NO152084B - RADIO OPERATING UNIT FOR FARTOEY - Google Patents

RADIO OPERATING UNIT FOR FARTOEY Download PDF

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Publication number
NO152084B
NO152084B NO81814014A NO814014A NO152084B NO 152084 B NO152084 B NO 152084B NO 81814014 A NO81814014 A NO 81814014A NO 814014 A NO814014 A NO 814014A NO 152084 B NO152084 B NO 152084B
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aza
thioxanthene
general formula
compound
methyl
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NO81814014A
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NO814014L (en
NO152084C (en
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Kjell Haglund
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Kamewa Ab
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B63—SHIPS OR OTHER WATERBORNE VESSELS; RELATED EQUIPMENT
    • B63H—MARINE PROPULSION OR STEERING
    • B63H11/00—Marine propulsion by water jets
    • B63H11/02—Marine propulsion by water jets the propulsive medium being ambient water
    • B63H11/10—Marine propulsion by water jets the propulsive medium being ambient water having means for deflecting jet or influencing cross-section thereof
    • B63H11/107—Direction control of propulsive fluid
    • B63H11/11—Direction control of propulsive fluid with bucket or clamshell-type reversing means
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B63—SHIPS OR OTHER WATERBORNE VESSELS; RELATED EQUIPMENT
    • B63H—MARINE PROPULSION OR STEERING
    • B63H11/00—Marine propulsion by water jets
    • B63H11/02—Marine propulsion by water jets the propulsive medium being ambient water
    • B63H11/04—Marine propulsion by water jets the propulsive medium being ambient water by means of pumps
    • B63H11/08—Marine propulsion by water jets the propulsive medium being ambient water by means of pumps of rotary type
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B63—SHIPS OR OTHER WATERBORNE VESSELS; RELATED EQUIPMENT
    • B63H—MARINE PROPULSION OR STEERING
    • B63H11/00—Marine propulsion by water jets
    • B63H11/02—Marine propulsion by water jets the propulsive medium being ambient water
    • B63H11/10—Marine propulsion by water jets the propulsive medium being ambient water having means for deflecting jet or influencing cross-section thereof
    • B63H11/107—Direction control of propulsive fluid
    • B63H11/113—Pivoted outlet

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  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Combustion & Propulsion (AREA)
  • Mechanical Engineering (AREA)
  • Ocean & Marine Engineering (AREA)
  • Structures Of Non-Positive Displacement Pumps (AREA)
  • Electrotherapy Devices (AREA)
  • Finger-Pressure Massage (AREA)
  • Circuits Of Receivers In General (AREA)

Description

Fremgangsmåte for fremstilling av nye, farmakodynamisk virksomme 1-aza-tioxanten-derivater. Process for the production of new, pharmacodynamically active 1-aza-thioxanthene derivatives.

Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av nye, The present invention relates to a method for the production of new,

farmakodynamisk virksomme 1-aza-tioxantenderivater med den alminnelige formel I pharmacodynamically active 1-aza-thioxanthene derivatives of the general formula I

hvori Rt betyr et hydrogen-, klor- eller bromatom og R2 betyr en lavere alkylgrup-pe, og x står for verdien 1 eller 2, og deres syreaddisjonsalter, og det særegne ved fremgangsmåten i henhold til oppfinnelsen er at et 1-aza-tioxantenderivat med den alminnelige formel II hvor Ri og Ro har den ovennevnte betyd-ning, a) oksyderes i surt miljø med den tilsvarende molare mengde natriummetaperjodat, en organisk persyre eller hydrogenperoksyd til en forbindelse med den alminnelige formel I hvori x = 1, eller b) oksyderes med den dobbelte molare mengde av en organisk persyre eller hydrogenperoksyd i nærvær av iseddik og/eller en sterk mineralsyre til en forbindelse med den alminnelige formel I hvori x = 2, in which Rt means a hydrogen, chlorine or bromine atom and R2 means a lower alkyl group, and x stands for the value 1 or 2, and their acid addition alter, and the peculiarity of the method according to the invention is that a 1-aza-thioxanthene derivative with the general formula II where Ri and Ro have the above meaning, a) is oxidized in an acidic environment with the corresponding molar amount of sodium metaperiodate, an organic peracid or hydrogen peroxide to a compound with the general formula I in which x = 1, or b) is oxidized with twice the molar amount of an organic peracid or hydrogen peroxide in the presence of glacial acetic acid and/or a strong mineral acid to a compound of the general formula I in which x = 2,

og de ved a) eller b) erholdte forbindelser overføres eventuelt i sine syreaddisjonssalter. and the compounds obtained by a) or b) are optionally transferred in their acid addition salts.

kan R2 stå for metyl-, etyl-, propyl-, iso-propyl- eller butyl-gruppen. R 2 can stand for the methyl, ethyl, propyl, iso-propyl or butyl group.

Fremgangsmåten kan med fordel ut-føres på følgende måte: Sluttprodukter med formel I hvori x står for verdien 1, fås ved at den eddiksure oppløsning av utgangssuatstansen (1 mol), som f. eks. 9-[l'-metyl-piperidyliden-(4')]r 1-aza-tioxanten, tilsettes et mol av en for-tynnet vandig natriummetaperjodatoppløs-ning i løpet av 3 til 5 timer ved romtemperatur. For fullstendig gjennomføring av reaksjonen får blandingen henstå ennå i 3 døgn ved romtemperatur. Etter fjernelse av utfelt natriumjodat og etter at blandingen er gjort alkalisk med ammoniakk eller alkalihydroksyd ekstraheres sluttproduk-tet med et indifferent organisk løsnings-middel, fortrinnsvis med metylenklorid, isoleres derav etter kjente metoder, renses og overføres eventuelt i et syreaddisjons-salt. I stedet for med en vandig natrium-metaperjodatoppløsning kan oksydasjonen også utføres med organiske persyrer, f. eks. med perbenzosyre eller med hydrogenperoksyd ved romtemperatur eller lett forhøyet temperatur, hvorved det i disse tilfelle anvendes et mol av oksydasjonsmidlet. The method can advantageously be carried out in the following way: End products with formula I in which x stands for the value 1, are obtained by the acetic acid solution of the starting suatstanse (1 mol), which e.g. To the 9-[1'-methyl-piperidylidene-(4')]r 1-aza-thioxanthene, one mole of a dilute aqueous sodium metaperiodate solution is added over the course of 3 to 5 hours at room temperature. For complete completion of the reaction, the mixture is allowed to stand for a further 3 days at room temperature. After removal of precipitated sodium iodate and after the mixture has been made alkaline with ammonia or alkali hydroxide, the final product is extracted with an indifferent organic solvent, preferably with methylene chloride, isolated from it by known methods, purified and optionally transferred into an acid addition salt. Instead of using an aqueous sodium metaperiodate solution, the oxidation can also be carried out with organic peracids, e.g. with perbenzoic acid or with hydrogen peroxide at room temperature or a slightly elevated temperature, whereby in these cases one mole of the oxidizing agent is used.

Sluttprodukter med formel I hvori x står for verdien 2, fås f. eks. ved at et mol av utgangsproduktet med formel II be-handles i nærvær av iseddik og/eller en sterk mineralsyre, f. eks. svovelsyre, ved rom- eller forhøyet temperatur med to mol hydrogenperoksyd. Oksydasjonen kan imidlertid like godt utføres med to mol av en organisk persyre, f. eks. perbenzosyre eller pereddiksyre. Etter flere timers reaksjonstid inndampes blandingen, resten opptas i vann, tilsettes ammoniakk eller en alkalilut til alkalisk reaksjon, den utskilte base opptas i et indifferent organisk oppløsnings-middel, fortrinnsvis i metylenklorid, og etter utvasking med vann avdampes opp-løsningsmidlet pånytt. Basene kan krystal-liseres direkte og/eller overføres i et egnet salt med organiske eller uorganiske syrer. End products with formula I in which x stands for the value 2, are obtained, e.g. in that one mole of the starting product with formula II is treated in the presence of glacial acetic acid and/or a strong mineral acid, e.g. sulfuric acid, at room or elevated temperature with two moles of hydrogen peroxide. However, the oxidation can just as well be carried out with two moles of an organic peracid, e.g. perbenzoic acid or peracetic acid. After a reaction time of several hours, the mixture is evaporated, the residue is taken up in water, ammonia or an alkaline solution is added for an alkaline reaction, the separated base is taken up in an indifferent organic solvent, preferably in methylene chloride, and after washing out with water, the solvent is evaporated again. The bases can be crystallized directly and/or transferred into a suitable salt with organic or inorganic acids.

De i henhold til oppfinnelsen fremstilte nye 1-aza-tioxantenderivater med formel I er basiske, ved romtemperatur krystalliserte salter med organiske og uorganiske syrer. Slike salter er f. eks. hydrokloridene, hydro-bromidene, sulfatene, fumaratene, malei-natene, malatene, acetatene, tartratene. The new 1-aza-thioxanthene derivatives of formula I produced according to the invention are basic, at room temperature crystallized salts with organic and inorganic acids. Such salts are e.g. the hydrochlorides, hydrobromides, sulphates, fumarates, maleates, malates, acetates, tartrates.

Utgangssubstansene hvori Ri betyr klor eller brom og R2 betyr en lavere alkylgrup-pe, kan fremstilles ved den i det belgiske patentskrift 601 668 beskrevne fremgangsmåte fra de tilsvarende 6-halogen-l-aza-tioxantener og l-alkyl-4-halogen-piperidi-ner ved Grignard-reaksjon og påfølgende vannavspalting. The starting substances in which R 1 means chlorine or bromine and R 2 means a lower alkyl group can be prepared by the method described in Belgian patent document 601 668 from the corresponding 6-halo-1-aza-thioxanthenes and 1-alkyl-4-halo-piperidine -ner by Grignard reaction and subsequent water splitting.

De nye 1-aza-tioxanten-derivater som er fremstillt i henhold til oppfinnelsen, har mange terapeutisk verdifulle farmakodyna-miske egenskaper. De utmerker seg ved at de samtidig som de tåles godt har utpregete og spesielle histaminhemmende, henhv. an-tiallergiske virkninger. Ved siden av antikolinergiske egenskaper har de også en sær-lig utpreget bronkolytisk virkning som ikke er å føre tilbake til en sympatikomimetisk effekt slik som ved de bronkolytika og antiastmatika som hittil har vært brukt. Også hostehemmende egenskaper er særegne for preparatene. The new 1-aza-thioxanthene derivatives which have been prepared according to the invention have many therapeutically valuable pharmacodynamic properties. They are distinguished by the fact that, at the same time as being well tolerated, they have distinct and special histamine-inhibiting, resp. anti-allergic effects. In addition to anticholinergic properties, they also have a particularly pronounced broncholytic effect which cannot be traced back to a sympathomimetic effect as with the broncholytics and antiasthmatics that have been used up until now. Cough-inhibiting properties are also characteristic of the preparations.

Ikke ønskede bivirkninger f. eks. seda-tive virkninger som opptrer ved tidligere kjente antihistaminika, hhv. antiallergika, er nedsatt til et minimum i de stoffer som er fremstilt i henhold til oppfinnelsen. De nye forbindelser skal derfor finne anvendelse som antihistaminika, antiallergika samt som antiastmatika og antitussiva, f. eks. ved rhinitis allergika, astma bronkiale og status astmatikus, bronkitt osv. På grunn av sine antikolinergiske egenskaper kan de også brukes for å dempe vagotone syk-domsbilder og som spasmolytika. Unwanted side effects, e.g. sedative effects that occur with previously known antihistamines, or antiallergics, is reduced to a minimum in the substances produced according to the invention. The new compounds will therefore find use as antihistamines, antiallergics and as antiasthmatics and antitussives, e.g. in allergic rhinitis, bronchial asthma and status asthmaticus, bronchitis, etc. Due to their anticholinergic properties, they can also be used to reduce vagotonic symptoms and as spasmolytics.

I den følgende tabell refereres resultatene av den farmakologiske undersøkelse av 9- [l'-metyl-piperidyliden- (4') ] -1-aza-tioxanten-10-oksyd (forbindelsen fra eks. 1), av 6-klor-9-[l'-metyl-piperidyliden-(4')]-l-aza-tioxanten-10-oksyd (forbindelsen fra eks. 2), samt av 9-[l'-metylpiperi-dyliden- (4') ]-azatioxanten 10,10-dioksyd (forbindelsen fra eks. 3) i sammenlikning med det tidligere kjente 9-[l'-metyl-piperidyliden- (4') ] - 1-aza-tioxanten. In the following table, the results of the pharmacological examination of 9-[1'-methyl-piperidylidene-(4')]-1-aza-thioxanthene-10-oxide (the compound from ex. 1), of 6-chloro-9 -[1'-methyl-piperidylidene-(4')]-1-aza-thioxanthene-10-oxide (the compound from ex. 2), as well as of 9-[1'-methylpiperidylidene-(4')]- azathioxanthene 10,10-dioxide (the compound from ex. 3) in comparison with the previously known 9-[1'-methyl-piperidylidene-(4')]-1-aza-thioxanthene.

Hemming av histamintoksisiteten. Inhibition of histamine toxicity.

Etter subkutan innsprøyting i stigende doser av den forbindelse som skulle un-dersøkes tilføres de som forsøksdyr an-vendte marsvin, likeledes subkutant en dose på 20 mg/kg histamindihydroklorid, som utgjør flere ganger den dødelige mengde. Som beskyttet anses de av dyrene som over-lever i 12 timer eller lenger. After subcutaneous injection in increasing doses of the compound to be investigated, the guinea pigs used as experimental animals are also given subcutaneously a dose of 20 mg/kg of histamine dihydrochloride, which is several times the lethal amount. Animals that survive for 12 hours or longer are considered protected.

Den dose som trenges for å beskytte 50 % av dyrene i 12 timer eller lenger The dose needed to protect 50% of the animals for 12 hours or longer

(ED50), bestemmes ved å utnytte metoden etter Probit. (ED50), is determined using the Probit method.

Bronkolytisk virkning. Broncholytic effect.

Ved stimulering av den perifere Vagus-stump ved narkotiserte og tosidig vago-tomerte marsvin frembringes en bronkie-krampe og åpningsgraden av bronkiene bestemmes etter metoden til H. Konzett og R. Rossler [Arch. exp. Pathol. Pharmakol. 195, 71 (1940); Wiener klin. Wschr. 67, 306 By stimulating the peripheral Vagus stump in anesthetized and bilaterally vagotomized guinea pigs, a bronchial spasm is produced and the degree of opening of the bronchi is determined according to the method of H. Konzett and R. Rossler [Arch. exp. Pathol. Pharmacol. 195, 71 (1940); Vienna Clinic. Wschr. 67, 306

Som sammenlikningsforbindelse ble/ som nevnt anvendt det tidligere kjente 9-! As a comparison compound, the previously known 9-!

[l'-metyl-piperidyliden-(4')]-l-aza-tioxan-, ten. [1'-methyl-piperidylidene-(4')]-1-aza-thioxan-, then.

Som kjent virker S-oksydene av fen-] tiaziner på liknende måte, men gjennom-J gående svakere enn de tilsvarende fentia-ziner i seg selv [(jfr. J. Pharmakol. expi Therapeut. 118, 328 (1956); Arzneimittel<* >Forsch. 10, 638 (1960)]. i As is known, the S-oxides of phen-] thiazines act in a similar way, but consistently weaker than the corresponding phenthiazines themselves [(cf. J. Pharmakol. expi Therapeut. 118, 328 (1956); Arzneimittel< * >Forsch. 10, 638 (1960)]. i

Ved den foreliggende 1-aza-tioxanten-rekke er imidlertid forholdene annerledes:, oksydasjon av svovelatomet til 10,10-dioksyd har riktignok en tydelig svekking av den histaminantagonistiske virkning som følge, men den bronkolytiske virkning der-imot forhøyes overraskende til det tidob-belte. Denne virkningsforskyvning kunne imidlertid ikke på noen måte forutsees og representerer ingen analogi overfor de ovennevnte forhold ved fentiazinrekken. <:.>In the present 1-aza-thioxanthene series, however, the conditions are different: oxidation of the sulfur atom to 10,10-dioxide does indeed result in a clear weakening of the histamine antagonistic effect, but the broncholytic effect, on the other hand, is surprisingly increased to tenfold belt. However, this shift in effect could not be predicted in any way and represents no analogy to the above-mentioned conditions in the phenthiazine series. <:.>

Videre oppnås det ved forbindelser med den alminnelige formel I, hvor n = 1, en farmakodynamisk virkningsforskyvning. Således er forbindelsene fra eksemplene 1 og 2 ved litt mindre hemming av histamintoksisiteten flere ganger overlegne sammenlikningsforbindelsen 9- [ l'-metyl-pipe-i ridyliden (4')]-1-aza-tioxanten med hensyn til tålbare doser. Den terapeutiske in-deks, altså forholdet DL50/ED50 er for forbindelsen fra eks. 1 større enn 25 x IO<4->for forbindelsen fra eks. 2 omtrent 25.4 x 10<4> og for sammenlikningsforbindelsen bare omtrent 6 x 10<4>, altså bare fjerdeparten av verdiene for de to forbindelser, og dette forhold kunne ikke forutsies. Furthermore, with compounds of the general formula I, where n = 1, a pharmacodynamic effect shift is achieved. Thus, with slightly less inhibition of histamine toxicity, the compounds from examples 1 and 2 are several times superior to the comparison compound 9-[1'-methyl-pipe-iridylidene (4')]-1-aza-thioxanthene with regard to tolerable doses. The therapeutic index, i.e. the ratio DL50/ED50 is for the compound from e.g. 1 greater than 25 x IO<4->for the connection from e.g. 2 approximately 25.4 x 10<4> and for the comparison compound only approximately 6 x 10<4>, i.e. only a quarter of the values for the two compounds, and this ratio could not be predicted.

(1955)]. Før stimuleringen tilføres forsøks-substansen på intravenøs måte og som ED50(1955)]. Before the stimulation, the test substance is administered intravenously and as ED50

defineres den dose som formål å hemme bronkiekrampen med 50 %. is defined as the dose aimed at inhibiting the bronchial spasm by 50%.

Histamin- hhv. acetylcholinhemming Histamine- or acetylcholine inhibition

in vitro. in vitro.

For bestemmelse av histaminhemmin-gen festes en isolert marsvintynntarm i en glukoseholdig Starling-Ringerløsning ved 37° C og forbindes med en indikator, som registrerer de under forsøket opptredende lengdeforandringer av organet. To determine the histamine inhibition gene, an isolated guinea pig small intestine is fixed in a glucose-containing Starling-Ringer solution at 37° C and connected to an indicator, which registers the changes in length of the organ occurring during the experiment.

Det foretas måling av hemmingen henhv. opphevingen av den ved histamin frem-kalte kontraksjon av marsvin-tynntarmen, hvorved den substans som undersøkes sam-menlignes med hensyn til hemmende virkning med l-metyl-4-amino-N'-fenyl-N'-(2'-tenyl)-piperidin. The inhibition is measured according to the abolition of the histamine-induced contraction of the guinea-pig small intestine, whereby the substance under investigation is compared with respect to inhibitory action with 1-methyl-4-amino-N'-phenyl-N'-(2'-thenyl) -piperidine.

Undersøkelsen på acetylcholinhemmin-gen ble gjennomført under de ovennevnte betingelser med atropin som sammenlig-ningssubstans. The investigation of acetylcholine inhibition was carried out under the above conditions with atropine as a comparison substance.

Hemming av histaminastma. Inhibition of histamine asthma.

3 timer etter subkutan forbehandling med forbindelsen som skal undersøkes ut-settes marsvin for en histamindusj og den tid bestemmes til det inntreffer en stor dyspnoe (sideleie for dyret). Ved en kon-trollgruppe på 90 dyr er dette inntruffet etter en gjennomsnittlig reaksjonstid på 1 min. Dyr som oppholder seg i 3 min. i 3 hours after subcutaneous pretreatment with the compound to be investigated, guinea pigs are exposed to a histamine shower and the time is determined until a major dyspnoea occurs (the animal lies on its side). In a control group of 90 animals, this occurred after an average reaction time of 1 min. Animals that stay for 3 min. in

dusj kammeret uten å innta sideleie be-traktes som beskyttet. Den dose av preparatene som trenges for å beskytte 50 % av dyrene bestemmes etter Probitmetoden og betegnes som ED50. showering the chamber without taking a side position is considered protected. The dose of the preparations needed to protect 50% of the animals is determined according to the Probit method and is designated as ED50.

Resultatene er oppført i den følgende tabell. The results are listed in the following table.

Forbindelsene kan anvendes som lege-middel i seg selv eller i tilsvarende medisinformer for enteral eller parenteral bruk. For å fremstille egnete medisinformer blir de opparbeidet med uorganiske eller organiske, farmakologisk indifferente hjelpestoffer. Som hjelpestoffer kan det eksem-pelvis benyttes: For tabletter og drageer: melkesukker, stivelse, talkum, The compounds can be used as medicine in themselves or in corresponding medicinal forms for enteral or parenteral use. In order to produce suitable medicinal forms, they are worked up with inorganic or organic, pharmacologically indifferent excipients. Excipients can be used, for example: For tablets and dragees: milk sugar, starch, talc,

for injeksjonspreparater vann, alkohol, glyserin, planteolje o. 1. for injection preparations water, alcohol, glycerin, vegetable oil etc. 1.

for suppositorier: naturlige eller her-dete oljer og voks. for suppositories: natural or hydrogenated oils and waxes.

Dessuten kan preparatene inneholde passende konserverings- og stabiliserings-midler, fuktemidler, oppløsningsformidlere, søte- og fargestoffer, aromatiske stoffer osv. In addition, the preparations may contain suitable preservatives and stabilizers, wetting agents, solubilizers, sweetening and coloring substances, aromatic substances, etc.

I de følgende eksempler som skal for-klare hvorledes fremgangsmåte kan utføres, er alle temperaturangivelser i celsiusgra-der og ikke korrigert. In the following examples which will explain how the method can be carried out, all temperature indications are in degrees Celsius and are not corrected.

Eksempel 1: 9-[ l'- metyl- piperidyliden-( 4') 1 - 1 - aza- tioxanten- 10- oksyd. Example 1: 9-[1'-methyl-piperidylidene-(4')1-1-azathioxanthene-10-oxide.

Til en oppløsning av 5,88 g av 9-[l'-metyl-piperidyliden- (4') ] -1-aza-tioxanten To a solution of 5.88 g of 9-[1'-methyl-piperidylidene-(4')]-1-aza-thioxanthene

(Smp. 154—156° fra aceton) i 20 cm:! vann og 1,2 cm<3> iseddik ble det under god om-røring i løpet av 4 timer dryppet inn 45 cm<3 >0,5 mol natriumperjodatoppløsning og deretter ble det foretatt røring i 3 dager ved romtemperatur. Deretter ble det natriumjodat som var felt ut filtrert fra, filtratet gjort alkalisk med kalilut og ekstrahert flere ganger med metylenklorid. Etter tør-king av de forenede ekstrakter over mag-nesiumsulfat og avdamping av oppløsnings-midlet ble resten oppløst i aceton hvor-etter 9- [ 1 '-metyl-piperidyliden- (4') ] -1 -aza-tioxanten-10-oksyd krystalliserte. Det smeltet etter to gangers omkrystallisering fra aceton ved 146—147°. (Mp. 154—156° from acetone) in 20 cm:! water and 1.2 cm<3> of glacial acetic acid, 45 cm<3 >0.5 mol sodium periodate solution was dripped in during 4 hours with good stirring and then stirring was carried out for 3 days at room temperature. The sodium iodate which had precipitated was then filtered off, the filtrate made alkaline with potassium hydroxide and extracted several times with methylene chloride. After drying the combined extracts over magnesium sulfate and evaporating the solvent, the residue was dissolved in acetone after which 9-[1'-methyl-piperidylidene-(4')]-1-aza-thioxanthene-10- oxide crystallized. It melted after two recrystallizations from acetone at 146-147°.

Eksempel 2: 6- klor- 9-[ V- metyl- piperidyliden- ( 4') - 1 - aza- tioxanten- 10- oksyd. Example 2: 6-chloro-9-[V-methyl-piperidylidene-(4')-1-azathioxanthene-10-oxide.

En oppløsning av 2,7 g 6-klor-9-[l'-metylpiperidyliden- (4') ] -1-aza-tioxanten i 40 cm<3> vann og 0,56 cm3 iseddik ble under A solution of 2.7 g of 6-chloro-9-[1'-methylpiperidylidene-(4')]-1-aza-thioxanthene in 40 cm<3> of water and 0.56 cm3 of glacial acetic acid was

god omrøring ved romtemperatur i løpet av good stirring at room temperature during

75 min. blandet med en oppløsning av 2,03 g 75 min. mixed with a solution of 2.03 g

natriummetaperjodat i 20 cm<8> vann. Etter røring i 128. timer ved romtemperatur og røring i 4 timer ved 50° ble reaksjonsblandingen gjort alkalisk med kons. ammoni-umhydroksydoppløsning og ekstrahert flere ganger med metylenklorid. Etter at de forenede ekstrakter var tørket over natriumsulfat og oppløsningsmidlet avdampet, ble resten omkrystallisert to ganger fra etanol-aceton (ca. 1 : 2). 6-klor-9[l'-metylpiperi-dyliden- (4') ] -l-aza-tioxanten-10-oksyd smeltet ved 178—180° under svak spalting. sodium metaperiodate in 20 cm<8> of water. After stirring for 128 hours at room temperature and stirring for 4 hours at 50°, the reaction mixture was made alkaline with conc. ammonium hydroxide solution and extracted several times with methylene chloride. After the combined extracts were dried over sodium sulfate and the solvent evaporated, the residue was recrystallized twice from ethanol-acetone (approx. 1:2). 6-chloro-9[1'-methylpiperidylidene-(4')]-1-aza-thioxanthene-10-oxide melted at 178-180° with slight decomposition.

Det 6-klor-9-[l'-metyl-piperidyliden-(4')]-1-aza-tioxanten som ble brukt som utgangsmaterial ble fremstillet på følgen-de måte: 2,43 g magnesiumspon som var aktivert med jod ble dekket med 10 cm<3> abs. tetrahydrofuran og blandet med 0,2 cm<3 >etylenbromid. Så snart reaksjonen kom i gang ble en oppløsning av 14,7 g 1-metyl-4-klor-piperidin i 25 cm<3> abs. tetrahydrofuran dryppet inn, hvorunder reaksjonsblandingen stadig kokte. Deretter ble det foretatt oppvarming i ennå ca. 2 timer under tilbakeløp inntil magnesiumet for den største del var oppløst. Etter avkjøling til 20° ble blandingen blandet porsjonsvis med 12,4 g finrevet 6-klor-l-aza-tioxanten og røring foretatt i ennå 30 min. ved romtemperatur. Reaksjonsblandingen ble deretter helt i 300 cm<3> 10-prosent-ammoniumklo-ridoppløsning og ekstrahert 3 ganger med metylenklorid. De forenede ekstrakter som var tørket over kaliumkarbonat ble inndampet og resten oppløst i aceton, hvor-ra 6-klor-9-[l'-metyl-piperidyl(4')]-l-aza-tioxantydrol krystalliserte. Smp. 166—167° etter 2 gangers omkrystallisering fra eta-nol. The 6-chloro-9-[1'-methyl-piperidylidene-(4')]-1-aza-thioxanthene which was used as starting material was prepared in the following way: 2.43 g of magnesium shavings which had been activated with iodine were covered with 10 cm<3> abs. tetrahydrofuran and mixed with 0.2 cm<3 >ethylene bromide. As soon as the reaction started, a solution of 14.7 g of 1-methyl-4-chloro-piperidine in 25 cm<3> abs. tetrahydrofuran was added dropwise, during which the reaction mixture was constantly boiling. Then heating was carried out for approx. 2 hours under reflux until most of the magnesium had dissolved. After cooling to 20°, the mixture was mixed in portions with 12.4 g of finely grated 6-chloro-1-aza-thioxanthene and stirring continued for a further 30 minutes. at room temperature. The reaction mixture was then poured into 300 cm3 of 10 percent ammonium chloride solution and extracted 3 times with methylene chloride. The combined extracts which had been dried over potassium carbonate were evaporated and the residue dissolved in acetone, from which 6-chloro-9-[1'-methyl-piperidyl(4')]-1-aza-thioxanthydrol crystallized. Temp. 166-167° after 2 times recrystallization from ethanol.

3,75 g av den forbindelse som ble opp-nådd ble oppvarmet sammen med en blanding av 22,5 cm<3> kons. svovelsyre og 7,5 cm<3>3.75 g of the compound obtained was heated together with a mixture of 22.5 cm<3> conc. sulfuric acid and 7.5 cm<3>

vann i 15 minutter til 140°. Deretter ble water for 15 minutes at 140°. Then became

reaksjonsblandingen helt i isvann og opp-løsningen ble, etter å være gjort alkalisk the reaction mixture completely in ice water and the solution became, after being made alkaline

med natronlut, ekstrahert med metylenklorid. Etter tørking av metylenkloridek-strakten over kaliumkarbonat og avdamping av oppløsningsmidlet, ble resten kry-stallisert fra aceton. 6-klor-9-[l'-metyl-piperidyliden-(4')] -1-aza-tioxanten smeltet ved 110—112°. with caustic soda, extracted with methylene chloride. After drying the methylene chloride extract over potassium carbonate and evaporating the solvent, the residue was crystallized from acetone. The 6-chloro-9-[1'-methyl-piperidylidene-(4')]-1-aza-thioxanthene melted at 110-112°.

Eksempel 3: 9-[ l'- metyl- piperidyliden-( 4') ]- 1 - aza- tioxanten- 10- dioksyd. Example 3: 9-[1'-methyl-piperidylidene-(4')]-1-azathioxanthene-10-dioxide.

En blanding av 9,5 g 9-[l'-metyl-piperidyliden-(4')]-l-azatioxanten (smp. 154— A mixture of 9.5 g of 9-[1'-methyl-piperidylidene-(4')]-1-azathioxanthene (m.p. 154—

156° etter sintring fra 152°), 140 cm<3> iseddik og 38 cm<3> kons. svovelsyre ble oppvarmet til 60° og under omrøring dråpevis 156° after sintering from 152°), 140 cm<3> glacial acetic acid and 38 cm<3> conc. sulfuric acid was heated to 60° and with stirring dropwise

blandet med en oppløsning av 17,1 cm<3>mixed with a resolution of 17.1 cm<3>

38,5-prosent vandig hydrogen-peroksyd-oppløsning i 17 cm<3> iseddik. Etter omrøring 38.5 percent aqueous hydrogen peroxide solution in 17 cm<3> glacial acetic acid. After stirring

i 16 timer ved 60° ble reaksjonsblandingen for 16 hours at 60°, the reaction mixt

inndampet under et trykk på 15 mm Hg. evaporated under a pressure of 15 mm Hg.

Deretter ble resten oppløst i vann, den van-dige oppløsning gjort alkalisk med kons. The residue was then dissolved in water, the aqueous solution made alkaline with conc.

ammoniumhydroksydoppløsning og ekstrahert flere ganger med metylenklorid. De ammonium hydroxide solution and extracted several times with methylene chloride. The

forenede ekstrakter ble vasket nøytral med combined extracts were washed neutral with

vann, tørket over natriumsulfat og inndampet under et trykk på 15 mm Hg til water, dried over sodium sulfate and evaporated under a pressure of 15 mm Hg to

tørr tilstand. Etter to gangers omkrystallisering fra metanol smeltet 9-[l'-metyl-piperidyliden- (4') ] -l-aza-tioxanten-10-dioksyd ved 188—189° (sp). dry condition. After recrystallization twice from methanol, 9-[1'-methyl-piperidylidene-(4')]-1-aza-thioxanthene-10-dioxide melted at 188-189° (mp).

Claims (1)

Fremgangsmåte for fremstilling avMethod of manufacture of nye farmakodynamisk virksomme 1-aza-tioxanten-derivater med den alminnelige formel (I) hvori Ri betyr et hydrogen-, klor- eller bromatom og R2 betyr en lavere alkylgrup-pe, og x står for verdien 1 eller 2, og deres syreaddisjonssalter, karakterisert ved at et 1-aza-tioxanten-derivat med den alminnelige formel (II) hvori Ri og R2 har den ovennevnte betyd-ning, a) oksyderes i surt miljø med den tilsvarende molare mengde natriummetaperjodat, en organisk persyre eller hydrogenperoksyd til en forbindelse med den alminnelige formel (I) hvor x = 1, eller b) oksyderes med den dobbelte molare mengde av en organisk persyre eller hydrogenperoksyd i nærvær av iseddik og/eller en sterk mineralsyre til en forbindelse med den alminnelige formel (I) hvori x = 2, og de ved a) eller b) erholdte forbindelser overføres eventuelt i sine syreaddisjonssalter.new pharmacodynamically active 1-aza-thioxanthene derivatives with the general formula (I) in which Ri means a hydrogen, chlorine or bromine atom and R2 means a lower alkyl group, and x stands for the value 1 or 2, and their acid addition salts, characterized in that a 1-aza-thioxanthene derivative with the general formula (II ) in which Ri and R2 have the above meaning, a) oxidized in an acidic environment with the corresponding molar amount of sodium metaperiodate, an organic peracid or hydrogen peroxide to a compound of the general formula (I) where x = 1, or b) oxidized with the double molar amount of an organic peracid or hydrogen peroxide in the presence of glacial acetic acid and/or a strong mineral acid to a compound of the general formula (I) in which x = 2, and the compounds obtained by a) or b) are optionally transferred in their acid addition salts.
NO81814014A 1980-11-26 1981-11-25 RADIO OPERATING UNIT FOR FARTOEY NO152084C (en)

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GB919216A (en) * 1959-03-24 1963-02-20 C W F Hamilton & Co Ltd Improvements in or relating to hydraulic jet propulsion apparatus for water-borne craft
FR1282741A (en) * 1960-12-17 1962-01-27 Snecma Application of the helical-centrifugal pump to the jet propulsion of ships
US3405526A (en) * 1967-03-01 1968-10-15 Twin Disc Inc Multiple stage, hydraulic jet propulsion apparatus for water craft
US3981262A (en) * 1971-01-22 1976-09-21 Sidewinder Marine, Inc. Water jet propulsion apparatus
GB1345517A (en) * 1971-04-19 1974-01-30 Norris Auto Products Ltd Boat propulsion unit
US3752110A (en) * 1972-03-20 1973-08-14 Berkeley Pump Co Afterplane for marine jet-powered boats
US3805731A (en) * 1972-05-05 1974-04-23 North American Rockwell Dual pump waterjet
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