NO128612B

NO128612B -

Info

Publication number: NO128612B
Application number: NO00165389A
Authority: NO
Inventors: A Meisel; E Schott
Original assignee: Ciba Geigy Ag
Priority date: 1965-10-29
Filing date: 1966-10-28
Publication date: 1973-12-17
Also published as: ES332859A1; GB1122604A; AT263769B; NL6615305A; DK121170B; YU256479A; ES332861A1; FR6874M; ES332860A1; YU256379A; FI48739B; NL149798B; US3746717A; YU203566A; YU36726B; AT267523B; IL26768A; DE1695095C3; CH459216A; FI48739C

Description

Analogifremgangsmåte for fremstillingAnalogy method of manufacture

av nye, farmakologisk virksomme 2,2'-aziner of new, pharmacologically active 2,2'-azines

av 2,4-tiazolidindioner.of 2,4-thiazolidinediones.

Nærværende oppfinnelse vedrorer en analogifremgangsmåte for fremstilling av hittil ukjente aziner som skal anvendes som legemidler. The present invention relates to an analogous method for the production of hitherto unknown azines to be used as pharmaceuticals.

Aziner med den generelle formel IAzines of the general formula I

hvor R^betyr hydrogen, en alkylgruppe méd hoyst 4 karbonatomer, en alkenylgruppe med 3 - 6 karbonatomer, en cykloalkenylgruppe med where R^means hydrogen, an alkyl group with at most 4 carbon atoms, an alkenyl group with 3 - 6 carbon atoms, a cycloalkenyl group with

hoyst 6 karbonatomer eller propargylresten,at most 6 carbon atoms or the propargyl residue,

og and

R2en alkenylgruppe med 3-6 karbonatomer, en cykloalkenylgruppe med hoyst 6 karbonatomer eller propargylresten, og R2 an alkenyl group with 3-6 carbon atoms, a cycloalkenyl group with at most 6 carbon atoms or the propargyl residue, and

R^og R^hydrogen eller lavere alkylrester med R^and R^hydrogen or lower alkyl residues with

1-3 karbonatomer,1-3 carbon atoms,

og deres salter er hittil ikke kjent. Som det nå overraskende er funnet, er disse forbindelser i besiddelse av verdifulle farmakologiske egenskaper, særlig tumorhemmende og antiviral virkning med gunstig terapeutisk indeks. Den tumorhemmende virkning kan fastslås ved dyreforsok ved subkutan og oral administrasjon f.eks. ved Yoshida-sarkom og Walker-carcinom hos rotter, og den antivirale virkning f.eks. ved subkutan og oral administrasjon overfor Columbia SK-virus. Dyreforsøkene ka-rakteriserer forbindelser med den generelle formel I, som oralt, rektalt og parenteralt anvendbare aktive stoffer for behandling av neoplasier såvel som virussykdommer, f.eks. encefalitis og encefalomyelitis. and their salts are not yet known. As has now surprisingly been found, these compounds possess valuable pharmacological properties, in particular tumor-inhibiting and antiviral action with a favorable therapeutic index. The tumor-inhibiting effect can be determined in animal experiments by subcutaneous and oral administration, e.g. in Yoshida sarcoma and Walker carcinoma in rats, and the antiviral effect e.g. by subcutaneous and oral administration against Columbia SK virus. The animal experiments characterize compounds of the general formula I, as orally, rectally and parenterally usable active substances for the treatment of neoplasias as well as viral diseases, e.g. encephalitis and encephalomyelitis.

I litteraturc;n er allerede noen fremstillingsmetoder for aziner beskrevet, se CA. 61, 5650-5651 (1964) "Structure of 2-amino-5-hydroxy-l,3,4-thiadiazine", E. Bulka et al. oppnådde f.eks. ved hydrolysen av N'-acetyl-2,4-tiazolidindion-2-hy-drazon 2,2'-azinet av 2,4-tiazolidindion. Videre ble av P.E. Gagnon et al. en fremstilling av 2,2'-azin av 2,4-tiazolidin-dion fra tiocyanoester og hydrazin beskrevet, se Can. J. Chem. 37, 1597-1607 (1959) "Synthesis of 2,4-thiazolidinedione-2-azines etc". For ingen av disse forbindelser ble i disse publikasjoner farmakologiske og særlig tumorhemmende egenskaper nevnt. Det var således på ingen måte å forutse at en kom-binasjon av strukturegenskapene, slik som de ble virkeliggjort i de foran angitte forbindelser med formel I, ville skaffe pro-dukter av farmakologisk interesse og terapeutisk virkning. Some preparation methods for azines are already described in the literature, see CA. 61, 5650-5651 (1964) "Structure of 2-amino-5-hydroxy-1,3,4-thiadiazine", E. Bulka et al. achieved e.g. by the hydrolysis of N'-acetyl-2,4-thiazolidinedione-2-hydrazone the 2,2'-azine of 2,4-thiazolidinedione. Furthermore, by P.E. Gagnon et al. a preparation of 2,2'-azine from 2,4-thiazolidinedione from thiocyanoester and hydrazine described, see Can. J. Chem. 37, 1597-1607 (1959) "Synthesis of 2,4-thiazolidinedione-2-azines etc". For none of these compounds were pharmacological and particularly tumor-inhibiting properties mentioned in these publications. It was thus in no way to be foreseen that a combination of the structural properties, as they were realized in the above-mentioned compounds of formula I, would provide products of pharmacological interest and therapeutic effect.

For fremstilling av aziner med den generelle formel I, hvorFor the preparation of azines of the general formula I, wherein

R^har samme betydning som R^ omsetter man et 2,5-ditio-bikarbamid med den generelle formel II hvor R-^ og R2har de foran angitte betydninger, eller et to-basisk salt av en tautomer form av karbamidet, med minst den dobbeltmolare mengde av en halogenhydrogensyre-henh. sulfonsyreester med hensyn til hydroksylfunksjonen av en oc-hydroksy-alkansyre med den generelle formel III R^ has the same meaning as R^, one reacts a 2,5-dithio-bicarbamide with the general formula II where R-^ and R2 have the previously stated meanings, or a dibasic salt of a tautomeric form of the carbamide, with at least the double-molar amount of a halogenohydrogen acid according to sulfonic acid ester with respect to the hydroxyl function of an oc-hydroxyalkanoic acid of the general formula III

hvor R^har foran angitte betydning, where R^ has the above meaning,

eller et anilid henh. en lavere alkylester av syren med hensyn til dens karboksylfunksjon,ved en temperatur på 50 - 150°C til en forbindelse med den generelle formel I. Det anvendte salt av en forbindelse med den generelle formel II fremstilles f.eks. in situ ved tilsétning av en base eller et salt av en svak syre, f.eks. av natriumacetat. Omsetningen gjennomfores f.eks. i en lavere alkanol, som etanol, propanol eller butanol, ved temperaturer mellom 50 til 150°C, fortrinnsvis ved koketemperatur for det anvendte opplosningsmiddel. Som reaksjonsdyktig ester hva angår hydroksylfunksjonen av syrer med den generelle formel III anvendes halogenhydrogensyre- og sulfonsyreester, særlig arensulfonsyre- og metansulfonsyreester, d.v.s. lavere 2-halogen-, 2-arensulfonyloksy- og metansulfonyloksy-alkansyrer. Som funksjonelle derivater av disse reaksjonsdyktige estere hva angår karboksylfunksjoner anvendes anilidet eller lavere alkylester, d.v.s. lavere 2-halogen-, 2-arensulfon yloksy- og 2-metansulfonyloksy-alkansyreanilider henh. de tilsvarende estere. or an anilide acc. a lower alkyl ester of the acid with respect to its carboxyl function, at a temperature of 50 - 150°C to a compound of the general formula I. The used salt of a compound of the general formula II is prepared, e.g. in situ by adding a base or a salt of a weak acid, e.g. of sodium acetate. The turnover is carried out e.g. in a lower alkanol, such as ethanol, propanol or butanol, at temperatures between 50 to 150°C, preferably at the boiling temperature of the solvent used. As reactive ester with regard to the hydroxyl function of acids with the general formula III, halohydrogen acid and sulfonic acid esters, in particular arenesulfonic acid and methanesulfonic acid esters, are used, i.e. lower 2-halo, 2-arenesulfonyloxy and methanesulfonyloxy alkanoic acids. As functional derivatives of these reactive esters with regard to carboxyl functions, the anilide or lower alkyl ester is used, i.e. lower 2-halo-, 2-arenesulfonyloxy- and 2-methanesulfonyloxy-alkanoic acid anilides acc. the corresponding esters.

Utgangsstoffer med den generelle formel II og III er delvis kjent og andre lar seg fremstille analogt. Starting substances with the general formulas II and III are partially known and others can be prepared analogously.

Etter en annen.fremgangsmåte som spesielt kommer i betraktning for fremstilling av forbindelser med den generelle formel I med innbyrdes forskjellige rester R^ og R^, omsetter man - i According to another method which comes into consideration in particular for the preparation of compounds of the general formula I with mutually different residues R^ and R^, one reacts - in

stedet for ét 2,5-ditio-bikarbamid med den generelle formel :instead of one 2,5-dithio-biurea with the general formula:

II - et tiosemikarbazon med den generelle formel IV eller V, II - a thiosemicarbazone of the general formula IV or V,

hvor R^, R2, R3°g R4^ar den under formel I where R1, R2, R3 and R4 are those under formula I

angitte betydning,stated meaning,

eller et salt av en tautomer form av karbazonet, med minst den ekvimolare mengde av de foran definerte derivater av en lavere a-hydroksy-alkansyre med den generelle formel III i varme. Omsetningen kan gjennomføres på samme måte som ved an-vendelsen av 2,5-ditio-bikarbamid. or a salt of a tautomeric form of the carbazone, with at least the equimolar amount of the above-defined derivatives of a lower α-hydroxyalkanoic acid of the general formula III in heat. The reaction can be carried out in the same way as when using 2,5-dithio-biurea.

Tiosemikarbazoner med den generelle formel IV og V oppnår man ved omsetning av i 3- og 5-stilling tilsvarende definisjonen for R2henh. R-^ og R^henh. R^substituerte rhodaniner med i 4-stilling med R-^ henh. R2 substituerte 3-tiosemikarbazider. Thiosemicarbazones of the general formula IV and V are obtained by reacting in the 3- and 5-position corresponding to the definition for R2henh. R-^ and R^henh. R^-substituted rhodanines with in the 4-position with R-^ acc. R2 substituted 3-thiosemicarbazides.

Etter en tredje fremgangsmåte oppnår man forbindelser med den generelle formel I, hvor R^stemmer overens med R2 og R^med R4, idet man omsetter et rhodanin med den generelle formel VI, According to a third method, compounds of the general formula I are obtained, where R^ corresponds to R2 and R^ to R4, by reacting a rhodanine of the general formula VI,

hvor Rj og har den under formal I angitte where Rj and has the under formal I specified

betydning, med den halvmolare mengde av et hydrazinsalt. Omsetningen meaning, with the half-molar amount of a hydrazine salt. The turnover

finner fortrinnsvis sted ved forhoyet temperatur, f.eks. ved kokning av reaksjonskomponentene i en egnet, lavere alkanol, som etanol eller butanol. preferably takes place at an elevated temperature, e.g. by boiling the reaction components in a suitable, lower alkanol, such as ethanol or butanol.

Endelig fremstilles forbindelser med den generelle formel I, hvor ikke er hydrogen, etter en fjerde fremgangsmåte, idet man omsetter et azin med den generelle formel VII Finally, compounds with the general formula I, where there is no hydrogen, are prepared according to a fourth method, by reacting an azine with the general formula VII

hvor R^, R^og R^har de foran angitte betydninger, where R^, R^ and R^ have the above meanings,

i nærvær av et syrebindende middel med en reaksjonsdyktig ester av en forbindelse med formelen VIII in the presence of an acid-binding agent with a reactive ester of a compound of formula VIII

hvor R2har foran angitte betydning, where R2 has the above meaning,

og da med minst den dobbeltmolare mengde av denne ester hvis i formel VII symbolet R^betyr hydrogen, eller med minst den ekvimolare mengde av denne ester hvis i formel VII symboletR^ikke er hydrogen, and then with at least the double molar amount of this ester if in formula VII the symbol R^ means hydrogen, or with at least the equimolar amount of this ester if in formula VII the symbol R^ is not hydrogen,

hvoretter man, om onsket, omsetter en oppnådd forbindelse hvor R^er hydrogen med minst den ekvimolare mengde av en reaksjonsdyktig ester av en forbindelse med formel IX after which, if desired, a compound obtained where R^ is hydrogen is reacted with at least the equimolar amount of a reactive ester of a compound of formula IX

hvorR^' har den under formel I angitte betydning where R^' has the meaning given under formula I

for R^ med unntagelse av hydrogen,for R^ with the exception of hydrogen,

og hvis onsket overforer en oppnådd forbindelse med den generelle formel I til et salt. and if desired, converts an obtained compound of the general formula I into a salt.

Som syrebindende midler tjener f.eks. alkalimetallforbindelser, som natrium- eller kaliuirihydroksyd, natriumamid, natrium- eller litiumhydridi Omsetningen gjennomofres i egnete organiske opp-losningsmidler, som f .eks. benzen, toluen, dj.metylforvnamid, eller ved anvendelse av alkalihydroksyder også i lavere alka-noler, som etanol. Reaksjonstemperaturene ligger fortrinnsvis mellom værelsestemperatur og koketemperatur for det anvendte opplosningsmiddel. Som reaksjonsdyktig ester av lavere alka-noler og alkenoler egner seg f.eks. deres halogenider, i sær-deleshet bromider, jodider og klorider, såvel, som sulfonsyreester, som f.eks. metansulfonsyreester og p-t<p>luensulfonsyre-ester. Videre .kommer f.eks. lett tilgjengelige svovelsyreeste-re, som dimetylsulfat og diétylsulfat i betraktning. As acid-binding agents, e.g. alkali metal compounds, such as sodium or potassium hydroxide, sodium amide, sodium or lithium hydride. The reaction is carried out in suitable organic solvents, such as e.g. benzene, toluene, dimethylformamide, or by using alkali hydroxides also in lower alkanols, such as ethanol. The reaction temperatures are preferably between room temperature and boiling temperature for the solvent used. As reactive esters of lower alkanols and alkenols, e.g. their halides, in particular bromides, iodides and chlorides, as well as sulphonic acid esters, such as e.g. methanesulfonic acid ester and p-t<p>luenesulfonic acid ester. Furthermore, e.g. readily available sulfuric acid esters, such as dimethyl sulfate and diethyl sulfate in consideration.

Forbindelser med den generelle formel VII med et hydrogenatom som R^kan oppnås etter den forste og den andre fremgangsmåte for fremstilling av forbindelser med den generelle formel I, Compounds of the general formula VII with a hydrogen atom as R^ can be obtained by the first and second methods for preparing compounds of the general formula I,

og slike med et hydrogenatom i stedet for R2analogt til disse to fremgangsmåter, mens forbindelser med hydrogenatomer som R^og R2 er oppnålig analogt til alle tre ovenfor nevnte fremgangsmåter for fremstilling av forbindelser med den generelle formel and those with a hydrogen atom instead of R2 analogous to these two methods, while compounds with hydrogen atoms such as R^ and R2 can be obtained analogously to all three above-mentioned methods for preparing compounds with the general formula

I. IN.

Aziner med den generelle formel I hvor R^betegner hydrogen er svakt sure stoffer som likeledes overfores f.eks. til natrium-, kalium- eller litiumsalter, eller salter med organiske baser, som etylamin, dimetylamin, dietylamin, aminoetanol, dietylami-no-etanol, dietanolamin, trietanolamin, etylendiamin eller mor-folin. De nevnte aziner kan f.eks. opploses i vandige oppløs-ninger av uorganiske, basiske stoffer, som natrium- eller kali-umhydroksyd, natrium- eller kaliumkarbonat. Azines with the general formula I where R^ denotes hydrogen are weakly acidic substances which are likewise transferred, e.g. to sodium, potassium or lithium salts, or salts with organic bases, such as ethylamine, dimethylamine, diethylamine, aminoethanol, diethylaminoethanol, diethanolamine, triethanolamine, ethylenediamine or morpholine. The mentioned azines can e.g. dissolves in aqueous solutions of inorganic, basic substances, such as sodium or potassium hydroxide, sodium or potassium carbonate.

De for behandling av virussykdommer og neoplasier egnede dag-lige doser av aziner med den generelle formel I og av farmasoy-tisk aksepterbare salter herav ligger hos voksne mennesker med normalvekt mellom 10 mg og 1000 mg, og innenfor dette område ved parenteral administrasjon i almindelighet lavere enn ved oral administrasjon. De nevnte dagsdoser administreres fortrinnsvis i doseenhetsformer med 5 til 250 mg aktivstoff, dog kan også tilsvarende mengder av ikke-enkeltdoserte administra-sjonsformer, som siruper, sprays, aerosoler, pudder og salver anvendes. The daily doses of azines of the general formula I and of pharmaceutically acceptable salts thereof suitable for the treatment of viral diseases and neoplasms are in adults of normal weight between 10 mg and 1000 mg, and within this range for parenteral administration generally lower than by oral administration. The mentioned daily doses are preferably administered in dosage unit forms with 5 to 250 mg of active substance, however, corresponding amounts of non-single dose administration forms, such as syrups, sprays, aerosols, powders and ointments can also be used.

De etterfolgende eksempler redegjor for fremstilling av de nye forbindelsene med den generelle formel I. Temperaturene er angitt i Celsiusgrader. The following examples describe the preparation of the new compounds of the general formula I. The temperatures are given in degrees Celsius.

EKSEMPEL 1EXAMPLE 1

20,4 g (0,1 mol) 1-(1-metylallyl)-2,5-ditio-bikarbamid (N-[(1-metylallyl)-tiokarbam<p>yl]-N'-tiokarbamoylhydrazin) (s.p. 179-181) (se nedenfor), 20,8 g (0,22 mol) kloreddiksyre og 20 g vannfritt natriumacetat oppvarmes i 100 ml etanol 6 timer under tilbakelop. Reaksjonsblandingen avkjoles deretter ved 0°, det hvite bunnfall suges fra og vaskes med meget vann. Det tilbakeblivende 2,2'-azin av 2,4-tiazolidin-dion og 3-(1-metylallyl)-2,4-tiazolidindion smelter etter to gangers omkrystallisasjon fra aceton-heksan ved 191-192°. 20.4 g (0.1 mol) 1-(1-methylallyl)-2,5-dithio-biurea (N-[(1-methylallyl)-thiocarbam<p>yl]-N'-thiocarbamoylhydrazine) (s.p. 179 -181) (see below), 20.8 g (0.22 mol) of chloroacetic acid and 20 g of anhydrous sodium acetate are heated in 100 ml of ethanol for 6 hours under reflux. The reaction mixture is then cooled at 0°, the white precipitate is sucked off and washed with plenty of water. The remaining 2,2'-azine of 2,4-thiazolidinedione and 3-(1-methylallyl)-2,4-thiazolidinedione melts after two recrystallizations from acetone-hexane at 191-192°.

På analog måte fremstilles:In an analogous way, the following is produced:

a) 2,2'-azin av 2,4-tiazolidindion og 3-allyl-2,4-tiazolidindion , s.p. 240-241° b) 2,2'-azin av 3-etyl-2,4-tiazolidindion og 3-allyl-2,4-tiazolidindion , s.p. 196-197°$c) 2,2 '-azin av ,3-metyl-2,4-tiazolidindion og 3- (1-metyl-allyl )-2,4-tiazolidindion. '., s.p. 148-149°; d) 2,2'-azin av 3-allyl-2,4-tiazolidindion , s.p. 210-211°, e) 2,2'-azin av 3-(1-metylallyl)-2,4-tiazolidindion, s.p. 157-158°, f) 2,2'-azin av 2,4-tiazolidindion og 3-(2-butenyl)- 2,4-tiazolidindion, s.p. 262-263°C, i) 2,2'-azin av 2,4-tiazolidindion og 3-(2-metylallyl)- 2,4-tiazolidindion, s.p. 225-227°, j) 2,2'-azin. av 3-metyl-2, 4-tiazolidindion og 3- (2-metyl-allyl )-2,4-tiazolidindion, s.p. 182-183°, k) 2,2'-azin av 3-(2-metylallyl)-2,4-tiazolidindion, s.p. 194-195° 1) 2,2'-azin av 2,4-tiazolidindion og 3-(1-metyl-2-butenyl)-2,4-tiazolidindion, s.p. 160-162°. a) 2,2'-azine of 2,4-thiazolidinedione and 3-allyl-2,4-thiazolidinedione, m.p. 240-241° b) 2,2'-azine of 3-ethyl-2,4-thiazolidinedione and 3-allyl-2,4-thiazolidinedione, m.p. 196-197°c) 2,2'-azine of ,3-methyl-2,4-thiazolidinedione and 3-(1-methyl-allyl)-2,4-thiazolidinedione. '., s.p. 148-149°; d) 2,2'-azine of 3-allyl-2,4-thiazolidinedione, m.p. 210-211°, e) 2,2'-azine of 3-(1-methylallyl)-2,4-thiazolidinedione, m.p. 157-158°, f) 2,2'-azine of 2,4-thiazolidinedione and 3-(2-butenyl)-2,4-thiazolidinedione, m.p. 262-263°C, i) 2,2'-azine of 2,4-thiazolidinedione and 3-(2-methylallyl)-2,4-thiazolidinedione, m.p. 225-227°, j) 2,2'-azine. of 3-methyl-2,4-thiazolidinedione and 3-(2-methylallyl)-2,4-thiazolidinedione, m.p. 182-183°, k) 2,2'-azine of 3-(2-methylallyl)-2,4-thiazolidinedione, m.p. 194-195° 1) 2,2'-azine of 2,4-thiazolidinedione and 3-(1-methyl-2-butenyl)-2,4-thiazolidinedione, m.p. 160-162°.

Det som utgangsstoff nodvendige 1-(1-metylallyl)-2,5-ditio-bikarbamid fremstilles f.eks. som folger: 46 g (0,5 mol) tiosemikarbazid, 62 g (0,55 mol) 1-metyl-allyl-isotiocyanat (fremstilt etter 0. Mumm og H. Richter, Ber. 73, 852 (1940) og 2000 ml etanol oppvarmes 14 timer under tilbakelop. Heretter avkjoles reaksjonsopplosningen til 0° og det ut-krystalliserte 1-(1-metylallyl)-2,5-ditiobikarbamid filtreres fra, vaskes med etanol og torkes. The starting material required 1-(1-methylallyl)-2,5-dithio-biurea is prepared, e.g. as follows: 46 g (0.5 mol) thiosemicarbazide, 62 g (0.55 mol) 1-methyl-allyl isothiocyanate (prepared according to 0. Mumm and H. Richter, Ber. 73, 852 (1940) and 2000 ml ethanol is heated under reflux for 14 hours.The reaction solution is then cooled to 0° and the crystallized 1-(1-methylallyl)-2,5-dithiobicarbamide is filtered off, washed with ethanol and dried.

EKSEMPEL 2.EXAMPLE 2.

30,6 g (0,15 mol) l-allyl-6-metyl-2,5-ditio-bikarbamid (s.p. 193-194°, fremstilt analogt siste del av eksempel 1) og 51 g (0,3 mol) kloracetanilid oppvarmes i 2000ml etanol 14 timer under tilbakelop. Ved avkjoling utkrystalliserer fra den kla-re opplosning 2,2'-azinet av 3-allyl-2,4-tiazolidindion. og 3-metyl-2,4-tiazolidindion. Det smelter etter en omkrystallisasjon fra etanol ved 186 - 187°. 30.6 g (0.15 mol) 1-allyl-6-methyl-2,5-dithio-bicarbamide (m.p. 193-194°, prepared analogously to the last part of example 1) and 51 g (0.3 mol) chloroacetanilide heated in 2000 ml of ethanol for 14 hours under reflux. On cooling, the 2,2'-azine of 3-allyl-2,4-thiazolidinedione crystallizes out from the clear solution. and 3-methyl-2,4-thiazolidinedione. It melts after recrystallization from ethanol at 186 - 187°.

EKSEMPEL 3EXAMPLE 3

20,4 g (0,1 mol) 1-(1-metylallyl)-2,5-ditio-bikarbamid (se eksempel 1), 33,6 g (0,22 mol) 2-brom-n-propionsyre og 40 g vannfritt natriumacetat oppvarmes i 200 ml etanol i 25 timer under tilbakelop. Etter avkjoling ved værelsestemperatur filtreres natriumsaltet fra, filtratet konsentreres sterkt i vannstrålevakuum og tilsettes forsiktig med vann. 2,2'-azinet av 5-metyl-2,4-tiazolidindion- og 5-metyl-3-(1-metylallyl)-2,4-tiazolidindion krystalliserer ved 0° fra opplosningen og smelter etter tre gangers omkrystallisasjon fra aceton-heksan ved 137-138°. 20.4 g (0.1 mol) 1-(1-methylallyl)-2,5-dithio-bicarbamide (see example 1), 33.6 g (0.22 mol) 2-bromo-n-propionic acid and 40 g of anhydrous sodium acetate is heated in 200 ml of ethanol for 25 hours under reflux. After cooling at room temperature, the sodium salt is filtered off, the filtrate is strongly concentrated in a water jet vacuum and carefully added with water. The 2,2'-azine of 5-methyl-2,4-thiazolidinedione and 5-methyl-3-(1-methylallyl)-2,4-thiazolidinedione crystallizes at 0° from solution and melts after three recrystallizations from acetone hexane at 137-138°.

På analog måte fremstilles:In an analogous way, the following is produced:

a) 2,2'-azin av 5-metyl-2,4-tiazolidindion og 3-allyl-5-metyl-tiazolidindion , s.p. 144-145°, b) 2,2'-azin av 3-allyl-5-metyl-2,4-tiazolidindion'og 3,5 dimetyl-2,4-tiazolidindion , s.p. 167-17f, c) 2,2'-azin av 3-etyl-5-metyl-2,4-tiazolidindion og 3-allyl-5-metyl-2,4-tiazolidindion , s.p. 112-113°; d) 2,2'-azin av 3,5-dimetyl-2,4-tiazolidindion og 5-metyl-3-(1-metylallyl)-2,4-tiazolidindion ., s.p. 94-95°, e) 2,2'-azin av 3-etyl-5-metyl-2,4-tiazolidindioh og 5-metyl-3-(1-metylallyl)-2,4-tiazolidindion , s.p. 92-93°. f) 2,2'-azin av 3-(2-butenyl)-5-metyl-2,4-tiazolidindion og 5-metyl-2,4-tiazolidindion , s.p. 131-132°, g) 2,2'-azin av 3-(2-butenyl)-5-metyl-2,4-tiazolidindion og 3,5-dimetyl-2,4-tiazolidindion , s.p. 164-165°, h) 2,2'-azin av 3-etyl-5-metyl-2,4-tiazolidindion og 3-(2-butenyl)-5-metyl-2,4-tiazolidindion , s.p. 90-91°, a) 2,2'-azine of 5-methyl-2,4-thiazolidinedione and 3-allyl-5-methyl-thiazolidinedione, m.p. 144-145°, b) 2,2'-azine of 3-allyl-5-methyl-2,4-thiazolidinedione and 3,5-dimethyl-2,4-thiazolidinedione, m.p. 167-17f, c) 2,2'-azine of 3-ethyl-5-methyl-2,4-thiazolidinedione and 3-allyl-5-methyl-2,4-thiazolidinedione, m.p. 112-113°; d) 2,2'-azine of 3,5-dimethyl-2,4-thiazolidinedione and 5-methyl-3-(1-methylallyl)-2,4-thiazolidinedione, m.p. 94-95°, e) 2,2'-azine of 3-ethyl-5-methyl-2,4-thiazolidinedioe and 5-methyl-3-(1-methylallyl)-2,4-thiazolidinedione, m.p. 92-93°. f) 2,2'-azine of 3-(2-butenyl)-5-methyl-2,4-thiazolidinedione and 5-methyl-2,4-thiazolidinedione, m.p. 131-132°, g) 2,2'-azine of 3-(2-butenyl)-5-methyl-2,4-thiazolidinedione and 3,5-dimethyl-2,4-thiazolidinedione, m.p. 164-165°, h) 2,2'-azine of 3-ethyl-5-methyl-2,4-thiazolidinedione and 3-(2-butenyl)-5-methyl-2,4-thiazolidinedione, m.p. 90-91°,

i) 2,2'-azin av 5-metyl-2, 4-tiazoli3Lndion og 5-metyl-3-(2-metylallyl)-2,4-tiazolidindion , s.p. 132-133°, i) 2,2'-azine of 5-methyl-2,4-thiazolidinedione and 5-methyl-3-(2-methylallyl)-2,4-thiazolidinedione, m.p. 132-133°,

j) 2,2'-azin av 3,5-dimetyl-2,4-tiazolidindion og 5-metyl-3-(2-metylallyl)-2,4-tiazolidindion , s.p. 158-159°, j) 2,2'-azine of 3,5-dimethyl-2,4-thiazolidinedione and 5-methyl-3-(2-methylallyl)-2,4-thiazolidinedione, m.p. 158-159°,

k) 2,2'-azin av 3-etyl-5-metyl-2,4-tiazolidindion og 5-metyl-3-(2-metylallyl)-2,4-tiazolidindion -, s.p. 121-122°, 1) 2,2'-azin av 5-metyl-2,4-tiazolidindion og 5-metyl-3-(1-metyl-2-butenyl)-2,4-tiazolidindion , s.p. 162-164°, k) 2,2'-azine of 3-ethyl-5-methyl-2,4-thiazolidinedione and 5-methyl-3-(2-methylallyl)-2,4-thiazolidinedione -, m.p. 121-122°, 1) 2,2'-azine of 5-methyl-2,4-thiazolidinedione and 5-methyl-3-(1-methyl-2-butenyl)-2,4-thiazolidinedione, m.p. 162-164°,

> >

m) 2,2'-azin av 3,5-dimetyl-2,4-tiazblidindion og 5-metyl-3-(1-metyl-2-butenyl)-2,4-tiazolidindion, s.p. 101-10 2°C5 n) 2,2'-azinav 3-cykloheks-2-enyl)-5-metyl-2,4-tiazolidin-dion og 5-metyl-2,4-tiazolidindion, s.p. 204°. m) 2,2'-azine of 3,5-dimethyl-2,4-thiazblidinedione and 5-methyl-3-(1-methyl-2-butenyl)-2,4-thiazolidinedione, m.p. 101-10 2°C5 n) 2,2'-azinav 3-cyclohex-2-enyl)-5-methyl-2,4-thiazolidinedione and 5-methyl-2,4-thiazolidinedione, m.p. 204°.

EKSEMPEL 4EXAMPLE 4

a) 2,2'-azinet av 5-etyl-2,3-tiazolidindion og 5-etyl-3-(1-metylallyl)-2,4-tiazolidindion oppnås analogt eksempel 3 ved a) The 2,2'-azine of 5-ethyl-2,3-thiazolidinedione and 5-ethyl-3-(1-methylallyl)-2,4-thiazolidinedione is obtained analogously to example 3 by

å gå ut fra 20,4 g (0,1 mol) 1-(1-metylallyl)-2,5-ditio-bikarbamid, 36,8 g (0,22 mol) 2-brom-n-smorsyre og 40 g vannfritt natriumacetat, s.p. 117-118°. starting from 20.4 g (0.1 mol) 1-(1-methylallyl)-2,5-dithio-bicarbamide, 36.8 g (0.22 mol) 2-bromo-n-butyric acid and 40 g anhydrous sodium acetate, m.p. 117-118°.

På analog måte fremstilles:In an analogous way, the following is produced:

b) 2,2'-azin av 5-etyl-2,4-tiazolidindiori og 5-etyl-3-(2-butenyl)-2,4-tiazolidindion, s.p. 136-137°, c) 2,2'-azin av 5-etyl-2,4-tiazolidindion og 5-etyl-3-(2-metylallyl)-2,4-tiazolidindion, s.p. 124-126°. b) 2,2'-azine of 5-ethyl-2,4-thiazolidinediore and 5-ethyl-3-(2-butenyl)-2,4-thiazolidinedione, m.p. 136-137°, c) 2,2'-azine of 5-ethyl-2,4-thiazolidinedione and 5-ethyl-3-(2-methylallyl)-2,4-thiazolidinedione, m.p. 124-126°.

EKSEMPEL 5EXAMPLE 5

a) 2,3 g (0,01 mol) 3-allyl-2,4-tiazolidindion-2-tiosemikarbazon (fremstillingen beskrives nedenfor), 1,04 g (0,11 a) 2.3 g (0.01 mol) 3-allyl-2,4-thiazolidinedione-2-thiosemicarbazone (the preparation is described below), 1.04 g (0.11

mol) kloreddiksyre og 2 g vannfritt natriumacetat oppvarmes i 10 ml etanol i 6 timer under tilbakelop. Reaksjonsblandin- mol) of chloroacetic acid and 2 g of anhydrous sodium acetate are heated in 10 ml of ethanol for 6 hours under reflux. reaction mixture

gen inndampes på en rotasjonsfordamper ved 11 torr og 45°C inntil ca. 6 ml og helles på 20 g is. Det utfelte 2,2'-azin av 3-allyl-2,4-tiazolidindion. og 2,4-tiazolidindion smelter etter to gangers omkrystallisasjon fra kloroform-heksan ved 240-241°. gene is evaporated on a rotary evaporator at 11 torr and 45°C until approx. 6 ml and pour over 20 g of ice. The precipitated 2,2'-azine of 3-allyl-2,4-thiazolidinedione. and 2,4-thiazolidinedione melts after recrystallization twice from chloroform-hexane at 240-241°.

Analogt til eksempel 5a) oppnås:Analogous to example 5a) is achieved:

2,2'-azinet av 3-allyl-2,4-tiazolidindion og av 3,5-dimetyl-2,4-tiazolidindion, s.p. 164-166° fra 3,5-dimetyl-2,4-tiazolidindion- 2- (4-allyl-3-tiosemikarbazon); The 2,2'-azine of 3-allyl-2,4-thiazolidinedione and of 3,5-dimethyl-2,4-thiazolidinedione, m.p. 164-166° from 3,5-dimethyl-2,4-thiazolidinedione-2-(4-allyl-3-thiosemicarbazone);

2,2'-azinet av 3-allyl-5-metyl-2,4-tiazolidindion og av 2-metyl-2,4-tiazolidindion, s.p. 166 - 167° fra 3-metyl-2,4-tiazolidindion-2-(4-allyl-3-tiosemikarbazon); The 2,2'-azine of 3-allyl-5-methyl-2,4-thiazolidinedione and of 2-methyl-2,4-thiazolidinedione, m.p. 166 - 167° from 3-methyl-2,4-thiazolidinedione-2-(4-allyl-3-thiosemicarbazone);

2,2'-azinet av 3-metyl-2,4-tiazolidindion og av 3-(2-metyl-allyl ) -5-metyl- 2 , 4-tiazolidindion , s.p. 154° fra 3-metyl-2,4-tiazolidndion-2-[4-(2-metyl-allyl)-3-tiosemikarbazon]; The 2,2'-azine of 3-methyl-2,4-thiazolidinedione and of 3-(2-methyl-allyl)-5-methyl-2,4-thiazolidinedione, m.p. 154° from 3-methyl-2,4-thiazolidinedione-2-[4-(2-methyl-allyl)-3-thiosemicarbazone];

2,2'-azinet av 3-allyl-5-metyl-2,4-tiazolidindion og av 3-(2-cykloheksen-l-yl)-5-metyl-2,4-tiazolidindion, s.p. 126° fra 3-allyl-5-metyl- 2, 4-tiazolidindion- 2- [4- (cykloheks-2-enyl) -3-tiosemikarbazon]5The 2,2'-azine of 3-allyl-5-methyl-2,4-thiazolidinedione and of 3-(2-cyclohexen-1-yl)-5-methyl-2,4-thiazolidinedione, m.p. 126° from 3-allyl-5-methyl-2,4-thiazolidinedione-2-[4-(cyclohex-2-enyl)-3-thiosemicarbazone]5

2,2'-azinet av 3-allyl-2,4-tiazolidindion og av 3-(2-metyl-allyl )- 2 , 4-tiazolidindion, s.p. 172° fra 3«allyl-2,4-tiazolidindion- 2-[4-(2-metyl-allyl)-3-tiosemikarbazon]; The 2,2'-azine of 3-allyl-2,4-thiazolidinedione and of 3-(2-methylallyl)-2,4-thiazolidinedione, m.p. 172° from 3'-allyl-2,4-thiazolidinedione-2-[4-(2-methyl-allyl)-3-thiosemicarbazone];

2,2'-azinet av 3,5-dimetyl-2,4-tiazolidindion og av 3-(2-metylallyl)-2,4-tiazolidindion, s.p. 174-175° fra 3-allyl-2,4-tiazolidindion- 2- [4- ( 2-metyl-allyl) -3-tiosemikarbazonj; The 2,2'-azine of 3,5-dimethyl-2,4-thiazolidinedione and of 3-(2-methylallyl)-2,4-thiazolidinedione, m.p. 174-175° from 3-allyl-2,4-thiazolidinedione-2-[4-(2-methyl-allyl)-3-thiosemicarbazone;

2,2'-azinet av 3-allyl-5-metyl-2,4-tiazolidindion og av 3-metyl-2,4-tiazolidindion, s.p. 166-167° fra 3-allyl-5-metyl-2,4-tiazolidindion-2-(4-metyl)-3-tiosemikarbazon; The 2,2'-azine of 3-allyl-5-methyl-2,4-thiazolidinedione and of 3-methyl-2,4-thiazolidinedione, m.p. 166-167° from 3-allyl-5-methyl-2,4-thiazolidinedione-2-(4-methyl)-3-thiosemicarbazone;

2,2'-azinet av 3-allyl-5-metyl-2,4-tiazolidindion og av 3-(2-metyl-allyl)-2,4-tiazolidindion, s.p. 178-179° fra 3-allyl- The 2,2'-azine of 3-allyl-5-methyl-2,4-thiazolidinedione and of 3-(2-methylallyl)-2,4-thiazolidinedione, m.p. 178-179° from 3-allyl-

5-metyl- 2,4-tiazolidindion- 2- [4- ( 2-metyl-allyl) - 3-tiosemikarbazon ; 5-methyl-2,4-thiazolidinedione-2-[4-(2-methyl-allyl)-3-thiosemicarbazone;

2,2'-azinet av 3-allyl-5-metyl-2,4-tiazolidindion og av 3-allyl-2,4-tiazolidindion, s.p. 162° fra 3-allyl-5-metyl-2,4-tiazolidindion-2-(4-allyl-3-tiosemikarbazon); The 2,2'-azine of 3-allyl-5-methyl-2,4-thiazolidinedione and of 3-allyl-2,4-thiazolidinedione, m.p. 162° from 3-allyl-5-methyl-2,4-thiazolidinedione-2-(4-allyl-3-thiosemicarbazone);

2,2'-azinet av 3-metyl-2,4-tiazolidindion og av 3-(2-metyl-allyl) -5-metyl- 2, 4-tiazolidindion, s.p. 154° fra 3-(2-metyl-allyl )-5-metyl-2,4-tiazolidindion-2-(4-metyl-3-tiosemikarbazon) . The 2,2'-azine of 3-methyl-2,4-thiazolidinedione and of 3-(2-methyl-allyl)-5-methyl-2,4-thiazolidinedione, m.p. 154° from 3-(2-methyl-allyl)-5-methyl-2,4-thiazolidinedione-2-(4-methyl-3-thiosemicarbazone).

b) Det som utgangsstoff nodvendige 3-allyl-2,4-tiazolidin-dion- 2-tiosemikarbazon fremstilles som folger: 1,73 g (0,01 mol) 3-allyl-rhodanin oppvarmes med 0,91 g (0,01 mol) tiosemikarbazid og 2 g vannfritt kaliumacetat i 15 ml etanol i lopet av 24 timer under tilbakelop. Etter avkjoling b) The 3-allyl-2,4-thiazolidine-dione-2-thiosemicarbazone required as starting material is prepared as follows: 1.73 g (0.01 mol) of 3-allyl-rhodanine is heated with 0.91 g (0.01 mol) of thiosemicarbazide and 2 g of anhydrous potassium acetate in 15 ml of ethanol over the course of 24 hours under reflux. After cooling down

konsentreres reaksjonsblandingen på en rotasjonsfordamper ved 11 torr og 45°C til ca. 8 ml og helles på 30 g is. Det utfelte 3-allyl-2,4-tiazolidindion-2-tiosemikarbazon nutsjes fra, vaskes med 10 ml kald metanol og omsettes igjen uten ytterli-gere rensning. the reaction mixture is concentrated on a rotary evaporator at 11 torr and 45°C to approx. 8 ml and pour over 30 g of ice. The precipitated 3-allyl-2,4-thiazolidinedione-2-thiosemicarbazone is filtered off, washed with 10 ml of cold methanol and reacted again without further purification.

Analogt eksempel 5b oppnås folgende utgangsstoffer: 3,5-dimetyl-2,4-tiazolidindion-2-(4-allyl-3-tiosemikarbazon), s.p. 115-116°; Analogous to example 5b, the following starting materials are obtained: 3,5-dimethyl-2,4-thiazolidinedione-2-(4-allyl-3-thiosemicarbazone), m.p. 115-116°;

3-metyl-2,4-tiazolidindion-2-(4-allyl-3-tiosemikarbazon),3-methyl-2,4-thiazolidinedione-2-(4-allyl-3-thiosemicarbazone),

s.p. 166 - 167°; s.p. 166 - 167°;

3-metyl-2,4-tiazolidindion-2-[4-(2-metyl-allyl)-3-tiosemikarbazon] , s.p. 134-135°; 3-methyl-2,4-thiazolidinedione-2-[4-(2-methyl-allyl)-3-thiosemicarbazone], m.p. 134-135°;

3-allyl-5-metyl-2,4-tiazolidindion-2-[4-(2-cykloheks-2-enyl)-3-tiosemikarbazon], s.p. 107-109°;3-allyl-5-methyl-2,4-thiazolidinedione-2-[4-(2-cyclohex-2-enyl)-3-thiosemicarbazone], m.p. 107-109°;

3-allyl-2,4-tiazolidindion-2- [4- ( 2-metyl-allyl) -3-tiosemikarbazon] , s.p. 106,5 - 108°; 3-allyl-2,4-thiazolidinedione-2-[4-(2-methyl-allyl)-3-thiosemicarbazone], m.p. 106.5 - 108°;

3,5-dimetyl-2,4-tiazolidindion-2-[4-(2-metyl-allyl)-3-tiosemikarbazon] , s.p. 130-131°; 3,5-dimethyl-2,4-thiazolidinedione-2-[4-(2-methyl-allyl)-3-thiosemicarbazone] , m.p. 130-131°;

3-allyl-5-metyl-2,4-tiazolidindion-2-[4-(2-metyl-allyl)-3-tiosemikarbazon], s.p. 79-81°; 3-allyl-5-methyl-2,4-thiazolidinedione-2-[4-(2-methylallyl)-3-thiosemicarbazone], m.p. 79-81°;

3-allyl-5-metyl-2,4-tiazolidindion-2-[4-(2-metyl-allyl)- 3-tiosemikarbazon], s.p. 67-69°; 3-allyl-5-methyl-2,4-thiazolidinedione-2-[4-(2-methyl-allyl)-3-thiosemicarbazone], m.p. 67-69°;

3-allyl-5-metyl-2,4-tiazolidindion-2-(4-allyl-3-tiosemikarbazon) , s.p. 106-108°; 3-allyl-5-methyl-2,4-thiazolidinedione-2-(4-allyl-3-thiosemicarbazone), m.p. 106-108°;

3-allyl-2,4-tiazolidindion-2-tiosemikarbazon, s.p. 187°; 3-allyl-2,4-thiazolidinedione-2-thiosemicarbazone, m.p. 187°;

3-(2-metyl-allyl)-5-metyl-2,4-tiazolidindion-2-(4-metyl-3-tiosemikarbazon), s.p. 115°. 3-(2-methyl-allyl)-5-methyl-2,4-thiazolidinedione-2-(4-methyl-3-thiosemicarbazone), m.p. 115°.

EKSEMPEL 6EXAMPLE 6

a) 1,73 g (0,01 mol) 3-allyl-rhodanin oppvarmes med0,54a) 1.73 g (0.01 mol) of 3-allyl-rhodanine is heated with 0.54

g (0,011 mol) hydrazinhydrat, 2 ml iseddik og 10 ml tri-etylenglykol i lopet av 2 timer til 120°. Etter avkjolingen nutsjes det utfelte 2,2'-azin av 3-allyl-2,4-tiazolidindion fra, vaskes med 10ml kald metanol og omkrystalliseres fra kloroform-heksari, s.p. 210-211°. g (0.011 mol) of hydrazine hydrate, 2 ml of glacial acetic acid and 10 ml of triethylene glycol over the course of 2 hours at 120°. After cooling, the precipitated 2,2'-azine of 3-allyl-2,4-thiazolidinedione is filtered off, washed with 10 ml of cold methanol and recrystallized from chloroform-hexari, m.p. 210-211°.

b) På analog måte fremstilles:b) Produce in an analogous way:

2,2'-azinet av 3-(2-butenyl)- 2,4-tiazolidindion , s.p. 194°. The 2,2'-azine of 3-(2-butenyl)-2,4-thiazolidinedione, m.p. 194°.

EKSEMPEL 7EXAMPLE 7

a) 2,54 g (0,01 mol) 2,2'-azin av 2,4-tiazolidindion , spaltning ca. 300°, (fremstilt ifolge G. Frerichs og P. For-ster, Ann. 371, 257 (1909)) suspenderes i 15 ml abs. dimetylformamid. Under roring tilsettes ved 15-20°0,46 g (0,02 mol) natriumhydrid. Etter endt hydrogenutvikling tildryppes 3 g (0,022 mol) krotylbromid og reaksjonsblandingen rores a) 2.54 g (0.01 mol) 2,2'-azine of 2,4-thiazolidinedione, cleavage approx. 300°, (prepared according to G. Frerichs and P. Forster, Ann. 371, 257 (1909)) is suspended in 15 ml of abs. dimethylformamide. While stirring, 0.46 g (0.02 mol) sodium hydride is added at 15-20°. After hydrogen evolution has ended, 3 g (0.022 mol) of crotyl bromide are added dropwise and the reaction mixture is stirred

12 timer ved 20-25° og 15 minutter ved 80°. Etter avkjoling 12 hours at 20-25° and 15 minutes at 80°. After cooling down

helles reaksjonsblandingen på 50 g is, det utfelte 2,2'-azin av 3-(2-butenyl)-2,4-tiazolidindion nutsjes fra, vaskes med 10 ml kald metanol og omkrystalliseres fra kloroform-heksan, s.p. 194°. the reaction mixture is poured onto 50 g of ice, the precipitated 2,2'-azine of 3-(2-butenyl)-2,4-thiazolidinedione is filtered off, washed with 10 ml of cold methanol and recrystallized from chloroform-hexane, m.p. 194°.

På analog måte fremstilles:In an analogous way, the following is produced:

b) 2,2'-azin av 3-(3-butényl)-5-metyl-2,4-tiazolidindion , s.p. 97°5c) 2,2'-azin av 3-(2-metylallyl)-5-metyl-2,4-tiazolidindion , s.p. 148°5 d) 2,2'-azin av 3-propargyl-5-metyl-2,4-tiazolidindion , s.p. 200°; e) 2,2'-azin av 3-allyl-5-metyl-2,4-tiazolidindion og 3-allyl-2,4-tiazolidindion , s.p. 162°; f) 2,2'-azin av 3- ( 2-metylallyl)-5-metyl- 2, 4-tiazolidindion og 3-(2-metylallyl)-2,4-tiazolidindion , s.p. 143°. b) 2,2'-azine of 3-(3-butenyl)-5-methyl-2,4-thiazolidinedione, m.p. 97°5c) 2,2'-azine of 3-(2-methylallyl)-5-methyl-2,4-thiazolidinedione, m.p. 148°5 d) 2,2'-azine of 3-propargyl-5-methyl-2,4-thiazolidinedione, m.p. 200°; e) 2,2'-azine of 3-allyl-5-methyl-2,4-thiazolidinedione and 3-allyl-2,4-thiazolidinedione, m.p. 162°; f) 2,2'-azine of 3-(2-methylallyl)-5-methyl-2,4-thiazolidinedione and 3-(2-methylallyl)-2,4-thiazolidinedione, m.p. 143°.

Det som utgangsstoff nodvendige 2,2'-azin av 2,4-tiazolidin-dion og 5-metyl-2,4-tiazolidindion fremstilles analogt eksempel 5 (s.p. 30 2-304°). The 2,2'-azine required as starting material from 2,4-thiazolidinedione and 5-methyl-2,4-thiazolidinedione is prepared analogously to example 5 (m.p. 30 2-304°).

EKSEMPEL bEXAMPLE b

a) 2,84 g (0,01 mol) 2,2'-azin av 3-(2-metylallyl)-2,4-tiazolidindion og 2,4-tiazolidindion (se eksempel li) j a) 2.84 g (0.01 mol) 2,2'-azine of 3-(2-methylallyl)-2,4-thiazolidinedione and 2,4-thiazolidinedione (see example li) j

suspenderes i 15 ml abs. dimetylformamid. Ved 15-20° tilsettes under roring 0,23 g (0,01 mol) natriumhydrid. Etter endt hydrogenutvikling tildryppes 1,84 g (0,011 mol) allyljodid og reaksjonsblandingen rores 12 timer ved værelsestemperatur og 10 minutter ved 80°. Etter avkjølingen helles reaksjonsblandingen på 50 g is, det utfelte 2,2'-azin av 3-allyl-2,4-tiazolidindion og 3-(2-metylallyl)-2,4-tiazolidindion nutsjes fra, vaskes med 10 ml kald metanol og omkrystalliseres fra kloroform-heksan, s.p. 172°. suspend in 15 ml abs. dimethylformamide. At 15-20°, 0.23 g (0.01 mol) sodium hydride is added while stirring. After complete hydrogen evolution, 1.84 g (0.011 mol) allyl iodide is added dropwise and the reaction mixture is stirred for 12 hours at room temperature and 10 minutes at 80°. After cooling, the reaction mixture is poured onto 50 g of ice, the precipitated 2,2'-azine of 3-allyl-2,4-thiazolidinedione and 3-(2-methylallyl)-2,4-thiazolidinedione is filtered off, washed with 10 ml of cold methanol and recrystallized from chloroform-hexane, m.p. 172°.

På analog måte fremstilles:In an analogous way, the following is produced:

b) 2,2'-azin av 3-allyl-5-metyl-2,4-tiazolidindion og 5-metyl-3-(l-metyl-allyl)-2,4-tiazolidindion, s.p. 95°; d) 2,2'-azin av 3-(3-butenyl)-5-metyl-2,4-tiazolidindion og 3,5-dimetyl-2,4-tiazolidindion, s.p. 108°5e) 2,2'-azin av 3-propargyl-5-metyl-2,4-tiazolidindion og 3,5-dimetyl-2,4-tiazolidindion, s.p. 204°. b) 2,2'-azine of 3-allyl-5-methyl-2,4-thiazolidinedione and 5-methyl-3-(1-methyl-allyl)-2,4-thiazolidinedione, m.p. 95°; d) 2,2'-azine of 3-(3-butenyl)-5-methyl-2,4-thiazolidinedione and 3,5-dimethyl-2,4-thiazolidinedione, m.p. 108°5e) 2,2'-azine of 3-propargyl-5-methyl-2,4-thiazolidinedione and 3,5-dimethyl-2,4-thiazolidinedione, m.p. 204°.

På analog måte fremstilles:In an analogous way, the following is produced:

2,2'-azin av 3-(2-propinyl)-2,4-tiazolidindion og av 3-metyl-2,4-tiazolidindion (GP 49130), s.p. 263 - 265°, 9,5 g ( 77 % av teorien) med utgang fra 10,8 g (0,044. mol) 2,2'-azin av 2,4-tiazolidindion og av 3-metyl-2,4-tiazolidindion, 1,06 g (0,044 mol) natriumhydrid og 5,8 g (0,049 mol) 2-propinyl-bromid. 2,2'-azine of 3-(2-propynyl)-2,4-thiazolidinedione and of 3-methyl-2,4-thiazolidinedione (GP 49130), m.p. 263 - 265°, 9.5 g (77% of theory) starting from 10.8 g (0.044 mol) 2,2'-azine of 2,4-thiazolidinedione and of 3-methyl-2,4-thiazolidinedione , 1.06 g (0.044 mol) of sodium hydride and 5.8 g (0.049 mol) of 2-propynyl bromide.

Claims

Analogy method for the preparation of new pharmacologically active azines with the general formula I

"where means hydrogen, an alkyl group with up to 4 carbon atoms, an alkenyl group with 3-6 carbon atoms, a cycloalkenyl group with up to 6 carbon atoms or the propargyl residue, and R2 an alkenyl group with 3-6 carbon atoms, a cycloalkenyl group with at most 6 carbon atoms or the propargyl residue, and R^ and R^ hydrogen or lower alkyl residues with 1-3 carbon atoms, and salts of these compounds, characterized in that mana) for the preparation of compounds, where R^ has the same meaning as R^ , reacts a 2,5-thiotibiurea with the general formula II

where R 1 and R 2 have the meanings given above, or a dibasic salt of a tautomeric form of such} with the double molar amount of a halogen hydrogen acid. sulfonic acid ester with respect to the hydroxyl function of an oc-hydroxyalkanoic acid of the general formula III

where R^ has the above meaning, or an anilide acc. lower alkyl ester of the acid with respect to its carboxyl function^at a temperature of 50 - 150°C, orb) reacts a thiosemicarbazone of the general formulas IV or V,

"where R-^ , R2> R3 °<3 R4 ^are å pre-specified meanings , or a salt of a tautomeric form of the carbazone^ with at least the equimolar amount of one of the above-defined derivatives of a lower α-hydroxyalkanoic acid of the general formula III in the heat, or c) for the preparation of compounds where R 1 and R 2 acc. R^ and R^ have the same meaning, reacts a rhodanine with the general formula Yl

where R 2 and R 3 have the above meanings, with the half-molar amount of a hydrazine salt, or d) for the preparation of compounds where R^ is not hydrogen, react an azine of the general formula VII where R^ , R, and R^ have the above meanings, in the presence of an acid-binding agent with a reactive ester of a compound of the formula VIII

where R2 has the above meaning, and then with at least the double molar amount of this ester if in formula VII the symbol R^ means hydrogen, or react with at least the equimolar amount of this ester if in formula VII the symbol is not hydrogen, after which one optionally reacts an obtained compound where R-^ is hydrogen, with at least the equimolar amount of a reactive ester of a compound of formula IX

where R^ ' has the meaning specified under formula I for R-^ with the exception of hydrogen, and if desired, converts an obtained compound of the general formula I into a salt.