CH496716A - 5h-dibenzo a d-cycloheptene derivs centrally active - Google Patents
5h-dibenzo a d-cycloheptene derivs centrally activeInfo
- Publication number
- CH496716A CH496716A CH589866A CH589866A CH496716A CH 496716 A CH496716 A CH 496716A CH 589866 A CH589866 A CH 589866A CH 589866 A CH589866 A CH 589866A CH 496716 A CH496716 A CH 496716A
- Authority
- CH
- Switzerland
- Prior art keywords
- dibenzo
- formula
- cycloheptene
- lower alkyl
- acid
- Prior art date
Links
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 5
- 239000002841 Lewis acid Substances 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- GSCKMHFCKGEORH-UHFFFAOYSA-N tetracyclo[7.6.1.02,7.010,15]hexadeca-2,4,6,10,12,14-hexaen-8-imine Chemical class C1C2C3=C(C(C1C1=C2C=CC=C1)=N)C=CC=C3 GSCKMHFCKGEORH-UHFFFAOYSA-N 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- 239000012458 free base Substances 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 8
- -1 amino acetaldehyde diethylacetal oxalate Chemical compound 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 238000001816 cooling Methods 0.000 abstract description 3
- 239000003158 myorelaxant agent Substances 0.000 abstract description 3
- 239000011541 reaction mixture Substances 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- 230000001773 anti-convulsant effect Effects 0.000 abstract description 2
- 229940125681 anticonvulsant agent Drugs 0.000 abstract description 2
- 239000001961 anticonvulsive agent Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 1
- 229940035363 muscle relaxants Drugs 0.000 abstract 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 abstract 1
- 239000001117 sulphuric acid Substances 0.000 abstract 1
- 235000011149 sulphuric acid Nutrition 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 150000001241 acetals Chemical class 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000700159 Rattus Species 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- GYKZIZUAMKGNCC-UHFFFAOYSA-N N-methyltetracyclo[9.5.0.02,13.05,10]hexadeca-1(16),2(13),5,7,9,14-hexaen-4-imine Chemical compound CN=C1CC2=C3C(C4=C1C=CC=C4)CC2=CC=C3 GYKZIZUAMKGNCC-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010058667 Oral toxicity Diseases 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- RZJLDZMIOKCPJA-UHFFFAOYSA-N cycloheptene;hydrochloride Chemical compound Cl.C1CCC=CCC1 RZJLDZMIOKCPJA-UHFFFAOYSA-N 0.000 description 1
- 150000001933 cycloheptenes Chemical class 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010438 heat treatment Methods 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 231100000418 oral toxicity Toxicity 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
(A) Compounds of formula (I):- where R1 is H, or lower alkyl R2 is H, lower alkyl, alkenyl or alkynyl excepting that R1 and R2 cannot both be H. (B) Acid addition salts of (I). (C) Quaternary ammonium salts of (I). (i) Centrally active muscle relaxants and anti-convulsants. (iI) Intermediates. beta(N-alpha-Dibenzyl-N-methyl) amino acetaldehyde diethylacetal oxalate (2.5 g.) in 75% sulphuric acid (25 ml.) is heated at 100 deg. for 1 hr. After cooling the reaction mixture is diluted with 20 ml. water, made alkaline with 30% sodium hydroxide soln. and shaken out 5 times with ether.
Description
Verfahren zur Herstellung von SH-Dibenzo[a,dlcyclohepten-Derivaten
Gegenstand der Erfindung ist ein Verfahren zur Herstellung von neuen 5,11 - Methylenirnino-10,1 1-dihydro- -SH-dibenzo[a,d]cycloheptenen der Formel
EMI1.1
sowie von Säure-Additionssalzen davon. In Formel I bedeutet R1 ein Wasserstoffatom oder eine niedrige Alkylgruppe, R stellt ein Wasserstoffatom oder eine niedrige Alkyl-, Alkenyl- oder Alkinylgruppe dar, wobei jedoch R1 und R2 nicht gleichzeitig die Bedeutung von Wasserstoffatomen haben können. Unter einer niedrigen Alkyl-, Alkenyl- oder Alkinylgruppe wird eine solche mit höchstens 5 C-Atomen verstanden.
Die genannten Verbindungen zeigen pharmakologische Wirkungen, welche auf Verwendbarkeit als Arzneimittel zur Behandlung von Nervenkrankheiten, insbesondere als zentrale Muskelrelaxantien und als Antikonvulsiva, schliessen lassen. In besonderem Masse wirksam sind diejenigen Verbindungen, in welchen R1 Wasserstoff und R. niedriges Alkyl-, Alkenyl- oder Alkinyl darstellt, sowie diejenigen Produkte, worin R1 Methyl und R Wasserstoff oder Methyl bedeutet.
In der nachfolgenden Tabelle, in welcher die pharmakologischen Wirkungen erfindungsgemäss erhältlicher Produkte zahlenmässig belegt sind, wird als Mass für die zentral muskelrelaxierende Wirkung der Verlust des Haltevermögens von Mäusen am schräg gestellen Gitter (Rutscheffekt) angegeben, wobei ED 50 diejenige Dosis an erfindungsgemässem Produkt bedeutet, bei welcher 50% der Mäuse am genannten Gitter abrutschen. Als Mass für die antikonvulsive Wirkung werden die Ergebnisse des Elektroschock-Tests [Methode von Goodmann et al.; J. Pharmacol 108, 168 (1953)] angegeben, wobei ED 50 diejenige Dosis an erfindungsgemässem Produkt bedeutet, bei welcher 50% der Versuchstiere (Ratten) vor dem Streckkrampf der hinteren Extremitäten geschützt sind. Zur Beurteilung des therapeutischen Index' sind in der Tabelle auch die oralen Toxizitäten bei der Maus als DL 50 angegeben.
TABELLE
Rutscheffekt Elektroschock Toxizität Erfindungsgemässe Substanz ED 50 mg/kg p.o. ED 50 mg/kg p.o. DL 50 mg/kg p.o.
(Maus) (Ratte) (Maus) 5,1 -Methylenimino- 10,11 l-dihydro-l l-methyl-SH- -dibenzo[a,d]cyclohepten 63 1,1 195 N-Methyl-5,1 -methylenimino- 10,11 -dihydro-5H- -dibenzo[a,d]cyclohepten 160 1,4 > 320 N-Allyl-5,1 1-methylenimino- 10,1 1-dihydro-5H -dibenzo[a,d]cyclohepten 140 1,5 320
Verbindungen entsprechend Formel I werden erhalten, wenn man einen Aminoaldehyd der Formel
EMI2.1
in welcher R, und R die genannte Bedeutung haben, oder ein reaktionsfähiges Derivat eines solchen, insbesondere ein Acetal, in Gegenwart einer Lewis-Säure ringschliessend kondensiert.
Als Lewis-Säuren eignen sich insbesondere Phosphorsäure, Schwefelsäure, Salzsäure, Phosphorpentoxid, Phosphoroxychlorid, Polyphosphorsäure, Bortrifluorid, Zinkchlorid und dgl. Der Ringschluss wird vorzugsweise durch Erwärmen der Ausgangsverbindung in Gegenwart der Lewis-Säure bewerkstelligt.
Als Ausgangsstoffe verwendbare Acetale von Aldehyden der Formel II können ihrerseits z.B. erhalten werden, wenn man ein Amin der Formel
EMI2.2
in welcher R1 und R2 die genannte Bedeutung haben, mit Bromacetal umsetzt.
Acetale von Aldehyden der Formel II, worin R3 Wasserstoff bedeutet, können auch erhalten werden, wenn man eine Schiff-Base der Formel
EMI2.3
in welcher R1 die genannte Bedeutung hat, mit einer Grignard-Verbindung der Formel umsetzt.
EMI2.4
Die erfindungsgemässen 5,11-Methylenimino-10,11- -dihydro-5H-dibenzo[a,d]cycloheptene entsprechend Formel I können sowohl als freie Basen als auch in Form ihrer Salze mit geeigneten Säuren, wie Halogenwasserstoffsäuren, Schwefelsäure, Salpetersäure, Phosphorsäure, Essigsäure, Oxalsäure, Malonsäure, Bernsteinsäure, Äpfelsäure, Maleinsäure oder Toluolsulfonsäuren, gewonnen und verwendet werden.
Beispiel 1
6,5 g , - [N-(1 - Phenyl - l-benzyl)äthyl]amino - acetaldehyd-diäthylacetal-Oxalat (Smp. 145-1460C) werden in 50 ml 75%iger Schwefelsäure während 1 Stunde unter Stickstoff-Atmosphäre auf 1000C erwärmt. Nach dem Abkühlen wird das Reaktionsgemisch mit 20 ml Wasser verdünnt, mit 30%iger Natronlauge alkalisch gestellt und sechsmal mit je 10 ml Chloroform ausgeschüttelt. Die Chloroformauszüge werden mit Natriumsulfat getrocknet und eingedampft. Als Rückstand erhält man 3,62 g (99% der Theorie) 5,1 l-Methylenimino-l0,l l-dihydro-1 1-me- thyl-5H-dibenzo[a,d]cyclohepten in Form eines fast farblosen Öls. Durch Behandeln dieses Öls mit alkoholischer Salzsäure erhält man 4,17 g des entsprechenden Hydrochlorids in Form von farblosen Nadeln vom Schmelzpunkt )3500C (aus Methanol/Aether).
Beispiel 2
2,5 g;P- [N-a-Dibenzyl-N-methyl]amino-acetaldehyd -diäthylacetal-Oxalat (Smp. 190-1920C) werden in 25 ml 75%iger Schwefelsäure während 1 Stunde auf 1000C erwärmt. Nach dem Abkühlen wird das Reaktionsgemisch mit 20 ml Wasser verdünnt, mit 30 %iger Natronlauge alkalisch gestellt und fünfmal mit je 40 ml Äther ausgeschüttelt. Die Ätherauszüge werden mit Natriumsulfat getrocknet und eingedampft. Aus dem Rückstand erhält man durch Behandeln mit äthanolischer Salzsäure 3,3 g (94% der Theorie) N-Methyl-5,1 l-methy- lenimino- 10,11 -dihydro-5H-dibenzo[a,d]cyclohepten-Hydrochlorid in Form von farblosen Nadeln vom Schmelzpunkt 22l-2220C (aus Methanol/Äther).
Bei analogem Vorgehen wie in den vorerwähnten Beispielen erhält man weiterhin z.B. die nachfolgend angegebenen Produkte gemäss Formel I N-Äthyl-5, 11 -methylenimino- 10,11 -dihydro-5H - dibenzo [a,d] -cyclohepten-Hydrochlorid vom Schmelzpunkt 216-2170C; N-n-Propyl-5, 11 -methylenimino- 10,11 -dihydro-5H- -dibenzo[a,d]-cyclohepten-Hydrochlorid vom Schmelzpunkt 255-2570C; N-Allyl-5,11 -methylenimino- 10,11 -dihydro-5H-dibenzo- [a,d]cyclohepten-Hydrochlorid vom Schmelzpunkt 210-2140C.
N-Propargyl-5,1 l-methylenimino-l0,l l-dihydro-5H- -dibenzo[a,d].cyclohepten-Hydrochlorid vom Schmelzpunkt 207-2080C; N-Methyl-5, 11 -methylenimino- 10,11 -dihydro- 11 -methyl -5H-dibenzo-[a,d]cyclohepten-Hydrochlorid vom Schmelzpunkt 211-2140C; N-n-Butyl-5, 11 -methylenimino- 10,11 -dihydro-5H-dibenzo -[a,d]-cyclohepten-Hydrochlorid vom Doppelschmelzpunkt 1550C und 217-222 C.
Process for the preparation of SH-dibenzo [a, dlcycloheptene derivatives
The invention relates to a process for the preparation of new 5,11-methylenimino-10,1 1-dihydro- —SH-dibenzo [a, d] cycloheptenes of the formula
EMI1.1
as well as acid addition salts thereof. In formula I, R1 denotes a hydrogen atom or a lower alkyl group, R denotes a hydrogen atom or a lower alkyl, alkenyl or alkynyl group, although R1 and R2 cannot simultaneously have the meaning of hydrogen atoms. A lower alkyl, alkenyl or alkynyl group is understood to mean one with a maximum of 5 carbon atoms.
The compounds mentioned show pharmacological effects which indicate their usefulness as medicaments for the treatment of nervous diseases, in particular as central muscle relaxants and as anticonvulsants. Particularly effective are those compounds in which R 1 is hydrogen and R is lower alkyl, alkenyl or alkynyl, and those products in which R 1 is methyl and R is hydrogen or methyl.
In the following table, in which the pharmacological effects of products according to the invention are numerically documented, the loss of the ability of mice to hold on to the inclined grid (sliding effect) is given as a measure of the central muscle relaxant effect, where ED 50 means the dose of product according to the invention in which 50% of the mice slide off the said grid. As a measure of the anticonvulsant effect, the results of the electric shock test [method by Goodmann et al .; J. Pharmacol 108, 168 (1953)], where ED 50 denotes the dose of product according to the invention at which 50% of the test animals (rats) are protected from spasms of the hind extremities. To assess the therapeutic index, the oral toxicities in the mouse are also given as DL 50 in the table.
TABLE
Slide effect Electric shock toxicity Substance according to the invention ED 50 mg / kg p.o. ED 50 mg / kg p.o. DL 50 mg / kg p.o.
(Mouse) (rat) (mouse) 5,1-methyleneimino- 10,11 l-dihydro-l l-methyl-SH- -dibenzo [a, d] cycloheptene 63 1,1 195 N-methyl-5,1 - methylenimino-10,11-dihydro-5H- -dibenzo [a, d] cycloheptene 160 1,4> 320 N-allyl-5,1 1-methylenimino-10,1 1-dihydro-5H -dibenzo [a, d] cycloheptene 140 1.5 320
Compounds corresponding to formula I are obtained if an aminoaldehyde of the formula
EMI2.1
in which R, and R have the meaning mentioned, or a reactive derivative of such, in particular an acetal, condensed in a ring-closing manner in the presence of a Lewis acid.
Particularly suitable Lewis acids are phosphoric acid, sulfuric acid, hydrochloric acid, phosphorus pentoxide, phosphorus oxychloride, polyphosphoric acid, boron trifluoride, zinc chloride and the like. The ring closure is preferably accomplished by heating the starting compound in the presence of the Lewis acid.
Acetals of aldehydes of the formula II which can be used as starting materials can in turn be e.g. can be obtained when using an amine of the formula
EMI2.2
in which R1 and R2 have the meaning mentioned, reacts with bromoacetal.
Acetals of aldehydes of the formula II, in which R3 is hydrogen, can also be obtained by using a Schiff base of the formula
EMI2.3
in which R1 has the meaning mentioned, reacts with a Grignard compound of the formula.
EMI2.4
The 5,11-methylenimino-10,11- dihydro-5H-dibenzo [a, d] cycloheptenes according to formula I can be used both as free bases and in the form of their salts with suitable acids such as hydrohalic acids, sulfuric acid, nitric acid, phosphoric acid , Acetic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid or toluenesulfonic acids, can be obtained and used.
example 1
6.5 g of - [N- (1-phenyl-1-benzyl) ethyl] amino-acetaldehyde diethylacetal oxalate (melting point 145-1460C) are dissolved in 50 ml of 75% sulfuric acid for 1 hour under a nitrogen atmosphere 1000C heated. After cooling, the reaction mixture is diluted with 20 ml of water, made alkaline with 30% sodium hydroxide solution and extracted six times with 10 ml of chloroform each time. The chloroform extracts are dried with sodium sulfate and evaporated. 3.62 g (99% of theory) of 5.1 l-methylenimino-10, l-dihydro-11-methyl-5H-dibenzo [a, d] cycloheptene are obtained as residue in the form of an almost colorless oil . Treatment of this oil with alcoholic hydrochloric acid gives 4.17 g of the corresponding hydrochloride in the form of colorless needles with a melting point of 3500 ° C. (from methanol / ether).
Example 2
2.5 g; P- [N-α-dibenzyl-N-methyl] amino-acetaldehyde diethylacetal oxalate (melting point 190-1920C) are heated to 1000C for 1 hour in 25 ml of 75% sulfuric acid. After cooling, the reaction mixture is diluted with 20 ml of water, made alkaline with 30% sodium hydroxide solution and extracted five times with 40 ml of ether each time. The ether extracts are dried with sodium sulfate and evaporated. Treatment with ethanolic hydrochloric acid gives 3.3 g (94% of theory) of N-methyl-5,1 l-methyleneimino-10,11-dihydro-5H-dibenzo [a, d] cycloheptene hydrochloride from the residue in the form of colorless needles with a melting point of 221-2220C (from methanol / ether).
If the procedure is analogous to that in the aforementioned examples, one still obtains e.g. the products given below according to formula I N-ethyl-5, 11 -methyleneimino-10,11 -dihydro-5H-dibenzo [a, d] -cycloheptene hydrochloride with a melting point of 216-2170C; N-n-Propyl-5, 11 -methyleneimino-10,11 -dihydro-5H- -dibenzo [a, d] -cycloheptene hydrochloride, melting point 255-2570C; N-allyl-5,11 -methyleneimino-10,11 -dihydro-5H-dibenzo- [a, d] cycloheptene hydrochloride, melting point 210-2140C.
N-propargyl-5,1 l-methylenimino-10,1 l-dihydro-5H- -dibenzo [a, d] .cycloheptene hydrochloride of melting point 207-2080C; N-methyl-5, 11 -methyleneimino-10,11-dihydro-11 -methyl -5H-dibenzo- [a, d] cycloheptene hydrochloride of melting point 211-2140C; N-n-Butyl-5, 11 -methyleneimino-10,11 -dihydro-5H-dibenzo - [a, d] -cycloheptene hydrochloride of double melting point 1550C and 217-222 C.
Claims (1)
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH589866A CH496716A (en) | 1966-04-22 | 1966-04-22 | 5h-dibenzo a d-cycloheptene derivs centrally active |
| IL2778567A IL27785A (en) | 1966-04-22 | 1967-04-13 | 5,11-methylenimino-10,11-dihydro-5h-dibenzo(a,d) cycloheptene derivatives |
| GB1697067A GB1146109A (en) | 1966-04-22 | 1967-04-13 | 5h-dibenzo[a,d]cycloheptene derivatives |
| DE19671720016 DE1720016A1 (en) | 1966-04-22 | 1967-04-13 | 5H-dibenzo [a, d] cycloheptene derivatives |
| FR102958A FR6143M (en) | 1966-04-22 | 1967-04-17 | |
| ES339452A ES339452A1 (en) | 1966-04-22 | 1967-04-18 | 5h-dibenzo[a,d]cycloheptene derivatives |
| DK212167A DK115116B (en) | 1966-04-22 | 1967-04-19 | Process for the preparation of 5H-dibenzo [a, d] cycloheptene derivatives. |
| SE559267A SE326962B (en) | 1966-04-22 | 1967-04-20 | |
| NL6705570A NL6705570A (en) | 1966-04-22 | 1967-04-20 | |
| AT379967A AT275538B (en) | 1966-04-22 | 1967-04-21 | Process for the preparation of new 5,11-methylenimino-10,11-dihydro-5H-dibenzo [a, d] cycloheptenes and their salts |
| BE697369D BE697369A (en) | 1966-04-22 | 1967-04-21 | |
| AT1035368A AT275540B (en) | 1966-04-22 | 1967-04-21 | Process for the preparation of new 5,11-methylenimino-10,11-dihydro-5H-dibenzo [a, d] cycloheptenes and their salts |
| GR670136289A GR36289B (en) | 1966-04-22 | 1967-04-22 | METHOD FOR THE MANUFACTURE OF PRODUCERS OF THE 5TH-DIVENZO (A, D) CYCLOEPTENE. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH589866A CH496716A (en) | 1966-04-22 | 1966-04-22 | 5h-dibenzo a d-cycloheptene derivs centrally active |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH496716A true CH496716A (en) | 1970-09-30 |
Family
ID=4301185
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH589866A CH496716A (en) | 1966-04-22 | 1966-04-22 | 5h-dibenzo a d-cycloheptene derivs centrally active |
Country Status (12)
| Country | Link |
|---|---|
| AT (2) | AT275538B (en) |
| BE (1) | BE697369A (en) |
| CH (1) | CH496716A (en) |
| DE (1) | DE1720016A1 (en) |
| DK (1) | DK115116B (en) |
| ES (1) | ES339452A1 (en) |
| FR (1) | FR6143M (en) |
| GB (1) | GB1146109A (en) |
| GR (1) | GR36289B (en) |
| IL (1) | IL27785A (en) |
| NL (1) | NL6705570A (en) |
| SE (1) | SE326962B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4950030A (en) * | 1986-05-30 | 1990-08-21 | Motor Wheel Corporation | Wheel for a track laying vehicle |
| US5011834A (en) * | 1989-04-14 | 1991-04-30 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon | PCP receptor ligands and the use thereof |
| US6017910A (en) * | 1989-04-14 | 2000-01-25 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon | PCP receptor ligands and the use thereof |
-
1966
- 1966-04-22 CH CH589866A patent/CH496716A/en not_active IP Right Cessation
-
1967
- 1967-04-13 GB GB1697067A patent/GB1146109A/en not_active Expired
- 1967-04-13 IL IL2778567A patent/IL27785A/en unknown
- 1967-04-13 DE DE19671720016 patent/DE1720016A1/en active Pending
- 1967-04-17 FR FR102958A patent/FR6143M/fr not_active Expired
- 1967-04-18 ES ES339452A patent/ES339452A1/en not_active Expired
- 1967-04-19 DK DK212167A patent/DK115116B/en unknown
- 1967-04-20 SE SE559267A patent/SE326962B/xx unknown
- 1967-04-20 NL NL6705570A patent/NL6705570A/xx unknown
- 1967-04-21 AT AT379967A patent/AT275538B/en active
- 1967-04-21 BE BE697369D patent/BE697369A/xx unknown
- 1967-04-21 AT AT1035368A patent/AT275540B/en active
- 1967-04-22 GR GR670136289A patent/GR36289B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AT275540B (en) | 1969-10-27 |
| GR36289B (en) | 1969-01-20 |
| NL6705570A (en) | 1967-10-23 |
| IL27785A (en) | 1971-03-24 |
| AT275538B (en) | 1969-10-27 |
| FR6143M (en) | 1968-06-24 |
| DK115116B (en) | 1969-09-08 |
| ES339452A1 (en) | 1968-05-16 |
| BE697369A (en) | 1967-10-23 |
| GB1146109A (en) | 1969-03-19 |
| SE326962B (en) | 1970-08-10 |
| DE1720016A1 (en) | 1971-05-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CH494766A (en) | Piperazine derivs having psychotropic analgesic and | |
| DE2828039A1 (en) | 2- (2-ALKOXYETHYL) -2'-HYDROXY-6,7-BENZOMORPHANES THEIR ACID ADDITION SALTS, THESE MEDICINAL PRODUCTS, AND METHOD FOR THE PRODUCTION THEREOF | |
| DE1795832C3 (en) | O-aminoarylketimines and processes for their preparation | |
| DE2013532A1 (en) | Butyrophenone derivatives and process for their preparation | |
| CH496716A (en) | 5h-dibenzo a d-cycloheptene derivs centrally active | |
| AT391866B (en) | METHOD FOR PRODUCING NEW S-TRIAZOLO (1,5-A) PYRIMIDINE | |
| DE2107356C3 (en) | Thieno [23-e] - [1,4] diazepin-2-ones, process for their preparation and pharmaceuticals containing them | |
| DE2542791C2 (en) | N, N'-Disubstituted Naphthylacetamidines | |
| DE1543388B1 (en) | Basically substituted, tricyclic heterocyclic compounds and their pharmacologically non-toxic salts and processes for their preparation | |
| CH675723A5 (en) | ||
| DE2311881A1 (en) | Morphinan derivs - prepd by acid cyclisation of substd n-formyloctahydroisoquinoline, show analgesic and morphin-antagonist | |
| CH513807A (en) | Tricyclic cpds antidepressive | |
| DE2361340C2 (en) | 1,3-Dioxan-5-methylamine and medicinal products containing these compounds | |
| DE2356830A1 (en) | 1,4,7,10-TETRAHYDRO-4,7-DIOXO-12HCYCLOPENTADICHINOLIN-2,9-DICARBONIC ACID DERIVATIVES, METHODS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS | |
| DE2057115A1 (en) | Process for the preparation of 1,2,3,4,5,6 hexahydro 2,6 methano 3 benzazocin 8 oils substituted in the 3 position | |
| AT131117B (en) | Process for the preparation of derivatives of 1-benzyl-6,7-dimethoxy- or -methylenedioxyisoquinoline. | |
| DE1543388C (en) | Basically substituted tricychic heterocyclic compounds and their pharmacologically non-toxic salts and processes for their preparation | |
| DE2340122A1 (en) | SPIRANE COMPOUNDS WITH CONDENSED HETEROCYCLES AND PROCESS FOR THEIR PRODUCTION | |
| CH485654A (en) | Process for the preparation of 10,11-dihydro-5H-dibenzo (a, d) -cycloheptene derivatives | |
| AT313890B (en) | Process for the production of new N- (furyl-methyl) -morphinanderivaten and their acid addition salts | |
| CH631714A5 (en) | Process for preparing novel quaternary derivatives of sandwicin | |
| AT378191B (en) | METHOD FOR PRODUCING NEW PYROGALLOLAETHER DERIVATIVES | |
| AT273973B (en) | Process for the preparation of new oxazepines and thiazepines and their non-toxic acid addition salts | |
| CH478754A (en) | Process for the preparation of 5-aminomethylated 5H-dibenzo (a, d) cycloheptene derivatives | |
| EP0011255B1 (en) | 1,2,3,4-tetrahydro-6-oxo-2,8a-methano-6h-dibenz(c,e)-azocines, medicaments containing them, and process for their preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |