NO127923B - - Google Patents

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Publication number
NO127923B
NO127923B NO02730/70A NO273070A NO127923B NO 127923 B NO127923 B NO 127923B NO 02730/70 A NO02730/70 A NO 02730/70A NO 273070 A NO273070 A NO 273070A NO 127923 B NO127923 B NO 127923B
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allyl
formula
thiazolidinedione
methyl
hydrazone
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NO02730/70A
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Norwegian (no)
Inventor
A Meisels
A Storni
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Ciba Geigy Ag
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Priority claimed from CH1091169A external-priority patent/CH511878A/en
Priority claimed from CH1091269A external-priority patent/CH511877A/en
Application filed by Ciba Geigy Ag filed Critical Ciba Geigy Ag
Publication of NO127923B publication Critical patent/NO127923B/no

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Nærværende oppfinnelse vedrorer en analogifremgangsmåte for fremstilling av et nytt tiosemikarbazon. The present invention relates to an analogous process for the production of a new thiosemicarbazone.

Det er overraskende blitt funnet at 3-allyl-5-metyl-2,4-tiazolidindion-2-(4-allyl-3-tiosemikarbazon) med formel I It has surprisingly been found that 3-allyl-5-methyl-2,4-thiazolidinedione-2-(4-allyl-3-thiosemicarbazone) of formula I

formår å hemme veksten av tumorer, slik som det kan fastslås manages to inhibit the growth of tumors, as can be determined

ved dyreforsok ved oral og subkutan administrasjon, f.eks. ved med dimetylbenzantracen indusert mammacarcinom og ved Walker-carcinom hos rotter. Videre egner den ifolge oppfinnelsen frem-stillbare forbindelse med formel I seg på grunn av sin immun-suppressive virkning f.eks. til forlengelse av overlevelses-evnen hos transplanterte organer og for behandling av auto-immun sykdommer . in animal experiments by oral and subcutaneous administration, e.g. in dimethylbenzanthracene-induced mammary carcinoma and in Walker carcinoma in rats. Furthermore, the compound of formula I which can be prepared according to the invention is suitable due to its immunosuppressive effect, e.g. for prolonging the survivability of transplanted organs and for the treatment of auto-immune diseases.

F.eks. bevirker det ifolge oppfinnelsen fremstilte 3-allyl-5-metyl-2,4-tiazolidindion-2-(4-allyl-3-tiosemikarbazon) ved peroral administrasjon med totalt 15 doser på hver 100 mg/kg i lopet av 3 uker en hemning av tumorveksten på 75 - 99% ved forstnevnte dyreforsok. E.g. the 3-allyl-5-methyl-2,4-thiazolidinedione-2-(4-allyl-3-thiosemicarbazone) produced according to the invention causes inhibition by oral administration with a total of 15 doses of 100 mg/kg each over the course of 3 weeks of tumor growth of 75 - 99% in the former animal experiment.

Ved Walker-carcinom hos rotter bevirker f.eks. 3-allyl-5-metyl-2,4-tiazolidindion-2-(4-allyl-3-tiosemikarbazon) ved subkutan administrasjon av hver 25 mg/kg i 4 på hverandre folgende dager en hemning av tumorveksten med 43%. In the case of Walker carcinoma in rats, e.g. 3-allyl-5-methyl-2,4-thiazolidinedione-2-(4-allyl-3-thiosemicarbazone) by subcutaneous administration of 25 mg/kg each for 4 consecutive days inhibited tumor growth by 43%.

Rottene med ved dimetylbenzantracen indusert mamma-careinom, som var blitt behandlet ved forannevnte dyreforsok med forbin-delsen med formel I fremstilt ifolge oppfinnelsen, ble kon-trollert oftalmologisk. Hos ingen av dyrene ble det ved lang-varig etter-iakttagelse fastslått en beskadigelse av Cornea ved pannus-rdannelse, d.v.s. uklarhet hos Cornea ved dannelse av granulasjonsvev. The rats with dimethylbenzanthracene-induced mammary carcinoma, which had been treated in the aforementioned animal experiment with the compound of formula I produced according to the invention, were checked ophthalmologically. In none of the animals, during long-term follow-up, was damage to the cornea determined by pannus formation, i.e. opacity of the Cornea due to the formation of granulation tissue.

3-allyl-5-metyl-2,4-tiazolidindion-2-(4-allyl-3-tiosemikarbazon) med formel I fremstilles ved at man omsetter hydrazonet med formelen VII 3-allyl-5-methyl-2,4-thiazolidinedione-2-(4-allyl-3-thiosemicarbazone) of formula I is prepared by reacting the hydrazone with formula VII

med allylisotiocyanat med formelen VIII Omsetningen skjer fortrinnsvis i et overfor hydraziner inert, organisk opplosningsmiddel, f.eks. i en lavere alkanol, som metanol, etanol, propanol eller isopropanol, et eterlignende opplosningsmiddel som dietyleter, dibutyleter, tetrahydrofuran eller dioksan, et hydrokarbon som benzen, toluen eller heksan, eller et halogenhydrokarbon som kloroform, ved-romtemperatur eller moderat forhoyete temperaturer inntil ca. 100° henh. koketemperaturen for det anvendte opplosningsmiddel. Reaksjons-tiden ligger, alt etter reaksjonstemperaturen og reaksjonsev-nen for utgangsstoffene, mellom ca. 1/2 til 24 timer. Utgangsmaterialet fremstilles ved en teknisk fordelaktig reak-sjonsrekkefolge med utgang fra 4-allyl-l-alkanoyl-3-tiosemi-karbazider med den generelle formel II hvor R^betyr hydrogen eller en lavere alkylgruppe, særlig metylgruppen. Forbindelsene med generell formel II lar seg fremstille fra 4-allyl-3-tiosemikarbazidet ved oppvarmning med vannfri maursyre henholdsvis med acetanhydrid eller an-hydrider av ytterligere lavere alkansyrer. Ved kondensasjon av forbindelsene med den generelle formel II med 2-halogen-propionsyre med den generelle formel III hvor Hal betyr klor, brom eller jod, ved hjelp av natriumacetat i en lavere alkanol, særlig etanol, ved dennes koketemperatur får man substituerte N'-alkanoyl-2,4-tiazolidindion- 2- hydrazoner med den generelle formel IV with allyl isothiocyanate of the formula VIII The reaction preferably takes place in an organic solvent inert to hydrazines, e.g. in a lower alkanol, such as methanol, ethanol, propanol or isopropanol, an ether-like solvent such as diethyl ether, dibutyl ether, tetrahydrofuran or dioxane, a hydrocarbon such as benzene, toluene or hexane, or a halogenated hydrocarbon such as chloroform, at room temperature or moderately elevated temperatures up to approx. . 100° acc. the boiling temperature of the solvent used. The reaction time is, depending on the reaction temperature and the reactivity of the starting materials, between approx. 1/2 to 24 hours. The starting material is prepared by a technically advantageous reaction sequence starting from 4-allyl-1-alkanoyl-3-thiosemicarbazides of the general formula II where R 2 means hydrogen or a lower alkyl group, especially the methyl group. The compounds of general formula II can be prepared from 4-allyl-3-thiosemicarbazide by heating with anhydrous formic acid or with acetic anhydride or anhydrides of further lower alkanoic acids. By condensation of the compounds of the general formula II with 2-halo-propionic acid of the general formula III where Hal means chlorine, bromine or iodine, with the aid of sodium acetate in a lower alkanol, especially ethanol, at its boiling temperature, substituted N'- alkanoyl-2,4-thiazolidinedione-2-hydrazones of the general formula IV

hvor har den under formel II angitte betydning. I stedet fbr 4-allyl-l-alkanoyl-3-tiosemikarbazider med den generelle for- where has the meaning given under formula II. Instead, 4-allyl-1-alkanoyl-3-thiosemicarbazides with the general for-

mel II kan man også anvende 1-alkanoyl-3-tiosemikarbazider og i de i dette tilfelle oppnådde kondensasjonsprodukter med den generelle formel V mel II, 1-alkanoyl-3-thiosemicarbazides can also be used and in the condensation products obtained in this case with the general formula V

hvor R^har den under formel II angitte betydning, etterpå innfore 3-substituenten allyl, idet man overforer en forbindelse med den generelle formel V til sine alkalimetallfor-bindelser og omsetter sistnevnte med reaksjonsdyktige estre av allylalkoholen med formel VI Alkalimetallforbindeisene kan f.eks. oppnås ved innvirkning av natriumhydrid, litium- eller natriumamid i dimetylformamid ved 0° til romtemperatur og omsettes i samme medium ved romtemperatur eller moderat forhoyete temperaturer med reaksjonsdyktige estre av allylalkoholen, f.eks. halogenider, som allyljodid, allylbromid eller også allylklorid. Videre kan også de tilsvarende alkansulfonsyre- eller arensulfonsyre-estre av allylalkoholen anvendes. De etter den ene eller annen fremgangsmåtevariant oppnådde forbindelsermed generell formel IV oppvarmes for avspaltning av alkanoylgruppen i en lavere alkanol i nærvær av klorhydrogen og eventuelt vann, hvorved man får 3-ållyl-5-metyl-2,4-tiazolidindion-2-hydrazonet med formel VII where R has the meaning given under formula II, after before the 3-substituent allyl, transferring a compound of the general formula V to its alkali metal compounds and reacting the latter with reactive esters of the allyl alcohol of formula VI The alkali metal compounds can e.g. is obtained by the action of sodium hydride, lithium or sodium amide in dimethylformamide at 0° to room temperature and reacted in the same medium at room temperature or moderately elevated temperatures with reactive esters of the allyl alcohol, e.g. halides, such as allyl iodide, allyl bromide or also allyl chloride. Furthermore, the corresponding alkanesulphonic acid or arenesulphonic acid esters of the allyl alcohol can also be used. The compounds of general formula IV obtained according to one or another method variant are heated to cleave off the alkanoyl group in a lower alkanol in the presence of hydrogen chloride and possibly water, thereby obtaining the 3-allyl-5-methyl-2,4-thiazolidinedione-2-hydrazone with formula VII

F.eks. koker man under tilbakelopskjoling et utgangsstoff med formlen IV ca. I - 15 timer i blandingen av en vannfri E.g. a starting substance with the formula IV is boiled under reflux for approx. I - 15 hours in the mixture of an anhydrous

. ' i . ' i

lavere alkanol, særlig etanol, dessuten metanol eller propanol, og absolutt eterisk klorhydrogenopplosning, hvis klor-hydrogeninnhold minst rekker til saltdannelse med det fri-gjorte hydrazon. I nevnte reaksjonsmedium krystalliserer det onskete hydrazon med formlen VII ut etterhvert i form av sitt hydroklorid og kan etter avsluttet reaksjon, avkjoling og eventuell tilforsel av en organisk væske, som nedsetter hydrokloridets opploselighet i reaksjonsmediet, som f.eks. lower alkanol, especially ethanol, also methanol or propanol, and absolutely ethereal chlorine hydrogen solution, whose chlorine hydrogen content is at least sufficient to form salts with the liberated hydrazone. In said reaction medium, the desired hydrazone with the formula VII eventually crystallizes out in the form of its hydrochloride and can, after completion of the reaction, cooling and possible addition of an organic liquid, which reduces the solubility of the hydrochloride in the reaction medium, such as e.g.

av petroleter eller ytterligere dietyleter, avfiltreres. I stedet for klorhydrogen kan man også anvende en tilsvarende, d.v.s. til den anvendte forbindelse med formlen VI minst ekvivalente mengde konsentrert saltsyre, hvormed reaksjonsmediet også gis et tilsvarende vanninnhold. I dette tilfelle gjennomfores reaksjonen fortrinnsvis i en lavere alkanol, f.eks. etanol, ved dennes koketemperatur. Det oppståtte hydroklorid av hydrazonet med formel VII er i det minste delvist opplost i dette reaksjonsmedium og isoleres f.eks. ved inn-dampning i vakuum. Frigjoringen av hydrazonet fra hydroklo-ridet kan skje på vanlig måte, f.eks. ved opplosning i vann, tilsetning av den beregnete mengde av en base, f.eks. natrium-karbonat eller natriumhydroksyd, og opptagning av det som olje utskilte hydrazon i et med vann ikke biandbart organisk opplosningsmiddel eller opplosningsmiddelblanding, f.eks. i metylenklorid og/eller petroleter. of petroleum ether or further diethyl ether, is filtered off. Instead of hydrogen chloride, you can also use an equivalent, i.e. to the used compound with the formula VI at least an equivalent amount of concentrated hydrochloric acid, with which the reaction medium is also given a corresponding water content. In this case, the reaction is preferably carried out in a lower alkanol, e.g. ethanol, at its boiling temperature. The resulting hydrochloride of the hydrazone of formula VII is at least partially dissolved in this reaction medium and is isolated, e.g. by evaporation in vacuum. The release of the hydrazone from the hydrochloride can take place in the usual way, e.g. by dissolving in water, adding the calculated amount of a base, e.g. sodium carbonate or sodium hydroxide, and taking up the hydrazone separated as oil in a water-immiscible organic solvent or solvent mixture, e.g. in methylene chloride and/or petroleum ether.

De for behandling av neoplasmer egnete daglige doser av tiosemikarbazon med formel I ligger for pattedyr mellom 1 og 100 mg/kg kroppsvekt og innenfor dette området ved parente-ral, særlig intramuskulær eller subkutan administrasjon van-ligvis lavere enn ved oral administrasjon. Tiosemikarbazonet The daily doses of thiosemicarbazone of formula I suitable for the treatment of neoplasms are for mammals between 1 and 100 mg/kg body weight and within this range for parenteral, especially intramuscular or subcutaneous administration is usually lower than for oral administration. The thiosemicarbazone

med formel I anvendes oralt eller rektalt fortrinnsvis i doséenhetsformer, som tabletter, dragéer eller kapsler henh. with formula I is used orally or rectally preferably in dosage unit forms, such as tablets, dragées or capsules acc.

suppositorier og parenteralt som injeksjonsopplosninger. suppositories and parenterally as injection solutions.

For fullstendighets skyld skal det nevnes at i norsk" patent , nr. 165.389 er visse semikarbazoner beskrevet som utelukkende tjener som mellomprodukter hénh. utgangsprodukter uten tumorhemmende egenskaper. Således oppviser f.eks. 3-allyl-5-metyl- 2,4-tiazolidindion-2-(4-allyl-3-tiosemikarbazon) som fremstilles etter nærværende oppfinnelse,per os en vesentlig bedre tumorhemmende virkning ved DMBA-carcinom enn det til sammen-ligning fremtrukne 2,2'-azin av 5-metyl-2,4-tiazolidindion og 5-metyl-3-(2-metylallyl)- 2,4-tiazolidindion. Denne overlegen-het for den ifolge oppfinnelsen fremstilte forbindelse med formel I administrert per os kan betegnes som spesifikk. For the sake of completeness, it should be mentioned that in Norwegian patent no. 165,389 certain semicarbazones are described which exclusively serve as intermediates or starting products without tumor-inhibiting properties. Thus, for example, 3-allyl-5-methyl-2,4-thiazolidinedione exhibits -2-(4-allyl-3-thiosemicarbazone) which is produced according to the present invention, per us a significantly better tumor-inhibiting effect in DMBA carcinoma than the comparatively preferred 2,2'-azine of 5-methyl-2,4 -thiazolidinedione and 5-methyl-3-(2-methylallyl)-2,4-thiazolidinedione This superiority for the compound of formula I produced according to the invention administered per os can be described as specific.

Det etterfolgende eksempel forklarer fremstillingen av tiosemikarbazonet med formel I og av hittil ikke kjente mellomprodukter hvorved temperaturene er angitt i Celsiusgrader. The following example explains the preparation of the thiosemicarbazone of formula I and of previously unknown intermediates, whereby the temperatures are indicated in degrees Celsius.

EKSEMPEL EXAMPLE

a) 474,1 g (3,612 mol) 4-allyl-3-tiosemikarbazid, fremstilt etter G. Pulvermacher og H. Hempel, Ber. 27, 625 (1894), a) 474.1 g (3.612 mol) of 4-allyl-3-thiosemicarbazide, prepared according to G. Pulvermacher and H. Hempel, Ber. 27, 625 (1894),

suspenderes i 3500 ml kloroform og tilsettes under omroring og avkjoling ved 25 - 30°C med 442,5 g (4,334 mol) acetanhydrid. Derpå kokes reaksjonsblandingen i 2 timer under omroring og tilbakelopskjoling. Derpå avkjoles den i et isbad på 5°. Det utfallende 1-acetyl-4-allyl-3-tiosemikarbazid nutsjes av, vaskes med eter og torkes i 20 timer i vannstrålevakuum ved 70°. Utbyttet utgjor 586,6 g (93,7% av det teoretiske) med smp. 131 - 132°. is suspended in 3500 ml of chloroform and added while stirring and cooling at 25 - 30°C with 442.5 g (4.334 mol) of acetic anhydride. The reaction mixture is then boiled for 2 hours with stirring and refluxing. It is then cooled in an ice bath at 5°. The precipitated 1-acetyl-4-allyl-3-thiosemicarbazide is filtered off, washed with ether and dried for 20 hours in a water jet vacuum at 70°. The yield amounts to 586.6 g (93.7% of the theoretical) with m.p. 131 - 132°.

b) 155,9 g (0,900 mol) l-acetyl-4-allyl-3-tiosemikarbazid, 158,4 g (1,035 mol) 2-brompropionsyre og 184,6 g (2,26 mol) b) 155.9 g (0.900 mol) of 1-acetyl-4-allyl-3-thiosemicarbazide, 158.4 g (1.035 mol) of 2-bromopropionic acid and 184.6 g (2.26 mol)

vannfritt natriumacetat kokes 3 timer i 1090 ml absolutt etanol under roring og tilbakelopskjoling. Derpå avkjoler man til 20° og filtrerer de utfalte uorganiske salter av. Filtratet konsentreres i vannstrålevakuum. Det tilbakeblivende smor-lignende stoff opptas i 500 ml metylenklorid og tilsettes 2-h natronlut inntil pH-verdien er 8. Blandingen rystes godt, og derpå skilles metylenkloridopplosningen fra og den vandige anhydrous sodium acetate is boiled for 3 hours in 1090 ml of absolute ethanol while stirring and refluxing. It is then cooled to 20° and the precipitated inorganic salts are filtered off. The filtrate is concentrated in a water jet vacuum. The remaining butter-like substance is taken up in 500 ml of methylene chloride and caustic soda is added for 2 hours until the pH value is 8. The mixture is shaken well, and then the methylene chloride solution is separated from and the aqueous

fase ekstraheres ennå 3 ganger hver gang med 150 ml metylenklorid. De forente metylenkloridopplosninger torkes over 30g vannfritt magnesiumsulfat. Dette filtreres fra og filtratet phase is further extracted 3 times each time with 150 ml of methylene chloride. The combined methylene chloride solutions are dried over 30 g of anhydrous magnesium sulfate. This is filtered off and the filtrate

- inndampes i vannstrålevakuum.Man.får 141,7 g (69,2% av det teoretiske) 3-allyl-5-metylT2,4^tiazolidindion-2-(2-acetyl- - evaporated in a water jet vacuum. One obtains 141.7 g (69.2% of the theoretical) 3-allyl-5-methylT2,4-thiazolidinedione-2-(2-acetyl-

hydrazon) med smp. 108-110°. hydrazone) with m.p. 108-110°.

c) 141,7 g (0,623 mol) 3-allyl-5-metyl-2,4-tiazolidindion-2-(2-acetyl-hydrazon) opploses i 500 ml absolutt etanol og tilsettes under omroring ved 35° 285 ml av en 0,67-n eterisk salt-syreopplosning. Derpå kokes reaksjonsblandingen i 3 timer under tilbakelopskjoling, hvorved etter 1 1/2 time en temmelig tykk krystallgrbt begynner å falle ut. Derpå avkjoles blandingen ved hjelp av et isbad til 5° og 500 ml petroleter (kp. 40-60°) tilsettes. Det utfalte 3-allyl-5-metyl-2,4-tiazolidindion- 2-hydrazon-hydroklorid nutsjes av og ettervaskes med 200 ml eter. Utbyttet er 108 g (87,5 % av det teoretiske) med smp. 167,5 - 169°. d) Eor frigjbring av basen opploses 108 g (0,486 mol) 3-allyl-5-metyl-2,4-tiazolidindion-2-hydrazon-hydroklorid i 300 ml vann, og opplosningen mettes under isavkjbling og omroring med kaliumkarbonat. Oljen som skiller seg ut opptas i en blanding av 150 ml metylenklorid og 150 ml petroleter (kp. 40 - 60°), skilles av fra den vandige fase og rystes ut med en opplosning av 50 g kaliumkarbonat i 150 ml vann. Den organiske fase skilles fra og inndampes i vannstrålevakuum. Man får 88,4 g (97,5 % av det teoretiske) 3-allyl-5-metyl-2,4-tiazolidindion-2-hydrazon som olje, som krystalliserer ved henstand, smp. 47 - 48°. c) 141.7 g (0.623 mol) of 3-allyl-5-methyl-2,4-thiazolidinedione-2-(2-acetyl-hydrazone) are dissolved in 500 ml of absolute ethanol and, while stirring at 35°, 285 ml of a 0.67-n ethereal salt-acid solution. The reaction mixture is then boiled for 3 hours under reflux, whereupon after 1 1/2 hours a fairly thick crystal grbt begins to fall out. The mixture is then cooled using an ice bath to 5° and 500 ml of petroleum ether (bp. 40-60°) is added. The precipitated 3-allyl-5-methyl-2,4-thiazolidinedione-2-hydrazone hydrochloride is filtered off and washed with 200 ml of ether. The yield is 108 g (87.5% of the theoretical) with m.p. 167.5 - 169°. d) To release the base, 108 g (0.486 mol) of 3-allyl-5-methyl-2,4-thiazolidinedione-2-hydrazone hydrochloride are dissolved in 300 ml of water, and the solution is saturated under ice cooling and stirring with potassium carbonate. The oil that separates is taken up in a mixture of 150 ml of methylene chloride and 150 ml of petroleum ether (bp. 40 - 60°), separated from the aqueous phase and shaken out with a solution of 50 g of potassium carbonate in 150 ml of water. The organic phase is separated and evaporated in a water jet vacuum. 88.4 g (97.5% of the theoretical) of 3-allyl-5-methyl-2,4-thiazolidinedione-2-hydrazone are obtained as an oil, which crystallizes on standing, m.p. 47 - 48°.

e) 13,1 g (0,071 mol) 3-allyl-5-metyl-2,4-tiazolidindion-2-hydrazon og 7,4 g (0,075 mol) allylisotiocyanat opploses i e) 13.1 g (0.071 mol) 3-allyl-5-methyl-2,4-thiazolidinedione-2-hydrazone and 7.4 g (0.075 mol) allyl isothiocyanate are dissolved in

400 ml metanol og kokes i 2 timer under tilbakelopskjoling. Derpå dampes metanolen av i vannstrålevakuum. Resten omkry-stalliseres 2 ganger fra kloroform-heksan. Man får 16,5 g (82,5% av det teoretiske) 3-allyl-5-metyl-2,4-tiazolidindion-2-(4-allyl-3-tiosemikarbazon) med smp. 106 108°. 400 ml of methanol and boil for 2 hours under reflux. The methanol is then evaporated off in a water jet vacuum. The residue is recrystallized twice from chloroform-hexane. 16.5 g (82.5% of the theoretical) of 3-allyl-5-methyl-2,4-thiazolidinedione-2-(4-allyl-3-thiosemicarbazone) with m.p. 106 108°.

Claims (1)

Analogifremgangsmåte for fremstilling av farmakody-namisk virksomt 3-allyl-5-metyl-2,4-tiazolidindion-(4-allyl-3-tiosemikarbazon) med formel I Analogous process for the preparation of pharmacodynamically active 3-allyl-5-methyl-2,4-thiazolidinedione-(4-allyl-3-thiosemicarbazone) of formula I karakterisert vedat man omsetter hydrazonet med formel VII characterized by reacting the hydrazone with formula VII med allylisotiocyanat med formel VIII with allyl isothiocyanate of formula VIII Anførte publikasjoner: Ålment tilgjengelig norsk søknad nr. 165389Listed publications: Generally available Norwegian application no. 165389
NO02730/70A 1969-07-17 1970-07-10 NO127923B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH1091169A CH511878A (en) 1969-07-17 1969-07-17 Process for the production of new azines
CH1091269A CH511877A (en) 1969-07-17 1969-07-17 Process for the production of a new thiosemicarbazone

Publications (1)

Publication Number Publication Date
NO127923B true NO127923B (en) 1973-09-03

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CA (1) CA933932A (en)
CS (1) CS153558B2 (en)
DK (1) DK127430B (en)
ES (1) ES381892A1 (en)
FI (1) FI52086B (en)
NO (1) NO127923B (en)
PL (1) PL71711B1 (en)
SE (1) SE362251B (en)
YU (1) YU33392B (en)

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YU33392B (en) 1976-12-31
FI52086B (en) 1977-02-28
DK127430B (en) 1973-11-05
PL71711B1 (en) 1974-06-29
CS153558B2 (en) 1974-02-25
SE362251B (en) 1973-12-03
ES381892A1 (en) 1972-12-01
YU178170A (en) 1976-06-30
CA933932A (en) 1973-09-18

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