CH405282A - Process for the preparation of basic compounds - Google Patents
Process for the preparation of basic compoundsInfo
- Publication number
- CH405282A CH405282A CH787365A CH787365A CH405282A CH 405282 A CH405282 A CH 405282A CH 787365 A CH787365 A CH 787365A CH 787365 A CH787365 A CH 787365A CH 405282 A CH405282 A CH 405282A
- Authority
- CH
- Switzerland
- Prior art keywords
- acid
- formula
- alkyl
- group
- carbon atoms
- Prior art date
Links
- 150000007514 bases Chemical class 0.000 title claims description 7
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 6
- 150000003839 salts Chemical class 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical compound C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 claims description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 2
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 150000003568 thioethers Chemical class 0.000 claims description 2
- JOOXCMJARBKPKM-UHFFFAOYSA-N 4-oxopentanoic acid Chemical compound CC(=O)CCC(O)=O JOOXCMJARBKPKM-UHFFFAOYSA-N 0.000 claims 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims 1
- 230000001419 dependent effect Effects 0.000 claims 1
- 239000000174 gluconic acid Substances 0.000 claims 1
- 235000013922 glutamic acid Nutrition 0.000 claims 1
- 239000004220 glutamic acid Substances 0.000 claims 1
- 229940040102 levulinic acid Drugs 0.000 claims 1
- -1 N ', N "' - bis (p - 2-imidazolin - 2-ylphenyl) terephthalamidine tetrahydrochloride Chemical compound 0.000 description 9
- 230000008018 melting Effects 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 238000000354 decomposition reaction Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- VNODPBNWSSSWCF-UHFFFAOYSA-N 4-(4,5-dihydroimidazol-1-yl)aniline dihydrochloride Chemical compound Cl.Cl.NC1=CC=C(C=C1)N1C=NCC1 VNODPBNWSSSWCF-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- ABSLZVQHYCSIIY-UHFFFAOYSA-N Cl.Cl.Cl.Cl.C(C)N=C(N)C1=CC=C(C=C1)NC(C1=CC=C(C(=N)N)C=C1)=NC1=CC=C(C=C1)C(N)=NCC Chemical compound Cl.Cl.Cl.Cl.C(C)N=C(N)C1=CC=C(C=C1)NC(C1=CC=C(C(=N)N)C=C1)=NC1=CC=C(C=C1)C(N)=NCC ABSLZVQHYCSIIY-UHFFFAOYSA-N 0.000 description 1
- KHTYEIWSQBUWOF-UHFFFAOYSA-N Cl.Cl.Cl.Cl.CNC(=N)C1=CC=C(C=C1)NC(C1=CC=C(C(=N)N)C=C1)=NC1=CC=C(C=C1)C(NC)=N Chemical compound Cl.Cl.Cl.Cl.CNC(=N)C1=CC=C(C=C1)NC(C1=CC=C(C(=N)N)C=C1)=NC1=CC=C(C=C1)C(NC)=N KHTYEIWSQBUWOF-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- UNMMLGAPDZGRJJ-UHFFFAOYSA-N benzene-1,4-dicarboximidamide Chemical compound NC(=N)C1=CC=C(C(N)=N)C=C1 UNMMLGAPDZGRJJ-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001549 tubercolostatic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D233/24—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung basischer Verbindungen Gegenstand der Ertindung ist ein Verfahren zur Herstellung basischer Verbindungen der Formel
EMI1.1
welche auch in der tautomeren Form
EMI1.2
auftreten können, sowie von Salzen davon. In Formel I stellt A eine direkt oder über ein Zwischenglied -NH- mit dem Benzolring verknüpfte Gruppe
EMI1.3
dar, in welcher R' und R" gleich oder verschieden sind und Wasserstoffatome oder gerade oder verzweigte Alkyl-, Alkenyl- oder Hydroxyalkylgruppen mit höchstens 7 C-Atomen bedeuten, oder in welcher R'und R" gemeinsam eine Äthylen- oder Propylengruppe darstellen, worin einzelne Wasserstoff atome durch Alkylgruppen mit zusammen höchstens
6 C-Atomen ersetzt sein können.
R1 steht für ein Wasserstoff- oder Halogenatom oder für eine
1 bis 3 C-Atome enthaltende Alkyl- oder Alkoxygruppe. R2 stellt ein Wasserstoff- oder Halogenatom, eine Nitrogruppe oder eine Alkyl- oder Alkoxygruppe mit höchstens 3 C-Atomen dar.
Die gewünschten Produkte werden ertindungs- gemäss erhalten, indem man ein freies Amin der
Formel
EMI1.4
mit einem Imidoäther der Formel
EMI1.5
worin R2 die genannte Bedeutung hat und R eine Alkylgruppe darstellt oder mit einem entsprechenden Thioäther umsetzt.
Der Imidoäther kann in freier Form oder als Hydrochlorid venvendet werden. Die Umsetzung erfolgt vorzugsweise in einem Lösungsmittel, zum Beispiel Dioxan, Chloroform oder einem Alkohol, unter mehrstündigem Erhitzen auf Rückflusstemperatur. Nach Eindampfen des Reaktionsgemisches und Auflösen des Rückstandes wird die Base zum Beispiel mit wässerigem Alkalihydroxyd freigesetzt und gegebenenfalls. in an sich bekannter Weise in ein Salz übergeführt.
Die Verbindungen entsprechend Formel I können als freie Basen oder in Form ihrer Salze mit anorganischen oder organischen Säuren gewonnen werden. Als Salze der Basen gemäss Formel I seien diejenigen der Schwefelsäure, Salzsäure, Bromwasserstoffsäure, Iodwasserstoffsäure, Phosphorsäure, Ameisensäure, Essigsäure, Propionsäure, Buttersäure, Weinsäure, Maleinsäure, Oxalsäure, Citronensäure, Salicylsäure und dergleichen erwähnt. Durch besonders gute Löslichkeit zeichnen sich die Salze von Hydroxycarbonsäuren, Ketocarbonsäuren und Aminocarbonsäuren aus, insbesondere die Salze der Glykolsäure, Milchsäure, Zuckersäure, Schleimsäure, Ascorbinsäure, Heptagluconsäure, Galactosidogluconsäure, Galactosido-heptagluconsäure, Lävulinsäure und der Glutaminsäure.
Die Herstellung löslicher Salze erfolgt zweckmässig, indem man die mehrbasische Verbindung in Wasser aufschlämmt und die zur Neutralisation erforderliche Menge der gewünschten Säure zusetzt, wobei die Base in Lösung geht. Gewünschtenfalls kann man das Salz durch Eindampfen oder Acetonzusatz in fester Form gewinnen. Die erhaltenen löslichen Salze ergeben haltbare, sterilisierbare Lösungen, die sich für Injektionszwecke eignen. Die Lösungen können auch weitere Substanzen enthalten, welche jedoch keine Fällungsmittel sein dürfen.
Die in der beschriebenen Weise erhaltenen basischen Verbindungen und ihre Salze sind neue Verbindungen, welche biologische Wirkungen zeigen.
Sie besitzen eine stark wachstumshemmende Wirkung auf verschiedene Bakterien und Protozoen, insbesondere Mycobacterium tuberculosis und Trypanosomen und können somit als Chemotherapeutika, insbesondere Tuberkulostatika, verwendet werden.
Ferner eignen sie sich zur Krebsbekämpfung, insbesondere zur Bekämpfung der Leukämie. Schliesslich können sie auch als Zwischenprodukte zur Herstellung weiterer, insbesondere pharmakologisch wirksamer Verbindungen benutzt werden.
Die antileukämische Wirkung wird bei der durch Übertragung von Krebszellen künstlich leukämisch gemachten Maus mit Wirkstoffmengen von etwa 1 bis 500mg/kg/Tag erzielt und äussert sich in einer Verlängerung der Uberlebenszeit gegenüber unbehandelten Kontrolltieren. Die Überlebenszeit der Kontrolltiere zu 100 /o gesetzt, beträgt die Überlebens- zeit zum Beispiel bei täglicher Verabreichung von 22 mglkg des Produktes gemäss nachfolgendem Beispiel 2 (Dihydrochlorid) 350 0/0. Der Wirkstoff wird zum Beispiel in gegebenenfalls isotonisch gemachter wässeriger Lösung beziehungsweise Suspension i. v. oder i. p. gespritzt.
Zur Bekämpfung anderer Krebsarten sowie für chemotherapeutische Zwecke, insbesondere zur Bekämpfung von Tuberkulose und Trypanosomenerkrankungen, eignen sich auch andere Arzneiformen und Applikationsweisen. Zum Beispiel können Carcinome, Sarcome oder Tuberkuloseherde lokal behandelt werden. Neben Lösungen beziehungsweise Suspensionen kommen für solche Zwecke auch pulver- oder salbenförmige Präparate in Frage, die ausser dem Wirkstoff die üblichen Träger- und Hilfsstoffe enthalten.
Beispiel 1
14,7 g (0,05 Mol) Terephthalbis(imidoäthyläther)- Dihydrochlorid und 23, 4 g (0,1 Mol) p-Amino phenylimidazolin-Dihydrochlorid werden in einem Gemisch aus 200ml absolutem Äthanol und 50 ml absolutem Pyridin 2 Stunden lang unter Rückfluss erhitzt. Das Reaktionsgemisch wird im Vakuum zur Trockne eingedampft. Man nimmt den Rückstand in Wasser auf und versetzt die wässerige Lösung mit gesättigter wässeriger Sodalösung im Überschuss, wobei die freie Base ausfällt. Diese wird durch Filtrieren isoliert und mit Wasser gewaschen.
Durch Aufnehmen der Base in absolutem Äthanol und Versetzen des äthanolischen Lösung mit ätherischer Salzsäure erhält man 17,0 g N',N"'- Bis (p - 2- imidazolin - 2- ylphenyl) terephthalamidin Tetrahydrochlorid vom Schmelzpunkt 3600 C (Zersetzung; ab 3200 C Braunfärbung).
Bei analogem Vorgehen wie im vorerwähnten Beispiel 1 erhält man beispielsweise die folgenden weiteren Verbindungen gemäss Formel 1:
2. N',N"'-Bis [p-(N'-methylamidino)phenyl] terephthalamidin-Tetrahydrochlorid,
Schmelzpunkt 2400 C (Zersetzung);
3. N',N"'-Bis[p-(N'-äthylamidino)phenyl] terephthalamidin-Tetrahydrochlorid,
Schmelzpunkt 2480 C (Zersetzung);
4. N',N"'-Bis [p-(N'-methylamidino)phenyl]- isophthalamidin-Tetrahydrochlorid,
Schmelzpunkt 2600 (Zersetzung);
5. 2-Chlor-N',N"'-Bis [p-(N'-methylamidino) phenyl] isophthalamidin-Tetrahydrochlorid,
Schmelzpunkt 2680 C (unter Aufschäumen);
6. N',N"'-Bis [p-(N'-äthylamidino)phenylj isophthalamidin-Tetrahydrochlorid,
Schmelzpunkt 2450 C (gelbe Schmelze);
7. 2-Chlor-N',N'11-Bis [p-(N'-methylamidino)- phenyl] terephthalamidin-Tetrahydrochlorid,
Schmelzpunkt 2650 C (Zersetzung; gelbe Schmelze); 8. N',N"'-Bis [p-(N'-n-propylamidino)phenyl] terephthalamidin-Tetrahydrochlorid,
Schmelzpunkt 3350 C (Zersetzung);
9. N',N"'-Bis (p-2-imidazolin-2-ylphenyl) isophthalamidin-Tetrahydrochlorid ; 10. N',N"'-Bis [p-(N',N"-dimethylamidino)phenyl] - terephthalamidin-Tetrahydrochlorid; 11. N',N"'-Bis [p-(l ,4,5,6-tetrahydro-2-pyrnnldinyl)- phenyl] terephthalamidin-Tetrahydrochlorid ; 12. N', N"'-Bis [p-(N', N"-diäthylamidino) phenyl]- terephthalamidin-Tetrahydrochlorid.
Process for the preparation of basic compounds The invention relates to a process for the preparation of basic compounds of the formula
EMI1.1
which also in the tautomeric form
EMI1.2
can occur, as well as salts thereof. In formula I, A represents a group linked directly or via an -NH- link to the benzene ring
EMI1.3
represents, in which R 'and R "are identical or different and represent hydrogen atoms or straight or branched alkyl, alkenyl or hydroxyalkyl groups with a maximum of 7 carbon atoms, or in which R' and R" together represent an ethylene or propylene group, wherein individual hydrogen atoms together with alkyl groups with at most
6 carbon atoms can be replaced.
R1 stands for a hydrogen or halogen atom or for one
Alkyl or alkoxy groups containing 1 to 3 carbon atoms. R2 represents a hydrogen or halogen atom, a nitro group or an alkyl or alkoxy group with a maximum of 3 carbon atoms.
The desired products are obtained according to the invention by adding a free amine to the
formula
EMI1.4
with an imido ether of the formula
EMI1.5
wherein R2 has the meaning mentioned and R represents an alkyl group or reacts with a corresponding thioether.
The imidoether can be used in free form or as the hydrochloride. The reaction is preferably carried out in a solvent, for example dioxane, chloroform or an alcohol, with heating at reflux temperature for several hours. After evaporation of the reaction mixture and dissolution of the residue, the base is liberated, for example with aqueous alkali metal hydroxide, and optionally. converted into a salt in a manner known per se.
The compounds corresponding to formula I can be obtained as free bases or in the form of their salts with inorganic or organic acids. Salts of the bases according to formula I include those of sulfuric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, oxalic acid, citric acid, salicylic acid and the like. The salts of hydroxycarboxylic acids, ketocarboxylic acids and aminocarboxylic acids are characterized by particularly good solubility, in particular the salts of glycolic acid, lactic acid, saccharic acid, mucic acid, ascorbic acid, heptagluconic acid, galactosidogluconic acid, galactosidoheptagluconic acid, levutamic acid and levutamic acid.
Soluble salts are conveniently prepared by suspending the polybasic compound in water and adding the amount of the desired acid required for neutralization, the base going into solution. If desired, the salt can be obtained in solid form by evaporation or by adding acetone. The soluble salts obtained result in stable, sterilizable solutions which are suitable for injection purposes. The solutions can also contain other substances which, however, must not be precipitants.
The basic compounds and their salts obtained in the manner described are novel compounds which show biological effects.
They have a strong growth-inhibiting effect on various bacteria and protozoa, in particular Mycobacterium tuberculosis and trypanosomes, and can thus be used as chemotherapeutic agents, in particular tuberculostatics.
They are also suitable for combating cancer, in particular for combating leukemia. Finally, they can also be used as intermediate products for the preparation of further, in particular pharmacologically active compounds.
The antileukemic effect is achieved in mice artificially made leukemic by transferring cancer cells with amounts of active ingredient of about 1 to 500 mg / kg / day and is expressed in an increase in survival time compared to untreated control animals. If the survival time of the control animals is set at 100%, the survival time, for example with daily administration of 22 mg / kg of the product according to the following example 2 (dihydrochloride), is 350%. The active ingredient is, for example, in an aqueous solution or suspension that has been made isotonic, i. v. or I. p. injected.
To combat other types of cancer and for chemotherapeutic purposes, in particular to combat tuberculosis and trypanosomal diseases, other drug forms and modes of administration are also suitable. For example, carcinomas, sarcomas or tuberculosis lesions can be treated locally. In addition to solutions or suspensions, preparations in powder or ointment form which contain the usual carriers and auxiliaries in addition to the active ingredient are also suitable for such purposes.
example 1
14.7 g (0.05 mol) of terephthalbis (imidoethyl ether) - dihydrochloride and 23.4 g (0.1 mol) of p-amino phenylimidazoline dihydrochloride are added to a mixture of 200 ml of absolute ethanol and 50 ml of absolute pyridine for 2 hours Heated to reflux. The reaction mixture is evaporated to dryness in vacuo. The residue is taken up in water and saturated aqueous sodium carbonate solution is added in excess to the aqueous solution, the free base precipitating out. This is isolated by filtration and washed with water.
By taking up the base in absolute ethanol and adding ethereal hydrochloric acid to the ethanolic solution, 17.0 g of N ', N "' - bis (p - 2-imidazolin - 2-ylphenyl) terephthalamidine tetrahydrochloride with a melting point of 3600 C (decomposition; ab 3200 C brown color).
With an analogous procedure as in the aforementioned example 1, the following further compounds according to formula 1 are obtained, for example:
2. N ', N "' - bis [p- (N'-methylamidino) phenyl] terephthalamidine tetrahydrochloride,
Melting point 2400 C (decomposition);
3. N ', N "' - bis [p- (N'-ethylamidino) phenyl] terephthalamidine tetrahydrochloride,
Melting point 2480 C (decomposition);
4. N ', N "' - bis [p- (N'-methylamidino) phenyl] - isophthalamidine tetrahydrochloride,
M.p. 2600 (decomposition);
5. 2-chloro-N ', N "' - bis [p- (N'-methylamidino) phenyl] isophthalamidine tetrahydrochloride,
Melting point 2680 C (with foaming);
6. N ', N "' - bis [p- (N'-ethylamidino) phenyl] isophthalamidine tetrahydrochloride,
Melting point 2450 C (yellow melt);
7. 2-chloro-N ', N'11-bis [p- (N'-methylamidino) phenyl] terephthalamidine tetrahydrochloride,
Melting point 2650 C (decomposition; yellow melt); 8. N ', N "' - bis [p- (N'-n-propylamidino) phenyl] terephthalamidine tetrahydrochloride,
Melting point 3350 C (decomposition);
9. N ', N "' - bis (p-2-imidazolin-2-ylphenyl) isophthalamidine tetrahydrochloride; 10. N ', N"' - bis [p- (N ', N "-dimethylamidino) phenyl] - terephthalamidine tetrahydrochloride; 11. N ', N "' - bis [p- (1,4,5,6-tetrahydro-2-pyrnnldinyl) phenyl] terephthalamidine tetrahydrochloride; 12. N ', N "' - bis [p- (N ', N" -diethylamidino) phenyl] - terephthalamidine tetrahydrochloride.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH787365A CH405282A (en) | 1961-11-24 | 1961-11-24 | Process for the preparation of basic compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH787365A CH405282A (en) | 1961-11-24 | 1961-11-24 | Process for the preparation of basic compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH405282A true CH405282A (en) | 1966-01-15 |
Family
ID=4331698
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH787365A CH405282A (en) | 1961-11-24 | 1961-11-24 | Process for the preparation of basic compounds |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH405282A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4405621A (en) * | 1974-02-07 | 1983-09-20 | Smith Kline & French Laboratories Limited | Heterocyclic thioureas, isothioureas, guanidines and nitromethylene-amidines |
| US4578388A (en) * | 1974-02-07 | 1986-03-25 | Smithkline & French Laboratories Limited | Unsymmetrical guanidino, thioureido, isothioureido and nitromethyleneamino derivatives |
-
1961
- 1961-11-24 CH CH787365A patent/CH405282A/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4405621A (en) * | 1974-02-07 | 1983-09-20 | Smith Kline & French Laboratories Limited | Heterocyclic thioureas, isothioureas, guanidines and nitromethylene-amidines |
| US4578388A (en) * | 1974-02-07 | 1986-03-25 | Smithkline & French Laboratories Limited | Unsymmetrical guanidino, thioureido, isothioureido and nitromethyleneamino derivatives |
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