp. 127 bis 1290, nach Kristallisation aus Petrol äther) in 50 ml absolutem Benzol zutropfen. Anschlie ssend erhitzt man die Reaktionslösung unter Rühren noch 2 Stunden zum Sieden, wäscht sie nach dem Abkühlen dreimal mit 1n Salzsäure, dann noch zweimal mit Wasser und trocknet sie über Natriumsulfat. Nach Abdampfen des Lösungsmittels wird der Rückstand in 180 ml 48 % iger Bromwasserstoffsäure gelöst.
Man erhitzt während 30 Minuten in einer Stickstoffatmosphäre zum Sieden, giesst die noch heisse Lösung in 1500 ml Eiswasser ein und stellt die erhaltene Lösung mit Natronlauge alkalisch. Nach mehrmaligem Ausschütteln mit Methylenchlorid wäscht man die vereinigten organischen Extrakte mit Wasser und trocknet sie über Natriumsulfat. Anschliessend dampft man das Lösungsmittel ab und kristallisiert den Rückstand aus Aceton um. Das erhaltene
4-(4-Piperidyl)-9,10-dihydro-4H-benzo[4,5] cyclohepta[ 1 ,2-blthiophen schmilzt bei 122 bis 1250.
Hydrogenoxalat: Eine Lösung von 0,9 g Base in 15 ml Aceton versetzt man mit einer Lösung von 0,45 g Oxalsäurehydrat in 15 ml Aceton. Nach Einengen. der Lösung auf 10 ml und Eiskühlung filtriert man das ausgefallene Hydrogenoxalat ab und kristallisiert es aus Aceton um. Smp. 255 bis 2590 (Zers.).
Das als Ausgangsprodukt verwendete 4-( 1 -Methyl-4-piperidyl)-9, 1 Odihydro-4H-benzo [4,5]cyclohepta[1 ,2-b]thiophen wird folgendermassen hergestellt:
Das Gemisch von 2,0 g
4-(1-Methyl-4-piperidyliden)-9,10-dihydro-4H benzo[4,5]cyclohepta[1,2-b]thiophen, 2,0 g rotem Phosphor und 10,6 ml 56 % iger Jodwasserstoffsäure in 60 ml Eisessig wird 1t/2 Stunden am Rückfluss zum Sieden erhitzt, heiss filtriert und das Filtrat unter vermindertem Druck eingedampft. Der Rückstand wird in einem Gemisch von 50 ml 20% der Natronlauge und 50 ml Methylenchlorid gelöst, die organische Phase abgetrennt und der wässrige Teil noch zweimal mit Methylenchlorid ausgeschüttelt.
Die vereinigten Methylenchloridlösungen wäscht man zweimal mit 5% einer Natriumthiosulfatlösung und zweimal mit Wasser, trocknet sie über Natriumsulfat und dampft das Lösungsmittel ab. Das erhaltene 4-( 1 -Methyl-4-piperidyl)-9, 10-dihydro-4H-benzo- [4,5]cyclohepta[1,2-b]thiophen schmilzt nach Umkristallisieren aus Petroläther bei 127 bis 1290.
EMI3.1
Process for the preparation of new 4H-benzo [4,5] cyclohepta [1,2-b] thiophene derivatives
The present invention relates to a process for the preparation of new 4H-benzo [4,5] cyclohepta- [1,2-b] thiophene derivatives of the general formula I and their acid addition salts, in which Z denotes the group -CH ° CHr and the both X are hydrogen or together form a further bond or Z is the grouping -CH = CH- and the two X together form a further bond.
According to the invention, the new compounds of general formula I and their acid addition salts are obtained by mixing a compound of general formula II, in which Z and X have the above meaning, with a chloroformic acid ester of general formula III, in which R is a lower alkyl or aralkyl group , reacts, the resulting compound of the general formula IV is subjected to hydrolysis and the resulting compound of the general formula I is optionally converted into its acid addition salts.
The procedure is carried out, for example, as follows:
The solution of a chloroformic acid ester, such as. B.
Ethyl chloroformate or benzyl chloroformate in an inert organic anhydrous solvent, preferably benzene, toluene, carbon tetrachloride or tetrahydrofuran, is treated with the compound of the formula II dissolved in the same solvent at room temperature. To complete the reaction, the mixture is heated to reflux for a further 1 to 3 hours or the reaction mixture is left to stand for several hours at room temperature. The compound of the formula IV obtained as an intermediate is isolated and purified by known methods.
In the next stage of the process, the alkoxy carbonyl or aralkoxycarbonyl group is replaced hydrolytically by a hydrogen atom. One proceeds z. B. in such a way that the compound in a lower alkanol, preferably n-butanol, with an alkali hydroxide, for. B. Potassium hydroxide, heated for several hours.
The cleavage of the alkoxycarbonyl or aralkoxycarbonyl radical is also possible in an acidic medium, e.g. B. with 48% hydrogen bromide. The compound obtained is isolated from the reaction mixture in a known manner and purified by crystallization or by conversion into a suitable salt. Such salts are, for example, the hydrochlorides, hydrobromides, phosphates, sulfates, acetates, malonates, fumarates, oxalates, maleates, tartrates, malates, hexahydrobenzoates, benzenesulfonates or p-toluenesulfonates.
That used as the starting product
4- (1-Methyl-4-piperidyl) -9,10-dihydro-4H benzo [4,5] cyclohepta [1 2-bithiophene is new. It can be prepared as follows: The solution of a 4- (I-methyl-4-piperidylidene) - or 4-hydroxy-4- (1-methyl-4-piperidyl) -9, 10-dihydro-4H-benzo [4, 5] cyclohepta [1, 2-b] thiophens in glacial acetic acid is refluxed with red phosphorus and hydriodic acid for 1¸ hours. After filtration of the reaction mixture and evaporation of the filtrate, the residue in the presence of alkalis, eg. B. 20% sodium hydroxide solution, added in an organic solvent, preferably methylene chloride.
Iodine is removed from the organic phase by means of sodium thiosulfate, and the desired end product is then isolated in a known manner and preferably purified by converting it into a suitable salt.
The compounds of the formula I have pronounced histaminolytic, anticholinergic and serotonin-antagonistic effects in the in vitro and in vivo tests, the 4- (4-piperidylidene) -9,110dihydro-4H-benzo- [4,5] cyclohepta, 2-b ] tbiophen particularly stands out for its histaminolytic effect. They also have moderate antidepressant and sedative properties.
They can be used as antihistamines or antiallergics against allergies of various origins, such as. B.
Urticaria, allergic rhinitis, hypersensitivity reactions or bronchial asthma are used in therapy. In psychiatry, the compounds can be used to treat psychotic disorders such as depression, psychosomatic disorders, etc. They are preferably administered in the form of their physiologically compatible, water-soluble salts.
The compounds can be used as medicaments alone or in corresponding medicament forms for enteral or parenteral administration. In order to produce suitable dosage forms, these are processed with inorganic or organic, pharmacologically indifferent auxiliaries. As auxiliaries are used, for. B. for tablets and dragees: milk sugar, starch, talc, stearic acid, etc .; for injectables: water, alcohols, glycerine, vegetable oils and the like; for suppositories: natural or hydrogenated oils and waxes, etc. a. more. In addition, the preparations can contain suitable preservatives, stabilizers, wetting agents, solubilizers, sweeteners, colorants, flavorings, etc.
In the following examples, which illustrate the implementation of the process but are not intended to restrict the scope of the invention in any way, all temperatures are given in degrees Celsius and are not corrected.
Example 1 4- (4-piperidylidene) -9, 1 dihydro-
4H-benzo [4.5] cyclohepta [1,2-b] thiophene a) To a solution of 12.4 g of ethyl chloroformate in 50 ml of abs. Benzene is left in a solution of 11.5 g within 1 hour
4- (1-Methyl-4-piperidylidene) -9,10-dihydro 4H-benzo [4, Sjcyclohepta [1, 2] thiophene in 50 ml abs. Add benzene dropwise. The reaction solution is then heated to boiling for a further 2 hours with stirring, washed three times with 1N hydrochloric acid and then twice with water after cooling, and dried over sodium sulfate. After evaporation of the solvent, the residue is recrystallized from a hexane fraction with a boiling point of 67 to 690.
The pure 4- (1-ethoxycarbonyl-4-piperidylidene) -9,10 dihydro-4H-benzo [4, 5] cyclohepta 1, 2-b] thiophene melts at 116 to 1170. b) A solution of 10, 0 g
Boiling 4- (1-ethoxycarbonyl-4-piperidylidene) -9,10 dihydro-4H-benzo [4,5] cyclohepta [1,2-b] thiophene in 180 ml of 48% strength hydrobromic acid for 30 minutes in a nitrogen atmosphere.
The still hot solution is poured into 1500 ml of ice water and the resulting solution is made alkaline with sodium hydroxide solution. After shaking out several times. the combined organic extracts are washed with methylene chloride with water and dried over sodium sulfate. The solvent is then evaporated off and the residue is recrystallized from acetone. The 4- (4-piperidylidene) -9,10-dihydro-4H-benzo- [4,5] cyclohepta [1,2-b] thiophene melts at 130-1310.
Hydrochloride: The ethanolic solution of the base is violated with the calculated amount of ethanolic chlorine hydrogen solution, the precipitated hydrochloride is filtered off and recrystallized from methanol / ethanol. M.p. 306-3080 (dec.).
Example 2
4- (4-Piperidylidene) -4H-benzo [4.5] cyclohepta [1,2-b] thiophene a) According to the procedure given in Example la, 17.0 g of ethyl chloroformate and 15.0 g are obtained
4- (1-Methyl-4-piperidylidene) -4H-benzo [4.5] cyclohepta [1,2-b] thiophene in 250 ml of abs. Benzene that
4- (1-Ethoxycarbonyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophene of m.p. 137 to 1380 (from hexane fraction). b) A solution of 7.0 g is heated in a nitrogen atmosphere and with stirring
4- (1-Ethoxycarbonyl-4-piperidylidene) -4H-benzo [4.5] cyclohepta [1,2-b] thiophene and 8.0 g of potassium hydroxide in 100 ml of methyl isobutylcarbinol for 3 hours to 1400. After cooling, it is washed the solution obtained is washed five times with water, dried over magnesium sulfate and the solvent is evaporated off under reduced pressure.
The 4- (4-piperidylidene) -4H-benzo [4,5] cyclohepta- [1,2-b] thiophene melts at 149 to 1510 after recrystallization from acetone.
Hydrochloride: An ethanolic solution of the pure base is mixed with the calculated amount of ethanolic hydrogen chloride solution and the solution is cooled. The precipitated, analytically pure hydrochloride melts at 309 to 3100 (decomp.).
Example 3
4- (4-piperidyl) -9,110ihydro-4H-benzo [4,5] - cyclohepta [12-bithiophene
A solution of 11.5 g is added to a solution of 12.6 g of ethyl chloroformate in 50 ml of absolute benzene within 1 hour
4- (1-Methyl-4-piperidyl) -9,10-dihydro-4H-benzo [4,5] cyclohepta [1,2-b] thiophene (m.p. 127 to 1290, after crystallization from petroleum ether) in 50 Add dropwise ml of absolute benzene. The reaction solution is then heated to boiling for a further 2 hours with stirring, washed three times with 1N hydrochloric acid and then twice with water after cooling, and dried over sodium sulfate. The solvent is evaporated and the residue is dissolved in 180 ml of 48% hydrobromic acid.
The mixture is heated to boiling for 30 minutes in a nitrogen atmosphere, the still hot solution is poured into 1500 ml of ice water and the resulting solution is made alkaline with sodium hydroxide solution. After shaking out several times with methylene chloride, the combined organic extracts are washed with water and dried over sodium sulfate. The solvent is then evaporated off and the residue is recrystallized from acetone. The received
4- (4-piperidyl) -9,10-dihydro-4H-benzo [4,5] cyclohepta [1,2-blthiophene melts at 122-1250.
Hydrogen oxalate: A solution of 0.9 g of base in 15 ml of acetone is mixed with a solution of 0.45 g of oxalic acid hydrate in 15 ml of acetone. After narrowing. the solution to 10 ml and ice cooling, the precipitated hydrogen oxalate is filtered off and recrystallized from acetone. M.p. 255-2590 (dec.).
The 4- (1-methyl-4-piperidyl) -9,1 Odihydro-4H-benzo [4,5] cyclohepta [1,2-b] thiophene used as starting material is prepared as follows:
The mixture of 2.0 g
4- (1-Methyl-4-piperidylidene) -9,10-dihydro-4H benzo [4.5] cyclohepta [1,2-b] thiophene, 2.0 g of red phosphorus and 10.6 ml of 56% hydroiodic acid in 60 ml of glacial acetic acid, the mixture is refluxed for 1 t / 2 hours, filtered hot and the filtrate is evaporated under reduced pressure. The residue is dissolved in a mixture of 50 ml of 20% sodium hydroxide solution and 50 ml of methylene chloride, the organic phase is separated off and the aqueous part is extracted twice more with methylene chloride.
The combined methylene chloride solutions are washed twice with 5% of a sodium thiosulphate solution and twice with water, dried over sodium sulphate and the solvent is evaporated off. The 4- (1-methyl-4-piperidyl) -9, 10-dihydro-4H-benzo- [4,5] cyclohepta [1,2-b] thiophene obtained melts at 127 to 1290 after recrystallization from petroleum ether.
EMI3.1
Claims (1)
Priority Applications (23)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3355/65A GB1089483A (en) | 1964-02-04 | 1965-01-26 | Improvements in or relating to 4h-benzo(4,5)cyclohepta (1,2-b) thiophene derivatives |
| OA51413A OA01524A (en) | 1964-02-04 | 1965-01-28 | New heterocyclic compounds derived from benzo-cyclocheptathiophene and process for their preparation. |
| NL6501154A NL125442C (en) | 1964-02-04 | 1965-01-29 | |
| DES95277A DE1238040B (en) | 1964-02-04 | 1965-02-01 | Process for the preparation of 4H-benzo [4, 5] -cyclohepta [1, 2-b] thiophenes |
| FI0244/65A FI42216B (en) | 1964-02-04 | 1965-02-02 | |
| BE659178A BE659178A (en) | 1964-02-04 | 1965-02-02 | |
| FR4164A FR1441486A (en) | 1964-02-04 | 1965-02-02 | New heterocyclic compounds derived from benzo-cyclohepta-thiophene and process for their preparation |
| SE1405/65A SE306323B (en) | 1964-02-04 | 1965-02-03 | |
| IL22905A IL22905A (en) | 1964-02-04 | 1965-02-03 | 4h-benzo-(4,5)-cyclohepta-(1,2-b)-thiophene derivatives and a process for their production |
| BR166936/65A BR6566936D0 (en) | 1964-02-04 | 1965-02-04 | PROCESS FOR THE MANUFACTURE OF NEW DERIVATIVES 4-4-BENZO (4,5) CYCLE-HEPTA (1,2- B) THIOPHENICS |
| FR15304A FR4369M (en) | 1964-02-04 | 1965-04-30 | |
| CH806165A CH473138A (en) | 1964-02-04 | 1965-06-09 | Process for the preparation of new 9,10-dihydro-4H-benzo (4,5) cyclohepta (1,2-b) thiophene derivatives |
| BE668052A BE668052A (en) | 1964-02-04 | 1965-08-09 | |
| NL6510326A NL6510326A (en) | 1964-02-04 | 1965-08-09 | |
| FR27925A FR91208E (en) | 1964-02-04 | 1965-08-10 | New heterocyclic compounds derived from benzo-cyclohepta-thiophene and process for their preparation |
| CH1519165A CH473146A (en) | 1964-02-04 | 1965-11-03 | Process for the preparation of new 4H-Benzo (4,5) cyclohepta (1,2-b) thiophene derivatives |
| GB47266/66A GB1159480A (en) | 1964-02-04 | 1966-10-21 | 4H-Benzo[4,5]Cyclohepta[1,2-b]-Thiophene Derivatives |
| DE19661620420 DE1620420A1 (en) | 1964-02-04 | 1966-10-28 | New 4H-Benzo [4,5] cyclohepta [1,2-b] thiophene derivatives |
| BR184229/66A BR6684229D0 (en) | 1964-02-04 | 1966-10-31 | MANUFACTURING PROCESS FOR NEW 4H-BENZO DERIVATIVES 4,5 CYCLE-HEPTA 1,2-B THIOPHENE |
| FR82202A FR92121E (en) | 1964-02-04 | 1966-11-02 | New heterocyclic compounds derived from benzo-cycloheptathiophene and process for their preparation |
| ES332985A ES332985A2 (en) | 1964-02-04 | 1966-11-02 | Improvements in or relating to 4h-benzo(4,5)cyclohepta (1,2-b) thiophene derivatives |
| US642295A US3464983A (en) | 1964-02-04 | 1967-05-31 | 4h-benzo(4,5)cyclohepta(1,2-b)thiophenes |
| US646194A US3491103A (en) | 1963-12-19 | 1967-06-15 | Certain 4h-benzo(4,5)cyclohepta-(1,2-b) thiophenes |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH127564A CH440321A (en) | 1964-02-04 | 1964-02-04 | Process for the preparation of new heterocyclic compounds |
| CH1324664 | 1964-10-13 | ||
| CH806165A CH473138A (en) | 1964-02-04 | 1965-06-09 | Process for the preparation of new 9,10-dihydro-4H-benzo (4,5) cyclohepta (1,2-b) thiophene derivatives |
| CH1519165A CH473146A (en) | 1964-02-04 | 1965-11-03 | Process for the preparation of new 4H-Benzo (4,5) cyclohepta (1,2-b) thiophene derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH473146A true CH473146A (en) | 1969-05-31 |
Family
ID=27428140
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH806165A CH473138A (en) | 1963-12-19 | 1965-06-09 | Process for the preparation of new 9,10-dihydro-4H-benzo (4,5) cyclohepta (1,2-b) thiophene derivatives |
| CH1519165A CH473146A (en) | 1963-12-19 | 1965-11-03 | Process for the preparation of new 4H-Benzo (4,5) cyclohepta (1,2-b) thiophene derivatives |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH806165A CH473138A (en) | 1963-12-19 | 1965-06-09 | Process for the preparation of new 9,10-dihydro-4H-benzo (4,5) cyclohepta (1,2-b) thiophene derivatives |
Country Status (12)
| Country | Link |
|---|---|
| BE (2) | BE659178A (en) |
| BR (2) | BR6566936D0 (en) |
| CH (2) | CH473138A (en) |
| DE (2) | DE1238040B (en) |
| ES (1) | ES332985A2 (en) |
| FI (1) | FI42216B (en) |
| FR (4) | FR1441486A (en) |
| GB (2) | GB1089483A (en) |
| IL (1) | IL22905A (en) |
| NL (2) | NL125442C (en) |
| OA (1) | OA01524A (en) |
| SE (1) | SE306323B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU195800B (en) * | 1983-10-13 | 1988-07-28 | Sandoz Ltd | Process for producing 4h-benzo/4,5/cylopenta/1,2-b/ thiofene derivatives and pharmaceutical compositions containing them |
| ATE516804T1 (en) | 1999-09-13 | 2011-08-15 | Bridge Pharma Inc | OPTICALLY ACTIVE ISOMERS OF KETOTIFEN AND THEIR THERAPEUTIC METABOLITES |
-
1965
- 1965-01-26 GB GB3355/65A patent/GB1089483A/en not_active Expired
- 1965-01-28 OA OA51413A patent/OA01524A/en unknown
- 1965-01-29 NL NL6501154A patent/NL125442C/xx active
- 1965-02-01 DE DES95277A patent/DE1238040B/en active Pending
- 1965-02-02 FI FI0244/65A patent/FI42216B/fi active
- 1965-02-02 BE BE659178A patent/BE659178A/xx unknown
- 1965-02-02 FR FR4164A patent/FR1441486A/en not_active Expired
- 1965-02-03 SE SE1405/65A patent/SE306323B/xx unknown
- 1965-02-03 IL IL22905A patent/IL22905A/en unknown
- 1965-02-04 BR BR166936/65A patent/BR6566936D0/en unknown
- 1965-04-30 FR FR15304A patent/FR4369M/fr not_active Expired
- 1965-06-09 CH CH806165A patent/CH473138A/en unknown
- 1965-08-09 NL NL6510326A patent/NL6510326A/xx unknown
- 1965-08-09 BE BE668052A patent/BE668052A/xx unknown
- 1965-08-10 FR FR27925A patent/FR91208E/en not_active Expired
- 1965-11-03 CH CH1519165A patent/CH473146A/en unknown
-
1966
- 1966-10-21 GB GB47266/66A patent/GB1159480A/en not_active Expired
- 1966-10-28 DE DE19661620420 patent/DE1620420A1/en active Pending
- 1966-10-31 BR BR184229/66A patent/BR6684229D0/en unknown
- 1966-11-02 ES ES332985A patent/ES332985A2/en not_active Expired
- 1966-11-02 FR FR82202A patent/FR92121E/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR4369M (en) | 1966-08-22 |
| NL6510326A (en) | 1966-12-12 |
| GB1159480A (en) | 1969-07-23 |
| NL125442C (en) | 1968-06-17 |
| GB1089483A (en) | 1967-11-01 |
| NL6501154A (en) | 1965-08-05 |
| FR1441486A (en) | 1966-06-10 |
| BR6684229D0 (en) | 1973-12-26 |
| BE668052A (en) | 1966-02-09 |
| OA01524A (en) | 1969-07-21 |
| DE1238040B (en) | 1967-04-06 |
| IL22905A (en) | 1969-01-29 |
| BE659178A (en) | 1965-08-02 |
| FR92121E (en) | 1968-09-27 |
| FI42216B (en) | 1970-03-02 |
| DE1620420A1 (en) | 1970-03-12 |
| SE306323B (en) | 1968-11-25 |
| CH473138A (en) | 1969-05-31 |
| ES332985A2 (en) | 1968-03-16 |
| FR91208E (en) | 1968-05-03 |
| BR6566936D0 (en) | 1973-08-14 |
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