DE1059462B - Process for the preparation of therapeutically active phenazine derivatives - Google Patents
Process for the preparation of therapeutically active phenazine derivativesInfo
- Publication number
- DE1059462B DE1059462B DEG22000A DEG0022000A DE1059462B DE 1059462 B DE1059462 B DE 1059462B DE G22000 A DEG22000 A DE G22000A DE G0022000 A DEG0022000 A DE G0022000A DE 1059462 B DE1059462 B DE 1059462B
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- general formula
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- hydrochloride
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- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 5
- 125000001791 phenazinyl group Chemical class C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 title claims 2
- -1 cycloalkyl radical Chemical group 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 150000002988 phenazines Chemical class 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- IUWMSZMVYMFVQK-UHFFFAOYSA-N 3-imino-n,5-diphenylphenazin-2-amine;hydrochloride Chemical compound Cl.C12=CC=CC=C2N=C2C=C(NC=3C=CC=CC=3)C(=N)C=C2N1C1=CC=CC=C1 IUWMSZMVYMFVQK-UHFFFAOYSA-N 0.000 description 4
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecylamine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 description 4
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001549 tubercolostatic effect Effects 0.000 description 2
- ZIZMDHZLHJBNSQ-UHFFFAOYSA-N 1,2-dihydrophenazine Chemical compound C1=CC=C2N=C(C=CCC3)C3=NC2=C1 ZIZMDHZLHJBNSQ-UHFFFAOYSA-N 0.000 description 1
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- IZBZQUREHISXFJ-UHFFFAOYSA-N 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]acetic acid Chemical compound CC1=C(Cl)C(C(F)(F)F)=NN1CC(O)=O IZBZQUREHISXFJ-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical group N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- IUQKSGPZLPDKFK-UHFFFAOYSA-N 3-dodecylimino-n,5-diphenylphenazin-2-amine Chemical compound C12=CC=CC=C2N=C2C=C(NC=3C=CC=CC=3)C(=NCCCCCCCCCCCC)C=C2N1C1=CC=CC=C1 IUQKSGPZLPDKFK-UHFFFAOYSA-N 0.000 description 1
- FUUNETATXBTDDS-UHFFFAOYSA-N 3-imino-n,5-diphenylphenazin-2-amine Chemical compound C12=CC=CC=C2N=C2C=C(NC=3C=CC=CC=3)C(=N)C=C2N1C1=CC=CC=C1 FUUNETATXBTDDS-UHFFFAOYSA-N 0.000 description 1
- HAAZMOAXEMIBAJ-UHFFFAOYSA-N 4-chloro-2-methylquinazoline Chemical compound C1=CC=CC2=NC(C)=NC(Cl)=C21 HAAZMOAXEMIBAJ-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- XTGVRWXXDDXLML-UHFFFAOYSA-N N,5-bis(4-chlorophenyl)-3-iminophenazin-2-amine hydrochloride Chemical compound Cl.ClC1=CC=C(NC2=CC3=NC4=CC=CC=C4N(C3=CC2=N)C2=CC=C(C=C2)Cl)C=C1 XTGVRWXXDDXLML-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical group O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000004467 aryl imino group Chemical group 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- VXVVUHQULXCUPF-UHFFFAOYSA-N cycloheptanamine Chemical compound NC1CCCCCC1 VXVVUHQULXCUPF-UHFFFAOYSA-N 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- SJEQTHLHNYYKDS-UHFFFAOYSA-N n,5-diphenyl-3-propan-2-yliminophenazin-2-amine Chemical compound C12=CC=CC=C2N=C2C=C(NC=3C=CC=CC=3)C(=NC(C)C)C=C2N1C1=CC=CC=C1 SJEQTHLHNYYKDS-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/46—Phenazines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
Verfahren zur Herstellung von therapeutisch wirksamen Phenazinderivaten Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung neuer Phenazinderivate, nach welchem man zu Verbindungen mit wertvollen chemotherapeutischen Eigenschaften gelangt.Process for the preparation of therapeutically active phenazine derivatives The present invention relates to a process for the preparation of new phenazine derivatives, after which one leads to compounds with valuable chemotherapeutic properties got.
Es ist bekannt, daß das durch Oxydation von N-Phenylo-phenylendiamin-hydrochlorid mit Ferrichlorid erhältliche 2-Anilino-3-imino-5-phenyl-3,5-dihydro-phenazin (Anilinoaposaphranin) tuberkulostatische Wirksamkeit besitzt (vgl. Nature, Bd. 162, S. 622, 623 [1948]).It is known that this is caused by the oxidation of N-phenylo-phenylenediamine hydrochloride 2-anilino-3-imino-5-phenyl-3,5-dihydrophenazine (anilinoaposaphranine) obtainable with ferric chloride Has tuberculostatic activity (cf. Nature, Vol. 162, pp. 622, 623 [1948]).
Überraschenderweise wurde nun gefunden, daß 2-Amino-3-imino-5-aryl-3,5-dihydro-phenazine, die sowohl in der Aminogruppe als auch in der Iminogruppe substituiert sind und die der allgemeinen Formel entsprechen, in der jedes Ar einen gegebenenfalls durch Chlor oder niedermolekulare Alkyl- oder Alkoxygruppen substituierten Phenylrest und R einen Alkyl- oder Cycloalkylrest oder den Diäthylaminoäthylrest bedeutet, eine wesentlich stärkere tuberkulostatische Wirkung als die bisher beschriebenen Phenazinderivate ausüben. Von bekannten Tuberkulostaticis unterscheiden sie sich im Tierversuch überdies dadurch, daß sie z. B. mit Tuberkelbazillen infizierte Mäuse weit über die Behandlungsdauer hinaus am Leben zu erhalten vermögen. Zur Behandlung tuberkulöser Krankheiten des Menschen werden sie peroral angewendet. Sie eignen sich auch vorzüglich zur gemeinsamen Verabreichung mit anderen peroral wirksamen Tuberkulostaticis wie Isonicotinsäurehydrazid, insbesondere zur Vermeidung der Entwicklung resistenter Tuberkelstämme.Surprisingly, it has now been found that 2-amino-3-imino-5-aryl-3,5-dihydro-phenazines which are substituted in both the amino group and in the imino group and those of the general formula in which each Ar is a phenyl radical optionally substituted by chlorine or low molecular weight alkyl or alkoxy groups and R is an alkyl or cycloalkyl radical or the diethylaminoethyl radical, exert a much stronger tuberculostatic effect than the phenazine derivatives described so far. From known tuberculostaticis they also differ in animal experiments in that they z. B. are able to keep mice infected with tubercle bacilli alive well beyond the duration of the treatment. They are used orally for the treatment of tubercular diseases in humans. They are also particularly suitable for joint administration with other perorally active tuberculostatic agents such as isonicotinic acid hydrazide, in particular to avoid the development of resistant tubercle strains.
Die oben definierten Verbindungen lassen sich in einfacher Weise dadurch herstellen, daß man ein Salz einer Verbindung der allgemeinen Formel mit einem Amin der allgemeinen Formel N H2 R III in der Ar und R die angegebene Bedeutung haben, erhitzt. Ausgangsstoffe der allgemeinen Formel II mit substituierten Arylresten Ar sind analog dem bekannten Anilinoaposafranin durch Oxydation von N-Aryl-o-phenylendiaminen, in denen der keine primäre Aminogruppe tragende Phenylrest wie angegeben substituiert ist, mit Ferrichlorid erhältlich.The compounds defined above can be prepared in a simple manner by adding a salt of a compound of the general formula with an amine of the general formula N H2 R III in which Ar and R have the meaning given, heated. Starting materials of the general formula II with substituted aryl radicals Ar can be obtained analogously to the known anilinoaposafranine by oxidation of N-aryl-o-phenylenediamines, in which the phenyl radical bearing no primary amino group is substituted as indicated, with ferric chloride.
Die 2-Arylamino-3-imino-5-aryl-3,5-dihydrophenazine der Formel II sind isomer mit 2-Amino-3-arylimino-5-aryl-3,5-dihydrophenazinen der allgemeinen Formel Bei der Oxydation von N-Aryl-o-phenylendiaminen nit Benzochinon an Stelle von Ferrichlorid entsteht ein semisch von Verbindungen der Formeln II und IV, in welchem die 2Amino-3-arylimino-5-aryl-3,5-dihydrophenazine der Formel IV überwiegen. Die Ausgangsstoffe der Formel II lassen sich aus diesem Gemisch chromato-;raphisch abtrennen. Es ist möglich, die Aminogruppe der Aryliminoverbindungen der Formel IV mit einem Amin der allgemeinen Formel III zu Phenazinderivaten der Formel zu alkylieren, jedoch wird auf ein Verfahren zur Herstellung der gemäß Formel V definierten Phenazine Schutzbegehren gerichtet.The 2-arylamino-3-imino-5-aryl-3,5-dihydrophenazines of the formula II are isomeric with 2-amino-3-arylimino-5-aryl-3,5-dihydrophenazines of the general formula The oxidation of N-aryl-o-phenylenediamines with benzoquinone instead of ferric chloride results in a semicircle of compounds of the formulas II and IV in which the 2-amino-3-arylimino-5-aryl-3,5-dihydrophenazines of the formula IV predominate . The starting materials of the formula II can be separated chromatographically from this mixture. It is possible to convert the amino group of the arylimino compounds of the formula IV with an amine of the general formula III to give phenazine derivatives of the formula to alkylate, but is directed to a process for the preparation of the phenazines defined according to formula V for protection.
In Form ihrer Salze, insbesondere Hydrochloride, können die Verbindungen der allgemeinen Formel II beispielsweise mit primären aliphatischen, cycloaliphatischen oder aromatischen Aminen umgesetzt werden.In the form of their salts, in particular hydrochlorides, the compounds of the general formula II, for example, with primary aliphatic, cycloaliphatic or aromatic amines are reacted.
In den nachfolgenden Beispielen bedeuten Teile Gewichtsteile, sofern nichts anderes bemerkt ist. Gewichtsteile verhalten sich zu Volumteilen wie g zu cm3. Beispiel 1 2 Teile 2-Anilino-3-imino-5-phenyl-3,5-dihydro-phenazin-hydrochlorid werden mit 45 Volumteilen Isopropylamin in einem Autoklav auf 80° C erhitzt, wobei ein Druck von 4 bis 5 at erreicht wird. Dann läßt man innerhalb 3 Stunden auf Zimmertemperatur abkühlen, filtriert den festen Niederschlag ab, -löst ihn in Benzol und chromatographiert ihn an einer Aluminiumoxydsäule. Aus der Hauptfraktion des Eluats kristallisiert nach Einengen und Steherlassen das 2 Anilino-3-isopropylimino-5-phenyl-3,5-dihydro-phenazin in Form goldgelber Nadeln vom F. 195 bis 197° C.In the following examples, parts mean parts by weight, provided nothing else is noticed. Parts by weight are related to parts by volume like g cm3. Example 1 2 parts of 2-anilino-3-imino-5-phenyl-3,5-dihydro-phenazine hydrochloride are heated with 45 parts by volume of isopropylamine in an autoclave to 80 ° C, wherein a pressure of 4 to 5 at is achieved. Then it is left at room temperature within 3 hours cool, filter off the solid precipitate, dissolve it in benzene and chromatograph him on an aluminum oxide column. Crystallized from the main fraction of the eluate after concentrating and leaving the 2-anilino-3-isopropylimino-5-phenyl-3,5-dihydrophenazine in the form of golden yellow needles from 195 to 197 ° C.
Beispiel 2 2 Teile 2-Anilino-3-imino-5-phenyl-3,5-dihydro-phenazin-liydrochlorid werden mit 30 Volumteilen Cyclohexylamin 1, Stunde unter Rückfluß gekocht. Das beim Erkalten sich abscheidende Cyclohexylamin-hydrochlorid wird abfiltriert und das Filtrat mit Petroläther vom Siedebereich 40 bis 60° C versetzt, worauf sich eine feste orangegelbe Substanz abscheidet. Bei der Umkristallisation derselben aus Benzol erhält man hellrote Nadeln, die beim Trocknen braungelb werden. Durch weitere Umkristallisation aus Alkohol erhält man das 2-Anilino-3 - cycloliexyliniino - 5 - phenyl - 3, 5 - dihydro - phenazin in Form langer, feiner orangefarbener Nadeln, die nach dem Trocknen bei 105° C und 15 mm Druck bei 162 bis 165° C schmelzen.Example 2 2 parts of 2-anilino-3-imino-5-phenyl-3,5-dihydro-phenazine hydrochloride are refluxed with 30 parts by volume of cyclohexylamine for 1 hour. That at If the cyclohexylamine hydrochloride which separates out cools, it is filtered off and that Filtrate mixed with petroleum ether boiling range 40 to 60 ° C, whereupon a solid orange-yellow substance separates. When recrystallizing the same from benzene light red needles are obtained that turn brownish-yellow on drying. By further recrystallization the 2-anilino-3 - cycloliexyliniino - 5 - phenyl - 3, 5 - is obtained from alcohol dihydrophenazine in the form of long, fine orange needles that after drying melt at 105 ° C and 15 mm pressure at 162 to 165 ° C.
Beispiel 3 Ein Gemisch aus 20 Teilen 2-Aiiilino-3-imino-5-phenyl-3,5-dihydro-phenazin-liydrochlorid und 80 Teilen n-Dodecylamin wird 30 Minuten unter Rühren auf 130 bis 140° C erhitzt. Nach dem Erkalten versetzt man das Reaktionsgemisch mit 150 Volumteilen Äther und 150 Volumteilen Petroläther. Der orangefarbene ungelöste Anteil enthält neben dem Reaktionsprodukt das Hydrochlorid des Dodecylamins. Er wird abfiltriert und das lufttrockene Filtergut aus 400 Volumteilen Methanol umkristallisiert. Das 2-Anilino-3-n-dodecylimino-5-phenyl-3,5-dihydro-phenazin kristallisiert in orangefarbenen Blättern vom F. 99 bis 101° C. Beispiel 4 Ein Gemisch aus 23 Teilen 2-(p-Chlor-anilino)-3-imino-5 - (p- chlor-phenyl) -3, 5 -dihydro -phenazin -hy drochlorid und 80 Teilen n-Dodecylamin wird unter Rühren 30 Minuten auf 130 bis 140° C erhitzt. Nach dem Erkalten versetzt man das Reaktionsgemisch mit 150 Volumteilen Äther und 100 Volumteilen Petroläther. In diesem Falle bleibt einzig das Hydrochlorid des Dodecylamins ungelöst zurück und wird abfiltriert. Das Filtrat wird mit 500 Teilen Wasser gerührt, das Gemisch mit Salzsäure kongosauer gestellt, hierauf mit etwa 2000 Volumteilen Äther versetzt und bis zur Trennung der Phasen stehengelassen. Hauptsächlich in der wäßrigen Phase schwimmt nun eine dunkelgefärbte Substanz. Diese wird abfiltriert, mit Äther gewaschen und getrocknet. Sie stellt das Hydrochlorid des 2-(p-Chlor-anilino)-3-n-dodecylimino-5-(p'-chlor-phenyl)-3,5-dihydro-phenazins dar und schmilzt bei 182 bis 183° C. Trotz der kongosauren Reaktion der wäßrigen Phase befindet sich das überschüssige n-Dodecylamin in der organischen Phase und kann durch Abdestillieren der Lösungsmittel zurückgewonnen werden.Example 3 A mixture of 20 parts of 2-silino-3-imino-5-phenyl-3,5-dihydro-phenazine hydrochloride and 80 parts of n-dodecylamine are heated to 130 to 140 ° C for 30 minutes with stirring. After cooling, the reaction mixture is mixed with 150 parts by volume of ether and 150 parts by volume of petroleum ether. The orange undissolved part contains in addition to Reaction product is the hydrochloride of dodecylamine. It is filtered off and that air-dry filter material recrystallized from 400 parts by volume of methanol. The 2-anilino-3-n-dodecylimino-5-phenyl-3,5-dihydro-phenazine crystallizes in orange leaves with a temperature of 99 to 101 ° C. Example 4 A mixture from 23 parts of 2- (p-chloro-anilino) -3-imino-5 - (p-chloro-phenyl) -3, 5 -dihydro-phenazine Hydrochloride and 80 parts of n-dodecylamine is increased to 130 for 30 minutes with stirring heated to 140 ° C. After cooling, 150 is added to the reaction mixture Parts by volume of ether and 100 parts by volume of petroleum ether. In this case there is only one the dodecylamine hydrochloride is returned undissolved and is filtered off. The filtrate is stirred with 500 parts of water, the mixture is made Congo acidic with hydrochloric acid, then mixed with about 2000 parts by volume of ether and up to the separation of the phases ditched. A dark-colored one now floats mainly in the aqueous phase Substance. This is filtered off, washed with ether and dried. She poses the hydrochloride of 2- (p-chloro-anilino) -3-n-dodecylimino-5- (p'-chloro-phenyl) -3,5-dihydro-phenazine and melts at 182 to 183 ° C. Despite the Congo acid reaction of the aqueous The excess n-dodecylamine is in the organic phase and phase can be recovered by distilling off the solvents.
Zur Überführung des Hydrochlorids in die freie Base dispergiert man es unter Rühren in einem Gemisch aus 250 Teilen Wasser und 150 Volumteilen Alkohol, läßt zu der Dispersion unter Rühren bei 60 bis 65° C 30 Volumteile konzentrierte wäßrige Ammoniaklösung zutropfen und rührt eine weitere Stunde bei derselben Temperatur. Nach dem Erkalten wird die ausgeschiedene Base abgesaugt, mit Wasser gewaschen und getrocknet. Sie schmilzt bei 90 bis 93° C.To convert the hydrochloride into the free base, it is dispersed it while stirring in a mixture of 250 parts of water and 150 parts by volume of alcohol, admits 30 parts by volume of concentrated to the dispersion with stirring at 60 to 65.degree Add dropwise aqueous ammonia solution and stir for a further hour at the same temperature. After cooling, the precipitated base is filtered off with suction, washed with water and dried. It melts at 90 to 93 ° C.
In ähnlicher Weise, wie in den vorstehenden Beispielen beschrieben, können, ausgehend aus 2 Teilen 2-(p-Toluidino) -3-imino-5- (p-tolyl) -3,5-dihydro-phenazin-hydrochlorid und 45 Volumteilen Isopropylamin, das 2-(p-Toluidino) -3-isopropylimino-5- (p-tolyl) -3, 5-dihydrophenazin vom F. = 202 bis 204° C, ausgehend aus 2 Teilen 2-(p-Isopropoxyphenylamino) -3-imino-5- (p-isopropoxyphenyl)-3,5-dihydrophenazin-hydrochlorid und 25 Volumteilen Cyclohexylamin, das 2-(p-Isopropoxyphenylamino)-3-cy cloliexylimino-5- (p-isopropoxyphenyl) -3,5-dihydrophenazin vom F. = 200° C, ausgehend von 2 Teilen 2- (o-Methoxyphenylamino) -3-imino-5- (o-metlioxyphenyl)-3,5-dihydrophenazin-hydrochlorid und 25 Volumteilen Cyclohexylamin, das 2-(o-Methoxyphenylamino)-3 - cyclohexylimino - 5 - (o - methoxyphenyl) - 3,5 - dihydrophenazin vom F. = 194 bis 196° C, ausgehend aus 2 Teilen 2-Anilino-3-imino-5-phenyl-3,5-dihydrophenazin-hydrochlorid und 35 Volumteilen Cycloheptylamin, das 2-Anilino-3-cy cloheptylimino-5-phenyl-3, 5-dihydro-phenazin vom F. = 191 bis 192° C, und, ausgehend aus 2 Teilen 2-Anilino-3-imino-5-phenyl-3,5-dihydrophenazin-hydrochlorid und 25 Volumteilen Cyclopentylamin, das 2-:@nilino - 3 - cyclopentylimino - 5 -phenyl- 3, 5 - dihydrophenazin vom F. = 201 bis 203° C hergestellt werden.In a manner similar to that described in the preceding examples, starting from 2 parts of 2- (p-toluidino) -3-imino-5- (p-tolyl) -3,5-dihydrophenazine hydrochloride and 45 parts by volume of isopropylamine , the 2- (p-toluidino) -3-isopropylimino-5- (p-tolyl) -3, 5-dihydrophenazine of mp = 202 to 204 ° C, starting from 2 parts of 2- (p-isopropoxyphenylamino) -3 -imino-5- (p-isopropoxyphenyl) -3,5-dihydrophenazine hydrochloride and 25 parts by volume of cyclohexylamine, 2- (p-isopropoxyphenylamino) -3-cy cloliexylimino-5- (p-isopropoxyphenyl) -3,5-dihydrophenazine from the temperature = 200 ° C, starting from 2 parts of 2- (o-methoxyphenylamino) -3-imino-5- (o-metlioxyphenyl) -3,5-dihydrophenazine hydrochloride and 25 parts by volume of cyclohexylamine, the 2- (o- Methoxyphenylamino) -3 - cyclohexylimino - 5 - (o - methoxyphenyl) - 3,5 - dihydrophenazine with a temperature of 194 to 196 ° C, starting from 2 parts of 2-anilino-3-imino-5-phenyl-3,5- dihydrophenazine hydrochloride and 35 parts by volume of cycloheptylamine, the 2-anilino-3-cy cloheptylimino-5-phe nyl-3, 5-dihydrophenazine of m.p. = 191 to 192 ° C, and, starting from 2 parts of 2-anilino-3-imino-5-phenyl-3,5-dihydrophenazine hydrochloride and 25 parts by volume of cyclopentylamine, the 2 -: @ nilino - 3 - cyclopentylimino - 5 -phenyl- 3, 5 - dihydrophenazine with a temperature of 201 to 203 ° C.
In der nachfolgenden Tabelle sind weitere analog den Beispielen 1
bis 4 hergestellte Endstoffe der allgemeinen Formel I mit ihren Schmelzpunkten aufgeführt.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1059462X | 1956-10-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1059462B true DE1059462B (en) | 1959-06-18 |
Family
ID=4555315
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEG22000A Pending DE1059462B (en) | 1956-10-04 | 1957-04-26 | Process for the preparation of therapeutically active phenazine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1059462B (en) |
-
1957
- 1957-04-26 DE DEG22000A patent/DE1059462B/en active Pending
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