CH521969A - Substd morphanthridene derivs - Google Patents
Substd morphanthridene derivsInfo
- Publication number
- CH521969A CH521969A CH399772A CH399772A CH521969A CH 521969 A CH521969 A CH 521969A CH 399772 A CH399772 A CH 399772A CH 399772 A CH399772 A CH 399772A CH 521969 A CH521969 A CH 521969A
- Authority
- CH
- Switzerland
- Prior art keywords
- formula
- addition salts
- acid addition
- acid
- methyl
- Prior art date
Links
- 239000002253 acid Substances 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 238000006356 dehydrogenation reaction Methods 0.000 claims abstract description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 235000005985 organic acids Nutrition 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000003125 aqueous solvent Substances 0.000 claims 1
- 230000003474 anti-emetic effect Effects 0.000 abstract description 2
- 230000001558 histaminolytic effect Effects 0.000 abstract description 2
- 239000000932 sedative agent Substances 0.000 abstract description 2
- 230000002048 spasmolytic effect Effects 0.000 abstract description 2
- 239000002111 antiemetic agent Substances 0.000 abstract 1
- 229940125683 antiemetic agent Drugs 0.000 abstract 1
- 229920000137 polyphosphoric acid Polymers 0.000 abstract 1
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract 1
- 229940125723 sedative agent Drugs 0.000 abstract 1
- -1 1-methyl-4-piperidylidene Chemical group 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000001624 sedative effect Effects 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000013213 extrapolation Methods 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 230000004899 motility Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- IDWNSAXOQLJYOF-UHFFFAOYSA-N 11h-benzo[c][1]benzazepine Chemical compound C1=NC2=CC=CC=C2CC2=CC=CC=C21 IDWNSAXOQLJYOF-UHFFFAOYSA-N 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- JEYCTXHKTXCGPB-UHFFFAOYSA-N Methaqualone Chemical compound CC1=CC=CC=C1N1C(=O)C2=CC=CC=C2N=C1C JEYCTXHKTXCGPB-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000000794 anti-serotonin Effects 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 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
- 239000011707 mineral Substances 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 150000004053 quinones Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 231100000916 relative toxicity Toxicity 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Morphanthridenes of formula (I) (where R1= H or Me, R1=H or forms a piperidine ring by linkage to R3 or R4, R3 R4=Me or is linked to R2, X and Y,=H and/or hal). and their acid addition salts are anti-emetics histaminolytics, sedatives, spasmolytics, antiserotonics, pysychotropics. (I) may be prepd. by (a) ring closure of a 2-formyl-or 2-acety-lamino-diphenyl-methane analogue, e.g. with polyphosphoric acid or (b) dehydrogenation of the 5,6-dihydro analogne.
Description
Verfahren zur Herstellung von neuen Morphanthridinen
Die Erfindung betrifft ein Verfahren zur Herstellung von neuen Morphanthridinen der Formel 1
EMI1.1
worin R1 ein Wasserstoffatom oder die Methylgruppe, R2 ein Wasserstoffatom oder zusammen mit R bzw. R und den dazwischenliegenden Kohlenstoffatomen und dem Stickstoffatom einen Piperidinring, R3 und/oder Rw Methylgruppen, X und Y, die gleich oder verschieden sein können,
Wasserstoff- oder Halogenatome bedeuten, sowie von deren Säureadditionssalzen mit anorganischen oder organischen Säuren.
Die neuen Verbindungen werden erfindungsgemäss hergestellt, indem man eine Verbindung der Formel 2
EMI1.2
durch ein Oxydationsmittel dehydriert.
Die Dehydrierung wird zweckmässig bei erhöhten Temperaturen, vorzugsweise bei Temperaturen zwischen 60 und 12()0C, zweckmässig in einem organischen Lösungsmittel oder in Wasser bzw. in einer verdünnten Mi- neralsäure durchgeführt. Es können alle üblichen Oxydationsmittel, beispielsweise Chinone, Wasserstoffperoxyd, Jod, Chromsäure, Kaliumpermanganat, Eisen-IIIchlorid, oder nitrose Gase verwendet werden. Die Oxydation erfolgt jedoch auch bereits bei mehrstündigem Durchblasen von Luft bei erhöhten Temperaturen. Sie lässt sich auch mit allen angeführten Oxydationsmitteln bei Zimmertemperatur durchführen, die Reaktionsdauer beträgt dann jedoch mehrere Tage.
Die nach dem Verfahren erhaltenen Verbindungen der Formel 1 können gewünschtenfalls nach üblichen Methoden in ihre Säureadditionssalze überführt werden.
Als Säuren kommen physiologisch verträgliche anorganische oder organische Säuren wie Salzsäure, Schwefelsäure, Phosphorsäure, Zitronensäure, Maleinsäure, Fumarsäure oder Weinsäure in Betracht.
Die als Ausgangsstoffe verwendeten Verbindungen der Formel 2 sind im belgischen Patent Nr. 652 938 [siehe C.A. 64, 19 575 h (1966)] beschrieben oder können analog dem beschriebenen Verfahren hergestellt werden.
Die neuen Verbindungen sowie ihre Säureadditionssalze besitzen wertvolle therapeutische Eigenschaften, insbesondere weisen sie eine histaminolytische, sedative, spasmolytische, eine Antiserotoninwirkung, psychotrope und antiemetische Wirkung auf.
Die pharmakologische Wirksamkeit von A 11 -(1 -Methyl-4-piperidyliden)-morphanthridin wurde im Vergleich zu B = SH-Dibenzo[a,d]-5-(1-methyl-4-piperidyliden)-cy- cloheptenhydrochloridmonohydrat, die von C = 3-Chlor- 11 -(3-dimethylaminopropyliden)-mor- phanthridin im Vergleich zu D = 2-Methyl-3-o-tolyl-4(3H)-chinazolon getestet.
1) Histamiaantagonistische Wirkung am intakten Meer schtveinchen:
Nach der Methode von Konzett-Rössler [Arch. exp.
Path. Pharmakol. 195, 71 (1940)] wurde die histaminantagonistische Wirkung vergleichend als eine den Histamin-bedingten Bronchospasmus des Meerschweinchens abschwächende Wirkung geprüft.
Durch graphische Extrapolation wurde für jede Substanz die Dosis bestimmt, die zu einer 50%igen Abschwächung des mit der Standarddosis des Histamins erzielten Effektes führte: Dosis Dosis Zahl der gemittelte Hemmeffekte y/kg i.v. Tiere i.v. in SO des Ausgangswertes
A 5,0 5 38,6
A 10,0 4 54,0
A 20,0 4 64,9
B 5.0 10 10,0
B 10.0 7 42,4
B 20,0 6 54,5
B 40,0 4 68,9
Die nachfolgende Tabelle gibt die relative Wirksamkeit der Substanz A im Vergleich zu der Substanz B in der Versuchsanordnung nach Konzett-Rössler wieder:
Substanz EDsp relative Wirksamkeit ylkg ylkg i.v.
A 8,6 1,92
B 16,5 1,00 2) Sedierende Wirkung:
Die sedierende Wirkung wurde an der Maus nach der Methode von Dews [Brit. J. Pharmacol. 8, 46 (1953)] bestimmt.
Durch graphische Extrapolation wurde für jede Substanz die Dosis bestimmt, bei der die Motilität der Versuchstiere auf 50% herabgesetzt wird:
Dosis Zahl der Motilität in %
Substanz mg/kg p.o. Tiere gegenüber Kontrollen
C 3,125 5 99
C 6,25 5 96
C 12,5 5 47
C 25,0 5 18
C 50,0 5 9
C 100,0 5 1
D 25,0 10 70,3
D 50,0 10 50,5
D 100,0 10 27,6
Die nachfolgende Tabelle gibt die relative Wirksamkeit der Substanz C im Vergleich zu der Substanz D in der Versuchsanordnung nach Dews wieder:
Substanz ED55 mg/kg p.o. relative Wirksamkeit
C 14 3,4
D 48 1 3) Akute Toxizität:
Die perorale akute Toxizität an der Maus wurde nach der Methode von Litchfield und Wilcoxon [J.
Pharmacol. exp. Therap. 94, 99 (1949)] berechnet:
Substanz DL5o mg/kg relative Toxizität
A 176 1
B 106 1,66
Die nachstehenden Beispiele sollen die Erfindung näher erläutern:
Beispiel I
11-(1-Methyl-4piperidyliden)-morphanthridin
288 mg 5,6 - Dihydro- 11- (1-methyl-4-piperidyliden) -morphanthridin werden in 15 ml Toluol mit 245 mg Chloranil 3 Stunden gekocht. Die Reaktionslösung wird nach Abkühlen filtriert und mit Salzsäure extrahiert.
Aus der salzsäuren Lösung wird mit Ammoniak die Base in Freiheit gesetzt und in Äther aufgenommen. Nach dem Trocknen über Natriumsulfat und Einengen der Ätherlösung erhält man 150 mg 1 1-(1-Methyl-4-piperi- dyliden)-morphanthridin vom Schmelzpunkt 1030C.
Die gleiche Verbindung wird auch erhalten, wenn man 288 mg 5,6-Dihydro-1 1-(l-methyl-4-piperidyliden)- -morphanthridin in 30 ml verdünnter Salzsäure löst und unter Erhitzen auf 1000C 8 Stunden lang Luft durchleitet.
Ausbeute: 170mg, Schmelzpunkt: 100 bis 102oC.
Beispiel 2
11-(3-Dimethylaminopropyliden)-morphanthridin
Aus 5,6 - Dihydro - 11 - (3-dimethylaminopropyliden) -morphanthridin analog Beispiel 1. Das erhaltene Produkt ist sirupartig, aber dünnschichtchromatographisch einheitlich.
Schmelzpunkt des Produktes: 175 bis 1760C.
Beispiel 3 3-Chlar-11-(3-dimethylaminopropyliden)-mmrphanthridin
Aus 3 -Chlor-5,6-dihydro- 1 1-(3-dimethylaminopropy- liden)-morphanthridin analog Beispiel 1.
Schmelzpunkt: 119 bis 1200C.
Die Verbindungen der Formel 1 können zur pharmazeutischen Anwendung in die üblichen pharmazeutischen Präparate eingearbeitet werden gegebenenfalls in Kombination mit anderen Wirksubstanzen. Die Einzeldosis beträgt für Erwachsene bei innerer Anwendung 0,25 bis 8,0 mg, vorzugsweise 2,0 bis 4,0 mg, die Tages dosis 5 bis 50 mg, für Kinder die Hälfte bis ein Viertel dieser Dosis. Bei lokaler Anwendung beträgt die Konzentration 0,1 bis 0,5%, vorzugsweise 0,2%.
Process for the preparation of new morphanthridines
The invention relates to a process for the preparation of new morphanthridines of the formula 1
EMI1.1
in which R1 is a hydrogen atom or the methyl group, R2 is a hydrogen atom or together with R or R and the carbon atoms in between and the nitrogen atom a piperidine ring, R3 and / or Rw are methyl groups, X and Y, which can be identical or different,
Mean hydrogen or halogen atoms, as well as their acid addition salts with inorganic or organic acids.
According to the invention, the new compounds are prepared by adding a compound of the formula 2
EMI1.2
dehydrated by an oxidizing agent.
The dehydrogenation is expediently carried out at elevated temperatures, preferably at temperatures between 60 and 12 ° C., expediently in an organic solvent or in water or in a dilute mineral acid. All the usual oxidizing agents, for example quinones, hydrogen peroxide, iodine, chromic acid, potassium permanganate, ferric chloride, or nitrous gases can be used. However, the oxidation also takes place when air is blown through for several hours at elevated temperatures. It can also be carried out with all the oxidizing agents mentioned at room temperature, but the reaction time is then several days.
The compounds of formula 1 obtained by the process can, if desired, be converted into their acid addition salts by customary methods.
Suitable acids are physiologically compatible inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, maleic acid, fumaric acid or tartaric acid.
The compounds of formula 2 used as starting materials are described in Belgian Patent No. 652 938 [see C.A. 64, 19 575 h (1966)] or can be prepared analogously to the process described.
The new compounds and their acid addition salts have valuable therapeutic properties, in particular they have a histaminolytic, sedative, spasmolytic, antiserotonin, psychotropic and antiemetic effect.
The pharmacological effectiveness of A 11 - (1-methyl-4-piperidylidene) -morphanthridine was compared to B = SH-dibenzo [a, d] -5- (1-methyl-4-piperidylidene) -cycloheptene hydrochloride monohydrate, the of C = 3-chloro-11 - (3-dimethylaminopropylidene) -morphanthridine compared to D = 2-methyl-3-o-tolyl-4 (3H) -quinazolone tested.
1) Histamia antagonistic effect on the intact sea schtveinchen:
According to the method of Konzett-Rössler [Arch. exp.
Path. Pharmacol. 195, 71 (1940)], the histamine-antagonistic effect was tested comparatively as an effect that attenuated the histamine-induced bronchospasm in guinea pigs.
The dose that led to a 50% weakening of the effect achieved with the standard dose of histamine was determined by graphical extrapolation for each substance: dose dose number of averaged inhibitory effects y / kg i.v. Animals i.v. in SO of the initial value
A 5.0 5 38.6
A 10.0 4 54.0
A 20.0 4 64.9
B 5.0 10 10.0
B 10.0 7 42.4
B 20.0 6 54.5
B 40.0 4 68.9
The following table shows the relative effectiveness of substance A in comparison to substance B in the experimental setup according to Konzett-Rössler:
Substance EDsp relative effectiveness ylkg ylkg i.v.
A 8.6 1.92
B 16.5 1.00 2) Sedative effect:
The sedative effect was determined on the mouse by the method of Dews [Brit. J. Pharmacol. 8, 46 (1953)].
The dose at which the motility of the test animals is reduced to 50% for each substance was determined by graphical extrapolation:
Dose number of motility in%
Substance mg / kg p.o. Animals versus controls
C 3.125 5 99
C 6.25 5 96
C 12.5 5 47
C 25.0 5 18
C 50.0 5 9
C 100.0 5 1
D 25.0 10 70.3
D 50.0 10 50.5
D 100.0 10 27.6
The following table shows the relative effectiveness of substance C in comparison to substance D in the test arrangement according to Dews:
Substance ED55 mg / kg p.o. relative effectiveness
C 14 3.4
D 48 1 3) Acute toxicity:
The acute peroral toxicity in the mouse was determined by the method of Litchfield and Wilcoxon [J.
Pharmacol. exp. Therap. 94, 99 (1949)] calculated:
Substance DL50 mg / kg relative toxicity
A 176 1
B 106 1.66
The following examples are intended to explain the invention in more detail:
Example I.
11- (1-methyl-4piperidylidene) -morphanthridine
288 mg of 5,6-dihydro-11- (1-methyl-4-piperidylidene) -morphanthridine are boiled in 15 ml of toluene with 245 mg of chloranil for 3 hours. After cooling, the reaction solution is filtered and extracted with hydrochloric acid.
The base is set free from the hydrochloric acid solution with ammonia and taken up in ether. After drying over sodium sulfate and concentrating the ether solution, 150 mg of 1 1- (1-methyl-4-piperidylidene) -morphanthridine with a melting point of 1030 ° C. are obtained.
The same compound is also obtained when 288 mg of 5,6-dihydro-1 1- (l-methyl-4-piperidylidene) - -morphanthridine is dissolved in 30 ml of dilute hydrochloric acid and air is passed through it for 8 hours while heating to 1000 ° C.
Yield: 170mg, melting point: 100 to 102oC.
Example 2
11- (3-dimethylaminopropylidene) morphanthridine
From 5,6-dihydro-11- (3-dimethylaminopropylidene) -morphanthridine analogously to Example 1. The product obtained is syrupy, but uniform according to thin-layer chromatography.
Melting point of the product: 175 to 1760C.
Example 3 3-Chlar-11- (3-dimethylaminopropylidene) -mmrphanthridine
From 3-chloro-5,6-dihydro-1 1- (3-dimethylaminopropylidene) -morphanthridine analogously to Example 1.
Melting point: 119 to 1200C.
For pharmaceutical use, the compounds of formula 1 can be incorporated into the customary pharmaceutical preparations, if appropriate in combination with other active substances. The single dose for adults for internal use is 0.25 to 8.0 mg, preferably 2.0 to 4.0 mg, the daily dose is 5 to 50 mg, and for children, half to a quarter of this dose. When applied locally, the concentration is 0.1 to 0.5%, preferably 0.2%.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH399772A CH521969A (en) | 1969-04-28 | 1969-04-28 | Substd morphanthridene derivs |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH645169A CH521974A (en) | 1969-04-28 | 1969-04-28 | Substd morphanthridene derivs |
| CH399772A CH521969A (en) | 1969-04-28 | 1969-04-28 | Substd morphanthridene derivs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH521969A true CH521969A (en) | 1972-04-30 |
Family
ID=4309839
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH645169A CH521974A (en) | 1969-04-28 | 1969-04-28 | Substd morphanthridene derivs |
| CH399772A CH521969A (en) | 1969-04-28 | 1969-04-28 | Substd morphanthridene derivs |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH645169A CH521974A (en) | 1969-04-28 | 1969-04-28 | Substd morphanthridene derivs |
Country Status (1)
| Country | Link |
|---|---|
| CH (2) | CH521974A (en) |
-
1969
- 1969-04-28 CH CH645169A patent/CH521974A/en not_active IP Right Cessation
- 1969-04-28 CH CH399772A patent/CH521969A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH521974A (en) | 1972-04-30 |
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