SE177318C1

SE177318C1 -

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Publication number: SE177318C1
Authority: SE
Publication date: 1961-01-01

Description

Prioritet begard frau den 29 november 1954 scant den 22 f ebruari och 13 ma) 19 (Storin.licamien) Foreliggande uppfinning avser ett forfarande for framstallning av nya fentiazinderivat. The present invention relates to a process for the preparation of novel phentiazine derivatives...........................

Det dr kant, att olika 10-aminoalkylfentiaziner ha intressanta terapeutiska egenskaper (t. ex. fran tyska patentskrifterna 824 944 och 844 154). Omfattande forskning har emellertid visat, att bade storleken av det terapeutiska index och typen av den terapeutiska effekt, som vissa foreningar av detta slag uppvisa kan andras radikalt (till och med elimineras) Sven genom sma fOrandringar i kemisk struktur. Detta Sr sarskilt fallet vid forandringar i egenskaperna lies och langden av den sidokedja, som är bunden till kvaveatomen i 10-stallning, och vid substitution i fentialdnkarnan. Det Sr sarskilt kant, att vissa 10-aminoalkylfentiaziner, som aro substituerade i 1- eller 3- stallning i fentiazinkarnan (Beilsteins numrering) med olika atomer eller grupper (och foretradesvis med halogenatomer eller alkyl-, alkoxi-, aryl-, aryloxi-, aralkyl- eller aralkoxigrupper) verka starkt aktiverande pa analgetika, hypnotika eller anestetika, under det att motsvarande i karnan osubstituerade foreningar endast ha denna verkan i avsevart mindre grad. Detta forhallande pekar pa den slutsatsen, att fentiazinderivatens aktiverande (potentiating) egenskaper beror p5 narvaro av sklana substituenter. It is clear that various 10-aminoalkylphentiazines have interesting therapeutic properties (eg from German Patents 824,944 and 844,154). Extensive research has shown, however, that both the size of the therapeutic index and the type of therapeutic effect that some compounds of this kind exhibit can radically change (even eliminate) others through small changes in chemical structure. This is especially the case with changes in the properties of lies and the length of the side chain bound to the nitrogen atom in the 10-position, and in the case of substitution in the fental think tank. It is particularly apparent that certain 10-aminoalkylphentiazines which are substituted in the 1- or 3-position in the phentiazine nucleus (Beilstein's numbering) with different atoms or groups (and preferably with halogen atoms or alkyl, alkoxy, aryl, aryloxy aralkyl or aralkoxy groups) have a strong activating effect on analgesics, hypnotics or anesthetics, while the corresponding compounds in the nucleus which are unsubstituted only have a considerably smaller degree. This ratio points to the conclusion that the activating properties of the phentiazine derivatives are due to the presence of clear substituents.

Det liar nu ovantat visat sig, att vissa hittills okdnda i karnan osubstituerade fentiazinderivat, innehallande en -viss form av sidokedja, tillsammans med sina syraadditions- och kvartara ammoniumsalter icke endast ha aktiverande egenskaper i mycket hog grad utan Sven i jamforelse med de hittills anfOrda kanda foreningarna uppvisa ett gynnsammare forhallande mellan terapeutiska och sekundara verkningar. Dessa nya foreningar aro Sven utmarkta som antihistaminer. It has now unexpectedly been found that certain hitherto unknown in the nucleus unsubstituted phentiazine derivatives, containing a certain form of side chain, together with their acid addition and quaternary ammonium salts not only have activating properties to a very high degree without Sven in comparison with the hitherto cited the associations show a more favorable relationship between therapeutic and secondary effects. These new associations aro Sven mark out as antihistamines.

Foreliggande uppfinning avser foljaktligen ett fbrfarande for framstallning av angivna, nya, racemiska och optiskt aktiva fentiazinderivat med den allmanna formeln /8 / 9 \ 1 \ 7I2 63 N /Ft' CH 2— TH—CH J\T "2 CH3 van i X betecknar en svavelatom eller en SO- eller SO rgrupp och R1 och R2 antingen bada beteckna lagre alkylgrupper eller en av dem betecknar en vateatom, varvid den andra betecknar en lagre alkylgrupp eller R, och R2 tillsammans med kvaveatomen, vid vilken de aro bundna, beteckna en mononukledr, heterocyklisk grupp, sasom en pyrrolidin-, pip eridin- eller morfolin-grupp. Det Sr klart, att fentiazinringen i pro dukterna enligt uppfinningen, sasom visas av formeln I, icke innehalla flagon substituent i 1- till 8-stallningarna. Beteckningen »lagre» anger, att gruppen ifraga icke innehaller men an 4 kolatomer. Accordingly, the present invention relates to a process for the preparation of novel, racemic and optically active phentiazine derivatives of the general formula / 8/9 \ 1 \ 7I2 63 N / Ft 'CH 2 - TH-CH J \ T "2 CH3 van i X represents a sulfur atom or an SO or SO 2 group and R 1 and R 2 either both represent lower alkyl groups or one of them represents a hydrogen atom, the other denotes a lower alkyl group or R, and R 2 together with the nitrogen atom to which they are attached denote a mononuclear heterocyclic group, such as a pyrrolidine, piperidine or morpholine group, It is clear that the phentiazine ring in the products of the invention, as shown by formula I, does not contain flake substituents in the 1- to 8-positions. "Bearing" indicates that the group in question does not contain but 4 carbon atoms.

Overlagsenheten has de terapeutiska egenskaperna for baserna med formeln I gentemot egenskaperna has kanda foreningar askadliggores av foljande varden. De anvanda provningarna voro folj ande: (1) Potentiering av eternarkos. The overlay unit has the therapeutic properties of the bases of formula I in relation to the properties, kanda compounds have been damaged by the following value. The tests used were as follows: (1) Potentiation of ether anesthesia.

De produkter, som skola undersiikas, tillforas moss i en dos av 20 mg/kg subkutant 30 minuter innan djuren inforas i en eterklocka, i vilken eter (5 ml) forangas. Narkosens varaktighet i minuter mates, efter det att mossen avlagsnats frau klockan (narkostid fOr kontrolldjur: 2 minuter). (2) Potentiering av analgesi med morfin (moss). Smarta astadkommes genom nypning av perineum has mOss (Hess's teknik) var 10:e minut under 3 timmar. Produkterna tillforas subkutant 2— — i en dos av 20 mg/kg 30 minuter fOre den subkutana injektionen av 5 mg/kg morfin. Procenthalten negativa utslag anger produktens verkan. (3) Antihistaminverkan (Bovet-Staub's prov). Den produkt, som skall studeras, tillfores marsvin subkutant i en dos av 20 mg/kg. 30 minuter senare injiceras histamin intravenost. Antalet letala doser (LD) histamin, som tolereras av 50 % av de behandlade djuren, bestammes. The products to be tested are fed to moss at a dose of 20 mg / kg subcutaneously 30 minutes before the animals are introduced into an ether bell, in which ether (5 ml) is evaporated. The duration of the anesthesia in minutes is fed, after the bog has been removed from the clock (anesthesia time for control animals: 2 minutes). (2) Potentiation of analgesia with morphine (moss). Smart is achieved by pinching the perineum has mOss (Hess's technique) every 10 minutes for 3 hours. The products are administered subcutaneously at a dose of 20 mg / kg 30 minutes before the subcutaneous injection of 5 mg / kg morphine. The percentage of negative effects indicates the effect of the product. (3) Antihistamine effect (Bovet-Staub's test). The product to be studied is fed to guinea pigs subcutaneously at a dose of 20 mg / kg. 30 minutes later, histamine is injected intravenously. The number of lethal doses (LD) of histamine, which are tolerated by 50% of the treated animals, is determined.

UndersOkta produkter. 3-(10-fentiaziny1)-2-mety1-1-dimetylaminopro- pan 3 - (10- fentiaziny1)-2-metyl - 1,1'- pyrrolidinyl- propan Vanstervridande 3-(10-fentiaziny1)-2-mety1 dimetylaminopropan 3-. (10 - fentiaziny1)-2-mety1-1-metylaminopropan 3-(9-oxi-10-fentiaziny1)-2-mety1-1-dimetylaminopropan F 3-(9 : 9-dioxi-10-fentiaziny1)-2-metyl - 1- dimetylaminopropan 10-(2-dimetylamino-2-metyletyl)fentiazin 10-(2-dimetylamino-2-metyletyl)fentiazin metosulfat I 2- metoxi - 10[1,-(8-hydroxiisopropyl-n-hexylamino)isobutylifentiazin Av de provade produkterna befinna sig A—F Mom den speciella undergrupp, som framstalles enligt fOreliggande uppfinning, och G, H och I aro forut kanda fOreningar. Foreningen G al. den aktivaste av de hittills kanda antihistaminerna. Examine products. 3- (10-Phentiazynyl) -2-methyl-1-dimethylaminopropane 3- (10-phentiazynyl) -2-methyl-1,1'-pyrrolidinylpropane De-starving 3- (10-phentiazynyl) -2-methyl dimethylaminopropane 3-. (10-Phentiazynyl) -2-methyl-1-methylaminopropane 3- (9-oxy-10-phentiazynyl) -2-methyl-1-dimethylaminopropane F 3- (9: 9-dioxy-10-phentiazynyl) -2-methyl - 1-dimethylaminopropane 10- (2-dimethylamino-2-methylethyl) phentiazine 10- (2-dimethylamino-2-methylethyl) phentiazine methosulfate I 2-methoxy - [1, - (8-hydroxyisopropyl-n-hexylamino) isobutylifentiazine the tested products are located in the special subgroup prepared according to the present invention, and G, H and I are known compounds. The association G al. the most active of the known antihistamines to date.

De i foregaende fors& erhallna resultaten voro fOlj ande; Enligt foreliggande uppf inning framstallas racemiska och optiskt aktiva fentiazinderivat med den allmanna formeln I och syraadditionssalter och kvartara ammoniumsalter darav enligt det f Orfarande, som innebar att en fentiazinforening med den allmanna formeln I I1 bringas att reagera med en forening Q, varvid gruppen R oak foreningen Q aro sadana, att Q kommer att reagera med fentiazinfOreningen med formeln II fOr inforande eller bildande i ringens 10-stallning av en substituentgrupp med strukturformeln: CH,—CH—CH,—N, `R,III CH3 van i X, R. och R2 ha angiven betydelse, samt att den salunda erhallna fentiazinbasen eventuellt overfores till ett syraadditionssalt eller ett kvartart ammonumsalt. The results obtained in the foregoing were as follows; According to the present invention, racemic and optically active phentiazine derivatives of the general formula I and acid addition salts and quaternary ammonium salts thereof are prepared according to the process which involved reacting a phentiazine compound of the general formula I1 with a compound Q, wherein the group R Q is such that Q will react with the phentiazine compound of formula II to introduce or form in the ring 10-position a substituent group of the structural formula: CH, -CH-CH, -N, R, III CH3 van in X, R. and R2 have the meaning indicated, and that the phentiazine base thus obtained is optionally transferred to an acid addition salt or a quaternary ammonium salt.

Specifika utforingsformer av detta fOrfarande aro fOljande: (1) Reaktion av en fentiazinfOrening med den allmanna formeln: II 601200 1000 632000 63300 500-600 1100-1200 1500 900 0mindre an Resultaten visa, att de nya foreningarna med formeln I ha en antihistaminverkan, som ãr jamforbar med verkan hos den basta av de hittills kanda antihistaminerna och att de samtidigt med avseende pa fyra av de provade produkterna ha en markbart overlagsen aktivitet med avseende pa nervsystemet, t. ex. sasom potentiatorer for analgetika och hypnotika. Denna ovantade, dubbla aktivitet harror frail narvaron av —G1-12—GH—GH2-grupperingen GH3 i proclukterna enligt uppfinningen. Specific embodiments of this process are as follows: (1) Reaction of a phenothiazine compound of the general formula: II 601200 1000 632000 63300 500-600 1100-1200 1500 900 0less the results show that the novel compounds of formula I have an antihistamine effect which is comparable to the action of the best of the antihistamines known to date and that they simultaneously with respect to four of the products tested have a markedly superior activity with respect to the nervous system, e.g. such as potentiators for analgesics and hypnotics. This above double activity is due to the presence of the -G1-12-GH-GH2 grouping GH3 in the procluents of the invention.

IV med en reaktionsbenagen ester av en aminoalkohol med formeln: /R, 'R2V GE13 van i Hal betecknar en halogenatom och de andra variablerna ha den ovan angivna betydelsen. IV with a reaction-derived ester of an amino alcohol of the formula: / R, 'R2V GE13 van in Hal denotes a halogen atom and the other variables have the meaning given above.

Denna reaktion genomfores med eller utan anvandning av lOsningsmedel och eventuellt i narvaro av ett kondensationsmedel. Det är lampligt att arbeta i ett aromatiskt kolvate som losningsmedel, t. ex. toluen eller zylen, I narvaro av ett kondensationsmedel, foretradesvis i form av en alkalimetall eller ett derivat darav, sasom en hydrid, amid, hydroxid, alkoholat eller metallalkyl eller -aryl, och sarskilt metalliskt natrium, natriumamid, pulverformig natrium- eller kaliumhydroxid, litiumhydrid, natrium-tert.butylat, butyllitium eller fenyllitium. Denna reaktor utfores foretradesvis vid losningsmedlets koktemperatur. Dot ãr lampligt att anvanda alkylaminen med forrneln V i form av den fria basen i losning, Produkt A Potentiering av eter- narkos, nar- kosens var- aktighet i minuter 28 26 34 29 3 4 Potentiering av morfinanalgesi, % analgesi i 3 timmar Anti- histamin- verkan antal LD histamin — — exempelvis i bensen, toluen eller xylen; och att sdtta denna losning till blandningen av de andra reaktionskomponenterna, i vilka fentiazinen redan kan vara narvarande atminstone delvis i form av ett alkalimetallsalt. Reaktionen kan aven genomforas med anvdndning av ett salt av alkylaminen men i detta fall maste en storre mangd kondensationsmedel anvdndas for neutralisation av syran i det anvanda saltet, (2) Kondensation av en amin HNR,R, med ett fentiazinderivat med formeln I VI CH,—CH—CH,—Y CH, van i Y betecknar resten av en reaktiv ester, sasom en halogenatom eller en svavelsyra- eller sulfonsyraestergrupp, och de andra symbolerna ha den ovan angivna betydelsen. This reaction is carried out with or without the use of solvents and optionally in the presence of a condensing agent. It is convenient to work in an aromatic carbonate as a solvent, e.g. toluene or zylene, in the presence of a condensing agent, preferably in the form of an alkali metal or a derivative thereof, such as a hydride, amide, hydroxide, alcoholate or metal alkyl or aryl, and especially metallic sodium, sodium amide, powdered sodium or potassium hydroxide, lithium hydride , sodium tert-butylate, butyllithium or phenyllithium. This reactor is preferably operated at the boiling temperature of the solvent. Dot is appropriate to use the alkylamine with formula V in the form of the free base in solution, Product A Potentiation of ether anesthesia, duration of anesthesia in minutes 28 26 34 29 3 4 Potentiation of morphine analgesia,% analgesia for 3 hours Anti histamine effect number of LD histamine - - for example in benzene, toluene or xylene; and adding this solution to the mixture of the other reactants in which the phenothiazine may already be present at least in part in the form of an alkali metal salt. The reaction can also be carried out using a salt of the alkylamine, but in this case a larger amount of condensing agent must be used to neutralize the acid in the salt used, (2) Condensation of an amine HNR, R, with a phentiazine derivative of the formula I VI CH, —CH — CH, —Y CH, van in Y denotes the residue of a reactive ester, such as a halogen atom or a sulfuric acid or sulfonic acid ester group, and the other symbols have the meaning given above.

Reaktionen kan utforas med eller utan anvandning av ett lbsningsmedel och eventuellt i ndrvaro av ett alkalimetallkondensationsmedel. Det är sdrskilt Idmpligt att anvdnda ett losningsmedel I form av en alkohol och overskott av aminen. Nar aminen Or en flyktig substans, t. ex. dimetylamin, är det ldmpligt att genomfora reaktionen i en autoklav. The reaction can be carried out with or without the use of a solvent and optionally in the presence of an alkali metal condensing agent. It is particularly convenient to use a solvent in the form of an alcohol and excess amine. When the amine Or a volatile substance, e.g. dimethylamine, it is exemplary to carry out the reaction in an autoclave.

I utforingsformerna (1) och (2) av foreliggande forfarande betecknar Q B—N: R2 och en av R och B betecknar en vateatom och den andra gruppen —CH2—CH—CH2—Y (3) Vid foreningar med formeln I, i vilka an-flagon R, och R, eller badadera beteckna ldgre alkylgrupper, alkylering enligt kanda metoder av en fentiazinforening med den allmanna for-mein: VII VII CH,—CH—CH,—NHR, CH, van i Rs betecknar en vateatom eller en lagre alkylgrupp och X har angiven betydelse. In embodiments (1) and (2) of the present process, QB represents -N: R 2 and one of R and B represents a hydrogen atom and the other group -CH 2 -CH-CH 2 -Y (3) In compounds of formula I, in which an- flagon R 1 and R 2, or both represent lower alkyl groups, alkylation according to known methods of a phentiazine compound of the general form: VII VII CH, -CH-CH, -NHR, CH, van in R 5 represents a hydrogen atom or a lower alkyl group and X is as defined.

I denna utforingsform ax foreliggande forfarande utgor R i grupperingen —CH,—CH—CH,—NHRs \ \ / CHs och foreningen Q ett alkyleringsmedel, sasom en alkylhalogenid, -sulf at eller nagon annan ester eller i handelse av ett metyleringsmedel formaldehyd och vate i narvaro av en katalysator. Dot Or 'bland lampligt att genomfOra alkyleringen i tva steg, genom acylering foljd av reduktion, och dessa tv6. steg kunna i vissa fall genomfOras samtidigt. In this embodiment of the present process, R in the grouping -CH, -CH-CH, -NHRs / CHs and the compound Q constitute an alkylating agent, such as an alkyl halide, sulphate or any other ester or in the trade of a methylating agent formaldehyde and hydrogen in the presence of a catalyst. Dot Or 'among suitable to carry out the alkylation in two steps, by acylation followed by reduction, and these tv6. steps can in some cases be carried out simultaneously.

De optiskt aktiva isomererna kunna erhallas genom upplosning av racematen eller genom syntes fran optiskt aktiva utgangsmaterial. The optically active isomers can be obtained by dissolving the racemates or by synthesis from optically active starting materials.

Baserna med formeln I ha de ovan angivna terapeutiska egenskaperna och anvandas for terapeutiska andamal faretradesvis i form av syraadditionssalter, innehallande farmaceutiskt godtagbara anjoner (sdsom hydroklorider och andra hydrohalogenider och 8-klorteafyllinat) eller i form av kvartara ammoniumsalter, erhallna genom reaktion med organiska halogenider, t. ex. metyljodid, eller andra reaktiva estrar. Sarskilt anvandbara p0 grund av sina antihistaminiska och aktiverande egenskaper Oro 3-(10-fentiaziny1)- 2-mety1-1-dimetylaminopropan (i form av racematet eller av endera aktiva isomeren, sarskilt 1-isomeren) och 3-(9,9-dioxi-10-fenLiaziny1)-2-metyl-1-dimetylaminopropan. The bases of formula I have the above therapeutic properties and are used for therapeutic purposes, preferably in the form of acid addition salts, containing pharmaceutically acceptable anions (such as hydrochlorides and other hydrohalides and 8-chlorotheaphyllinate) or in the form of quaternary ammonium salts, obtained by reaction with organic halides, e.g. methyl iodide, or other reactive esters. Particularly useful due to their antihistamine and activating properties Oro 3- (10-phentiazynyl) -2-methyl-1-dimethylaminopropane (in the form of the racemate or of either the active isomer, especially the 1-isomer) and 3- (9,9- dioxy-10-pheniazolyl) -2-methyl-1-dimethylaminopropane.

FOljande icke begransande exempel visa hur fOrfarandet enligt uppfinningen kan genomforas i praktiken. Smaltpunkterna Oro bestamda pa Koflers block. The following non-limiting examples show how the process according to the invention can be carried out in practice. The melting points of concern are determined on Kofler's block.

Exempel 1. 95-procentig natriumamid (2,27 g) sates till en losning av fentiazin (9,6 g) i xylen (140 cm,) vid en temperatur av 130° C och blandningen upphettas 2 timmar under aterflodeskylning. Example 1. 95% sodium amide (2.27 g) is added to a solution of phentiazine (9.6 g) in xylene (140 cm 3) at a temperature of 130 ° C and the mixture is heated for 2 hours under reflux.

En 0,61-n lOsning (90 cm') av 1-klor-2-mety1-3- dimetylaminopropan i xylen tillsattes sedan Mom 50 minuter och upphettas under aterflOdskylning ytterligare 20 timmar. Efter kylning behandlas blandningen med vatten (40 cm') och 1-n metansulfonsyra (70 cm'). Vattenskiktet tvattas med eter, behandlas med vattenhaltig natriumhydroxid (d = 1,33; 10 cm') och extraheras med eter. Extraktet torkas Over kaliumkarbonat och indunstas och dterstoden destilleras i vakuum. 3(10 - fentiazinyl) - 2-mety1-1-dimetylaminopropan (12,6 g) uppsamlas vid destillation mellan 150° och 175° C under ett try& av ungefdr 0,3 mm Hg. Genom upplosning av denna has i aceton och tillsats av klorvdte i eterlosning erhalles en hydroklorid med smaltpunkten 216-217° C, del, sura maleatet smaller vid 187-188° C. A 0.61 n solution (90 cm 3) of 1-chloro-2-methyl-3-dimethylaminopropane in xylene was then added to Mom for 50 minutes and heated under reflux for another 20 hours. After cooling, the mixture is treated with water (40 cm 3) and 1-n methanesulfonic acid (70 cm 3). The aqueous layer is washed with ether, treated with aqueous sodium hydroxide (d = 1.33; 10 cm -1) and extracted with ether. The extract is dried over potassium carbonate and evaporated and the residue is distilled in vacuo. 3 (10-Phentiazinyl) -2-methyl-1-dimethylaminopropane (12.6 g) is collected by distillation between 150 ° and 175 ° C under a pressure of about 0.3 mm Hg. By dissolving this hash in acetone and adding chlorine tea in ether solution, a hydrochloride having a melting point of 216-217 ° C, part, of the acid maleate smaller at 187-188 ° C is obtained.

Exempel 2. Man forfar sdsom beskrivits i exempel 1 men utgdr frd.n. fentiazin (15,7 g), teknisk natriumamid (4,5 g) och 1-klor-2-mety1-3-dimetylaminopropan (15,6 g) och erhdller ddrvid 3-(10- fentiaziny1)-2-mety1-1-dietyl-aminopropan (23 g) med kokpunkten 180-182° Ci0,5 mm Hg. Vid 4— — tillsats av torrt klorvate till en laming av den sistna.mnda basen i aceton kristalliserar en hydro- klorid, som efter omkristallisering ur en blandning .av aceton och isopropanol smatter vid 158° C. 1-klor-2-metyl- 3- dietylaminopropan erhalles som hydrokloriden genom inverkan av tionylklo- rid ph 3- dietylamino- 2 -metylpropan-1-ol (kok- punkt 81° C/12 mm Hg) i kokande bensenlosning. Den sistnamnda produkten framstalles ge- nom reduktion med litiumaluminiumhydrid av mety1-3- dietylamino-2-metylpropionat, som erMlles enligt Bieber, C. R. Acad. Sci. Paris 231, 291 (1950). Example 2. Procedure as described in Example 1 but starting from phentiazine (15.7 g), technical sodium amide (4.5 g) and 1-chloro-2-methyl-3-dimethylaminopropane (15.6 g) to give 3- (10-phentiazynyl) -2-methyl-1 -diethyl-aminopropane (23 g) with a boiling point of 180-182 ° Ci0.5 mm Hg. Upon addition of dry chlorine to a laminate of the latter base in acetone, a hydrochloride crystallizes, which after recrystallization from a mixture of acetone and isopropanol melts at 158 DEG C. 1-chloro-2-methyl- 3-Diethylaminopropane is obtained as the hydrochloride by the action of thionyl chloride ph 3-Diethylamino-2-methylpropan-1-ol (boiling point 81 ° C / 12 mm Hg) in boiling benzene solution. The latter product is prepared by reduction with lithium aluminum hydride of methyl 3-diethylamino-2-methylpropionate, which is prepared according to Bieber, C. R. Acad. Sci. Paris 231, 291 (1950).

Exempel 3. Om man forfar sasom beskrivits i exempel 2 men utgar frau fentiazin (15,7 g), teknisk natriumamid (4,g) och 1-klor-2-mety1- 3-piperidinpropan (16,7 g) erhaller man 3-(10- fentiaziny1)-2-mety1-1-piperidinopropan (22 g) med kokpunkten omkring 215° C/1 mm Hg. Example 3. If the procedure is as described in Example 2 but starting from frafentiazine (15.7 g), technical sodium amide (4 g) and 1-chloro-2-methyl-3-piperidinepropane (16.7 g), 3 - (10-Phentiazynyl) -2-methyl-1-piperidinopropane (22 g) with a boiling point of about 215 ° C / 1 mm Hg.

Vid tillsats av klorvate till en losning av den sistnamnda basen i aceton kristalliserar en hydro- klorid, som efter omkristallisering ur en blandning av aceton och isopropanol smaller vid 186° C. 1-klor-2-mety1-3-piperidinpropan erhalles i form av hydrokloriden genom inverkan av tionylklorid i kokande bensen pa 3-piperidin-2-metyl-propan- 1-01 (kokpunkt 104° C/12 mm Hg), som framstalles genom reduktion av 3-piperidin-2-metyl- propionat (kokpunkt 97-98° C/13 mm Hg) med litiumaluminiumhydrid. Detta propionat kan erhallas genom kondensation av piperidin med metylmetakrylat. Upon addition of hydrogen chloride to a solution of the latter base in acetone, a hydrochloride crystallizes, which after recrystallization from a mixture of acetone and isopropanol smaller at 186 ° C. 1-chloro-2-methyl-3-piperidinepropane is obtained in the form of the hydrochloride by the action of thionyl chloride in boiling benzene on 3-piperidine-2-methyl-propane-1-01 (b.p. 104 ° C / 12 mm Hg), which is produced by reduction of 3-piperidine-2-methyl-propionate (b.p. 97 -98 ° C / 13 mm Hg) with lithium aluminum hydride. This propionate can be obtained by condensation of piperidine with methyl methacrylate.

Exempel 4. Man forfar sasom beskrivits i exempel 2 men utgar frau fentiazin (11,5 g), teknisk natriumamid (3,3 g) och 1-klor-2-mety1-3,1'-pyrrolidinyl-propan ()eh erhaller salunda 3-(10-fentiaziny1)-2-metyl-1,1'-pyrrolidinyl-propan (18 g). Vid tillsats av oxalsyra till en lOsning av den sistnamnda basen i isopropanol kristalliserar ett syraoxalat, som efter omkristallisering ur 50-procentig etanol smatter -vid 188° C. 1-klor-2-mety1-3,1`-pyrrolidinylpropan erhalles i form av hydrokloriden genom inverkan av tionyl- klorid i kokande bensenlosning ph 3,1'-pyrrolidiny1-2-metylpropan-1-ol med kok-punkten 91° C/15 mm Hg. Den sistnamnda produkten erhalles genom reduktion med litiumaluminiumhydrid av mety1-3,1'-pyrrolidiny1-2-metylpropionat (kokpunkt 92-93° C/15 mm Hg), vilket erhalles genom kondensation av pyrrolidin med metylmetakrylat. Example 4. The procedure is as described in Example 2 but yields frauentiazine (11.5 g), technical sodium amide (3.3 g) and 1-chloro-2-methyl-1,3,1'-pyrrolidinyl-propane () and salunda 3- (10-phentiazynyl) -2-methyl-1,1'-pyrrolidinyl-propane (18 g). When oxalic acid is added to a solution of the latter base in isopropanol, an acid oxalate crystallizes, which after recrystallization from 50% ethanol melts at 188 DEG C. 1-chloro-2-methyl-1,3,1-pyrrolidinylpropane is obtained in the form of the hydrochloride by the action of thionyl chloride in boiling benzene solution ph 3,1'-pyrrolidinyl-2-methylpropan-1-ol with a boiling point of 91 ° C / 15 mm Hg. The latter product is obtained by reduction with lithium aluminum hydride of methyl -3,1'-pyrrolidinyl-2-methylpropionate (b.p. 92-93 ° C / 15 mm Hg), which is obtained by condensation of pyrrolidine with methyl methacrylate.

Exempel 5. Racemisk 3-(10-fentiaziny1)-2-metyl-l-aminopropan (5 g) med smaltpunkten 100104° C omriires med attiksyra (150 cm3) under vatgasatmosfar i narvaro av en 30-pro centig vattentosning (10 g) av formaldehyd och 5-procentig palladium-pa-kol (1 g). Den teoretiska volymen vate absorberas Mom 2 timmar. Katalysatorn franfiltreras, filtratet indunstas till torrhet under forminskat tryck och den oljiga aterstoden behandlas med vattenhaltig natriumhydroxid och eter. Vattenskiktet franskiljes och eterlosningen indunstas, varvid man erhaller 3410- fentiaziny1)-2-metyl- 1- dimetylaminopropan (5,4 g), som redan beskrivits i exempel 1. Den ur aceton erhallna hydrokloriden smatter vid 216218° C och den bas, som erhalles av denna hydro- klorid smatter vid 68° C. Example 5. Racemic 3- (10-phentiazynyl) -2-methyl-1-aminopropane (5 g) with a melting point of 100104 ° C is mixed with acetic acid (150 cm 3) under a hydrogen atmosphere in the presence of a 30% aqueous solution (10 g). of formaldehyde and 5% palladium-pa-carbon (1 g). The theoretical volume of vate is absorbed Mom 2 hours. The catalyst is filtered off, the filtrate is evaporated to dryness under reduced pressure and the oily residue is treated with aqueous sodium hydroxide and ether. The aqueous layer is separated and the ether solution is evaporated to give 3410-phentiazynyl) -2-methyl-1-dimethylaminopropane (5.4 g), as already described in Example 1. The hydrochloride obtained from acetone is slurried at 216218 ° C and the base obtained from this hydrochloride slab at 68 ° C.

Den ursprungliga primara aminen relines genom hydrogenering under tryck av 3-(10-fentiaziny1)-2-metylpropionitril (smaltpunkt 104° C) med Raney-nickel i narvaro av ammoniak. Nitrilen framstalles genom inverkan av kaliumcyanid I kokande vattenhaltig etanol pa 10'-fentiazin.ylisopropyl-toluen-p-sulfonat (smaltpunkt 150151° C). Den sistnaranda produkten erhalles genom inverkan av toluen-p-sulfonylklorid ph 1- (10-fentiaziny1)-propan-2-ol i pyridin. The original primary amine is relined by hydrogenation under pressure of 3- (10-phentiazynyl) -2-methylpropionitrile (m.p. 104 ° C) with Raney nickel in the presence of ammonia. The nitrile is prepared by the action of potassium cyanide in boiling aqueous ethanol on 10'-phentiazine.ylisopropyl-toluene-p-sulfonate (m.p. 150151 ° C). The latter product is obtained by the action of toluene-p-sulfonyl chloride ph 1- (10-phentiazynyl) -propan-2-ol in pyridine.

Exempel 6. 3-(10-fentiaziny1)-2-metylpropyltoluen-p-sulfonat (3 g) (smaltpunkt 134-135° C) upphettas i ett slutet ror vid 100° C 4 timmar med dimetylamin (1,5 g), lost i propanol (30 cm3). Ay den aterstod, som erhalles genom avdunstning av losningsmedlet, framstalles 3-(10-fentiaziny1)-2- mety1-1- dimetylaminopropan - syramaleat med smaltpunkten 187° C. Den fria bas, som erhalles av detta salt, liar redan beskrivits i exempel 1 och smatter vid 68° C. Example 6. 3- (10-Phentiazynyl) -2-methylpropyltoluene p-sulfonate (3 g) (m.p. 134-135 ° C) is heated in a closed tube at 100 ° C for 4 hours with dimethylamine (1.5 g). lost in propanol (30 cm3). In the residue obtained by evaporation of the solvent, 3- (10-phentiazynyl) -2-methyl-1-dimethylaminopropane - acid maleate having a melting point of 187 DEG C. is prepared. The free base obtained from this salt is already described in Example 1 and slaps at 68 ° C.

Det ursprungliga toluen-p-sulfonatet erhalles genom inverkan av toluen-p-sulfonylklorid ph 3- (10-fentiaziny1)-2-metylpropan-l-ol (smaltpunkt 115° C) i pyridin. Denna alkohol erhalles genom reduktion av mety1-3-(10-fentiaziny1)-2-metylpropionat med litiumaluminiumhydrid. Estem reduceras i form av en rh olja, sa som den erhalles genom inverkan av diazometan pa syran (smallpunkt 148° C), vilken erhalles genom hydrolys av 3-(10-fentiaziny1)-2-metylpropionitril, som beskrivits i exempel 5, med natriumhydroxid i en kokande blandning av metanol och vatten. The original toluene-p-sulfonate is obtained by the action of toluene-p-sulfonyl chloride ph 3- (10-phentiazynyl) -2-methylpropan-1-ol (m.p. 115 ° C) in pyridine. This alcohol is obtained by reduction of methyl 3- (10-phentiazynyl) -2-methylpropionate with lithium aluminum hydride. The ester is reduced in the form of a crude oil, as obtained by the action of diazomethane on the acid (m.p. 148 ° C), which is obtained by hydrolysis of 3- (10-phentiazynyl) -2-methylpropionitrile, as described in Example 5, with sodium hydroxide in a boiling mixture of methanol and water.

Exempel 7. 3-(10-fentiaziny1)-2-mety1-1-aminopropan (5 g) (smaltpunkt 100° C; [a] = — 6,3° (e = 3,7, attiksyra) omrores i attiksyra (150 cm3) I vatgasatmosfar vid vanlig temp eratur och i narvaro av en 30-procentig vattenitisning (10 g) av formaldehyd och Adams platinakatalysator (0,25 g). Den teoretiska volymen vate adsorberas Mom 2 timmar. Katalysatom franfiltreras, filtratet indunstas till torrhet under reducerat tryck och den oljiga aterstoden behandlas med natriumhydroxid i vattenlasning och eter. Vattenskiktet franskiljes och eterldsningen indunstas, varvid en oljig aterstod (4,5 g erhalles, semi etylacetat Overfores till ett syramaleat med smaltpunkten 175° C och [a]7= + 10,7' (c = 4,41 metanol)). Den 3- (10- fentiazinyl) - 2 -metyl-1- dimetyl-aminopropan, som frigOres frau detta maleat, Or oljig och har en optisk aktivitet av [a]L7 = 5,5° (c = 3,0 i etanol). Example 7. 3- (10-Phentiazynyl) -2-methyl-1-aminopropane (5 g) (m.p. 100 ° C; [α] = - 6.3 ° (e = 3.7, acetic acid) is stirred in acetic acid ( 150 cm3) In a hydrogen atmosphere at normal temperature and in the presence of a 30% water icing (10 g) of formaldehyde and Adam's platinum catalyst (0.25 g) The theoretical volume of vate is adsorbed for 2 hours The catalyst is filtered off, the filtrate is evaporated to dryness under reduced pressure and the oily residue is treated with sodium hydroxide in aqueous solution and ether, the aqueous layer is separated and the ether solution is evaporated to give an oily residue (4.5 g, semi-ethyl acetate is transferred to an acid maleate with a melting point of 175 ° C and [a] 7 = + 10.7 '(c = 4.41 methanol)) The 3- (10-phentiazinyl) -2-methyl-1-dimethylaminopropane, which is liberated from this maleate, is oily and has an optical activity of [a] L7 = 5.5 ° (c = 3.0 in ethanol).

Den ursprungliga primara aminen erhalles genom hydrogenering av 3-(10-fentiaziny1)-2-metyl- propionitril (smaltpunkt 119-120° C,= = — 11,2° (c = 4,5, tetrahydrofuran) i tetrahydrofuran med litiumhydrid. Nitrilen framstalles genom inverkan av kaliumcyanid 1 vattenhaltig etanol pa optiskt aktiv 1-(10-fentiaziny1)- — prop-2-yl-toluen-p-sulfonat, erhallen av 1-brompropan-2-ol (Levene och Wahl., J. Biol. Chem. 68, 415 (1928)), vilken framstdlles av propan-1,2- diol genom jasning (Levene och Walt, Org. Synth. 10, 84 (1930)). The original primary amine is obtained by hydrogenation of 3- (10-phentiazynyl) -2-methylpropionitrile (m.p. 119-120 ° C, = = - 11.2 ° (c = 4.5, tetrahydrofuran) in tetrahydrofuran with lithium hydride. The nitrile is prepared by the action of potassium cyanide 1 aqueous ethanol on optically active 1- (10-phentiazynyl) -prop-2-yl-toluene-p-sulfonate, obtained from 1-bromopropan-2-ol (Levene and Wahl., J. Biol. Chem. 68, 415 (1928)), which is produced from propane-1,2-diol by fermentation (Levene and Walt, Org. Synth. 10, 84 (1930)).

Exempel 8. Man forfar sasom beskrivits i exempel 7 men utgar &An 3-(10-fentiaziny1)-2- mety1-1-aminopropan (6 g) (smaltpunkt 100° C), vilken dr hogervridande i attiksyra, och erhalles salunda oljig 3-(10-fentiaziny1)-2-mety1-1-dimetylamino-propan (2,3 g), som dr vanstervridande i etanol och vars syramaleat (2,1 g) smdlter vid 174-17° C och liar optiska aktiviteten [a]b7 = = — 12,5° (c = 4,0, metanol). Example 8. The procedure is as described in Example 7, but yielding 3- (10-phentiazynyl) -2-methyl-1-aminopropane (6 g) (m.p. 100 ° C), which rotates higher in attic acid, and thus obtained oily. - (10-Phentiazynyl) -2-methyl-1-dimethylamino-propane (2.3 g), which is de-steroidal in ethanol and whose acid maleate (2.1 g) melts at 174-17 ° C and has the optical activity [a ] b7 = = - 12.5 ° (c = 4.0, methanol).

De erforderliga utgangsmaterialen erhallas, sâsom beskrivits forut, om man utgar frail hogervridande propan-1,2-diol som erhalles genom nedbrytning av mannitol enligt Baer & Fischer, J. Amer. Chem. Soc. 70, 609 (1948). The required starting materials are obtained, as described above, starting from the free-propellant 1,2-diol obtained by the decomposition of mannitol according to Baer & Fischer, J. Amer. Chem. Soc. 70, 609 (1948).

Exempel 9. 3-(10-fentiaziny1)-2-metylpropyl- toluen-p-sulfonat (7 monometylamin (2 g) och propanol (35 ems) upphettas 6 timmar i eft slutet ror vid 120° C. Efter avdunstning av propanolen under fOrminskat tryck behandlas aterstoden med utspddd saltsyra och syralosningarna tvattas med eter och instdllas sedan pa alkalisk reaktion med ett overskott av natriumhydroxid i vattenlosning (d = 1,33). Den produkt, som franskiljes, extraheras med eter och vid avdunstning av etern erhalles 3-(10-fentiaziny1)-2-mety1-1-metylaminopropan (4 g) i form av en rá, oljig bas. Den motsvarande hydrokloriden smdlter vid 195-196° C efter omkristallisering ur en blandning av aceton (8 volymdelar) och isopropanol (2 volymdelar). 3-(10-fentiaziny1)-2-metylpropyl-toluen-p-sulfo- nat med smdltpunkten 134-135° C erhalles genom inverkan av toluen-p-sulfonylklorid pa 3- (10-fentiaziny1)-2-metylpropan-1-ol (smaltpunkt 115° C) i pyridin. Denna alkohol erhalles genom reduktion av metylestern av 3-(10-fentiaziny1)-2- metylpropionsyra med litiumaluminiumhydrid. Syran (smdltpunkt 148° C) kan erhallas genom alkalisk hydrolys av motsvarande nitril, som beskrivits i exempel 5. Example 9. 3- (10-Phentiazynyl) -2-methylpropyl-toluene-p-sulfonate (7 monomethylamine (2 g) and propanol (35 cm 3) are heated for 6 hours after the end of stirring at 120 ° C. After evaporation of the propanol under Reduced pressure, the residue is treated with dilute hydrochloric acid and the acid solutions are washed with ether and then reacted in an alkaline reaction with an excess of sodium hydroxide in aqueous solution (d = 1.33). The product which is separated is extracted with ether and on evaporation of the ether (10-Phentiazynyl) -2-methyl-1-methylaminopropane (4 g) in the form of a crude oily base The corresponding hydrochloride melts at 195-196 ° C after recrystallization from a mixture of acetone (8 parts by volume) and isopropanol ( 3- (10-Phentiazynyl) -2-methylpropyl-toluene-p-sulfonate, m.p. 134-135 ° C is obtained by the action of toluene-p-sulfonyl chloride on 3- (10-phentiazynyl) -2- methylpropan-1-ol (m.p. 115 ° C) in pyridine, this alcohol is obtained by reduction of the methyl ester of 3- (10-phentiazynyl) -2- tylpropionic acid with lithium aluminum hydride. The acid (m.p. 148 ° C) can be obtained by alkaline hydrolysis of the corresponding nitrile, as described in Example 5.

Exempel 10. Man fOrfar sasom beskrivits i exempel 9 men utgar frail 3-(10-fentiaziny1)-2- metylpropyl-toluen-p-sulfonat (5 g) och monoetylamin (6 g) och erhdller salunda 3-(10-fentiaziny1)-2-mety1-1-etylaminopropan (3 g) i form av en rd, oljig bas. Den motsvarande hydrokloriden smdlter vid 200-201° C efter omkristallisering ur isopropanol. Example 10. The procedure is as described in Example 9 but starting from 3- (10-phentiazynyl) -2-methylpropyl-toluene-p-sulfonate (5 g) and monoethylamine (6 g) to give salunda 3- (10-phentiazinyl) -2-methyl-1-ethylaminopropane (3 g) as a red, oily base. The corresponding hydrochloride melts at 200-201 ° C after recrystallization from isopropanol.

Enligt det i foregdende exempel beskrivna for- farandet kan man Sven framstdlla fbljande produkter: 3-(9-oxi-10-fentiaziny1)-2-mety1-1-dimetylaminopropan, smdltpunkt 98° C, vars sura maleat smatter vid 160° C, och 3-(9: 9-dioxi-10- fentiazinyl) - 2 - metyl - 1 - dimetylaminopropan, smdltpunkt 1° C, vars hydroklorid smalter vid 250° C. According to the procedure described in the foregoing example, the following products can be prepared: 3- (9-oxy-10-phentiazynyl) -2-methyl-1-dimethylaminopropane, m.p. 98 ° C, the acidic maleate of which is 160 ° C. and 3- (9: 9-dioxi-10-phentiazinyl) -2-methyl-1-dimethylaminopropane, m.p. 1 ° C, whose hydrochloride melts at 250 ° C.

Exempel 11. 3-(10-fentiaziny1)-2-mety1-1-dimetylaminopropan (5,96 g) och etyljodid (2,5 cm3) liisas i aceton (5 cm3). Blandningen ldmnas att sta 24 timmar vid rumstemperatur och efter ympning kristalliserar massan. Produkten fran= filtreras, tvattas med aceton och eter och torkas i vakuum Over svavelsyra. [3-(10-fentiaziny1)-2- metylpropyl]-dimetyletylammonium-jodid (7,9 g) erhalles salunda och har smdltpunkten 180-190° C (icke skarp). Example 11. 3- (10-Phentiazynyl) -2-methyl-1-dimethylaminopropane (5.96 g) and ethyl iodide (2.5 cm 3) are dissolved in acetone (5 cm 3). The mixture is allowed to stand for 24 hours at room temperature and after inoculation the mass crystallizes. The product is filtered off, washed with acetone and ether and dried in vacuo over sulfuric acid. [3- (10-Phentiazynyl) -2-methylpropyl] -dimethylethylammonium iodide (7.9 g) is thus obtained and has a melting point of 180-190 ° C (not sharp).

Claims

P at ent ans p rã k:

A process for the preparation of phentiazine derivatives having therapeutic properties, characterized in that a phentiazine compound of the general formula is reacted with a compound Q, wherein the group R and the compound Q are such that Q will react with the compound of the indicated formula during introduction or formation at the 10-position of the ring of a substituent grouping having the structure: CH, van in X represents a sulfur atom or an SO or SOr group and R, and R, both represent lower alkyl groups or one of them represents a hydrogen atom, the other represents an Idgre alkyl group, or R, and R, together with the nitrogen atom to which they are attached, represent a mononuclear heterocyclic group, to form a phentiazine derivative of the formula: 11 / R, CH a-CH-CH, -Nc R , CH, van in X, R, and R, have the meaning indicated, and that a phentiazine base thus obtained may be transferred to an acid addition salt or a quaternary ammonium salt.

2. A process according to claim 1, characterized in that a phentiazine compound of the general formula: X 6 - is reacted with an alkylamine having the characterization of a phentiazine having the general formula: / R 1 Hal-CH 2 - CH — CH. — N, "CH, or an acid addition salt thereof, wherein Hal denotes halogen and other designations have the meaning given above.

3. A process according to claim 1, characterized in that an amine HNR, R, is condensed with a phentiazine derivative of the formula \ 2 \ / \ / CH2-CH-CH2-Y CH, van in Y represents the acid ester of a reactive ester, and other designations have the meaning given above.

A process according to claim 1, can \ / \ N '/ \ CH, -CH-CH, -NHR, CH, van in 11.3 represents a hydrogen atom or a lower alkyl group and X has the meaning given, alkylated on per se edge satt, e.g. methylated with formaldehyde and vate in the presence of a catalyst, to compounds in which either or had the designations B1 and 1:12 form lower alkyl groups.

5. A process according to any one of claims 1-4, characterized in that X represents a sulfur atom or an SO 2 group and R 1 and R 2 represent methyl groups. Request publications: Patents frthz Germany 824 944, 844 154; U. S. A. 2 512 520.