CH518974A - Antihistaminic 9-(4-piperidylidene)-thioxanthene-n-oxides - prodn - from corresp thioxanthenes with hydrogen peroxide or periodat - Google Patents
Antihistaminic 9-(4-piperidylidene)-thioxanthene-n-oxides - prodn - from corresp thioxanthenes with hydrogen peroxide or periodatInfo
- Publication number
- CH518974A CH518974A CH1745369A CH1745369A CH518974A CH 518974 A CH518974 A CH 518974A CH 1745369 A CH1745369 A CH 1745369A CH 1745369 A CH1745369 A CH 1745369A CH 518974 A CH518974 A CH 518974A
- Authority
- CH
- Switzerland
- Prior art keywords
- thioxanthene
- thioxanthenes
- corresp
- hydrogen peroxide
- piperidylidene
- Prior art date
Links
- 150000005075 thioxanthenes Chemical class 0.000 title claims abstract description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 title abstract description 9
- 230000001387 anti-histamine Effects 0.000 title abstract 2
- 239000000739 antihistaminic agent Substances 0.000 title abstract 2
- 239000002253 acid Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000003513 alkali Substances 0.000 abstract 1
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 abstract 1
- 229940125715 antihistaminic agent Drugs 0.000 abstract 1
- 229940082988 antihypertensives serotonin antagonists Drugs 0.000 abstract 1
- 239000003420 antiserotonin agent Substances 0.000 abstract 1
- 239000000812 cholinergic antagonist Substances 0.000 abstract 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical class OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 231100000820 toxicity test Toxicity 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- -1 alkali metal periodates Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 241000700198 Cavia Species 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 206010040108 Serotonin syndrome Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000001558 histaminolytic effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Novel cpds. of the formula (I) and their acid addn. salts (R = 1-4O alkyl) for use as antihistaminics, serotonin- antagonists and anticholinergics are prepd. by oxidising the corresp. thioxanthenes with H2O2 at 30-100 degrees or with alkali periodates at 0-30 degrees.
Description
Verfahren zur Herstellung neuer Thioxanthen-Verbindungen
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von Thioxanthen-Verbindungen der Formel I, worin R eine niedere Alkylgruppe bedeutet, und ihrer Säureadditionssalze.
Erfindungsgemäss werden die Verbindungen der Formel I und ihre Säureadditionssalze erhalten, indem man Verbindungen der Formel II, worin R obige Bedeutung besitzt, in einem unter den Reaktionsbedingungen inerten Lösungsmittel oxidiert und gewünschtenfalls die erhaltenen Verbindungen der Formel I in ihre Säureadditionssalze überführt.
Aus den freien Basen lassen sich in bekannter Weise Säureadditionssalze herstellen und umgekehrt.
Als Oxidationsmittel verwendet man vorzugsweise Wasserstoffperoxid oder Alkalimetallperjodate in neutraler Lösung, als Lösungsmittel vorzugsweise Alkohole wie Methanol, Äthanol oder auch Aceton. Die Oxidation mit Wasserstoffperoxid wird vorzugsweise bei etwa 30 bis 1000, die Oxidation mit Alkalimetallperjodaten bei etwa 0 bis 30 durchgeführt. Nach Beendigung der Reaktion wird allfälliges überschüssiges Oxidationsmittel zerstört bzw. entfernt und das gebildete N-Oxid auf an sich bekannte Weise aus dem Reaktionsgemisch isoliert und gereinigt, z. B. durch Kristallisation und/oder Chromatographie.
In den Verbindungen der Formel I kann die niedere Alkylgruppe, die durch das Symbol R repräsentiert wird, unverzweigt oder verzweigt sein und enthält vorzugsweise 1 bis 4 Kohlenstoffatome.
Die Verbindungen der Formel I besitzen wertvolle pharmakodynamische Eigenschaften und sollen als Heilmittel verwendet werden. Sie zeichnen sich durch histaminolytische, serotoninantagonistische und anticholinerge Eigenschaften aus, wie aus den Resultaten im Histamin-Toxizitäts-Test, Serotonin-Toxizitäts-Test und im Acetylcholin-Toxizitäts-Test am Meerschweinchen hervorgeht.
Die zu verwendenden Dosen variieren naturgemäss je nach der Art der Administration und des zu behandelnden Zustandes. Im allgemeinen werden jedoch bei Säugetieren befriedigende Resultate mit einer Tagesdosis von 0,05 bis 1 mg/kg Körpergewicht erhalten; diese Tagesdosis kann nötigenfalls in 2 bis 3 Anteilen oder auch als Retardform verabreicht werden. Für grössere Säugetiere liegt die Tagesdosis bei etwa 1 bis 5 mg. Für orale Applikationen enthalten die Teildosen etwa 0,3 bis 2,5 mg der Verbindungen der Formel I neben festen oder flüssigen Trägersubstanzen oder Verdünnungsmitteln.
Als Heilmittel können die neuen Verbindungen der Formel I allein oder in geeigneter Arzneiform wie Tabletten, Dragees, Injektionslösungen, Suppositorien usw. enteral oder parenteral verabreicht werden.
Soweit die Herstellung der Ausgangsverbindungen nicht beschrieben wird, sind diese bekannt oder nach an sich bekannten Verfahren bzw. analog zu den hier beschriebenen oder analog zu an sich bekannten Verfahren herstellbar.
In dem nachfolgenden Beispiel, das die Erfindung näher erläutern, ihren Umfang aber in keiner Weise einschränken soll, erfolgen alle Temperaturangaben in Celsiusgraden und sind unkorrigiert.
EMI2.1
EMI2.2
Beispiel: 9-(1 -Methyl-piperidyliden-4)- thioxanten-N-oxid
Ein Gemisch von 100 g 9-(1-Methyl-piperidyliden4)thioxanten (Base, 34,7 g Wasserstoffperoxid (350/oig) und 1000 ccm Äthanol wird unter Rühren während 10 Stunden bei 1200 C Ölbadtemperatur am Rückfluss erhitzt. Anschliessend werden 5 g Aktivkohle zugegeben und zur Zerstörung des überschüssigen Peroxids 1 Stunde weiter erhitzt. Die Lösung wird filtriert, im Vakuum eingeengt und der Rückstand mit 800 ccm Essigsäureäthylester aufgekocht und die kristallin ausgefallene Substanz abfiltriert. 71,7 g der getrockneten Substanz werden in 100 ccm Chloroform, das 5 O/o Methanol enthält, gelöst und an 1500 g Kieselgel G adsorbiert.
Anschliessend wird mit Chloroform, das 5 O/o Methanol enthält, eluiert, wobei die ersten 10 1 Eluat verworfen und die darauffolgenden 30 1 zusammen eingedampft werden. Der erhaltene Rückstand wird mit 200 ccm Essigsäureäthylester aufgekocht, die kristallisierte Substanz-abfiltriert und getrocknet. 66 g dieser Substanz löst man in der Siedehitze in 140 ccm Wasser und lässt bei 5 C auskristallisieren. Das Kristallisat wird bei 1100 C zur Gewichtskonstanz getrocknet. Auf diese Weise wird das reine 9-(1 -Methyl-piperidyliden-4)thioxanten-N-oxid (Base) als Monohydrat erhalten, das bei 193-195" C schmilzt.
Process for the preparation of new thioxanthene compounds
The present invention relates to a process for the preparation of thioxanthene compounds of the formula I, in which R denotes a lower alkyl group, and their acid addition salts.
According to the invention, the compounds of the formula I and their acid addition salts are obtained by oxidizing compounds of the formula II in which R has the above meaning in a solvent which is inert under the reaction conditions and, if desired, converting the resulting compounds of the formula I into their acid addition salts.
Acid addition salts can be prepared from the free bases in a known manner and vice versa.
The oxidizing agent used is preferably hydrogen peroxide or alkali metal periodates in neutral solution, while the solvent used is preferably alcohols such as methanol, ethanol or even acetone. The oxidation with hydrogen peroxide is preferably carried out at about 30 to 1000, the oxidation with alkali metal periodates at about 0 to 30. After the reaction has ended, any excess oxidizing agent is destroyed or removed and the N-oxide formed is isolated from the reaction mixture in a known manner and purified, e.g. B. by crystallization and / or chromatography.
In the compounds of formula I, the lower alkyl group represented by the symbol R can be unbranched or branched and preferably contains 1 to 4 carbon atoms.
The compounds of the formula I have valuable pharmacodynamic properties and are intended to be used as medicinal products. They are characterized by histaminolytic, serotonin-antagonistic and anticholinergic properties, as can be seen from the results of the histamine toxicity test, serotonin toxicity test and the acetylcholine toxicity test on guinea pigs.
The doses to be used naturally vary depending on the type of administration and the condition to be treated. In general, however, satisfactory results are obtained in mammals with a daily dose of 0.05 to 1 mg / kg body weight; this daily dose can, if necessary, be administered in 2 to 3 portions or as a sustained release form. For larger mammals, the daily dose is around 1 to 5 mg. For oral administration, the partial doses contain about 0.3 to 2.5 mg of the compounds of the formula I in addition to solid or liquid carriers or diluents.
As medicaments, the new compounds of the formula I can be administered enterally or parenterally, either alone or in suitable medicinal form such as tablets, coated tablets, injection solutions, suppositories, etc.
If the preparation of the starting compounds is not described, they are known or can be prepared by processes known per se or analogously to those described here or analogously to processes known per se.
In the following example, which is intended to explain the invention in more detail but in no way restrict its scope, all temperatures are given in degrees Celsius and are uncorrected.
EMI2.1
EMI2.2
Example: 9- (1-methyl-piperidylidene-4) -thioxanten-N-oxide
A mixture of 100 g of 9- (1-methylpiperidylidene4) thioxanten (base, 34.7 g of hydrogen peroxide (350 / oig) and 1000 ccm of ethanol is refluxed with stirring for 10 hours at an oil bath temperature of 1200 C. Then 5 g Activated charcoal is added and the mixture is heated for 1 hour to destroy the excess peroxide. The solution is filtered, concentrated in vacuo and the residue is boiled up with 800 cc of ethyl acetate and the crystalline substance is filtered off. 71.7 g of the dried substance are dissolved in 100 cc of chloroform, the Contains 5 O / o methanol, dissolved and adsorbed on 1500 g of silica gel G.
It is then eluted with chloroform, which contains 5% methanol, the first 10 liters of eluate being discarded and the subsequent 30 liters being evaporated together. The residue obtained is boiled with 200 cc of ethyl acetate, and the crystallized substance is filtered off and dried. 66 g of this substance are dissolved in 140 ccm of water at the boiling point and allowed to crystallize at 5 ° C. The crystals are dried at 1100 ° C. to constant weight. In this way, pure 9- (1-methyl-piperidylidene-4) thioxanten-N-oxide (base) is obtained as a monohydrate which melts at 193-195 "C.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1745369A CH518974A (en) | 1969-11-24 | 1969-11-24 | Antihistaminic 9-(4-piperidylidene)-thioxanthene-n-oxides - prodn - from corresp thioxanthenes with hydrogen peroxide or periodat |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1745369A CH518974A (en) | 1969-11-24 | 1969-11-24 | Antihistaminic 9-(4-piperidylidene)-thioxanthene-n-oxides - prodn - from corresp thioxanthenes with hydrogen peroxide or periodat |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH518974A true CH518974A (en) | 1972-02-15 |
Family
ID=4425513
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1745369A CH518974A (en) | 1969-11-24 | 1969-11-24 | Antihistaminic 9-(4-piperidylidene)-thioxanthene-n-oxides - prodn - from corresp thioxanthenes with hydrogen peroxide or periodat |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH518974A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USB426802I5 (en) * | 1972-11-20 | 1976-02-17 | ||
| US4777177A (en) * | 1984-10-19 | 1988-10-11 | Ciba-Geigy Corporation | Pesticidal thioxanthen-9-ylidenepiperidines |
-
1969
- 1969-11-24 CH CH1745369A patent/CH518974A/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USB426802I5 (en) * | 1972-11-20 | 1976-02-17 | ||
| US4777177A (en) * | 1984-10-19 | 1988-10-11 | Ciba-Geigy Corporation | Pesticidal thioxanthen-9-ylidenepiperidines |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |